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+Impact of body composition on very-low-density lipoprotein-triglycerides kinetics - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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+            government site. The site is secure. The https:// ensures that you are connecting to the
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+            and transmitted securely. Log in Show account info Close Account Logged in as: username Dashboard Publications Account settings Log out Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Search: Search Advanced Clipboard User Guide Save Email Send to Clipboard My Bibliography Collections Citation manager Display options Display options Format Abstract PubMed PMID Save citation to file Format: Summary (text) PubMed PMID Abstract (text) CSV Create file Cancel Email citation Subject: 1 selected item: 18984851 - PubMed To: From: Format: Summary Summary (text) Abstract Abstract (text) MeSH and other data Send email Cancel Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Add to My Bibliography My Bibliography Unable to load your delegates due to an error Please try again Add Cancel Your saved search Name of saved search: Search terms: Test search terms Would you like email updates of new search results? Saved Search Alert Radio Buttons Yes No Email: ( change ) Frequency: Monthly Weekly Daily Which day? The first Sunday The first Monday The first Tuesday The first Wednesday The first Thursday The first Friday The first Saturday The first day The first weekday Which day? Sunday Monday Tuesday Wednesday Thursday Friday Saturday Report format: Summary Summary (text) Abstract Abstract (text) PubMed Send at most: 1 item 5 items 10 items 20 items 50 items 100 items 200 items Send even when there aren't any new results Optional text in email: Save Cancel Create a file for external citation management software Create file Cancel Your RSS Feed Name of RSS Feed: Number of items displayed: 5 10 15 20 50 100 Create RSS Cancel RSS Link Copy Full text links Atypon Full text links Actions Cite Collections Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Display options Display options Format Abstract PubMed PMID Share Permalink Copy Page navigation Title & authors Abstract Similar articles Cited by Publication types MeSH terms Substances Related information LinkOut - more resources Title & authors Abstract Similar articles Cited by Publication types MeSH terms Substances Related information LinkOut - more resources Am J Physiol Endocrinol Metab Actions Search in PubMed Search in NLM Catalog Add to Search . 2009 Jan;296(1):E165-73. doi: 10.1152/ajpendo.90675.2008. Epub 2008 Nov 4. Impact of body composition on very-low-density lipoprotein-triglycerides kinetics Lars C Gormsen 1 , Birgitte Nellemann , Lars P Sørensen , Michael D Jensen , Jens S Christiansen , Søren Nielsen Affiliations Expand Affiliation 1 Dept. of Nuclear Medicine, Aarhus Univ. Hospital, DK-8000 Aarhus C, Denmark. lars.christian.gormsen@ki.au.dk PMID: 18984851 DOI: 10.1152/ajpendo.90675.2008 Free article Item in Clipboard Impact of body composition on very-low-density lipoprotein-triglycerides kinetics Lars C Gormsen et al. Am J Physiol Endocrinol Metab . 2009 Jan . Free article Show details Display options Display options Format Abstract PubMed PMID Am J Physiol Endocrinol Metab Actions Search in PubMed Search in NLM Catalog Add to Search . 2009 Jan;296(1):E165-73. doi: 10.1152/ajpendo.90675.2008. Epub 2008 Nov 4. Authors Lars C Gormsen 1 , Birgitte Nellemann , Lars P Sørensen , Michael D Jensen , Jens S Christiansen , Søren Nielsen Affiliation 1 Dept. of Nuclear Medicine, Aarhus Univ. Hospital, DK-8000 Aarhus C, Denmark. lars.christian.gormsen@ki.au.dk PMID: 18984851 DOI: 10.1152/ajpendo.90675.2008 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Upper body obese (UBO) subjects have greater cardiovascular disease risk than lower body obese (LBO) or lean subjects. Obesity is also associated with hypertriglyceridemia that may involve greater production and impaired removal of very-low-density lipoprotein (VLDL)-triglycerides (TG). In these studies, we assessed the impact of body composition on basal VLDL-TG production, VLDL-TG oxidation, and VLDL-TG storage. VLDL-TG kinetics were assessed in 10 UBO, 10 LBO, and 10 lean women using a bolus injection of [1-(14)C]VLDL-TG. VLDL-TG oxidation was measured by (14)CO(2) production (hyamine trapping) and VLDL-TG adipose tissue storage by fat biopsies. Insulin sensititvity was assessed by the hyperinsulinemic-euglycemic clamp technique and body composition by dual X-ray absorptiometry in combination with computed tomography. Hepatic VLDL-TG production was significantly greater in UBO than in lean women [(mumol/min) UBO: 64.8 (SD 40.0) vs. LBO: 42.5 (SD 25.6) vs. lean: 31.8 (SD 13.3), P = 0.04], whereas VLDL-TG oxidation was similar in the three groups and averaged 20% of resting energy expenditure [(mumol/min) UBO: 38.3 (SD 26.5) vs. LBO: 23.5 (SD 13.5) vs. lean: 21.1 (SD 9.7), P = 0.09]. In UBO women, more VLDL-TG was deposited in upper body subcutaneous fat [VLDL-TG redeposition in abdominal adipose tissue (mumol/min): UBO: 5.0 (SD 2.9) vs. LBO: 4.0 (SD 3.2) vs. lean: 1.3 (SD 1.0), ANOVA P = 0.01]; in LBO women, more VLDL-TG was deposited in femoral fat [VLDL-TG redeposition in femoral adipose tissue (mumol/min): UBO: 5.1 (SD 3.1) vs. LBO: 5.8 (SD 4.3) vs. lean: 2.3 (SD 1.5), ANOVA P = 0.04]. Only a small proportion of VLDL-TG (8-16%) was partitioned into redeposition in either group. We found that elevated VLDL-TG production without concomitant increased clearance via oxidation and adipose tissue redeposition contributes to hypertriglyceridemia in UBO women. PubMed Disclaimer Similar articles Impaired insulin-mediated antilipolysis and lactate release in adipose tissue of upper-body obese women. Nellemann B, Gormsen LC, Sørensen LP, Christiansen JS, Nielsen S. Nellemann B, et al. Obesity (Silver Spring). 2012 Jan;20(1):57-64. doi: 10.1038/oby.2011.290. Epub 2011 Sep 29. Obesity (Silver Spring). 2012. PMID: 21959346 Body composition determines direct FFA storage pattern in overweight women. Søndergaard E, Gormsen LC, Nellemann B, Jensen MD, Nielsen S. Søndergaard E, et al. Am J Physiol Endocrinol Metab. 2012 Jun 15;302(12):E1599-604. doi: 10.1152/ajpendo.00015.2012. Epub 2012 Apr 17. Am J Physiol Endocrinol Metab. 2012. PMID: 22510710 VLDL-triglyceride kinetics during hyperglycemia-hyperinsulinemia: effects of sex and obesity. Mittendorfer B, Patterson BW, Klein S, Sidossis LS. Mittendorfer B, et al. Am J Physiol Endocrinol Metab. 2003 Apr;284(4):E708-15. doi: 10.1152/ajpendo.00411.2002. Epub 2002 Dec 10. Am J Physiol Endocrinol Metab. 2003. PMID: 12475756 Determinants of VLDL-triglycerides production. Nielsen S, Karpe F. Nielsen S, et al. Curr Opin Lipidol. 2012 Aug;23(4):321-6. doi: 10.1097/MOL.0b013e3283544956. Curr Opin Lipidol. 2012. PMID: 22617755 Review. Removal of triacylglycerols from chylomicrons and VLDL by capillary beds: the basis of lipoprotein remnant formation. Karpe F, Bickerton AS, Hodson L, Fielding BA, Tan GD, Frayn KN. Karpe F, et al. Biochem Soc Trans. 2007 Jun;35(Pt 3):472-6. doi: 10.1042/BST0350472. Biochem Soc Trans. 2007. PMID: 17511631 Review. See all similar articles Cited by TG/HDL Ratio Is an Independent Predictor for Estimating Resting Energy Expenditure in Adults with Normal Weight, Overweight, and Obesity. Widmer A, Mercante MG, Silver HJ. Widmer A, et al. Nutrients. 2022 Dec 1;14(23):5106. doi: 10.3390/nu14235106. Nutrients. 2022. PMID: 36501139 Free PMC article. Emerging Evidence of Pathological Roles of Very-Low-Density Lipoprotein (VLDL). Huang JK, Lee HC. Huang JK, et al. Int J Mol Sci. 2022 Apr 13;23(8):4300. doi: 10.3390/ijms23084300. Int J Mol Sci. 2022. PMID: 35457118 Free PMC article. Review. Adipocyte Proteins and Storage of Endogenous Fatty Acids in Visceral and Subcutaneous Adipose Tissue in Severe Obesity. Lytle KA, Bush NC, Triay JM, Kellogg TA, Kendrick ML, Swain JM, Gathaiya NW, Hames KC, Jensen MD. Lytle KA, et al. Obesity (Silver Spring). 2021 Jun;29(6):1014-1021. doi: 10.1002/oby.23149. Epub 2021 Apr 24. Obesity (Silver Spring). 2021. PMID: 33893721 Free PMC article. Clinical Trial. Metabolic communication during exercise. Murphy RM, Watt MJ, Febbraio MA. Murphy RM, et al. Nat Metab. 2020 Sep;2(9):805-816. doi: 10.1038/s42255-020-0258-x. Epub 2020 Aug 3. Nat Metab. 2020. PMID: 32747791 Review. Visceral fat does not contribute to metabolic disease in lipodystrophy. Malandrino N, Reynolds JC, Brychta RJ, Chen KY, Auh S, Gharib AM, Startzell M, Cochran EK, Brown RJ. Malandrino N, et al. Obes Sci Pract. 2019 Jan 24;5(1):75-82. doi: 10.1002/osp4.319. eCollection 2019 Feb. Obes Sci Pract. 2019. PMID: 30847226 Free PMC article. See all "Cited by" articles Publication types Research Support, Non-U.S. Gov't Actions Search in PubMed Search in MeSH Add to Search MeSH terms Absorptiometry, Photon Actions Search in PubMed Search in MeSH Add to Search Adipose Tissue / metabolism* Actions Search in PubMed Search in MeSH Add to Search Adult Actions Search in PubMed Search in MeSH Add to Search Blood Glucose / metabolism Actions Search in PubMed Search in MeSH Add to Search Body Composition / physiology* Actions Search in PubMed Search in MeSH Add to Search Calorimetry, Indirect Actions Search in PubMed Search in MeSH Add to Search Female Actions Search in PubMed Search in MeSH Add to Search Humans Actions Search in PubMed Search in MeSH Add to Search Insulin / blood Actions Search in PubMed Search in MeSH Add to Search Insulin / metabolism Actions Search in PubMed Search in MeSH Add to Search Kinetics Actions Search in PubMed Search in MeSH Add to Search Lipoproteins, VLDL / metabolism* Actions Search in PubMed Search in MeSH Add to Search Middle Aged Actions Search in PubMed Search in MeSH Add to Search Obesity / metabolism* Actions Search in PubMed Search in MeSH Add to Search Triglycerides / metabolism* Actions Search in PubMed Search in MeSH Add to Search Young Adult Actions Search in PubMed Search in MeSH Add to Search Substances Blood Glucose Actions Search in PubMed Search in MeSH Add to Search Insulin Actions Search in PubMed Search in MeSH Add to Search Lipoproteins, VLDL Actions Search in PubMed Search in MeSH Add to Search Triglycerides Actions Search in PubMed Search in MeSH Add to Search very low density lipoprotein triglyceride Actions Search in PubMed Search in MeSH Add to Search Related information MedGen PubChem Compound PubChem Compound (MeSH Keyword) PubChem Substance LinkOut - more resources Full Text Sources Atypon Medical MedlinePlus Health Information Miscellaneous NCI CPTAC Assay Portal Full text links [x] Atypon [x] Cite Copy Download .nbib .nbib Format: AMA APA MLA NLM Send To Clipboard Email Save My Bibliography Collections Citation Manager [x] NCBI Literature Resources MeSH PMC Bookshelf Disclaimer The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). 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+Bilirubin; a diagnostic marker for appendicitis - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
+            sharing sensitive information, make sure you’re on a federal
+            government site. The site is secure. The https:// ensures that you are connecting to the
+            official website and that any information you provide is encrypted
+            and transmitted securely. Log in Show account info Close Account Logged in as: username Dashboard Publications Account settings Log out Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Search: Search Advanced Clipboard User Guide Save Email Send to Clipboard My Bibliography Collections Citation manager Display options Display options Format Abstract PubMed PMID Save citation to file Format: Summary (text) PubMed PMID Abstract (text) CSV Create file Cancel Email citation Subject: 1 selected item: 24080115 - PubMed To: From: Format: Summary Summary (text) Abstract Abstract (text) MeSH and other data Send email Cancel Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Add to My Bibliography My Bibliography Unable to load your delegates due to an error Please try again Add Cancel Your saved search Name of saved search: Search terms: Test search terms Would you like email updates of new search results? Saved Search Alert Radio Buttons Yes No Email: ( change ) Frequency: Monthly Weekly Daily Which day? The first Sunday The first Monday The first Tuesday The first Wednesday The first Thursday The first Friday The first Saturday The first day The first weekday Which day? Sunday Monday Tuesday Wednesday Thursday Friday Saturday Report format: Summary Summary (text) Abstract Abstract (text) PubMed Send at most: 1 item 5 items 10 items 20 items 50 items 100 items 200 items Send even when there aren't any new results Optional text in email: Save Cancel Create a file for external citation management software Create file Cancel Your RSS Feed Name of RSS Feed: Number of items displayed: 5 10 15 20 50 100 Create RSS Cancel RSS Link Copy Full text links Elsevier Science Full text links Actions Cite Collections Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Display options Display options Format Abstract PubMed PMID Share Permalink Copy Page navigation Title & authors Abstract Comment in Similar articles Cited by Publication types MeSH terms Substances Related information LinkOut - more resources Title & authors Abstract Comment in Similar articles Cited by Publication types MeSH terms Substances Related information LinkOut - more resources Observational Study Int J Surg Actions Search in PubMed Search in NLM Catalog Add to Search . 2013;11(10):1114-7. doi: 10.1016/j.ijsu.2013.09.006. Epub 2013 Sep 27. Bilirubin; a diagnostic marker for appendicitis N D'Souza 1 , D Karim , R Sunthareswaran Affiliations Expand Affiliation 1 Poole Hospital, UK. Electronic address: nige@doctors.net.uk. PMID: 24080115 DOI: 10.1016/j.ijsu.2013.09.006 Free article Item in Clipboard Observational Study Bilirubin; a diagnostic marker for appendicitis N D'Souza et al. Int J Surg . 2013 . Free article Show details Display options Display options Format Abstract PubMed PMID Int J Surg Actions Search in PubMed Search in NLM Catalog Add to Search . 2013;11(10):1114-7. doi: 10.1016/j.ijsu.2013.09.006. Epub 2013 Sep 27. Authors N D'Souza 1 , D Karim , R Sunthareswaran Affiliation 1 Poole Hospital, UK. Electronic address: nige@doctors.net.uk. PMID: 24080115 DOI: 10.1016/j.ijsu.2013.09.006 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Introduction: Every investigation that can contribute towards a diagnosis of appendicitis is valuable to the emergency general surgeon. Previous research has suggested that hyperbilirubinaemia is a more specific marker for both simple and perforated appendicitis than WBC (white blood count) and CRP (C-reactive protein), but this investigation is not commonly used to help diagnose appendicitis. Aims: This study investigated whether there is an association between hyperbilirubinaemia and appendicitis. We also reviewed the diagnostic value of bilirubin in perforated vs simple appendicitis, and compared it with the serum C-reactive protein (CRP) and white blood cell count (WBC). Methods: This single centre, prospective observational study included all patients admitted with right iliac fossa (RIF) pain who had liver function tests performed. Statistical analysis was performed using Fisher's exact test to compare bilirubin, WBC and CRP levels for normal appendices, simple appendicitis, and perforated appendicitis. Results: 242 patients were included in this study, of whom 143 were managed operatively for RIF pain. Hyperbilirubinaemia was significantly associated with appendicitis vs RIF pain of other aetiologies (p < 0.0001). Bilirubin had a higher specificity (0.96), than WBC (0.71) and CRP (0.62), but a lower sensitivity (0.27 vs 0.68 and 0.82 respectively). Hyperbilirubinaemia was associated with perforated appendicitis vs simple appendicitis with statistical significance (p < 0.0001). Bilirubin had a higher specificity (0.82) than both WBC (0.34) and CRP (0.21), but a lower sensitivity (0.70 vs 0.80 and 0.95 respectively). Conclusion: Our findings confirm that hyperbilirubinaemia has a high specificity for distinguishing acute appendicitis, especially when perforated, from other causes of RIF pain, particularly those not requiring surgery. Keywords: Appendicitis; Diagnostic techniques and procedures; Hyperbilirubinaemia; Sensitivity and specificity. Copyright © 2013 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved. PubMed Disclaimer Comment in Correspondence to: Bilirubin; a diagnostic marker for appendicitis. Dholakia S, Khalid U. Dholakia S, et al. Int J Surg. 2014;12(2):188. doi: 10.1016/j.ijsu.2013.11.015. Epub 2013 Dec 1. Int J Surg. 2014. PMID: 24296156 No abstract available. Similar articles The value of biochemical markers in predicting a perforation in acute appendicitis. McGowan DR, Sims HM, Zia K, Uheba M, Shaikh IA. McGowan DR, et al. ANZ J Surg. 2013 Jan;83(1-2):79-83. doi: 10.1111/ans.12032. Epub 2012 Dec 12. ANZ J Surg. 2013. PMID: 23231057 Hyperbilirubinaemia: its utility in non-perforated appendicitis. Sandstrom A, Grieve DA. Sandstrom A, et al. ANZ J Surg. 2017 Jul;87(7-8):587-590. doi: 10.1111/ans.13373. Epub 2015 Nov 17. ANZ J Surg. 2017. PMID: 26573997 Hyperbilirubinaemia in appendicitis: the diagnostic value for prediction of appendicitis and appendiceal perforation. Adams HL, Jaunoo SS. Adams HL, et al. Eur J Trauma Emerg Surg. 2016 Apr;42(2):249-52. doi: 10.1007/s00068-015-0540-x. Epub 2015 May 22. Eur J Trauma Emerg Surg. 2016. PMID: 26038057 Elevated serum bilirubin in assessing the likelihood of perforation in acute appendicitis: a diagnostic meta-analysis. Giordano S, Pääkkönen M, Salminen P, Grönroos JM. Giordano S, et al. Int J Surg. 2013;11(9):795-800. doi: 10.1016/j.ijsu.2013.05.029. Epub 2013 May 31. Int J Surg. 2013. PMID: 23732757 Review. Hyperbilirubinemia as a predictor for appendiceal perforation: a systematic review. Burcharth J, Pommergaard HC, Rosenberg J, Gögenur I. Burcharth J, et al. Scand J Surg. 2013;102(2):55-60. doi: 10.1177/1457496913482248. Scand J Surg. 2013. PMID: 23820677 Review. See all similar articles Cited by Elevated total and direct bilirubin are associated with acute complicated appendicitis: a single-center based study in Saudi Arabia. Alfehaid MS, Babiker AM, Alkharraz AH, Alsaeed HY, Alzunaydi AA, Aldubaiyan AA, Sinyan HA, Alkhalaf BK, Alshuwaykan R, Khalil R, Al-Wutayd O. Alfehaid MS, et al. BMC Surg. 2023 Nov 10;23(1):342. doi: 10.1186/s12893-023-02258-2. BMC Surg. 2023. PMID: 37950198 Free PMC article. The Diagnostic Accuracy of Hyperbilirubinemia in Predicting Appendicitis and Appendiceal Perforation. Khalid SY, Elamin A. Khalid SY, et al. Cureus. 2023 Nov 3;15(11):e48203. doi: 10.7759/cureus.48203. eCollection 2023 Nov. Cureus. 2023. PMID: 37929270 Free PMC article. Bilirubin as a Predictor of Complicated Appendicitis in a District General Hospital: A Retrospective Analysis. Halaseh SA, Kostalas M, Kopec C, Nimer A. Halaseh SA, et al. Cureus. 2022 Sep 11;14(9):e29036. doi: 10.7759/cureus.29036. eCollection 2022 Sep. Cureus. 2022. PMID: 36237793 Free PMC article. The predictive value of ischemia-modified albumin in the diagnosis of acute appendicitis: A prospective case-control study. Ünsal A, Turhan VB, Öztürk D, Buluş H, Türkeş GF, Erel Ö. Ünsal A, et al. Ulus Travma Acil Cerrahi Derg. 2022 Apr;28(4):523-528. doi: 10.14744/tjtes.2020.58675. Ulus Travma Acil Cerrahi Derg. 2022. PMID: 35485513 Free PMC article. Magnetic resonance imaging (MRI) for diagnosis of acute appendicitis. D'Souza N, Hicks G, Beable R, Higginson A, Rud B. D'Souza N, et al. Cochrane Database Syst Rev. 2021 Dec 14;12(12):CD012028. doi: 10.1002/14651858.CD012028.pub2. Cochrane Database Syst Rev. 2021. PMID: 34905621 Free PMC article. Review. See all "Cited by" articles Publication types Observational Study Actions Search in PubMed Search in MeSH Add to Search MeSH terms Abdominal Pain / blood Actions Search in PubMed Search in MeSH Add to Search Abdominal Pain / etiology Actions Search in PubMed Search in MeSH Add to Search Adolescent Actions Search in PubMed Search in MeSH Add to Search Adult Actions Search in PubMed Search in MeSH Add to Search Aged Actions Search in PubMed Search in MeSH Add to Search Aged, 80 and over Actions Search in PubMed Search in MeSH Add to Search Appendicitis / blood* Actions Search in PubMed Search in MeSH Add to Search Appendicitis / diagnosis Actions Search in PubMed Search in MeSH Add to Search Bilirubin / blood* Actions Search in PubMed Search in MeSH Add to Search Biomarkers / blood Actions Search in PubMed Search in MeSH Add to Search Child Actions Search in PubMed Search in MeSH Add to Search Child, Preschool Actions Search in PubMed Search in MeSH Add to Search Humans Actions Search in PubMed Search in MeSH Add to Search Hyperbilirubinemia / blood Actions Search in PubMed Search in MeSH Add to Search Male Actions Search in PubMed Search in MeSH Add to Search Middle Aged Actions Search in PubMed Search in MeSH Add to Search Prospective Studies Actions Search in PubMed Search in MeSH Add to Search Young Adult Actions Search in PubMed Search in MeSH Add to Search Substances Biomarkers Actions Search in PubMed Search in MeSH Add to Search Bilirubin Actions Search in PubMed Search in MeSH Add to Search Related information Cited in Books MedGen PubChem Compound (MeSH Keyword) LinkOut - more resources Full Text Sources Elsevier Science Ovid Technologies, Inc. Other Literature Sources The Lens - Patent Citations scite Smart Citations Medical MedlinePlus Health Information Research Materials NCI CPTC Antibody Characterization Program Miscellaneous NCI CPTAC Assay Portal Full text links [x] Elsevier Science [x] Cite Copy Download .nbib .nbib Format: AMA APA MLA NLM Send To Clipboard Email Save My Bibliography Collections Citation Manager [x] NCBI Literature Resources MeSH PMC Bookshelf Disclaimer The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited. Follow NCBI Twitter Facebook LinkedIn GitHub Connect with NLM Twitter SM-Facebook SM-Youtube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov

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+Coffee for Cardioprotection and Longevity - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
+            sharing sensitive information, make sure you’re on a federal
+            government site. The site is secure. The https:// ensures that you are connecting to the
+            official website and that any information you provide is encrypted
+            and transmitted securely. Log in Show account info Close Account Logged in as: username Dashboard Publications Account settings Log out Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Search: Search Advanced Clipboard User Guide Save Email Send to Clipboard My Bibliography Collections Citation manager Display options Display options Format Abstract PubMed PMID Save citation to file Format: Summary (text) PubMed PMID Abstract (text) CSV Create file Cancel Email citation Subject: 1 selected item: 29474816 - PubMed To: From: Format: Summary Summary (text) Abstract Abstract (text) MeSH and other data Send email Cancel Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Add to My Bibliography My Bibliography Unable to load your delegates due to an error Please try again Add Cancel Your saved search Name of saved search: Search terms: Test search terms Would you like email updates of new search results? Saved Search Alert Radio Buttons Yes No Email: ( change ) Frequency: Monthly Weekly Daily Which day? The first Sunday The first Monday The first Tuesday The first Wednesday The first Thursday The first Friday The first Saturday The first day The first weekday Which day? Sunday Monday Tuesday Wednesday Thursday Friday Saturday Report format: Summary Summary (text) Abstract Abstract (text) PubMed Send at most: 1 item 5 items 10 items 20 items 50 items 100 items 200 items Send even when there aren't any new results Optional text in email: Save Cancel Create a file for external citation management software Create file Cancel Your RSS Feed Name of RSS Feed: Number of items displayed: 5 10 15 20 50 100 Create RSS Cancel RSS Link Copy Full text links Elsevier Science Full text links Actions Cite Collections Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Display options Display options Format Abstract PubMed PMID Share Permalink Copy Page navigation Title & authors Abstract Similar articles Cited by Publication types MeSH terms Substances Related information LinkOut - more resources Title & authors Abstract Similar articles Cited by Publication types MeSH terms Substances Related information LinkOut - more resources Review Prog Cardiovasc Dis Actions Search in PubMed Search in NLM Catalog Add to Search . 2018 May-Jun;61(1):38-42. doi: 10.1016/j.pcad.2018.02.002. Epub 2018 Feb 21. Coffee for Cardioprotection and Longevity James H O'Keefe 1 , James J DiNicolantonio 2 , Carl J Lavie 3 Affiliations Expand Affiliations 1 Saint Luke's Mid America Heart Institute, Kansas City, MO, United States. Electronic address: jokeefe@saint-lukes.org. 2 Saint Luke's Mid America Heart Institute, Kansas City, MO, United States. 3 Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, LA, United States. PMID: 29474816 DOI: 10.1016/j.pcad.2018.02.002 Item in Clipboard Review Coffee for Cardioprotection and Longevity James H O'Keefe et al. Prog Cardiovasc Dis . 2018 May-Jun . Show details Display options Display options Format Abstract PubMed PMID Prog Cardiovasc Dis Actions Search in PubMed Search in NLM Catalog Add to Search . 2018 May-Jun;61(1):38-42. doi: 10.1016/j.pcad.2018.02.002. Epub 2018 Feb 21. Authors James H O'Keefe 1 , James J DiNicolantonio 2 , Carl J Lavie 3 Affiliations 1 Saint Luke's Mid America Heart Institute, Kansas City, MO, United States. Electronic address: jokeefe@saint-lukes.org. 2 Saint Luke's Mid America Heart Institute, Kansas City, MO, United States. 3 Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, LA, United States. PMID: 29474816 DOI: 10.1016/j.pcad.2018.02.002 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Coffee, a complex brew containing hundreds of biologically active compounds, exerts potent effects on long-term human health. Recently, a plethora of studies have been published focusing on health outcomes associated with coffee intake. An inverse association between coffee consumption and all-cause mortality has been seen consistently in large prospective studies. Habitual coffee consumption is also associated with lower risks for cardiovascular (CV) death and a variety of adverse CV outcomes, including coronary heart disease (CHD), congestive heart failure (HF), and stroke; coffee's effects on arrhythmias and hypertension are neutral. Coffee consumption is associated with improvements in some CV risk factors, including type 2 diabetes (T2D), depression, and obesity. Chronic coffee consumption also appears to protect against some neurodegenerative diseases, and is associated with improved asthma control, and lower risks for liver disease and cancer. Habitual intake of 3 to 4 cups of coffee appears to be safe and is associated with the most robust beneficial effects. However, most of the studies regarding coffee's health effects are based on observational data, with very few randomized controlled trials. Furthermore, the possible benefits of coffee drinking must be weighed against potential risks, which are generally due to its high caffeine content, including anxiety, insomnia, headaches, tremulousness, and palpitations. Coffee may also increase risk of fracture in women, and when consumed in pregnancy coffee increases risk for low birth weight and preterm labor. Keywords: Cancer; Cardiovascular disease; Coffee; Coronary heart disease; Diabetes; Heart failure; Stroke. Copyright © 2018. Published by Elsevier Inc. PubMed Disclaimer Similar articles Effects of habitual coffee consumption on cardiometabolic disease, cardiovascular health, and all-cause mortality. O'Keefe JH, Bhatti SK, Patil HR, DiNicolantonio JJ, Lucan SC, Lavie CJ. O'Keefe JH, et al. J Am Coll Cardiol. 2013 Sep 17;62(12):1043-1051. doi: 10.1016/j.jacc.2013.06.035. Epub 2013 Jul 17. J Am Coll Cardiol. 2013. PMID: 23871889 Review. Coffee and tea: perks for health and longevity? Bhatti SK, O'Keefe JH, Lavie CJ. Bhatti SK, et al. Curr Opin Clin Nutr Metab Care. 2013 Nov;16(6):688-97. doi: 10.1097/MCO.0b013e328365b9a0. Curr Opin Clin Nutr Metab Care. 2013. PMID: 24071782 Review. Coffee consumption and health: umbrella review of meta-analyses of multiple health outcomes. Poole R, Kennedy OJ, Roderick P, Fallowfield JA, Hayes PC, Parkes J. Poole R, et al. BMJ. 2017 Nov 22;359:j5024. doi: 10.1136/bmj.j5024. BMJ. 2017. PMID: 29167102 Free PMC article. Review. Coffee: A Selected Overview of Beneficial or Harmful Effects on the Cardiovascular System? Whayne TF Jr. Whayne TF Jr. Curr Vasc Pharmacol. 2015;13(5):637-48. Curr Vasc Pharmacol. 2015. PMID: 25277696 Review. Coffee consumption and cardiovascular diseases and mortality in patients with type 2 diabetes: A systematic review and dose-response meta-analysis of cohort studies. Shahinfar H, Jayedi A, Khan TA, Shab-Bidar S. Shahinfar H, et al. Nutr Metab Cardiovasc Dis. 2021 Aug 26;31(9):2526-2538. doi: 10.1016/j.numecd.2021.05.014. Epub 2021 May 24. Nutr Metab Cardiovasc Dis. 2021. PMID: 34112583 See all similar articles Cited by Association of daily sitting time and coffee consumption with the risk of all-cause and cardiovascular disease mortality among US adults. Zhou H, Nie J, Cao Y, Diao L, Zhang X, Li J, Chen S, Zhang X, Chen G, Zhang Z, Li B. Zhou H, et al. BMC Public Health. 2024 Apr 17;24(1):1069. doi: 10.1186/s12889-024-18515-9. BMC Public Health. 2024. PMID: 38632571 Free PMC article. Acute Effects of Coffee Consumption on Blood Pressure and Endothelial Function in Individuals with Hypertension on Antihypertensive Drug Treatment: A Randomized Crossover Trial. Lima de Castro FBA, Castro FG, da Cunha MR, Pacheco S, Freitas-Silva O, Neves MF, Klein MRST. Lima de Castro FBA, et al. High Blood Press Cardiovasc Prev. 2024 Jan;31(1):65-76. doi: 10.1007/s40292-024-00622-8. Epub 2024 Feb 3. High Blood Press Cardiovasc Prev. 2024. PMID: 38308805 Clinical Trial. Exploring the connection between caffeine intake and constipation: a cross-sectional study using national health and nutrition examination survey data. Kang Y, Yan J. Kang Y, et al. BMC Public Health. 2024 Jan 2;24(1):3. doi: 10.1186/s12889-023-17502-w. BMC Public Health. 2024. PMID: 38167025 Free PMC article. Plants of the Rubiaceae Family with Effect on Metabolic Syndrome: Constituents, Pharmacology, and Molecular Targets. González-Castelazo F, Soria-Jasso LE, Torre-Villalvazo I, Cariño-Cortés R, Muñoz-Pérez VM, Ortiz MI, Fernández-Martínez E. González-Castelazo F, et al. Plants (Basel). 2023 Oct 15;12(20):3583. doi: 10.3390/plants12203583. Plants (Basel). 2023. PMID: 37896046 Free PMC article. Review. Caffeine causes cell cycle arrest at G0/G1 and increases of ubiquitinated proteins, ATP and mitochondrial membrane potential in renal cells. Kanlaya R, Subkod C, Nanthawuttiphan S, Thongboonkerd V. Kanlaya R, et al. Comput Struct Biotechnol J. 2023 Sep 21;21:4552-4566. doi: 10.1016/j.csbj.2023.09.023. eCollection 2023. Comput Struct Biotechnol J. 2023. PMID: 37799542 Free PMC article. 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+Familial hypercholesterolemia: A review - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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+    the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Ann Pediatr Cardiol. 2014 May-Aug; 7(2): 107–117. doi: 10.4103/0974-2069.132478 PMCID: PMC4070199 PMID: 24987256 Familial hypercholesterolemia: A review Mithun J Varghese Mithun J Varghese Department of Cardiology, Christian Medical College, Vellore, Tamil Nadu, India Find articles by Mithun J Varghese Author information Copyright and License information PMC Disclaimer Department of Cardiology, Christian Medical College, Vellore, Tamil Nadu, India Address for correspondence: Dr. Mithun J Varghese, Department of Cardiology, Christian Medical College, Vellore - 632 004, Tamil Nadu, India. E-mail: moc.liamg@vjnuhtimrd Copyright : © Annals of Pediatric Cardiology This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism resulting in elevated serum low-density lipoprotein (LDL) cholesterol levels leading to increased risk for premature cardiovascular diseases (CVDs). The diagnosis of this condition is based on clinical features, family history, and elevated LDL-cholesterol levels aided more recently by genetic testing. As the atherosclerotic burden is dependent on the degree and duration of exposure to raised LDL-cholesterol levels, early diagnosis and initiation of treatment is paramount. Statins are presently the mainstay in the management of these patients, although newer drugs, LDL apheresis, and other investigational therapies may play a role in certain subsets of FH, which are challenging to treat. Together these novel treatments have notably improved the prognosis of FH, especially that of the heterozygous patients. Despite these achievements, a majority of children fail to attain targeted lipid goals owing to persistent shortcomings in diagnosis, monitoring, and treatment. This review aims to highlight the screening, diagnosis, goals of therapy, and management options in patients with FH. Keywords: Familial hypercholesterolemia, heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, low-density lipoprotein receptor mutation INTRODUCTION Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism characterized by highly elevated plasma total-cholesterol levels with detrimental cardiovascular consequences that commence in childhood. Although atherosclerosis due to FH manifests primarily in adulthood, it has a precocious inception as early as the 1 st decade of life.[ 1 ] That early treatment of risk factors can reverse the atherosclerotic changes in the arterial system[ 2 ] underscores the need for prompt detection and treatment of children with this condition. Fagge identified this disorder more than a century ago as a skin ailment,[ 3 ] but its correlation with atherosclerosis was first recognized in 1939 by Norwegian physician Carl Muller.[ 4 ] The past decade saw a flurry of research in this disease with respect to its genetic basis and therapy. However, FH remains underdiagnosed till late due to the lack of awareness among pediatricians and the general public and the diagnosis is often arrived at only after the irreversible consequences of atherosclerosis have been established. This review describes the current status of the diagnosis, screening, and management of this malady. GENETICS OF FH ’Familial hypercholesterolemia’ represents the phenotypic manifestation of abnormal lipoprotein metabolism caused by a variety of genetic abnormalities. After the seminal discovery by Brown and Goldstein that mutations in the low-density lipoprotein receptor (LDLR) was the cause of monogenetic FH, over 1,500 mutations of this gene have been detected[ 5 , 6 ] and these account for more than 80% of cases of monogenetic FH.[ 7 ] Heterozygous FH (HeFH) is not an uncommon disorder in children, with an estimated prevalence of 1 in 500 in the western world.[ 8 ] Homozygous FH (HoFH), although uncommon (prevalence is less than one per million in the general population), is a critical condition which commences in the first few years of life.[ 9 ] It is principally noted in countries such as Lebanon, Canada, and South Africa possibly because of the founder mutations and isolation of population.[ 10 ] In addition to the LDLR defect, two other sets of autosomal dominant mutations play a central role in the pathogenesis of FH; one, a defective apo-B100 component of LDL, known as familial defective apoB-100 (clinically indistinguishable from heterozygous LDLR mutations).[ 11 , 12 , 13 ] Secondly, a gain of function mutation affecting proprotein convertase subtilisin/kexin 9 (PCSK9) encoded by chromosome 1 has also been shown to trigger FH by negatively modulating LDL receptor expression.[ 14 ] Although the rare autosomal recessive form of FH called autosomal recessive hypercholesterolemia has been described in a few families,[ 15 , 16 ] in clinical practice, monogenetic hypercholesterolemia is primarily an autosomal dominant disorder with greater than 90% penetrance. Though single gene disorders play a crucial role in the etiology of FH, linkage studies have exposed that the majority of cases of FH are caused by numerous unexceptional genetic variations.[ 11 ] An interplay of these polygenic variations together with environmental factors remains the leading cause for hypercholesterolemia in the general population.[ 17 , 18 ] However, a monogenetic etiology is usually the reason for more severe forms of LDL elevation and also for phenotypic expression of FH in the 1 st decade of life. SCREENING FOR FH The ideal strategy to screen for FH is currently a controversial issue. Former lipid guidelines advocated ‘targeted screening’, which comprised a fasting lipid profile test in children with risk factors for FH such as a family history of premature cardiovascular diseases (CVDs), dyslipidemia, or obesity.[ 19 ] However, despite its cost effectiveness, this approach entailed the risk of missing 30-60% of affected patients.[ 20 ] An alternative approach to screening is termed ‘cascade screening’,[ 21 , 22 ] wherein health workers actively screen for disease among the first and second degree relatives of patients diagnosed by targeted screening. Although this method is associated with improved detection rates, there remains a considerable risk of missing affected individuals. This shortcoming has prompted some of the recent guidelines to recommend a strategy of universal lipid screening.[ 23 , 24 ] However, the cost effectiveness or utility of universal screening as well as the psychological impact on the children and the parents are not well-studied. Furthermore, a minority of patients of FH (7%) may have a normal lipid profile at the time of screening,[ 25 ] thus, facing the risk of missing the diagnosis in some despite screening of the entire population. An equally important question is what to screen — lipids or genes? Genetic screening strategy involves searching for the common genes causing FH among suspected children and their close relatives. Recent National Institute for Health and Care Excellence (NICE) guidelines recommend a DNA testing on all patients diagnosed with FH and a subsequent genetic screening among their close relatives in order to augment case detection rates.[ 26 ] Although intuitively attractive, a significant number of patients clinically diagnosed with FH are negative for mutations conventionally tested for by genetic screening, probably due to polygenic inheritance.[ 27 ] In such patients, genetic cascade testing is expected to have a very low yield and is unlikely to be cost effective.[ 17 ] Hence, genetic cascade screening is likely to benefit only probands where a definite mutation is identified; in others, a strategy of lipid profile-based cascade screening is preferable. The ideal age of lipid screening among children is also a keenly debated issue. The normal cord blood levels of LDL-cholesterol ranges from 35 to 70 mg/dl.[ 28 ] Although cord blood LDL levels for screening for FH is an appealing concept, studies have shown significant overlap in these levels between neonates with and without HeFH,[ 29 ] thus precluding this as a screening strategy. The Lipid Research Clinics prevalence studies demonstrated that by the age of 2 years, the serum lipid level reached that of young adults,[ 30 ] while the National Health and Nutrition Examination Surveys (NHANESs)[ 31 ], reported that the peak lipid levels are reached by the age of 9-11 years. Therefore, universal screening is best performed between 9 and 11 years of age, whereas a screening at any time after the age of 2 years is preferred in those who are candidates of targeted screening.[ 11 , 32 , 33 ] Table 1 summarizes national lipid association guidelines for screening children for FH. Table 1 National lipid association key screening recommendations for FH Open in a separate window Clinical features and diagnosis Patients with HeFH are, by and large, asymptomatic in childhood and adolescence and typically diagnosed by screening methods. Their total and LDL-cholesterol levels are characteristically over the 95 th centile of the recommended levels and a strong family history corroborates the diagnosis. Some involved persons may bear peripheral markers of fat deposition such as tendon xanthoma or arcus lipoides. Homozygous or compound HeFH, on the other hand, presents in the 1 st decade of life with a distinctive and severe clinical phenotype. The age at presentation depends on the degree of LDL receptor activity,[ 16 ] those with the null phenotype (<2% LDL receptor activity) tend to present earlier, resulting even in intrauterine death. These patients have primarily dermatological and ocular manifestations — tendon xanthomas and interdigital xanthomas are pathognomic of HoFH [ Figure 1 ]. Tendon xanthomas are frequently missed on visual inspection alone and necessitate careful palpation in the Achilles, biceps and triceps tendons for early detection. Although tuberous xanthomas, xanthelasma, and corneal arcus appear in conditions other than FH,[ 34 ] their occurrence at a younger age should prompt evaluation for FH. Severe atherosclerosis involving multiple vascular beds, including coronary, cerebral, and peripheral vascular system, manifest in a myriad ways. Though coronary atherosclerosis is frequently the cause of premature death, calcific aortic valve stenosis and aortic root disease, including supravalvular aortic stenosis due to cholesterol and inflammatory cell infiltration, may result in significant morbidity in these patients, often requiring aortic valve and root replacement.[ 35 ] Open in a separate window Figure 1 Dermatological manifestations: (a) Eruptive xanthoma, (b) tendon xanthoma, and (c) tuberous xanthoma in a 12-year-old girl with homozygous familial hypercholesterolemia (FH). (d) Her father who was diagnosed to have heterozygous FH with coronary artery disease had xanthelasma When FH is suspected based on elevated lipid levels and clinical features, secondary dyslipidemias such as diabetes, endocrine disorders including hypothyroidism, renal disorders, obesity, and incriminating drugs must be ruled out before arriving at the diagnosis. A detailed family history should be taken not only to assess the mode of transmission but also to identify other affected individuals for early commencement of treatment. A comprehensive CVD risk assessment is required in all diagnosed patients and correction of modifiable risk factors must be pursued. The value of CVD risk assessment tools used in adults such as Framingham Risk Score have not been validated in the pediatric and adolescent populations with FH and are liable to underestimate the risk.[ 11 ] Ancillary investigations such as carotid intima medial thickness and ankle brachial index, which are usually used in research settings, may be helpful in monitoring the progression of disease in selected cases. The diagnosis of FH is typically based on elevation of total-, LDL-, and non-HDL-cholesterol above the 95 th centile recommended for the age and sex of the patient together with positive family history or identification of a causative mutation. The MEDPED criteria from the United States,[ 36 ] the Dutch Lipid Clinic criteria,[ 37 ] and the British Simon Broome Registry criteria[ 38 ] [ Table 2 ] are validated diagnostic systems in this regard. The first relies solely on the age and the blood lipid levels of the patient, while the latter two require family history and clinical findings as well. These criteria are credited with simplicity and ease of use; however, they may be relatively ineffective at diagnosing index cases. Moreover, these criteria may not be clinically sensitive when applied to mild phenotypes and children in whom phenotypic expression is not yet completed. Table 2 Criteria for diagnosis of familial hypercholesterolemia Open in a separate window Management Lipid targets Recommendations differ with respect to target lipid levels in pediatric and adolescent patients. National Lipid Association guidelines recommend a target LDL level of <130 mg/dl or >50% reduction from baseline values.[ 24 ] More rigorous targets are proposed in patients with additional risk factors such as diabetes, obesity, and a family history of CVD. Belgian multisocietal guidelines, on the other hand, recommend age-specific targets.[ 33 ] In children aged 10-14 years, an LDL level of <160 mg/dl or >30% reduction from baseline levels is targeted. A rigorous target lipid level of <130 mg/dl is recommended in children between the ages of 14 and 18 years. In patients older than 18 years, a lipid target of <100 mg/dl is deemed appropriate. It should be noted that, a recent cross-sectional study in the Netherlands showed that no more than 21% of HeFH patients realized their lipid goals despite the recent advances in therapy.[ 39 ] Among patients who failed to achieve LDL-cholesterol goal, only 21% were on maximal dose of approved drugs, suggesting shortcomings in adequate monitoring and implementation of therapy.[ 39 ] Lifestyle changes Therapeutic lifestyle adjustments forman important part in the management of FH. This encompasses specific dietary manipulations, physical activity, limitation of alcohol intake, and total avoidance of tobacco products. Recent guidelines recommend a low calorie diet with a total fat intake of ≤3% of the total dietary intake including <8% of saturated fat and <75 mg/1,000 kcal cholesterol for these patients.[ 33 ] However, dietary restrictions are noted to have a modest effect in lowering lipid levels,[ 40 ] with unproven long-term clinical benefits.[ 41 ] Consequently, a concurrent drug therapy is indicated in patients with severe hypercholesterolemia. Dietary supplementation of phytosterol esters and stanol esters is controversial: Although a few recent studies have demonstrated a reduction of LDL levels in children with FH,[ 42 ] there are concerns regarding their accumulation in atheromas[ 43 ] and lowering of serum levels of lipid soluble vitamins.[ 44 ] Similarly, dietary supplementation of soy proteins and polyunsaturated fatty acids in this population is not substantiated by clinical evidence and is, hence, not currently recommended.[ 33 ] Drug therapy-when to start? The former guidelines issued by National Heart, Lung, and Blood Institute (NHLBI) advised treatment with bile acid sequestrants, the lowest age recommended for initiation being 10 years.[ 19 ] This was based on the excellent long-term safety profile of this group of drugs owing to lack of their systemic absorption. However, modest efficacy[ 45 ] and poor tolerability of these drugs resulted in alterations in the recent expert opinions and consensus papers.[ 23 , 24 , 33 ] In a recent statement by the American Heart Association,[ 46 ] later endorsed by the American Academy of Pediatrics,[ 20 ] statins were proposed as first-line drugs and the age of initiation of therapy was lowered to 8 years. Bile acid Sequestrants Formerly, this class of drugs was deemed the first-line of therapy of FH in children owing to their lack of systemic uptake. They bind to bile acids in the intestine, thereby, preventing their systemic absorption; this results in a greater conversion of cholesterol to bile acids and an enhanced production of LDL receptors by the liver. Cholestyramine and colestipol were the most frequently used drugs in this class; however, they fell out of favor due to their modest efficacy (10-20% LDL reduction) and gastrointestinal intolerance. Of late, a novel drug in this class, colesevelam hydrochloride, has been studied in HeFH patients. A short-term, randomized trial showed good tolerability and efficacy of colesevelam alone and in combination with statins leading to a renewed interest in this class of drugs.[ 47 ] Statins Statins (3-hydroxy-3methyl-glutaryl-CoA reductase inhibitors) are currently the first line of drugs in the treatment of FH in children and adolescents. They inhibit the rate-limiting step in cholesterol synthesis, thus, increasing the expression of LDL receptors, resulting in the rapid clearance of LDL from the blood. However, they have a restricted role in patients of HoFH with null phenotype in view of the need for receptor production for their action. Among the various generic statins available, the Food and Drug Administration (FDA) has approved of pravastatin in children over 8 years of age and lovastatin, atorvastatin, and simvastatin above the age of 10 years.[ 48 ] The prepubertal commencement of statin therapy remains controversial,[ 49 ] as this can potentially hamper the production of steroid hormones in the body. Moreover, their effects on muscles and the liver are still an issue of grave concern. A recent Cochrane review[ 50 ] and two meta-analysis[ 51 , 52 ] of placebo-controlled trials on statins in children and adolescents with FH showed no major side effects with regard to growth, sexual development, muscle, and liver toxicity. Concurrently, they showed excellent efficacy in lipid lowering with a 26.5% mean relative reduction in LDL-cholesterol levels. The apprehension regarding growth disruption by statins at puberty was allayed, in part, by the paradoxical finding of increased growth in the children treated with the drug.[ 51 , 52 ] However, it is noteworthy that all the trials included in these meta-analyses studied only short-term outcomes; the long-term safety of statins in this population is unknown. The longest follow-up data on the effects of statin therapy in pediatric population is a retrospective study over a 7-year period in 185 children with FH treated with pravastatin, which revealed minor side effects in 13% of patients and myopathy in four patients.[ 53 ] Modern trends of drug usage among children indicate that the utilization of statins in the pediatric population is in the upswing,[ 54 ] despite the aforementioned concerns in relation to long-term safety. There are specific recommendations on the subject of monitoring of patients commencing statin therapy. Creatine phosphokinase (CK) to assess muscle toxicity and aspartate amino transferase (AST), and alanine amino transferase (ALT) to monitor liver toxicity are mandatory prior to initiation of statins. Follow-up measurements must be done 1-3 months after starting the drug and yearly thereafter. Drug therapy should be interrupted when CK levels reach five times and AST and ALT three times over the upper limit of normal; the same drug at a lower dose or a different statin may be introduced after a drug-free interval of 3 months. Other drugs may be tried if the patient does not tolerate statins despite these measures.[ 33 ] Ezetimibe Ezetimibe is a new class of cholesterol absorption inhibitors that acts on the brush border of the small intestinal epithelium. The specific site of its action is believed to be the epithelial cell Niemann — Pick C1-like protein.[ 55 ] As their mechanism of action is not based on the expression of LDL receptors, they are especially beneficial in the management of HoFH. Clinical trials have displayed their efficacy in reducing LDL levels when used alone[ 56 ] or in combination with statins.[ 57 , 58 ] However, the initial fervor over their use was dampened by the largest prospective trial (ENHANCE trial) on cholesterol absorption inhibitors until this time, which demonstrated that ezetimibe added to high dose simvastatin failed to lessen carotid intima medial thickness in spite of a significant diminution in LDL levels.[ 59 ] Lastly, the discovery of a small but significant rise in the incidence of cancer in patients treated with ezetimibe patients in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial[ 60 ] is a cause for concern in view of the need for lifelong therapy required in patients with FH. Therefore, additional data is required on clinically significant outcomes as well as safety endpoints before their widespread adoption in pediatric practice. Although US Food and Drug Administration (FDA) has approved of ezetemibe therapy in children over the age of 10years, current guidelines recommend drug initiation before 18 years of age only in patients intolerant to statins and in patients who fail to realize lipid goals with statin monotherapy.[ 11 , 33 ] Therapeutic options in patients who failed to attain lipid targets despite maximal medical therapy Newer drugs Mipomirsen, an antisense oligonucleotide that targets apoB-100 mRNA in the liver, is presently under investigation in the therapy of FH. This drug significantly lowered LDL and lipoprotein (a) levels in adults with heterozygous[ 61 ] and homozygous[ 62 ] hypercholesterolemia in recent phase 3 trials. Although the mean LDL reduction with 200 mg of subcutaneous mipomirsen administered weekly was significant in patients with HoFH (-24.7% in treatment group and -3.3% in the placebo group, P = 0.0003), the response to therapy was inconsistent and compounded by a significant number of nonresponders.[ 62 ] The most frequent side effects of mipomirsen include reactions at the site of injection and flu-like symptoms, but apprehension regarding their hepatic toxicity, especially steatosis, still remains. Moreover, as they have not been studied in the pediatric population in a prospective clinical trial, their safety profile in this group of patients is not defined. Serum PCSK9 are proteins which bind to LDL receptors and promote their degradation, thus, raising LDL levels in the blood. A variety of molecular techniques based on terminating the effect of PCSK9 in order to lower LDL-cholesterol levels is under investigation, including the development of monoclonal antibodies that bind to PCSK9,[ 63 ] antisense nucleotide-based therapy,[ 64 ] and small interfering RNAs.[ 65 ] In a randomized control trial experimenting on monoclonal antibodies in adults with various forms of hypercholesterolemia, the combination of this drug with 10 and 80 mg of atorvastatin was more efficacious than80mg of atorvastatin alone in reducing LDL levels.[ 66 ] However, as this antibody requires some residual LDL receptor function to fulfill its function, it is useful only in patients with HeFH and non-null phenotype HoFH. Lomitapide is a new lipid-lowering agent with a novel method of action: It inhibits the microsomal triglyceride transfer protein(MTP). The role of MTP in the production of LDL involves assisting inthe transfer of triglycerides to apolipoprotein B.[ 67 ] The US FDA has approved of its use as an orphan drug in the treatment of HoFH.[ 68 ] In a recently published phase 3 dose escalation trial, lomitapide reduced LDL-cholesterol by 50% in HoFH patients with poorly controlled LDL levels.[ 69 ] Although this small study showed a satisfactory safety profile of the drug, there are still lingering doubts regarding the hepatic side effects like steatosis and transaminitis owing to their distinctive mechanism of action. In addition to the aforementioned drugs, other classes of drugs like thyroid mimetics (e.g., eprotirome and sobetirome),[ 70 ] HDL-bound enzyme cholesterol ester transfer protein (CETP) inhibitors (e.g., torcetrapib, anacetrapib, and evacetrapib) and reconstituted high-density lipoprotein (rHDL)[ 71 ] are currently under research in the treatment of elevated LDL-cholesterol and shows variable efficacy and safety. All the ongoing trials on modern drug therapy of dyslipidemia focuses on adult patients and excludes the pediatric population. Given that a majority of these novel therapies are yet unproven with regard to clinical efficacy and safety endpoints, their role is presently confined to that of a lipid apheresis-sparing therapy in patients with HoFH who have fallen short of their lipid goals. Additional studies in the pediatric population are required prior to their clinical adoption in the treatment of heterozygous patients. LDL apheresis Patients with homozygous and compound HeFH frequently have elevated lipid levels in spite of optimal medical therapy. These are fitting candidates for LDL apheresis, which has proved to be a very beneficial treatment option to reducing LDL levels. Numerous studies have affirmed its capability to lower LDL-cholesterol levels by 55-75%.[ 72 ] Commonly used techniques of LDL apheresis include heparin-induced extracorporeal LDL-cholesterol precipitation (HELP), dextran sulfate cellulose adsorption (DSA), double filtration plasmapheresis (DFPP), polyacrylate full blood adsorption (PFBA also known as DALI), and immune adsorption. Details on the techniques are beyond the scope of this update and interested readers may consult excellent reviews available on the subject.[ 73 , 74 , 75 ] The decline in LDL-cholesterol levels by apheresis is a transitory event and is associated with a rebound escalation of lipid levels after the procedure. This rebound is expeditious in patients without FH, slower in those with HeFH and delayed in patients in HoFH.[ 76 ] Weekly to fortnightly sessions are advocated for patients with HoFH, as such episodic sittings have been shown to reduce the degree of rebound and retard the progression of atherosclerosis.[ 77 , 78 ] Regular apheresis therapy along with medications in patients of HoFH has improved the average life expectancy to over 50 years of age compared to the formerly bleak prognosis of death in the2 nd or 3 rd decade.[ 79 ] Despite its established efficacy, lipid apheresis has not yet been widely embraced in clinical practice due to lack of accessibility for the majority of patients, the prohibitive cost involved, the invasive nature of the procedure, and the lack of motivation among patients. Gene therapy HoFH was among the first disorders wherein gene therapy was experimented. Contrary to other treatment alternatives, the possibility of a definitive cure by a one-time procedure for a disease that lasts a lifetime renders this an appealing choice. However, due to the problems related to appropriate gene vector, lack of persistent gene expression as well as due to safety concerns,[ 80 ] this modality failed to demonstrate substantial clinical efficacy in preliminary trials. Upcoming research should focus on improving gene vectors and transfer techniques, while concurrently reducing their oncogenic dangers before it can be relevant to clinical practice.[ 81 ] Surgical options In addition to the therapies enumerated prior, surgical options including ileal bypass and portocaval shunt have been tried earlier in refractory cases. Owing to the significant comorbidities involved and the need for treatment before the onset of clinical effects of atherosclerosis, these never became a popular choice of treatment. Recent case reports of successful pediatric liver transplant done for the treatment of HoFH suggest excellent efficacy and good safety profile of this option.[ 82 , 83 ] However, in view of the scarcity of donor liver available and complexities of the transplant and post-transplant management, such a decision should be taken only after carefully assessing the risk benefit ratio. Natural and modified natural history of FH The natural history of FH depends primarily on the degree of functional LDL receptor activity present, and in turn, on LDL-cholesterol levels, resulting in widely varying prognosis even among homozygous individuals.[ 84 ] Symptom onset is age-dependent and typically occurs in the 2 nd decade in homozygous patients. The extent of atherosclerosis is primarily determined by the degree of LDL elevation and its duration, calculated by the cholesterol year score.[ 85 ] Precocious onset of clinically significant atherosclerotic changes are very common and involve multiple vascular beds including coronary, cerebral, and peripheral systems.[ 85 ] Studies in the pre-statin era indicated poor outcomes in the majority of patients with HoFH, cardiovascular events being the chief cause of morbidity and mortality.[ 86 ] Aortic root disease was reported to be the commonest cardiac manifestation followed by coronary artery disease.[ 86 ] While some studies in this interval purported a mean survival of 18 years among patients with HoFH,[ 87 ] others observed an average survival of 40 years;[ 86 ] this variation may be ascribed to the differences in the proportion of receptor-negative patients included in these studies. It was conventionally believed that modern day drug therapy for HoFH does not alter prognosis owing to the lack of significant reduction in LDL. However, this assumption was challenged by a recent retrospective analysis by Raal et al ., involving 149 patients, wherein patients treated with statins had hazard ratios for mortality and cardiovascular events of 0.34 and 0.49, respectively when compared with patients in the pre-statin era, despite achieving only a modest 26% reduction in LDL levels. 87 Although this result may be partly influenced by the beneficial effects of cardiovascular preventive drugs such as antiplatelet agents and beta blockers, this study underscores the benefit of statin therapy even in FH homozygous individuals. Among patients with untreated HeFH, coronary artery disease (CAD) develops in about 50% of males by the age of 50 years and 30% of females by 60 years. Although CAD appears 10years later in females compared to males, an accelerated development of CAD is observed after menopause.[ 88 , 89 ] Simon Broome registry data from England in the pre-statin era showed that mortality associated with CAD was increased a 100-fold in the age group of 20-40 years and four-fold in the 40-59 year age group.[ 38 ] Among those surviving to the age of 60 years, however, the risk seems akin to that in the general population.[ 38 ] The benefits of present day therapeutic advances in this population is confirmed by a large prospective study from the UK, which reveals a 37% relative reduction in standardized mortality rate from 3.4 in the pre-statin era to 2.1 after widespread use of statins.[ 90 ] Despite strong association of FH with coronary and peripheral vascular disease, its relation with stroke risk is more controversial. A large prospective registry data from United Kingdom showed that ischemic stroke mortality among treated HeFH patients not to be different from general population.[ 91 ] The reason for this difference is presently unknown. CONCLUSION FH is a grave ailment with its genesis in early childhood resulting in damaging consequences in later life. Although the need for a screening strategy to detect this disease early is widely accepted, there is no consensus regarding whom and when to screen. Early initiation of lipid-lowering therapy and lifestyle measures might improve the clinical outcome. While such treatment initiatives have notably improved the prognosis of HeFH, the outcomes of familial homozygous hypercholesterolemia remain disappointing. Although most cases may be treated with a combination of statins and cholesterol absorption inhibitors, some will have need of more invasive therapies such as LDL apheresis. 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Epub 2010 Jan 20. Long-term walnut supplementation without dietary advice induces favorable serum lipid changes in free-living individuals S Torabian 1 , E Haddad , Z Cordero-MacIntyre , J Tanzman , M L Fernandez , J Sabate Affiliations Expand Affiliation 1 Department of Nutrition, School of Public Health, Loma Linda University, Loma Linda, CA, USA. svriasati@aol.com PMID: 20087377 DOI: 10.1038/ejcn.2009.152 Item in Clipboard Randomized Controlled Trial Long-term walnut supplementation without dietary advice induces favorable serum lipid changes in free-living individuals S Torabian et al. Eur J Clin Nutr . 2010 Mar . Show details Display options Display options Format Abstract PubMed PMID Eur J Clin Nutr Actions Search in PubMed Search in NLM Catalog Add to Search . 2010 Mar;64(3):274-9. doi: 10.1038/ejcn.2009.152. Epub 2010 Jan 20. Authors S Torabian 1 , E Haddad , Z Cordero-MacIntyre , J Tanzman , M L Fernandez , J Sabate Affiliation 1 Department of Nutrition, School of Public Health, Loma Linda University, Loma Linda, CA, USA. svriasati@aol.com PMID: 20087377 DOI: 10.1038/ejcn.2009.152 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Background/objectives: Walnuts have been shown to reduce serum lipids in short-term well-controlled feeding trials. Little information exists on the effect and sustainability of walnut consumption for longer duration in a free-living situation. Subjects/methods: A randomized crossover design in which 87 subjects with normal to moderate high plasma total cholesterol were initially assigned to a walnut-supplemented diet or habitual (control) diet for a 6-month period, then switched to the alternate dietary intervention for a second 6-month period. Each subject attended seven clinics 2 months apart. At each clinic, body weight was measured, and in five clinics (months 0, 4, 6, 10 and 12), a blood sample was collected. Results: Our study showed that supplementing a habitual diet with walnuts (12% of total daily energy intake equivalent) improves the plasma lipid profile. This beneficial effect was more significant in subjects with high plasma total cholesterol at baseline. Significant changes in serum concentrations of total cholesterol (P=0.02) and triglycerides (P=0.03) were seen and nearly significant changes in low-density lipoprotein cholesterol (LDL-C) (P=0.06) were found. No significant change was detected in either high-density lipoprotein (HDL) cholesterol LDL to HDL ratio. Conclusions: Including walnuts as part of a habitual diet favorably altered the plasma lipid profile. The lipid-lowering effects of walnuts were more evident among subjects with higher lipid baseline values, precisely those people with greater need of reducing plasma total and LDL-C. PubMed Disclaimer Comment in Long-term walnut supplementation without dietary advice induces favorable serum lipid changes in free-living individuals. Um CY, He K. Um CY, et al. Eur J Clin Nutr. 2011 Mar;65(3):421; author reply 422. doi: 10.1038/ejcn.2010.246. Epub 2010 Nov 10. Eur J Clin Nutr. 2011. PMID: 21063430 No abstract available. Similar articles Long-term walnut supplementation without dietary advice induces favorable serum lipid changes in free-living individuals. Um CY, He K. Um CY, et al. Eur J Clin Nutr. 2011 Mar;65(3):421; author reply 422. doi: 10.1038/ejcn.2010.246. Epub 2010 Nov 10. Eur J Clin Nutr. 2011. PMID: 21063430 No abstract available. Influence of body mass index and serum lipids on the cholesterol-lowering effects of almonds in free-living individuals. Jaceldo-Siegl K, Sabaté J, Batech M, Fraser GE. Jaceldo-Siegl K, et al. Nutr Metab Cardiovasc Dis. 2011 Jun;21 Suppl 1:S7-13. doi: 10.1016/j.numecd.2011.03.007. Epub 2011 May 12. Nutr Metab Cardiovasc Dis. 2011. PMID: 21570268 Serum lipid profiles in Japanese women and men during consumption of walnuts. Iwamoto M, Imaizumi K, Sato M, Hirooka Y, Sakai K, Takeshita A, Kono M. Iwamoto M, et al. Eur J Clin Nutr. 2002 Jul;56(7):629-37. doi: 10.1038/sj.ejcn.1601400. Eur J Clin Nutr. 2002. PMID: 12080402 Clinical Trial. Almonds have a neutral effect on serum lipid profiles: a meta-analysis of randomized trials. Phung OJ, Makanji SS, White CM, Coleman CI. Phung OJ, et al. J Am Diet Assoc. 2009 May;109(5):865-73. doi: 10.1016/j.jada.2009.02.014. J Am Diet Assoc. 2009. PMID: 19394473 Review. Walnuts decrease risk of cardiovascular disease: a summary of efficacy and biologic mechanisms. Kris-Etherton PM. Kris-Etherton PM. J Nutr. 2014 Apr;144(4 Suppl):547S-554S. doi: 10.3945/jn.113.182907. Epub 2014 Feb 5. J Nutr. 2014. PMID: 24500935 Review. See all similar articles Cited by In Vitro Assessment of the Bioaccessibility of Zn, Ca, Mg, and Se from Various Types of Nuts. Moskwa J, Naliwajko SK, Puścion-Jakubik A, Soroczyńska J, Socha K, Koch W, Markiewicz-Żukowska R. Moskwa J, et al. Foods. 2023 Dec 12;12(24):4453. doi: 10.3390/foods12244453. Foods. 2023. PMID: 38137257 Free PMC article. Tree Nut and Peanut Consumption and Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Houston L, Probst YC, Chandra Singh M, Neale EP. Houston L, et al. Adv Nutr. 2023 Sep;14(5):1029-1049. doi: 10.1016/j.advnut.2023.05.004. Epub 2023 May 5. Adv Nutr. 2023. PMID: 37149262 Free PMC article. Review. Nuts and seeds consumption and risk of cardiovascular disease, type 2 diabetes and their risk factors: a systematic review and meta-analysis. Arnesen EK, Thorisdottir B, Bärebring L, Söderlund F, Nwaru BI, Spielau U, Dierkes J, Ramel A, Lamberg-Allardt C, Åkesson A. Arnesen EK, et al. Food Nutr Res. 2023 Feb 14;67. doi: 10.29219/fnr.v67.8961. eCollection 2023. Food Nutr Res. 2023. PMID: 36816545 Free PMC article. Review. The Effect of Walnut Intake on Lipids: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Alshahrani SM, Mashat RM, Almutairi D, Mathkour A, Alqahtani SS, Alasmari A, Alzahrani AH, Ayed R, Asiri MY, Elsherif A, Alsabaani A. Alshahrani SM, et al. Nutrients. 2022 Oct 23;14(21):4460. doi: 10.3390/nu14214460. Nutrients. 2022. PMID: 36364723 Free PMC article. Review. Association of nut consumption with CVD risk factors in young to middle-aged adults: The Coronary Artery Risk Development in Young Adults (CARDIA) study. Yi SY, Steffen LM, Zhou X, Shikany JM, Jacobs DR Jr. Yi SY, et al. Nutr Metab Cardiovasc Dis. 2022 Oct;32(10):2321-2329. doi: 10.1016/j.numecd.2022.07.013. Epub 2022 Jul 31. Nutr Metab Cardiovasc Dis. 2022. PMID: 35970686 Free PMC article. 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+Walnut consumption in a weight reduction intervention: effects on body weight, biological measures, blood pressure and satiety - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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+    the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Nutr J. 2017; 16: 76. Published online 2017 Dec 4. doi: 10.1186/s12937-017-0304-z PMCID: PMC5715655 PMID: 29202751 Walnut consumption in a weight reduction intervention: effects on body weight, biological measures, blood pressure and satiety Cheryl L. Rock , Shirley W. Flatt , Hava-Shoshana Barkai , Bilge Pakiz , and Dennis D. Heath Cheryl L. Rock Department of Family Medicine and Public Health, School of Medicine, University of California, 3855 Health Sciences Drive, Room 3077, La Jolla, CA 92093-0901 USA Find articles by Cheryl L. Rock Shirley W. Flatt Department of Family Medicine and Public Health, School of Medicine, University of California, 3855 Health Sciences Drive, Room 3077, La Jolla, CA 92093-0901 USA Find articles by Shirley W. Flatt Hava-Shoshana Barkai Department of Family Medicine and Public Health, School of Medicine, University of California, 3855 Health Sciences Drive, Room 3077, La Jolla, CA 92093-0901 USA Find articles by Hava-Shoshana Barkai Bilge Pakiz Department of Family Medicine and Public Health, School of Medicine, University of California, 3855 Health Sciences Drive, Room 3077, La Jolla, CA 92093-0901 USA Find articles by Bilge Pakiz Dennis D. Heath Department of Family Medicine and Public Health, School of Medicine, University of California, 3855 Health Sciences Drive, Room 3077, La Jolla, CA 92093-0901 USA Find articles by Dennis D. Heath Author information Article notes Copyright and License information PMC Disclaimer Department of Family Medicine and Public Health, School of Medicine, University of California, 3855 Health Sciences Drive, Room 3077, La Jolla, CA 92093-0901 USA Cheryl L. Rock, Phone: 858-822-1126, Email: ude.dscu@kcorlc . Corresponding author. Received 2017 Sep 21; Accepted 2017 Nov 27. Copyright © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated. Associated Data Data Availability Statement The datasets generated and/or analyzed during the current study are not publicly available due to the private (and not public) sponsorship but are available from the corresponding author on reasonable request. Abstract Background Dietary strategies that help patients adhere to a weight reduction diet may increase the likelihood of weight loss maintenance and improved long-term health outcomes. Regular nut consumption has been associated with better weight management and less adiposity. The objective of this study was to compare the effects of a walnut-enriched reduced-energy diet to a standard reduced-energy-density diet on weight, cardiovascular disease risk factors, and satiety. Methods Overweight and obese men and women ( n = 100) were randomly assigned to a standard reduced-energy-density diet or a walnut-enriched (15% of energy) reduced-energy diet in the context of a behavioral weight loss intervention. Measurements were obtained at baseline and 3- and 6-month clinic visits. Participants rated hunger, fullness and anticipated prospective consumption at 3 time points during the intervention. Body measurements, blood pressure, physical activity, lipids, tocopherols and fatty acids were analyzed using repeated measures mixed models. Results Both study groups reduced body weight, body mass index and waist circumference (time effect p < 0.001 for each). Change in weight was −9.4 (0.9)% vs. -8.9 (0.7)% (mean [SE]), for the standard vs. walnut-enriched diet groups, respectively. Systolic blood pressure decreased in both groups at 3 months, but only the walnut-enriched diet group maintained a lower systolic blood pressure at 6 months. The walnut-enriched diet group, but not the standard reduced-energy-density diet group, reduced total cholesterol and low-density lipoprotein cholesterol (LDL-C) at 6 months, from 203 to 194 mg/dL and 121 to 112 mg/dL, respectively ( p < 0.05). Self-reported satiety was similar in the groups. Conclusions These findings provide further evidence that a walnut-enriched reduced-energy diet can promote weight loss that is comparable to a standard reduced-energy-density diet in the context of a behavioral weight loss intervention. Although weight loss in response to both dietary strategies was associated with improvements in cardiovascular disease risk factors, the walnut-enriched diet promoted more favorable effects on LDL-C and systolic blood pressure. Trial registration The trial is registered at ( {"type":"clinical-trial","attrs":{"text":"NCT02501889","term_id":"NCT02501889"}} NCT02501889 ). Keywords: Weight loss, Nuts, Satiety, Cardiovascular disease risk factors, Blood pressure Introduction Current guidelines for the management of overweight and obesity recommend prescribing a reduced-energy diet as a primary treatment intervention to promote weight loss, as part of a comprehensive lifestyle intervention, and conclude that a variety of dietary approaches can produce weight loss [ 1 ]. However, dietary patterns, specific foods, and macronutrient composition may differentially affect metabolic factors, satiety, and the postprandial gastrointestinal peptide response that could affect hunger and appetite [ 2 , 3 ]. Dietary strategies that help patients reduce energy intake and adhere to a reduced-energy diet may increase the likelihood of improved long-term health outcomes and reduced risk for obesity-related conditions and diseases. In several large cohorts and a few clinical trials, a dietary pattern that includes regular nut consumption has been associated with less weight gain in adulthood and a lower degree of adiposity [ 4 – 11 ]. In a few previous studies, the effects of consuming almonds, pistachios, walnuts and peanuts on weight change and cardiovascular disease risk factors in the context of a weight loss intervention have been examined, with mixed results [ 12 – 18 ]. A proposed mechanism for the favorable effect of nuts on weight control is that they promote increased satiety, resulting in a compensatory reduction in total energy intake [ 4 , 5 ]. Feelings of satiety, fullness, and hunger following walnut consumption has been examined in only a few previous studies. In those studies, acute postprandial peptide response and early phase satiety was observed to be similar following a meal with or without walnuts, although increased satiety and fullness were found on days 3 and 4 following a walnut-containing meal [ 19 , 20 ]. Measuring responses over the long-term would better model the observational studies that have linked regular nut consumption with lower adiposity and better weight control. In the present study, we compared the effects of a walnut-enriched reduced-energy diet to a reduced-energy-density diet, which has been suggested to be a useful dietary strategy to promote reduced energy intake without compromising meal satiety [ 21 ]. The primary objective of this study was to compare the effects of a walnut-enriched reduced-energy diet to a standard reduced-energy-density diet on body weight and cardiovascular disease risk factors in a sample of overweight and obese adults in an intensive 6-month weight loss intervention. A secondary objective was to examine whether there is a differential response in satiety- and appetite-related ratings scales in association with a walnut-enriched reduced-energy diet and a reduced-energy-density diet among the participants in this weight-loss study. Methods Subjects One hundred non-diabetic overweight and obese men and women were randomized from a screened sample of 647 (Fig. 1 ). To be included in the study, participants had to meet the following criteria: Aged 21 years and older, body mass index (BMI) between 27 and 40 kg/m 2 ; willing and able to participate in clinic visits, group sessions, and telephone and internet communications; able to provide data through questionnaires and telephone; willing to maintain contact with investigators for 6 months; willing to allow blood collections; no known allergy to tree nuts; and capable of performing a simple test for assessing cardiopulmonary fitness. Exclusion criteria were any of the following: Inability to participate in physical activity due to severe disability; history or presence of a comorbid diseases where diet modification and increased physical activity may be contraindicated; self-reported pregnancy or breastfeeding or planning a pregnancy within the next year; currently involved in another diet intervention study or weight loss program; and having a history or presence of a significant psychiatric disorder or any condition that would interfere with participation in the trial. The University of California, San Diego (UCSD), institutional review board approved the study protocol, and all participants provided written informed consent. Open in a separate window Fig. 1 Flow chart for study participants Prior to enrollment, potential participants were screened for diabetes and considered ineligible with a fasting blood glucose ≥125 mg/dL. At screening and recruitment, the ability to participate in moderate intensity physical activity was assessed by questionnaire, a standard procedure for screening participants for community-based weight loss programs of this nature. Participants were additionally asked to report all prescription medications and were asked if they had ever been told by a doctor that they had high blood cholesterol. Once enrolled, participants were randomly assigned to one of the two study arms using a sequence stratified by age (≤52 vs. >52 years) and BMI (≤33 vs. >33 kg/m 2 ). Intervention All participants were provided a detailed diet prescription in an individual counseling session with a dietitian, in which a caloric deficit was set based on the participant’s goals, and a sample meal plan was developed according to study arm and participant food preferences. The overall goal of the dietary guidance was to promote a reduction in energy intake, aiming for a 500- to 1000-kcal/day deficit relative to expenditure. All participants had follow-up contact with the dietitian by telephone or email a minimum of every 1–2 weeks for additional support and to reinforce adherence throughout the intervention. Participants assigned to the standard reduced-energy-density diet arm were provided diet plans that emphasized lower energy density food choices such as vegetables, fruit and whole grains, as well as lean protein sources and reduced-fat dairy foods, with macronutrient composition within current guidelines ( https://www.choosemyplate.gov/MyPlate ). Participants assigned to this study group were asked to refrain from eating any nuts (and products containing them) for the duration of the study. Participants assigned to the walnut-enriched reduced-energy study group were instructed to consume an average of 42 g (1.5 oz) of walnuts/day for diet prescriptions that were ≥1500 kcal/day, or 28 g (1 oz) of walnuts/ for diet prescriptions <1500 kcal/day, all within their energy-reduced diet plan (thus, walnuts provided approximately 15% of total energy intake). Participants were provided meal and snack suggestions and recipes to facilitate adherence, and the nuts were distributed to participants assigned to that group on a weekly basis for 12 weeks and then biweekly for the remainder of the study. Also, participants were queried about walnut consumption for the previous week when the walnuts were distributed, and adherence was recorded. Use of a Web-based planning and tracking program that enabled tracking kilocalories was encouraged. All participants were provided a scale and were asked to weigh themselves daily and to record their progress. An activity tracker was provided and participants were asked to gradually build up to a minimum of 10,000 steps per day within the first month and then to maintain or increase that level of lifestyle activity. An additional daily exercise goal was an average of at least 60 min/day of purposeful aerobic activity at a moderate level of intensity. Strength training 2–3 times/week also was encouraged. Tools such as measuring cups, small exercise equipment, and videos were provided to encourage adherence. In addition to individualized diet prescription and counseling, all participants were assigned to a series of closed group sessions (weekly for 12 weeks, then biweekly), based on a semi-structured cognitive-behavioral weight loss intervention. Briefly, strategies discussed included: Planning and tracking meals and exercise; environmental control; realistic goal-setting; triggers to eating and ways to deal with them; problem-solving; dealing with negative thoughts; promoting self-efficacy through goal accomplishments and other strategies; self-nurturing; dealing with lapses; and addressing body image concerns. Measurements Study data were collected and managed using a Research Electronic Data Capture (REDcap) database hosted at UCSD [ 22 ]. At baseline and 3- and 6-month follow-up data collection clinic visits, weight, height (baseline only), waist circumference, and blood pressure were measured, and a fasting (≥6 h) blood sample and questionnaires were collected. Systolic and diastolic blood pressure was averaged from two sitting blood pressure measurements. The 3-min step test, which measures heart rate during the first 30 s of recovery from stepping, was used to assess cardiopulmonary fitness. This test has high reliability and is sensitive to change [ 23 ]. Physical activity was estimated using the Godin Leisure-Time Exercise Questionnaire, a validated self-report measure of physical activity that has been widely used in previous research [ 24 ]. This questionnaire assesses weekly hours of moderate and strenuous physical activity. These data were compared with current recommendations for physical activity in adults, which are 150 min weekly of moderate physical activity, or 75 min weekly of strenuous physical activity, or a combination of these [ 25 ]. Participants were asked to rate general (rather than meal-specific) satiation by using a visual analog scale (VAS), an approach which has been shown to have validity, reliability, and reproducibility [ 26 ]. Similar to other studies in which satiety and satiation over time (rather than meal-specific) have been assessed [ 19 ], participants were asked to complete these scales before lunch and dinner meals at three time points during the 6 months of active participation (weeks 1, 6, and 13). Specifically, subjects were asked to rate their satiety by answering three questions. Each of the questions was completed by the participant and transferred by staff (blinded to study arm assignment) to a REDCap (Vanderbilt University, Nashville, TN, USA) file database, with a 100 mm horizontal line anchored at either end, so that answers can be quantified on a continuous scale. The questions are: “How hungry do you feel?” with anchor values ranging from “I have never been more hungry” (scored as 0) to “I am not hungry at all” (scored as 100); “How full do you feel?”, with anchor values ranging from “Not at all full” (scored as 0) to “Totally full” (scored as 100); and “How much do you think you could eat now?” with anchor values ranging from “Nothing at all” (scored as 0) to “A lot” (scored as 100). Laboratory measures Laboratory measurements were conducted with plasma samples that had been frozen at -80 ο C after blood collection and processing. Total cholesterol, triglycerides, and high-density lipoprotein cholesterol (HDL-C) were measured by Arup Laboratories (Salt Lake City, UT, USA) using enzymatic methods. The coefficient of variation (CV) for human serum for cholesterol at 76.2 mg/dL and 276 mg/dL is 1.6% and 1.4%, respectively; for triglycerides at 104 mg/dL and 261 mg/dL is 1.9% and 1.8%, respectively; and for HDL-C at 46.4 mg/dL and 80.4 mg/dL is 0.6% and 0.7%, respectively. Low-density lipoprotein cholesterol (LDL-C) values were calculated by the Friedewald equation [ 27 ]. Tocopherols and fatty acids were measured as dietary biomarkers because we anticipated that the walnut-enriched diet group could have different circulating concentrations compared to participants in the standard diet arm, reflecting differential intake of these dietary constituents due to regular walnut consumption. The detection and quantification of plasma tocopherols was accomplished by high performance liquid chromatography, using fluorescent detection at a wavelength of 295 nm excitation and 325 nm emission. Tocopherols were quantified by peak height using a standard curve prepared in bovine serum matrix from pure external compounds. Additionally, pooled in-house quality control samples were analyzed concurrently with batches of study samples, together with other commercially available reference samples, to monitor accuracy and precision. Also, the laboratory participates in the National Institute of Standards and Technology quality assurance program. Red blood cell (RBC) fatty acids were measured by OmegaQuant Laboratories (Sioux Falls, SD, USA) by gas chromatography (GC) with flame ionization detection. GC was carried out using a GC2010 Gas Chromatograph (Shimadzu Corporation, Columbia, MD, USA) equipped with a SP2560, 100-m fused silica capillary column (0.25 mm internal diameter, 0.2 um film thickness; Supelco, Bellefonte, PA, USA). Fatty acids were identified by comparison with a standard mixture of fatty acids characteristic of RBCs (GLC OQ-A, NuCheck Prep, Elysian, MN, USA) which was also used to determine individual fatty acid calibration curves. Fatty acid composition was expressed as a percent of total identified fatty acids. Statistical analysis Demographic characteristics were compared at baseline between groups using chi-square tests for categorical variables and t-tests for continuous variables. Body measurements (weight, BMI, waist circumference), blood pressure, physical activity, lipids, tocopherols and fatty acids were analyzed using repeated measures mixed models assuming unstructured covariance. Change in an indicator of adiposity between groups (weight change as a percentage of initial weight) was also analyzed. Study time, diet group, and the group by time interaction were modeled as fixed effects in each model. Variables that were skewed were log transformed in analysis. Lipid concentrations were examined by sex to assess significant differences at baseline. We tested to see which of the lipids changed between baseline and 6 months, and if a significant change was observed, we performed multivariate analysis to identify predictors of such a lipid change. Power analysis for our sample size was based on published literature for nut consumption in a weight loss intervention [ 15 – 17 ]. Significance was set at alpha = 0.05. All statistical analysis was performed using the SAS software version 9.4 for Windows (SAS Institute Inc., Cary, North Carolina, USA). Results During the course of the study, 3 participants dropped out (one in the standard diet group and 2 in the walnut-enriched diet group). Overall compliance with prescribed walnut consumption in that study arm was 98%; review of monitoring records indicated that of the 47 participants, 43 reported consuming 97–100%, 2 reported consuming 92–96%, and 2 reported consuming 67–69% of the walnuts prescribed during the study. As shown in Table 1 , the randomized study groups did not differ by sex, age, education, or race/ethnicity. Both groups demonstrated a reduction in body weight, BMI, and waist circumference (time effect p < 0.001 for each) during the course of the study, and the two diet groups did not differ in degree of weight lost, with no significant group by time interactions, as shown in Table 2 . Both groups decreased their systolic blood pressure at 3 months, but only those in the walnut-enriched diet group maintained a lower systolic blood pressure at 6 months compared to baseline (Table 3 ). Participants in both study groups also decreased their diastolic blood pressure at 3 and 6 months, and increased their physical activity ( p < 0.001 for each). There was no significant group by time interaction observed in the blood pressure or physical activity models (Table 3 ). Cardiopulmonary fitness, as indicated by the step test recovery heart rate, improved in both study groups. Table 1 Characteristics of study participants in the weight reduction intervention Standard reduced-energy-density diet ( n = 51) Walnut-enriched reduced-energy diet ( n = 49) p (between groups) * Sex (N [%]) 0.53 Female 27 (53%) 31 (63%) Male 24 (47%) 18 (37%) Age (years), mean (SE) 52.2 (1.6) 53.3 (1.4) 0.63 Education (years), mean (SE) 16.1 (0.3) 16.2 (0.3) 0.88 Race/ethnicity (%) 0.84 Non-Hispanic white 73 73 Hispanic/Latino 14 18 African-American 6 2 Asian-American 2 2 Mixed/other 6 4 Open in a separate window *p values are from chi-square tests (categorical variables), or t-tests (continuous variables) Table 2 Body measurements of study participants in the weight reduction intervention Standard reduced- energy-density diet Walnut-enriched reduced-energy diet p (between groups) n Mean (SE) n Mean (SE) Body weight, kg a Baseline 51 90.9 (1.8) 49 91.1 (2.3) 0.96 3 Months 51 84.7 (1.8) 48 85.9 (2.3) 0.70 6 Months 50 82.1 (2.0) 47 82.4 (2.2) 0.92 Body mass index, kg/m 2 a Baseline 51 32.4 (0.4) 49 32.4 (0.5) 0.96 3 Months 51 30.3 (0.5) 48 30.6 (0.5) 0.63 6 Months 50 29.4 (0.6) 47 29.6 (0.5) 0.77 Weight change, kg 3 Months 51 −6.0 (0.6) 48 −5.5 (0.5) 0.51 6 Months 50 −8.5 (0.9) 47 −7.9 (0.6) 0.58 % Weight change 3 Months 51 −6.6 (0.6) 48 −6.1 (0.6) 0.53 6 Months 50 −9.4 (0.9) 47 −8.9 (0.7) 0.63 Waist circumference, cm a Baseline 51 109.9 (1.2) 49 111.5 (1.6) 0.42 3 Months 51 101.7 (1.3) 48 104.6 (1.6) 0.16 6 Months 50 98.9 (1.4) 47 100.7 (1.5) 0.39 Open in a separate window a Body weight, body mass index, and waist circumference showed a significant time effect compared with baseline, p < 0.001 for each variable, in both study groups at each follow-up point Table 3 Blood pressure and physical activity variables for study participants in the weight reduction intervention Standard reduced-energy-density diet Walnut-enriched reduced-energy diet p (between groups) n Mean(SE) n Mean(SE) Systolic blood pressure, mm Hg Baseline 51 123 (2) 49 124 (3) 0.77 3 Months 49 117 (2) * 48 116 (2) * 0.73 6 Months 49 119 (2) 46 118 (2) * 0.68 Diastolic blood pressure, mm Hg Baseline 51 82 (1) 49 82 (2) 0.72 3 Months 49 77 (1) * 48 76 (1) * 0.57 6 Months 49 78 (2) * 46 77 (1) * 0.70 Moderate/strenuous physical activity, minutes/week Baseline 51 120 (22) 49 133 (18) 0.53 3 Months 51 328 (31) * 48 337 (33) * 0.84 6 Months 49 351 (31) * 47 321 (29) * 0.48 % Meeting physical activity recommendations Baseline 51 25 49 45 0.04 3 Months 51 78 48 79 0.93 6 Months 47 85 47 81 0.58 Step test, heart rate/30s Baseline 51 57 (2) 49 60 (2) 0.14 3 Months 47 47 (1) * 47 49 (1) * 0.33 6 Months 47 45 (1)* 45 47 (1) * 0.18 Open in a separate window * Different from baseline within group, p < 0.01 for each Participants assigned to the walnut-enriched diet group, but not the standard reduced-energy-density diet group, had a reduction in total cholesterol concentration at 6 months, from 203 to 194 mg/dL ( p = 0.04), as shown in Table 4 . Triglycerides decreased in the standard diet group at 3 months and in both groups at 6 months, which decreased an average of 22 mg/dL from 128 to 106 ( p < 0.01 in log-transformed analysis). HDL-C did not change significantly between baseline and 6 months in either of the diet groups. In a subgroup analysis among the 21 men in the study, those assigned to the walnut-rich diet group had lower HDL-C levels (42 [ 10 ] vs. 50 [ 7 ] mg/dL [mean (SD)]) than those assigned to the standard reduced-energy-density diet at baseline ( p = 0.05) and at 3 months, 41(9) vs 54 (13) mg/dL ( p = 0.02) (data not shown). By 6 months, the men assigned to the walnut-enriched diet group had increased their HDL-C to 49 (18) mg/dL, and those in the standard reduced-energy-density diet group had also increased HDL-C to 59 (13) mg/dL (data not shown). Although 27% of the cohort reported having been told by a doctor that they had high cholesterol, only 10% of the cohort reported taking prescription medications to lower lipids. Table 4 Biological measures of study participants in the weight reduction intervention Standard reduced-energy-density diet Walnut-enriched reduced-energy diet p (between groups) p (group x time interaction) Mean(SE) Mean(SE) Cholesterol, mg/dL 0.84 Baseline 200 (5) 203 (6) 0.76 3 Months 199 (5) 198 (5) 0.95 6 Months 194 (6) 194 (6) a 0.91 Triglycerides, mg/dL 0.50 Baseline 130 (10) 123 (7) 0.55 3 Months 110 (8) a 115 (9) 0.66 6 Months 109 (9) a 103 (6) a 0.61 HDL cholesterol, mg/dL 0.08 Baseline 58 (2) 59 (2) 0.70 3 Months 60 (2) 58 (2) 0.37 6 Months 60 (2) 61 (2) 0.94 LDL Cholesterol, mg/dL 0.60 Baseline 116 (4) 121 (5) 0.42 3 Months 116 (5) 116 (4) 0.80 6 Months 112 (5) 112 (5) a 0.96 Alpha-tocopherol, μmol/L 0.96 Baseline 30.5 (1.3) 30.8 (1.0) 0.83 3 Months 30.0 (1.1) 30.3 (1.2) 0.72 6 Months 31.6 (1.2) 32.2 (1.3) 0.84 Beta-tocopherol, μmol/L 0.70 Baseline 0.33 (0.02) 0.33 (0.01) 0.38 3 Months 0.38 (0.01) a 0.27 (0.01) a 0.38 6 Months 0.28 (0.01) a 0.26 (0.01) a 0.99 Gamma-tocopherol, μmol/L 0.48 Baseline 4.23 (0.29) 3.99 (0.27) 0.55 3 Months 4.04 (0.31) 4.13 (0.20) 0.82 6 Months 4.08 (0.33) 4.30 (0.29) 0.74 Delta-tocopherol, μmol/L 0.98 Baseline 0.11 (0.01) 0.11 (0.01) 0.82 3 Months 0.10 (0.01) 0.10 (0.01) 0.88 6 Months 0.09 (0.01) a 0.08 (0.01) a 0.76 Linoleic acid, % <0.001 Baseline 0.111 (0.002) 0.110 (0.002) 0.77 3 Months 0.104 (0.002) a 0.111 (0.002) 0.004 6 Months 0.107 (0.002) a 0.112 (0.001) a 0.01 Alpha-linolenic acid, % <0.001 Baseline 0.00122 (0.00006) 0.00118 (0.00004) 0.57 3 Months 0.00105 (0.00006) a 0.00147 (0.00005) a <0.001 6 Months 0.00118 (0.00005) 0.00158 (0.00007) a <0.001 Open in a separate window a Different from baseline within group, p < 0.05 The overall change (in both groups combined) in total cholesterol at 6 months was −7 mg/dL and for triglycerides was −20 mg/dL. A multivariate model for change in triglycerides did not show that diet group assignment, weight loss, age, sex, or level of physical activity were significantly associated; however, a model for change in total cholesterol showed that weight change and age were significantly associated. In the multivariate model for change in cholesterol at 6 months, R-squared was 0.17 and the two factors significantly associated were age ( p = 0.002) and weight change ( p = 0.02). Diet, baseline BMI, baseline physical activity, and change in physical activity were not significantly related to cholesterol change. Participants >50 years of age decreased their cholesterol by 2 mg/dL compared with a decrease of 19 mg/dL for subjects younger than 50 years of age. Those who lost ≥5% of initial weight decreased their cholesterol by an average of 13 mg/dL compared with an increase in cholesterol of 18 mg/dL in subjects who did not lose at least 5% of initial body weight. As shown in Table 4 , we did not observe changes in alpha- or gamma-tocopherol, which are the major tocopherols in the plasma, and only minor changes in beta- and delta-tocopherol concentrations. Also, we observed increased concentrations of alpha-linolenic acid and linoleic acid in the walnut-enriched diet group over the study period, but not in the standard reduced-energy-density diet group (Table 4 ). Self-reported satiety was similar across the study in the diet groups (Table 5 ). Feelings of hunger decreased and fullness was greater at week 12 than week 1 in the standard reduced-energy-density diet group ( p < 0.05). Fullness was lower in the walnut-rich diet arm at week 12 ( p = 0.04). Table 5 Self-reported satiety (on a 100-point visual analog scale where Hunger is scored 0 = very hungry, 100 = not hungry at all; Fullness is scored 0 = not full, 100 = full; Quantity is scored 0 = nothing, 100 = a lot) in the weight reduction intervention Standard reduced-energy-density diet, mean(SEM) Walnut-enriched reduced-energy diet, mean(SEM) Lunch Dinner Lunch Dinner Hunger Week 1 43 (3) 40 (4) 49 (3) 40 (3) Week 6 50 (4) 43 (4) 42 (4) 45 (4) Week 12 53 (5) a 49 (4) a 44 (4) 44 (4) Fullness Week 1 44(4) 48 (5) 51(4) 51(5) Week 6 53 (5) 53 (42) 58 (4) 52 (5) Week 12 52 (6) a 61 (5) a 48 (4) b 49 (4) b Quantity Week 1 44(4) 50 (4) 49 (3) 55(4) Week 6 49 (4) 53 (4) 48 (4) 47 (4) Week 12 41 (4) 38 (5) 44 (3) 49 (4) Open in a separate window a Both hunger and fullness were greater at week 12 than week 1 in the standard reduced-energy-density diet group ( p < 0.05) b At week 12, fullness was lower in the walnut-rich diet arm than in the standard reduced-energy-density diet group ( p = 0.04) Discussion Findings from this study provide further evidence that a walnut-enriched reduced-energy diet can promote weight loss that is comparable to a standard reduced-energy-density diet in the context of a behavioral weight loss intervention. Although weight loss in response to both dietary strategies was associated with improvements in lipids and blood pressure, the walnut-enriched diet promoted more favorable effects on some cardiovascular disease risk factors, such as LDL-C and systolic blood pressure. Previous studies that have examined the effect of prescribing regular nut consumption on weight change in a weight loss intervention have had mixed results. Two studies found more weight loss in association with almond consumption (at doses of 50–84 g/day for 3 months) compared with controls [ 12 , 16 ], while a study examining the effect of a similar amount of almonds over a longer time frame (18 months) did not observe more weight loss compared to controls [ 15 ]. In a study that examined the effects of prescribing peanuts (16% of energy), weight loss was similar to controls, although the peanut-containing study arm had more favorable effects on cardiovascular disease risk factors [ 13 ]. Providing a daily snack of pistachios (53 g/day) vs. pretzels promoted a greater reduction of BMI and plasma triglyceride concentration but only a trend for a difference in body weight change in another study [ 14 ]. In a 12-month intervention study aimed to promote weight loss and healthy lifestyle, prescribing 30 g/day walnuts was associated with greater weight loss and improved diet quality compared to providing general dietary advice during the 3-month intensive phase of the intervention, although these differences were not evident at study end [ 17 ]. We recently examined the effects of a walnut-rich or higher-monounsaturated fat diet vs. a lower-fat diet prescription on weight loss and selected lipids and biomarkers in the context of a 12-month behavioral weight loss program [ 18 , 28 ]. Participants were stratified by insulin resistance status to allow examination of whether insulin resistance might be associated with differential response to diet composition. Similar to the present study, we observed that prescribing walnuts was associated with weight loss that was comparable to a standard lower fat diet, but better than a higher fat, lower carbohydrate diet without walnuts with regard to biomarker response [ 18 ]. In addition to promoting a similar degree of weight loss, we observed similar self-reported satiety in response to a walnut-enriched reduced-energy diet and a reduced-energy-density diet, that has been proposed to promote reduced energy intake without compromising meal satiety [ 21 ]. Notably, walnuts are very high in energy density, but when consumed as a component of a reduced-energy diet, this strategy may help to promote adherence to restricted total energy intake. The effects of tree nuts on blood lipids and several other cardiovascular disease risk factors were recently examined in a systematic review and meta-analysis [ 29 ], as well as in an earlier pooled analysis [ 30 ], and our observations of lower cholesterol and LDL-C in response to walnut consumption are in agreement with their conclusions. Across the 61 trials that met the eligibility criteria for the meta-analysis, that study found an average reduction of −4.7 and −4.8 mg/dL for total cholesterol and LDL-C, respectively, per one ounce/day serving of tree nuts in interventions ranging from 3 to 26 weeks [ 29 ]. Results of the present study, in which we observed this walnut-specific effect to be even greater in the context of a weight loss intervention, add to the evidence base. We also observed the effect to be modulated by age and degree of weight loss, with a greater reduction in cholesterol in younger individuals (<50 years) and those with greater weight loss (≥5% of initial weight). Previous meta-analyses of the effects of nut consumption on blood pressure are not in agreement, with one of them concluding that there are no significant effects [ 29 ] and another showing a reduction in systolic blood pressure in participants without type 2 diabetes [ 31 ] as observed in the present study. Walnuts are rich in gamma-tocopherol and polyunsaturated fatty acids, particularly alpha-linolenic and linoleic fatty acids [ 32 ]. In previous studies, an increase in gamma-tocopherol concentration has been observed in participants who were prescribed daily walnut consumption [ 33 , 34 ]. In our previous trial that prescribed walnuts in a weight loss intervention [ 18 , 35 ], we observed that walnut prescription minimized the reduction in plasma gamma-tocopherol that occurs in association with reduced energy intake and weight loss, as was observed in the present study. The increase in RBC alpha-linolenic and linoleic fatty acid concentrations in those assigned to the walnut-enriched reduced-energy study arm, and the differences across diet groups, is consistent with previous walnut feeding and walnut-rich diet interventions [ 18 , 33 , 36 ]. These changes in dietary biomarkers also provide strong support for the self-reported high level of adherence in participants instructed to consume walnuts daily in the present study. Notably, replacing saturated fats with polyunsaturated fats has been consistently associated with reduced risk for cardiovascular disease [ 37 , 38 ]. This study has some strengths and limitations. A strength is the heterogeneity of the study sample, which included both men and women and participants across racial/ethnic groups. Also, the retention rate was very high, which is not typical of weight loss intervention studies, and this reduces ambiguity in drawing inferences from this study. A limitation of the study is the lack of detailed information about dietary intake. We encouraged study participants to self-monitor dietary intake as a component of the behavioral strategies to promote weight control, but we did not collect detailed dietary data in an effort to minimize subject burden. Because this was a sample of free-living individuals, some variability in adherence to the prescribed diet is likely. However, the weight loss demonstrated by study participants suggests that most were consuming a reduced-energy diet, and the RBC fatty acid biomarker is indicative of good compliance by participants in the walnut-enriched diet group. Conclusions In conclusion, findings from this study provide further evidence that a walnut-enriched reduced-energy diet can promote weight loss that is comparable to a standard reduced-energy-density diet in the context of a behavioral weight loss intervention. Weight loss in response to both of these dietary strategies was associated with improvements in lipids and blood pressure, although the walnut-enriched diet promoted more favorable effects on LDL-C and systolic blood pressure. Acknowledgements We thank David Wang, Sam Sobrevinas, Jamie Fletcher, Daniel Wang, Jessica Hawks, and Pey-Lih Littler for their valuable assistance with the conduct of this study. We also thank Lita Hinton for her assistance with manuscript preparation and submission. Funding This study was funded by the American Institute for Cancer Research (AICR) and the California Walnut Commission through the AICR Matching Grant Program. The funding agencies had no role in the design of study, data collection and analysis, or presentation of the results. The California Walnut Commission provided the walnuts that were distributed to the participants in that study group. Availability of data and materials The datasets generated and/or analyzed during the current study are not publicly available due to the private (and not public) sponsorship but are available from the corresponding author on reasonable request. Abbreviations BMI Body mass index CV Coefficient of variation GC Gas chromatography HDL-C High-density lipoprotein cholesterol LDL-C Low-density lipoprotein RBC Red blood cell REDcap Research Electronic Data Capture SE Standard error UCSD University of California, San Diego VAS Visual analog scale Authors’ contributions CLR designed and led the study throughout all phases, including the interpretation of the results and the development of the manuscript. SWF was responsible for data management, statistical analysis and interpretation, and presentation of the findings and results. HSB coordinated and operationalized the study, including screening, recruitment and enrollment, data collection and management, and conducted the intervention and dietary counseling of participants. BP contributed to the study design and analysis, and was responsible for all necessary intramural study activities, including institutional review board approval and monitoring. DDH conducted the laboratory analysis and contributed to interpretation of those data. All authors contributed to the writing of the manuscript, and all authors read and approved the final manuscript. Notes Ethics approval and consent to participate The UCSD institutional review board approved the study protocol (#151015), and all participants provided written informed consent. 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+2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease - American College of Cardiology Guidelines JACC ACC.24 Members About Join Create Free Account or Log in to MyACC Menu Home Clinical Topics Acute Coronary Syndromes Anticoagulation Management Arrhythmias and Clinical EP Cardiac Surgery Cardio-Oncology Cardiovascular Care Team Congenital Heart Disease and Pediatric Cardiology COVID-19 Hub Diabetes and Cardiometabolic Disease Dyslipidemia Geriatric Cardiology Heart Failure and Cardiomyopathies Invasive Cardiovascular Angiography and Intervention Noninvasive Imaging Pericardial Disease Prevention Pulmonary Hypertension and Venous Thromboembolism Sports and Exercise Cardiology Stable Ischemic Heart Disease Valvular Heart Disease Vascular Medicine Latest In Cardiology Clinical Updates & Discoveries Advocacy & Policy Perspectives & Analysis Meeting Coverage ACC Member Publications ACC Podcasts View All Cardiology Updates Education and Meetings Online Learning Catalog Earn Credit View the Education Catalog Products ACC Anywhere: The Cardiology Video Library ACCSAP ACCEL CardioSource Plus for Institutions and Practices CathSAP ECG Drill and Practice EchoSAP EP SAP HF SAP Heart Songs Nuclear Cardiology Online Courses Collaborative Maintenance Pathway (CMP) Resources Understanding MOC Image and Slide Gallery Meetings Annual Scientific Session and Related Events Chapter Meetings Live Meetings Live Meetings - International Webinars - Live Webinars - OnDemand Certificates and Certifications Tools and Practice Support ACC Accreditation Services ACC Quality Improvement for Institutions Program CardioSmart National Cardiovascular Data Registry (NCDR) MedAxiom Advocacy at the ACC Cardiology as a Career Path Cardiology Careers Cardiovascular Buyers Guide Clinical Solutions Clinician Well-Being Portal Diversity and Inclusion Infographics Innovation Program Mobile and Web Apps < Back to Listings 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease Mar 17, 2019
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+  | Melvyn Rubenfire, MD, FACC Print Font Size A A A Authors: Arnett DK, Blumenthal RS, Albert MA, et al. Citation: 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;March 17:[Epub ahead of print]. The following are key perspectives from the 2019 American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Primary Prevention of Cardiovascular Disease (CVD): Scope of Guideline The guideline is a compilation of the most important studies and guidelines for atherosclerotic CVD (ASCVD) outcomes related to nine topic areas. The focus is primary prevention in adults to reduce the risk of ASCVD (acute coronary syndromes, myocardial infarction, stable or unstable angina, arterial revascularization, stroke/transient ischemic attack, peripheral arterial disease), as well as heart failure and atrial fibrillation. The guideline emphasizes patient-physician shared decisions with a multidisciplinary team-based approach to the implementation of recommended preventive strategies with sensitivities to the social determinants of health that may include specific barriers to care, limited health literacy, financial distress, cultural influences, education level, and other socioeconomic risk factors related to short- and long-term health goals. Assessment of ASCVD Risk Assessment of ASCVD risk is the foundation of primary prevention. For those aged 20-39 years, it is reasonable to measure traditional risk factors every 4-6 years to identify major factors (e.g., tobacco, dyslipidemia, family history of premature ASCVD, chronic inflammatory diseases, hypertension, or type 2 diabetes mellitus [T2DM]) that provide rationale for optimizing lifestyle and tracking risk factor progression and need for treatment. For adults aged 20-39 years and those aged 40-59 years who are not already at elevated (≥7.5%) 10-year risk, estimating a lifetime or 30-year risk for ASCVD may be considered ( ASCVD Risk Estimator Plus ). For those aged 20-59 years not at high short-term risk, the 30-year and lifetime risk would be reasons for a communication strategy for reinforcing adherence to lifestyle recommendations and for some drug therapy (e.g., familial hypercholesterolemia, hypertension, prediabetes, family history of premature ASCVD with dyslipidemia or elevated lipoprotein [a] Lp[a]). Estimating Risk of ASCVD Electronic and paper chart risk estimators are available that utilize population-based and clinical trial outcomes with the goal of matching need and intensity of preventive therapies to absolute risk (generally 10 years) for ASCVD events. The guideline suggests the race- and sex-specific Pooled Cohort Equation (PCE) ( ASCVD Risk Estimator Plus ) to estimate 10-year ASCVD risk for asymptomatic adults aged 40-79 years. Adults should be categorized into low (<5%), borderline (5 to <7.5%), intermediate (≥7.5 to <20%), or high (≥20%) 10-year risk. The PCEs are best validated among non-Hispanic whites and non-Hispanic blacks living in the United States. In other race/ethnic groups and some non-US populations, the PCE may over- or under-estimate risk (e.g., HIV infection, chronic inflammatory or autoimmune disease, and low socioeconomic levels). Consideration should be given to use of other risk prediction tools if validated in a population with similar characteristics. Examples include the general Framingham CVD risk score, Reynolds risk score, SCORE, and QRISK/JBS3 tools. Among borderline and intermediate-risk adults, one may consider additional individual "risk-enhancing" clinical factors that can be used to revise the 10-year ASCVD risk estimate. For initiating or intensifying statin therapy, include: family history of premature ASCVD (men <55 years, women <65 years); low-density lipoprotein cholesterol (LDL-C) ≥160 mg/dl or non-high-density lipoprotein cholesterol (non-HDL-C) ≥190 mg/dl; chronic kidney disease (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m 2 ); metabolic syndrome; pre-eclampsia and premature menopause (<40 years); inflammatory diseases including rheumatoid arthritis, lupus, psoriasis, HIV; South Asian ancestry; biomarkers including fasting triglycerides ≥175 mg/dl, Lp(a) ≥50 mg/dl, high-sensitivity C-reactive protein ≥2 mg/L, apolipoprotein B >130 mg/dl, and ankle-brachial index (ABI) <0.9. After considering these clinically available risk-enhancing factors, if there is still uncertainty about the reliability of the risk estimate for individuals in the borderline or intermediate-risk categories, further testing to document subclinical coronary atherosclerosis with computed tomography-derived coronary artery calcium score (CACs) is reasonable to more accurately reclassify the risk estimate upward or downward. For persons at intermediate predicted risk (≥7.5 to <20%) by the PCE or borderline (5 to <7.5%) predicted risk, CACs helps refine risk assessment. CACs can re-classify risk upward (particularly when score is ≥100 or ≥75th age/sex/race percentile) or downward (if CACs = 0), which is not uncommon, particularly in men <50 and women <60 years. In MESA (Multi-Ethnic Study of Atherosclerosis), the CACs was strongly associated with 10-year ASCVD risk in a graded fashion across age, sex, and race/ethnic groups, and independent of traditional risk factors. CAC may refine ASCVD risk estimates among lower-risk women (<7.5% 10-year risk), younger adults (<45 years), and older adults (≥75 years), but more data are needed to support its use in these subgroups. A CACs = 0 identifies individuals at lower risk of ASCVD events and mortality over a ≥10-year period, who appear to derive little or no benefit from statins and for which drug interventions can be delayed. The absence of CAC does not rule out noncalcified plaque, and clinical judgment about risk should prevail. CAC might also be considered in refining risk for selected low-risk adults (<5% 10-year risk) such as those with a strong family history of premature coronary heart disease (CHD). There are Internet-available risk estimation tools (MESA and ASTROCHARM), which incorporate both risk factors and CAC for estimating 10-year CHD or ASCVD risk, respectively. CAC measurement is not intended as a "screening" test for all, but rather is a decision aid in select adults to facilitate the clinician-patient risk discussion. Nutrition Dietary patterns associated with CVD mortality include—sugar, low-calorie sweeteners, high-carbohydrate diets, low-carbohydrate diets, refined grains, trans fat, saturated fat, sodium, red meat, and processed red meat (such as bacon, salami, ham, hot dogs, and sausage). All adults should consume a healthy plant-based or Mediterranean-like diet high in vegetables, fruits, nuts, whole grains, lean vegetable or animal protein (preferably fish), and vegetable fiber, which has been shown to lower the risk of all-cause mortality compared to control or standard diet. Longstanding dietary patterns that focus on low intake of carbohydrates and a high intake of animal fat and protein as well as high carbohydrate diets are associated with increased cardiac and noncardiac mortality. The increased availability of affordable, palatable, and high-calorie foods along with decreased physical demands of many jobs have fueled the epidemic of obesity and the consequent increases in hypertension and T2DM. Obesity Adults diagnosed as obese (body mass index [BMI] ≥30 kg/m 2 ) or overweight (BMI 25-29.9 kg/m 2 ) are at increased risk of ASCVD, heart failure, and atrial fibrillation compared with those of a normal weight. Obese and overweight adults are advised to participate in comprehensive lifestyle programs for 6 months that assist participants in adhering to a low-calorie diet (decrease by 500 kcal or 800-1500 kcal/day) and high levels of physical activity (200-300 minutes/week). Clinically meaningful weight loss (≥5% initial weight) is associated with improvement in blood pressure (BP), LDL-C, triglycerides, and glucose levels among obese or overweight individuals, and delays the development of T2DM. In addition to diet and exercise, FDA-approved pharmacologic therapies and bariatric surgery may have a role for weight loss in select patients. Physical Activity Despite the public health emphasis for regular exercise based on extensive observational data that aerobic physical activity lowers ASCVD, approximately 50% of adults in the United States do not meet minimum recommendations. There is a strong inverse dose-response relationship between the amount of moderate-to-vigorous physical activity and incident ASCVD events and mortality. Adults should engage in at least 150 minutes/week of moderate-intensity or 75 minutes/week of vigorous-intensity physical activity including resistance exercise. Diabetes T2DM, defined as a hemoglobin A1c (HbA1c) >6.5%, is a metabolic disorder characterized by insulin resistance leading to hyperglycemia. The development and progression are heavily influenced by dietary pattern, physical activity, and body weight. All with T2DM should undergo dietary counseling for a heart-healthy diet that in T2DM lowers CVD events and CVD mortality. Among options include the Mediterranean, DASH, and vegetarian/vegan diets that achieve weight loss and improve glycemic control. At least 150 minutes/week of moderate to vigorous physical activity (aerobic and resistance) in T2DM lowers HbA1c about 0.7% with an additional similar decrease by weight loss. Other risk factors should be identified and treated aggressively. For younger individuals, or those with a mildly elevated HbA1c at the time of diagnosis of T2DM, clinicians can consider a trial of lifestyle therapies for 3-6 months before drug therapy. First-line therapy to improve glycemic control and reduce CVD risk is metformin. Compared to lifestyle modifications, metformin resulted in a 32% reduction in micro- and macrovascular diabetes-related outcomes, a 39% reduction in myocardial infarction, and a 36% reduction in all-cause mortality. The goal is a HbA1c 6.5-7%. Several classes of medications have been shown to effectively lower blood glucose but may not affect ASCVD risk including the often-used sulfonylureas. Two classes of glucose-lowering medications have recently demonstrated a reduction in ASCVD events in adults with T2DM and ASCVD. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors act in the proximal tubule to increase urinary excretion of glucose and sodium, leading to a reduction in HbA1c, weight, and BP and in randomized clinical trials, significant reduction in ASCVD events and heart failure. The majority of patients studied had established CVD at baseline, although limited data suggest this class of medications may be beneficial for primary prevention. The glucagon-like peptide-1 receptor (GLP-1R) agonists increase insulin and glucagon production in the liver, increase glucose uptake in muscle and adipose tissue, and decrease hepatic glucose production. GLP-1R agonists have been found to significantly reduce the risk of ASCVD events in adults with T2DM at high ASCVD risk. In patients with T2DM and additional risk factors for CVD, it may be reasonable to initiate these two classes of medications for primary prevention of CVD. Lipids Primary ASCVD prevention requires assessing risk factors beginning in childhood. For those <19 years of age with familial hypercholesterolemia, a statin is indicated. For young adults (ages 20-39 years), priority should be given to estimating lifetime risk and promoting a healthy lifestyle. Statin should be considered in those with a family history of premature ASCVD and LDL-C ≥160 mg/dl. ASCVD risk-enhancing factors, (see risk estimate section), should be considered in all patients. Statin Treatment Recommendations The following are guideline recommendations for statin treatment: Patients ages 20-75 years and LDL-C ≥190 mg/dl, use high-intensity statin without risk assessment. T2DM and age 40-75 years, use moderate-intensity statin and risk estimate to consider high-intensity statins. Risk-enhancers in diabetics include ≥10 years for T2DM and 20 years for type 1 DM, ≥30 mcg albumin/mg creatinine, eGFR <60 ml/min/1.73 m 2 , retinopathy, neuropathy, ABI <0.9. In those with multiple ASCVD risk factors, consider high-intensity statin with aim of lowering LDL-C by 50% or more. Age >75 years, clinical assessment and risk discussion. Age 40-75 years and LDL-C ≥70 mg/dl and <190 mg/dl without diabetes, use the risk estimator that best fits the patient and risk-enhancing factors to decide intensity of statin. Risk 5% to <7.5% (borderline risk). Risk discussion: if risk-enhancing factors are present, discuss moderate-intensity statin and consider coronary CACs in select cases. Risk ≥7.5-20% (intermediate risk). Risk discussion: use moderate-intensity statins and increase to high-intensity with risk enhancers. Option of CACs to risk stratify if there is uncertainty about risk. If CAC = 0, can avoid statins and repeat CAC in the future (5-10 years), the exceptions being high-risk conditions such as diabetes, family history of premature CHD, and smoking. If CACs 1-100, it is reasonable to initiate moderate-intensity statin for persons ≥55 years. If CAC >100 or 75th percentile or higher, use statin at any age. Risk ≥20% (high risk). Risk discussion to initiate high-intensity statin to reduce LDL-C by ≥50%. Both moderate- and high-intensity statin therapy reduce ASCVD risk, but a greater reduction in LDL-C is associated with a greater reduction in ASCVD outcomes. The dose response and tolerance should be assessed in about 6-8 weeks. If LDL-C reduction is adequate (≥30% reduction with intermediate- and 50% with high-intensity statins), regular interval monitoring of risk factors and compliance with statin therapy are necessary to determine adherence and adequacy of effect (about 1 year). For patients aged >75 years, assessment of risk status and a clinician-patient risk discussion are needed to decide whether to continue or initiate statin treatment. The CACs may help refine ASCVD risk estimates among lower-risk women (<7.5%) and younger adults (<45 years), particularly in the setting of risk enhancers. Hypertension In the United States, hypertension accounts for more ASCVD deaths than any other modifiable risk factor. The prevalence of stage I hypertension defined as systolic BP (SBP) ≥130 or diastolic BP (DBP) ≥80 mm Hg among US adults is 46%, higher in blacks, Asians, and Hispanic Americans, and increases dramatically with increasing age. A meta-analysis of 61 prospective studies observed a log-linear association between SBP levels <115 to >180 mm Hg and DBP levels <75 to 105 mm Hg and risk of ASCVD. In that analysis, 20 mm Hg higher SBP and 10 mm Hg higher DBP were each associated with a doubling in the risk of death from stroke, heart disease, or other vascular disease. An increased risk of ASCVD is associated with higher SBP and SBP has been reported across a broad age spectrum, from 30 to >80 years of age. In adults with elevated or borderline hypertension (BP 120-129/<80 mm Hg) or hypertension, the initial recommendations include weight loss, heart-healthy diet (DASH or DASH Mediterranean), sodium restriction of 1000 mg reduction and optimal <1500 mg/d), diet rich in potassium with supplements as necessary, exercise as described including aerobic, isometric resistance (hand-grip), dynamic resistance (weights), and limited alcohol (men <3 and women <2 per day). In adults with stage I hypertension (BP 130-139/80-89 mm Hg) and estimated 10-year ASCVD risk of <10%, nonpharmacologic therapy is recommended. In those with a 10% or higher 10-year ASCVD risk, use of BP-lowering medication is recommended with a BP target of <130/80 mm Hg including persons with chronic kidney disease and diabetes. A target of <130/80 mm Hg is also recommended for Stage 2 hypertension, defined as BP ≥140/90 mm Hg with nonpharmacological and BP-lowering medication. Tobacco Tobacco use is the leading preventable cause of disease, disability, and death in the United States. Smoking and smokeless tobacco (e.g., chewing tobacco) increases the risk for all-cause mortality and causal for ASCVD. Secondhand smoke is a cause of ASCVD and stroke, and almost one third of CHD deaths are attributable to smoking and exposure to secondhand smoke. Even low levels of smoking increase risks of acute myocardial infarction; thus, reducing the number of cigarettes per day does not totally eliminate risk. Electronic Nicotine Delivery Systems (ENDS), known as e-cigarettes and vaping, are a new class of tobacco products that emit aerosol containing fine and ultrafine particulates, nicotine, and toxic gases that may increase risk for CV and pulmonary diseases. Arrhythmias and hypertension with e-cigarette use have been reported. Chronic use is associated with persistent increases in oxidative stress and sympathetic stimulation in the healthy young. All adults should be assessed at every visit for tobacco use, and those who use tobacco should be assisted and strongly advised to quit on every visit. Referral to specialists is helpful for both behavioral modification, nicotine replacement, and drug treatments. Amongst the treatments include varieties of nicotine replacement, the nicotine receptor blocker varenicline, and bupropion, an antidepressant. Aspirin For decades, low-dose aspirin (75-100 mg with US 81 mg/day) has been widely administered for ASCVD prevention. By irreversibly inhibiting platelet function, aspirin reduces risk of atherothrombosis but at the risk of bleeding, particularly in the gastrointestinal (GI) tract. Aspirin is well established for secondary prevention of ASCVD and is widely recommended for this indication, but recent studies have shown that in the modern era, aspirin should not be used in the routine primary prevention of ASCVD due to lack of net benefit. Most important is to avoid aspirin in persons with increased risk of bleeding including a history of GI bleeding or peptic ulcer disease, bleeding from other sites, age >70 years, thrombocytopenia, coagulopathy, chronic kidney disease, and concurrent use of nonsteroidal anti-inflammatory drugs, steroids, and anticoagulants. The following are recommendations based on meta-analysis and three recent trials: Low-dose aspirin might be considered for primary prevention of ASCVD in select higher ASCVD adults aged 40-70 years who are not at increased bleeding risk. Low-dose aspirin should not be administered on a routine basis for primary prevention of ASCVD among adults >70 years. Low-dose aspirin should not be administered for primary prevention among adults at any age who are at increased bleeding risk. Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Atrial Fibrillation/Supraventricular Arrhythmias, Homozygous Familial Hypercholesterolemia, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Diet, Exercise, Hypertension, Smoking Keywords: ACC Annual Scientific Session, ACC19, Aspirin, Atherosclerosis, Atrial Fibrillation, Bariatric Surgery, Blood Pressure, Cholesterol, LDL, Coronary Disease, Diabetes Mellitus, Type 2, Diet, Dyslipidemias, Exercise, Heart Failure, HIV, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperglycemia, Hypertension, Inflammation, Kidney Failure, Chronic, Lipids, Lipoproteins, Metabolic Syndrome, Metformin, Myocardial Infarction, Obesity, Plaque, Atherosclerotic, Pre-Eclampsia, Primary Prevention, Risk Factors, Smoking, Stroke, Tobacco, Triglycerides, Weight Loss < Back to Listings x You must be logged in to save to your library. 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+Meditative Movements for Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Published online 2020 Feb 1. doi: 10.1155/2020/5745013 PMCID: PMC7016481 PMID: 32089725 Meditative Movements for Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis Tingwei Xia , 1 Yue Yang , 2 Weihong Li , 1 Zhaohui- Tang , 1 Qingsong Huang , 1 Zongrun Li , 1 and Yongsong Guo 1 Tingwei Xia 1 Chengdu University of TCM, Chengdu, Sichuan Province, China Find articles by Tingwei Xia Yue Yang 2 Department of TCM, Qingyang District People's Hospital, Chengdu, Sichuan Province, China Find articles by Yue Yang Weihong Li 1 Chengdu University of TCM, Chengdu, Sichuan Province, China Find articles by Weihong Li Zhaohui- Tang 1 Chengdu University of TCM, Chengdu, Sichuan Province, China Find articles by Zhaohui- Tang Qingsong Huang 1 Chengdu University of TCM, Chengdu, Sichuan Province, China Find articles by Qingsong Huang Zongrun Li 1 Chengdu University of TCM, Chengdu, Sichuan Province, China Find articles by Zongrun Li Yongsong Guo 1 Chengdu University of TCM, Chengdu, Sichuan Province, China Find articles by Yongsong Guo Author information Article notes Copyright and License information PMC Disclaimer 1 Chengdu University of TCM, Chengdu, Sichuan Province, China 2 Department of TCM, Qingyang District People's Hospital, Chengdu, Sichuan Province, China Weihong Li: nc.ude.mctudc@hwl Academic Editor: Martin Offenbaecher Received 2019 Aug 20; Accepted 2019 Dec 28. Copyright © 2020 Tingwei Xia et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Objective Physical activity plays a specific role in the fundamental aspect of diabetes care. It is necessary to develop exercise programs for these patients. The aim of this systematic review is to summarize current evidence regarding the effectiveness of meditative movement in patients with type 2 diabetes. Methods The following databases were searched: PubMed, CENTRAL, Web of Science, Ovid LWW, and EMBASE. Two independent investigators searched and screened the studies by finding duplications, excluding irrelevant titles and abstracts, and then selecting eligible studies by reviewing full texts. 21 studies fulfilled the inclusion criteria. Meta-analyses were performed on glycated hemoglobin (HbA1c), fasting blood glucose (FBG) and postprandial blood glucose (PPBG), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and body mass index (BMI). Results Meta-analyses showed that meditative movements significantly improved FBG, HbA1c, PPBG, TC, LDL-C, and HDL-C. No improvement was found in BMI. Conclusions The results demonstrated a favorable effect or tendency of meditative movements to improve blood glucose and blood lipid levels in patients with type 2 diabetes mellitus. The special effects of meditative movements in type 2 diabetes mellitus patients need further research. 1. Background Physical activity is an important part of the diabetes lifestyle management and negatively associated with the risk of type 2 diabetes mellitus (T2DM). It plays a specific role in the fundamental aspect of diabetes care [ 1 – 3 ]. Type 2 diabetes is one of the most common diseases in older adults. However, the incidence of children, adolescents, or young people is on the rise, due to the rising level of obesity, lack of physical activity, and poor diet [ 2 ]. As the International Diabetes Federation reported, there are approximately 451 million people (ages 18–99 years) with diabetes in the world [ 3 ]. And approximately 90–95% of all cases are type 2 diabetes [ 2 ]. By 2017, nearly 5 million people between the ages of 20 and 99 had died of diabetes and its complications [ 4 ]. At the same time, there are 374 million people with impaired glucose tolerance who are at high risk of developing diabetes [ 4 ]. Diabetic complications affect hundreds of millions of patients with type 2 diabetes [ 5 ]. T2DM patients have a high risk of liver fibrosis and liver steatosis [ 6 , 7 ]. Due to the presentation and progression of these complications, patients may lose their vision, kidney, and nerve function. Their activity and cognitive ability may be impaired, and their quality of life may deteriorate. This leads to limited employment and productivity and increased costs for the patient and society [ 8 – 11 ]. Meditative movements, combining breath control, relaxation, musculoskeletal stretching, and a meditative state of mind, have been shown to be effective for treating type 2 diabetes [ 12 ]. Meditative movements, including Tai Chi, Yoga, and Qigong, reported by the National Health Interview Survey, are popular among American adults in workplace [ 13 ]. Yoga and Tai Chi, especially, are recommended by the American Diabetes Association for older adults with type 2 diabetes to increase flexibility, muscular strength, and balance [ 1 ]. Plenty of clinical researches have focused on the effectiveness of meditative movements on type 2 diabetes. Present systematic reviews or meta-analyses about meditative movements have shown that it is beneficial to chronic obstructive pulmonary disease, sleep quality, cancer, and major depressive disorder [ 14 – 17 ]. However, the systematic review and meta-analysis of meditative movements on type 2 diabetes have not been conducted. Therefore, we performed a systematic review and meta-analysis to evaluate the effectiveness of meditative movements as a complementary therapy for patients with type 2 diabetes. 2. Data and Methods This review was performed according to our previous protocol [ 18 ]. Our protocol of this systematic review and meta-analysis on PROSPERO was registered in advance (no. CRD42019128495 , https://www.crd.york.ac.uk/PROSPERO ). 2.1. Data Sources and Search Strategies The following databases were searched using the developed search strategy [ 18 ] from inception to December 2018: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Ovid LWW, and EMBASE. 2.2. Inclusion and Exclusion Criteria We identified studies using the following inclusion criteria as in our protocol [ 18 ]: participants (with a clear diagnosis of type 2 diabetes), intervention (Tai Chi or Qigong or Yoga), control (any type of control group), primary outcomes (HbA1c, FBG, and PPBG), secondary outcomes (TC, TG, HDL-C, LDL-C, and BMI), and study type (randomized controlled trials (RCTs)). 2.3. Trials Inclusion and Data Extraction Two investigators independently searched and screened the studies. The process of study selection was performed using the methods according to the PRISMA guidelines [ 19 ]. Data extraction was performed by two investigators independently. Data extraction contained, in addition to outcomes, information regarding country of origin, number of randomized participants, number of participants included in type of intervention, frequency of intervention, and duration of intervention. Finally, all differences were resolved by consensus. 2.4. Trials Quality Assessment Definitions in the assessment of bias risk of a trial were conducted according to the Cochrane Handbook criteria for judging the ROB with the “risk of bias” assessment tool [ 20 ]. The following domains should be evaluated: random sequence generation, allocation concealment, blinding of participants and investigators, the blindness of outcome assessments, incomplete outcome data, selective outcome reporting, and other biases. The quality of studies was divided into three categories: low, unclear, or high bias. 2.5. Statistical Analysis We used the RevMan 5.3.0 provided by Cochrane Collaboration to analyze the results of the studies. This meta-analysis only included continuous data, so we expressed them as the mean ± standard deviation and then calculated the standardized mean difference (SMD) and obtained the two-sided P value and 95% confidence interval (CI). The complete case data was used as the analysis data. The degree of heterogeneity was quantified using the χ 2 test and I 2 value. We performed subgroup analysis according to total sample size (>60 versus ≤ 60), duration (>3 months versus ≤ 3 months), control type (nonexercise versus other active exercises), type of meditative movement (Tai Chi/Qigong versus Yoga), and region (Asia versus non-Asia), as well as a sensitivity analysis if necessary. A test for the interaction between the treatment and subgroups was performed to examine whether treatment effects differed among subgroups. An interaction of P value ≥0.05 was considered to indicate that the effect of treatment did not differ significantly among subgroups. Publication bias was assessed by visual inspection of a funnel plot. 3. Results 3.1. Literature Screening We retrieved 818 original papers from the electronic bibliographic databases. The full text of 127 articles was assessed according to the predetermined inclusion criteria. Finally, 21 studies fulfilled the inclusion criteria and were further analyzed [ 21 – 44 ]. The detailed process of the studies evaluation and the reasons for exclusion are shown in Figure 1 . Open in a separate window Figure 1 Flow chart of selection process. 3.2. Characteristics of Included Studies The characteristics of these included trials are described in Table 1 . Among them, the data of three studies were reported by six different articles [ 24 – 27 , 37 , 38 ]. Patients included in these studies were from China [ 23 , 39 ], Taiwan (China) [ 29 ], India [ 22 , 24 – 27 , 31 – 35 ], Iran [ 41 ], Japan [ 42 ], Thailand [ 30 ], Australia [ 40 , 43 , 44 ], Cuba [ 37 , 38 ], and USA [ 21 , 28 , 36 ]. Six studies offered Tai Chi [ 23 , 29 , 30 , 39 , 40 , 44 ], three studies offered Qigong [ 28 , 42 , 43 ], and twelve studies offered Yoga [ 21 , 22 , 24 – 27 , 31 – 38 , 41 ]. The sample sizes of the included studies ranged from 10 to 277. The treatment duration lasted from 45 days to 36 weeks. The frequency ranged from 2 to 7 times weekly, and exercise time lasted 10–120 min per session. Controls were divided into nonexercise groups and other active exercise groups. The exercise forms of other active exercise groups include seated calisthenics, stretching, aerobic exercise plus home-based exercise, progressive resistance training, and physical activity. In three studies, two control groups were set up in each, including nonexercise and other active exercises [ 28 , 31 , 37 , 38 ]. Table 1 Characteristics of included studies. Authors, year Location Participants Number Experimental group Control group Follow-up Outcome measures Types of treatment Duration (min) Frequency Zhang Y., 2008 China Women with T2DM E: 10; C: 10 Tai Chi 60 min Five times weekly Nonexercise 14 weeks (1)FBG (2)TC, HDL-C, LDL-C, TG Chen S. C., 2010 Taiwan (China) Patients with T2DM E: 56; C: 48 Tai Chi 60 min Three times weekly Other active exercises (aerobic exercise plus home-based exercise) 12 weeks (1)HbA1c, FBG Lam P., 2008 Australia Adults with T2DM E: 28; C: 25 Tai Chi 60 min Two classes weekly Nonexercise 24 weeks (1)HbA1c (2)TC, TG Youngwanichsetha S., 2013 Thailand Women with T2DM E:32; CG:32 Tai Chi 50 min Three times weekly Nonexercise 12 weeks (1)HbA1c, FBG (2) BMI ORR R., 2006 Australia Older adults with T2DM E: 17; C: 18 Tai Chi 60 min Twice weekly Other active exercises (sham exercise, e.g., seated calisthenics and stretching) 16 weeks (1) FBG Xiao C. M., 2015 China Older adults with DM E: 16; C: 16 Tai Chi 1 to 2 hours Three sessions per week Nonexercise 12 weeks (1)HbA1c Sreedevi A., 2017 India Women with diabetes E:41; C1:42; C2:41 Yoga 60 min Twice weekly C1: other active exercises (physical activity); C2: nonexercise 12 weeks (1)HbA1c, FBG (2) TC, BMI Hegde S. V., 2011 India People with type 2 diabetes E:60; C:63 Yoga n.r. Three times weekly Nonexercise 12 weeks (1)HbA1c, FBG, PPBG (2) BMI Keerthi G. S., 2017 India People with type 2 diabetes E:62; C:62 Yoga 45 min Three times weekly Nonexercise 12 weeks (1) FBG Gordon L. A., 2008 and Gordon L.,2008 Cuba People with type 2 diabetes E:77; C1:77; C2:77 Yoga 60 min 3–4 times per week C1: other active exercises (conventional physical training); C2: Nonexercise 24 weeks (1)HbA1c, FBG (2)TG, TC, HDL-C, LDL-C, BMI Singh S., 2008 and Kyizom T., 2010 India People with type 2 diabetes E:30; C:30 Yoga 45 min 5 days per week Nonexercise 45 days (1)FBG, PPBG (2)TG, TC, HDL-C, LDL-C, BMI Mullur R. S., 2016 USA People with type 2 diabetes E:5; C:5 Yoga 10 min n.r. Nonexercise 12 weeks (1)HbA1c, FBG (2)BMI Yang K., 2009 USA People with type 2 diabetes E:13; C:10 Yoga 60 min Twice per week Nonexercise 12 weeks (1)FBG (2)TG, TC, HDL-C, LDL-C Jyotsna V. P., 2013 India People with type 2 diabetes E:36; C:28 Yoga n.r. 7 days per week Other active exercises (brisk walking) 24 weeks (1)HbA1c, FBG, PPBG Nagarathna R., 2012 India People with type 2 diabetes E:141; C:136 Yoga 60 min 5–7 days per week Other active exercises (physical exercises) 36 weeks (1)HbA1c, FBG, PPBG (2)TG, TC, HDL-C, LDL-C Habibi N., 2013 Iran Women with T2DM E:16; C:10 Yoga 75 min Three times weekly n.r. 12 weeks (1)FBG (2)BMI Shantakumari N., 2012 and Shantakumari N., 2013 India People with type 2 diabetes E:50; C:50 Yoga 60 min 7 days per week Nonexercise 12 weeks (1)FBG, PPBG (2)TG, TC, HDL-C, LDL-C, BMI Vaishali K., 2012 India People with type 2 diabetes E:27; C:30 Yoga 45–60 min 6 days per week Nonexercise 12 weeks (1)HbA1c, FBG (2)TC, TG, HDL-C, LDL-C Liu X., 2011 Australia People with type 2 diabetes E:20; C:21 Qigong 1–1.5 hour Three times weekly Nonexercise 12 weeks (1)HbA1c, FBG, PPBG (2)HDL-C, TG Sun G. C., 2010 USA Adults with type 2 diabetes E:11; C1:10; C2:11 Qigong 30–60 min Three times weekly C1: nonexercise; C2: Other active exercises (the progressive resistance training) 12 weeks (1)HbA1c, FBG; Tsujiuchi T., 2002 Japan Adults with type 2 diabetes E:16; C:10 Qigong 2 h n.r. Nonexercise 16 weeks (1)HbA1c Open in a separate window E: experimental; C: control; FBG: fasting blood glucose; HbA1c: glycated hemoglobin; TC: total cholesterol; TG: triglycerides; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; BMI: body mass index; n.r.: not reported. 3.3. Risk of Bias of Studies The bias condition of selected studies was shown in Figures ​ Figures2 2 and ​ and3. 3 . We assessed the risk of bias in all included articles. Eleven studies used the generation of the allocation sequence. Allocation concealment was used in 6 studies. None of the studies blinded their participants. However, nine studies were blinding of outcome assessors to the treatment allocation, whereas the risk of selective reporting bias was not reported in most studies. Open in a separate window Figure 2 Risk of bias graph. Open in a separate window Figure 3 Risk of bias summary. 4. Outcome 4.1. Glycemic Control Sixteen RCTs, with three studies setting up two control groups in each, reported FBG as a primary outcome. We split the study with two control groups into two sets of data for summary analysis. A total of 19 sets of data were included. The combined result was statistically significant (SMD = 0.81, 95% CI (0.38, 1.24), P =0.0002) compared to the control group, with high heterogeneity ( I 2 = 93%, P < 0.00001) ( Figure 4 ). We carried out sensitivity analyses to explore potential sources of heterogeneity, and the results did not change substantively. The heterogeneity ranged from 67% to 93%. So, we conducted subgroup analyses and interaction tests according to the total sample size, duration, control type, intervention type, and region. Test for interaction showed significant results between subgroups of the nonexercise and other active exercises ( P -interaction = 0.002). The result indicated that the difference of the control types was partly the reason why there was severe heterogeneity in the overall analysis. The detailed results are shown in Table 2 . Open in a separate window Figure 4 Forest plot of the comparison between meditation movements and the control group for the outcome FBG. Table 2 Subgroup analyses based on various exclusion criteria for FBG. Subgroup n SMDs, mmol/L (95% CI) I 2 (%) Heterogeneity, P value P interaction Total sample size 0.87 >60 10 0.84 (0.22, 1.47) 96 <0.00001 ≤60 9 0.91 (0.38, 1.44) 76 <0.0001 Duration 0.11 >3 months 5 1.79 (0.30, 3.28) 98 <0.00001 ≤3 months 14 0.55 (0.29, 0.80) 65 0.0004 Control type 0.002 Nonexercise 12 1.42 (0.71, 2.13) 93 0.64 Other active exercises 6 0.27 (0.15, 0.38) 0 <0.00001 Intervention type 0.71 Tai Chi/Qigong 5 0.74 (0.16, 1.32) 72 0.007 Yoga 14 0.89 (0.35, 1.44) 95 <0.00001 Region 0.28 Asia 13 1.50 (-0.25, 3.25) 78 <0.00001 Non-Asia 6 0.53 (0.25, 0.80) 97 <0.00001 Open in a separate window CIs, confidence intervals; n, number of trials; SMDs, standardized mean differences. Thirteen studies reported HbA1c. Sixteen sets of data were included. The heterogeneity was high ( P < 0.00001, I 2 = 92%). We carried out sensitivity analyses to investigate the potential sources of heterogeneity. After removing one set of data, the results changed obviously. The heterogeneity was calculated as P =0.64, I 2 = 0%. The combined result was statistically significant (SMD = 0.36, 95% CI (0.24, 0.48), and P < 0.00001) ( Figure 5 ). It showed that one study was the potential source of heterogeneity. However, when we looked up the study again, we did not find differences in methodology and other aspects. The study showed that meditation movements had more significant effects on HbA1c than other studies. Five studies reported the PPBG. It showed a favorable effect of meditation movements on reducing PPBG (SMD = 0.30, 95% CI (0.14, 0.46), and P =0.0002), with low heterogeneity ( P =0.29, I 2 = 19%) ( Figure 6 ). Open in a separate window Figure 5 Forest plot of the comparison between meditation movements and the control group for the outcome HbA1c. Open in a separate window Figure 6 Forest plot of the comparison between meditation movements and the control group for the outcome PPBG. 4.2. Lipid Profile The aggregated results suggested that the meditation movements had significant effects on TC (SMD = 0.64, 95% CI (0.02, 1.26), and P =0.04; P for heterogeneity < 0.00001, I 2 = 95%) ( Figure 7 ), LDL-C (SMD = 0.61, 95% CI (0.16, 1.06), and P =0.008; P for heterogeneity < 0.00001, I 2 = 88%) ( Figure 8 ), triglycerides (SMD = 0.19, 95% CI (0.06, 0.31), and P =0.004; P for heterogeneity = 0.14, I 2 = 33%) ( Figure 9 ), and HDL-C (SMD = −0.53, 95% CI (−0.90, −0.15), and P =0.006; P for heterogeneity < 0.00001, I 2 = 85%) ( Figure 10 ). Open in a separate window Figure 7 Forest plot of the comparison between meditation movements and the control group for the outcome TC. Open in a separate window Figure 8 Forest plot of the comparison between meditation movements and the control group for the outcome LDL. Open in a separate window Figure 9 Forest plot of the comparison between meditation movements and the control group for the outcome TG. Open in a separate window Figure 10 Forest plot of the comparison between meditation movements and the control group for the outcome HDL. It showed no effects of meditation movements on reducing BMI (SMD = 0.42, 95% CI (−0.20, 1.03), and P =0.18) with low heterogeneity ( P < 0.00001, I 2 = 95%) ( Figure 11 ). Open in a separate window Figure 11 Forest plot of the comparison between meditation movements and the control group for the outcome BMI. 4.3. Publication Bias The FBG included in the study was selected as an indicator. It can be seen that the graph is not obviously asymmetrical ( Figure 12 ). There might have been no publication bias in the comparison of meditation movements and the control group. Open in a separate window Figure 12 Evaluation of publication bias for FBG. 5. Discussion Meditative movements (specifically Tai Chi, Qigong, and Yoga), including a focus of the mind on the body and breathing for deep relaxation, are special forms of exercise. More and more studies have been conducted on the effectiveness of these practices in health and healing [ 14 ]. As the first systematic review and meta-analysis synthesize the evidence of the effects of meditative movements on type 2 diabetes, we found that meditative movements may have positive effects on the treatment of type 2 diabetes. This evidence suggests that there is a possibility for using these exercises as an augmentation approach to control blood glucose for type 2 diabetes. 5.1. Summary of Main Results The present results showed that the meditative movements significantly improved FBG, HbA1c, PPBG, TC, LDL-C, and HDL-C in patients with type 2 diabetes mellitus. No improvement was found in BMI. As for the primary outcomes, significant heterogeneity was noted during our analyses of FBG and HbA1c. Sensitivity analyses were carried out to explore the potential sources of heterogeneity for FBG. We found that the heterogeneity or the synthesized results of studies on FBG did not change substantively. Therefore, subgroup analyses and interaction tests were carried out to investigate the impact of various exclusion criteria according to the total sample size, duration, control type, intervention type, and region. No evidence of heterogeneity was observed within the total sample size, duration, intervention type, and region. However, the overall combined effects of the trials showed significant results between subgroups of the nonexercise and other active exercises. It indicated that the reason for heterogeneity might be caused by the difference of the control types. Although the results showed a significant difference in reducing FBG between meditative movements and other active exercises, it was more significant compared to the nonexercise group. There is no doubt that other active exercises had a better effect on lowering blood sugar than nonexercise. Sensitivity subgroup analyses were also conducted to explore the potential sources of heterogeneity for HbA1c. We found only one study was the potential source of heterogeneity where no differences were found in methodology and other aspects. It showed more significant effects of meditation movements on HbA1c than other studies. Psychological stress has been proven to play a role in the etiology of type 2 diabetes [ 45 ]. It is regarded both as a predictor of new-onset type 2 diabetes and as a prognostic factor in people with existing type 2 diabetes. The disturbances across multiple biological systems reflecting chronic allostatic load might exist [ 46 ]. Numerous studies have shown that it is a common independent risk factor for disease occurrence [ 47 – 50 ]. Meditative movements could be regarded as a combination of mindfulness intervention and physical activity [ 51 ]. This characteristic determines that its intervention in type 2 diabetes is multifaceted. Diaphragmatic breathing practice might be beneficial to reduce negative subjective and physiological consequences of stress in healthy adults [ 52 ]. This might partly explain why meditative movements have a more positive influence on type 2 diabetes, comparing to other active exercises and nonexercises. Yoga and Tai Chi are mainly recommended to increase flexibility, muscle strength, and balance, which shows that the particularity of meditative movements is not yet well-known. Plenty of studies have shown that meditative movements are effective for glucose control in patients with type 2 diabetes [ 53 – 56 ]. It is necessary to develop exercise programs because the optimal form of exercise and appropriate parameters of exercise in type 2 diabetes patients are not yet clear. 5.2. Limitations Several limitations have to be mentioned. Heterogeneity among the studies was significant. We conducted sensitivity analyses and subgroup analyses. The control types, other active exercises and nonexercises, might be the main source of heterogeneity. To some extent, they could explain the source of heterogeneity. But the risk of bias and heterogeneity could also be caused by study quality or the exercise intensity. Because participants cannot be blinded to the meditative movements, performance bias could not be ruled out. The distribution of the included studies is also a great concern. Most trials were conducted in Asia or America. No studies were from the European countries. Due to the limited number of included studies in Qigong, more comprehensive subgroups could not be made. This may have influenced the explanatory effect and the soundness of the pooled effects. Since we only performed a search for English studies, it is possible that articles may have been published in other languages. 5.3. Implications for Research There are a few points that should be considered in the future. The methodological quality of these studies was poor in random sequence generation, allocation concealment, and blinding of outcome assessment. More studies with rigorous design and normative description are needed in this field. We first summarized the current condition of meditative movements for type 2 diabetes. The particularity of meditative movements, which differs from purely physical activity, should be valued in future studies. In summary, based on the evidence, meditative movements have significant effects on controlling blood glucose and blood lipid levels in patients with type 2 diabetes mellitus. These results support the idea that meditative movements are a possible alternative exercise for type 2 diabetes mellitus management. Due to the aforementioned limitations and potential bias, more high-quality randomized controlled studies should be conducted. In addition to increasing flexibility, muscle strength, and balance, the special effects of meditative movements in type 2 diabetes mellitus patients still need further research. Acknowledgments The authors would like to thank Mr. Tao Yin for data collection. This work was funded by the National Key Research and Development Program of China (no. 2017YFC1703304), International Science and Technology Cooperation Project of the Department of Science and Technology of Sichuan Province (no. 18GJHZ0235), and the National Natural Science Foundation of China (no. 81873204). Ethical Approval This study was based on previously published studies; therefore, ethical approval and patient consent are not relevant. Disclosure This paper was not commissioned and was externally peer-reviewed. TWX and YY are co-first authors. Conflicts of Interest The authors declare that they have no conflicts of interest. Authors' Contributions TWX and YY contributed equally to this work. References 1. 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Published online 2015 Nov 11. doi: 10.3945/ajcn.115.110965 PMCID: PMC4658458 PMID: 26561616 Effects of tree nuts on blood lipids, apolipoproteins, and blood pressure: systematic review, meta-analysis, and dose-response of 61 controlled intervention trials 1, 2, 3 Liana C Del Gobbo , 4, * Michael C Falk , 5 Robin Feldman , 5 Kara Lewis , 5 and Dariush Mozaffarian 4 Liana C Del Gobbo 4 Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA; and Find articles by Liana C Del Gobbo Michael C Falk 5 Life Sciences Research Organization, Bethesda, MD Find articles by Michael C Falk Robin Feldman 5 Life Sciences Research Organization, Bethesda, MD Find articles by Robin Feldman Kara Lewis 5 Life Sciences Research Organization, Bethesda, MD Find articles by Kara Lewis Dariush Mozaffarian 4 Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA; and Find articles by Dariush Mozaffarian Author information Article notes Copyright and License information PMC Disclaimer 4 Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA; and 5 Life Sciences Research Organization, Bethesda, MD * To whom correspondence should be addressed. E-mail: ude.drofnats@obbogled . 1 Supported by National Heart, Lung, and Blood Institute grant R01-HL085710-07. 2 The International Tree Nut Council (ITNC) had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. 3 Supplemental Tables 1–4, Supplemental Figures 1–10, and Supplemental Material are available from the “Online Supporting Material” link in the online posting of the article and from the same link in the online table of contents at http://ajcn.nutrition.org . Received 2015 Mar 11; Accepted 2015 Sep 23. Copyright © 2015 American Society for Nutrition Abstract Background: The effects of nuts on major cardiovascular disease (CVD) risk factors, including dose-responses and potential heterogeneity by nut type or phytosterol content, are not well established. Objectives: We examined the effects of tree nuts (walnuts, pistachios, macadamia nuts, pecans, cashews, almonds, hazelnuts, and Brazil nuts) on blood lipids [total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein, and triglycerides], lipoproteins [apolipoprotein A1, apolipoprotein B (ApoB), and apolipoprotein B100], blood pressure, and inflammation (C-reactive protein) in adults aged ≥18 y without prevalent CVD. Design: We conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two investigators screened 1301 potentially eligible PubMed articles in duplicate. We calculated mean differences between nut intervention and control arms, dose-standardized to one 1-oz (28.4 g) serving/d, by using inverse-variance fixed-effects meta-analysis. Dose-response for nut intake was examined by using linear regression and fractional polynomial modeling. Heterogeneity by age, sex, background diet, baseline risk factors, nut type, disease condition, duration, and quality score was assessed with meta-regression. Publication bias was evaluated by using funnel plots and Egger’s and Begg’s tests. Results: Sixty-one trials met eligibility criteria ( n = 2582). Interventions ranged from 3 to 26 wk. Nut intake (per serving/d) lowered total cholesterol (−4.7 mg/dL; 95% CI: −5.3, −4.0 mg/dL), LDL cholesterol (−4.8 mg/dL; 95% CI: −5.5, −4.2 mg/dL), ApoB (−3.7 mg/dL; 95% CI: −5.2, −2.3 mg/dL), and triglycerides (−2.2 mg/dL; 95% CI: −3.8, −0.5 mg/dL) with no statistically significant effects on other outcomes. The dose-response between nut intake and total cholesterol and LDL cholesterol was nonlinear ( P -nonlinearity < 0.001 each); stronger effects were observed for ≥60 g nuts/d. Significant heterogeneity was not observed by nut type or other factors. For ApoB, stronger effects were observed in populations with type 2 diabetes (−11.5 mg/dL; 95% CI: −16.2, −6.8 mg/dL) than in healthy populations (−2.5 mg/dL; 95% CI: −4.7, −0.3 mg/dL) ( P -heterogeneity = 0.015). Little evidence of publication bias was found. Conclusions: Tree nut intake lowers total cholesterol, LDL cholesterol, ApoB, and triglycerides. The major determinant of cholesterol lowering appears to be nut dose rather than nut type. Our findings also highlight the need for investigation of possible stronger effects at high nut doses and among diabetic populations. Keywords: nuts, cholesterol, lipids, apolipoprotein, cardiovascular INTRODUCTION Accumulating evidence from prospective observational studies and a large clinical trial suggests that nut intake lowers the risk of cardiovascular disease (CVD) 6 ( 1 , 2 ). Tree nuts are rich in unsaturated fats, soluble fiber, antioxidants, and phytosterols ( 3 ), which separately or together may produce beneficial effects on serum lipids, blood pressure, and inflammation ( 4 , 5 ). Prior meta-analyses of controlled trials have shown that tree nut intake lowers total and LDL cholesterol ( 6 – 8 ). However, effects of nut consumption on other key CVD risk factors, including specific lipoproteins, blood pressure, and inflammation, are not established. In addition, 2 of these prior meta-analyses evaluated only one type of nuts—almonds ( 6 ) ( n = 5 trials) and walnuts ( 7 ) ( n = 13 trials)—and potential effects of other tree nuts remain unclear. Furthermore, previous analyses ( 6 – 9 ) have not standardized pooled effects to a common dose or tested for nonlinearity of dose-responses, preventing conclusions about the magnitude of effects for a given intake of nuts or potential for nonlinear effects. Therefore, key questions remain on the major cardiovascular mechanisms influenced by tree nuts, on whether some types of nuts are preferential for improving risk, and on dose-response relations of these effects. To address these knowledge gaps, we performed a systematic review and meta-analysis of controlled interventional trials to examine the effects of tree nuts (walnuts, pistachios, macadamia nuts, pecans, cashews, almonds, hazelnuts, pine nuts, and Brazil nuts) on major CVD risk factors, including blood lipids (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides), lipoproteins [apolipoprotein A1, apolipoprotein (ApoB), and apolipoprotein B100], blood pressure (systolic and diastolic), and inflammation (C-reactive protein, CRP) in adults aged ≥18 y without prevalent CVD. We hypothesized that tree nuts would lower concentrations of LDL cholesterol and its primary lipoprotein, ApoB. As a secondary hypothesis, we evaluated potential differences in effects by nut type. METHODS We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines ( 10 ) during all stages of implementation, analysis, and reporting of this meta-analysis. A review protocol has not been published. Eligibility criteria We searched for all published controlled trials that reported the effect of tree nut consumption on blood lipids (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides), lipoproteins (apolipoprotein A1, ApoB, and apolipoprotein B100), blood pressure (systolic and diastolic), or inflammation (CRP). We did not include body weight or adiposity as outcomes because a meta-analysis of nut intake and body weight was recently reported ( 11 ). Trials had to be controlled but could be randomized or nonrandomized (with plans to evaluate only randomized trials and all trials combined) and provided mean levels of the outcome in each group with an accompanying measure of statistical uncertainty (e.g., 95% CI, SE) or other data to calculate variance. We excluded trials testing nonnut parts of the plant, nut oils, nuts other than tree nuts (e.g., areca, betel), or legumes (e.g., peanuts) and trials testing mixed dietary interventions for which the specific effect of nuts could not be evaluated. We also excluded trials among children (aged <18 y), participants with known CVD (myocardial infarction, angina, stroke, severe heart failure, coronary revascularization, or peripheral vascular disease), and participants receiving medication treatment of diabetes, obesity, metabolic syndrome, hypertension, or hyperlipidemia. For crossover trials without a washout period, we excluded trials with an intervention period <3 wk to minimize carryover effects ( 12 ). Trials with ≥20% dropout rates or having imbalanced dropout between intervention and control groups were also excluded. Articles presenting only observational data, editorials/commentaries, letters, and reviews were not eligible. Search and selection of articles Potentially eligible articles were identified by means of a systematic search in PubMed from the earliest available online indexing year to March 2013, without language restrictions. Query terms were as follows: ( Apolipoproteins B [MeSH]) OR Apolipoprotein A-1 [MeSH]) OR ( Cholesterol, HDL [MeSH] OR Cholesterol, LDL [MeSH])) OR Triglycerides [MeSH]) OR Lipoprotein(a) [MeSH]) OR C-Reactive Protein [MeSH] OR Factor VIII [MeSH]) OR Fibrinogen [MeSH] OR von Willebrand Factor [MeSH]) OR Carotid Intima-Media Thickness [MeSH]) OR Blood Pressure [MeSH]) OR Heart Rate [MeSH] OR ( diabetes or cardiovascular ) AND ( Nuts [MeSH] or Tree nuts or almonds or pecans or brazil nuts or hazelnuts or macadamia or pine nuts or pistachios or walnuts ). Two investigators (MF, KL) screened the titles and abstracts of all potentially eligible articles in duplicate, as well as the full text of all articles identified for further review. In addition, citation lists and the first 20 “related citations” on PubMed of all final included articles were hand-searched for additional eligible trials. Data extraction Data were screened and extracted independently and in duplicate by 2 investigators (MF, KL) by using a standardized electronic form, including information on study randomization (yes, no), design (parallel, crossover), nut type, age (mean), sex (percent male), baseline disease condition, treatment duration, dose (g/d), and description of the placebo or control condition. Differences in data extraction between investigators were infrequent and were resolved by consensus. For each outcome, we extracted its mean value (concentration/amount), variance measure, and the number of participants in the treatment and control arms for all reported periods (e.g., baseline, end treatment). Study quality was assessed by using the Academy of Nutrition and Dietetics (formerly American Dietetic Association) Evidence Analysis Process ( 13 ), which evaluates relevance and validity by using a 14-question quality control checklist, including questions on comparability of control and intervention groups, handling of dropouts, blinding, appropriateness of statistical methods, and potential biases (see “Assessment” on last page of Supplemental Material ). Studies meeting criteria for ≥6 of the 10 validity questions, including questions 2, 3, 6, and 7, were given a positive quality rating; studies meeting ≥6 of the 10 validity questions, but not questions 2, 3, 6, and 7, were given a quality rating of neutral; and studies not meeting at least 6 of 10 validity questions were considered of lower quality ( 13 ). Statistical analysis For parallel trials, the primary effect measure was the mean difference in change from baseline to follow-up in the intervention vs. control group ( 14 ). For crossover trials, the primary effect measure was the mean difference at follow-up in the intervention vs. control periods. The SE of the difference measure was extracted (when directly reported), calculated by using a related statistical measure of uncertainty, or estimated by using the IQR of the difference measure provided in studies. To address within-individual correlation in crossover trials, the median reported correlation across all crossover trials ( r = 0.60) was used in calculating the SE of the difference when the study-specific correlation coefficient was not otherwise provided. In trials with repeated measures, we included the estimate closest to the median duration of follow-up across trials (4 wk). For trials with more than one comparison group, we included estimates from the control diet most like the intervention diet other than the inclusion of nuts. For each trial, the effect size and corresponding variance were standardized to one 1-oz daily serving (28.4 g) of nuts. Meta-analyses were performed by using fixed-effects inverse-variance weighting, evaluating randomized trials, nonrandomized trials, and all trials combined. Heterogeneity was quantified by using the I 2 statistic ( 15 ), with >30% considered at least moderate heterogeneity. Heterogeneity was evaluated by prespecified sources, including randomized vs. nonrandomized trials, age, sex, background diet, baseline risk factor level, nut type, comorbidity, intervention duration, and quality score by using meta-regression. For categorical sources of heterogeneity with ≥3 subgroups, P -heterogeneity from meta-regression was obtained for each indicator category relative to the primary reference category ( 16 ). To test dose-response relations, we plotted the relation between absolute nut intake (g/d) and the absolute mean difference in each outcome, with nonlinearity evaluated by using the F test of linear lack of fit. Fractional polynomial models were used to evaluate nonlinear dose-response relations, with the best-fitting model considered the one with the lowest deviance. Publication bias was evaluated by visual inspection of funnel plots and by Egger’s ( 17 ) and Begg’s ( 18 ) tests. All analyses were performed with STATA 12 (StataCorp LP), with 2-tailed α = 0.05. RESULTS Study characteristics Of 1301 articles, 61 trials met eligibility criteria ( 19 – 80 ) ( Figure 1 ), totaling 2582 unique participants in 42 randomized and 18 nonrandomized trials ( Table 1 ). Trials directly provided nuts to the intervention group, rather than relying only on dietary advice to consume nuts. Compliance was most often assessed by using self-reported dietary recalls or direct supervision of nut consumption. Median participant age was 45 y, and two-thirds of trials (41/61) included both men and women (see Supplemental Table 1 for individual study details). Open in a separate window FIGURE 1 Screening and selection of randomized ( n = 42) and nonrandomized controlled trials ( n = 19) on tree nut intake and lipids/apolipoproteins, blood pressure, and C-reactive protein ( 19 – 80 ). TABLE 1 Summary of 61 trials included in meta-analysis of the effect of tree nut intake on lipids/apolipoproteins, blood pressure, and C-reactive protein, stratified by randomization status and tree nut type 1 Study type/nut type Trials, n Participants (maximum), n Median age, y Male, % Cardiovascular (CVD) comorbidities 2 Median duration, wk Median nut dose, 3 g/d Quality score, n trials 4 Randomized controlled trials Walnut 17 939 54 47 5 trials ( n = 1 with diabetes) 5 49 10(+), 5(Ø), 2(−) Pistachio 6 229 48 50 2 trials ( n = 1 with prostate disease) 4 60 4(+), 2(Ø) Macadamia 2 68 48 70 1 trial (overweight/obese) 4.5 59 2(Ø) Pecan 2 65 41 45 2 trials (high cholesterol, MetS) 6 70 1(+), 1(Ø) Cashew 2 54 64 83 2 trials ( n = 1 with diabetes) 8 85.5 1(+), 1(Ø) Almond 9 429 50 56 3 trials (obese, high cholesterol, diabetes) 4 60 6(+), 3(Ø) Hazelnut 2 201 46 68 2 trials (high cholesterol) 8 36 2(Ø) Mixed nuts 2 106 51 51 2 trials (obese, MetS) 9 30 1(+), 1(Ø) Overall 42 2101 53 53 19/42 trials (45%) with CVD comorbidities 5.5 59.5 23(+), 17(Ø), 2(−) Nonrandomized trials Walnut 4 78 60 43 0 trials 6 45 3(Ø), 1(−) Pistachio 1 17 48 100 0 trials 3 100 1(Ø) Macadamia 2 41 37 50 0 trials 3.5 43 2(−) Almond 7 199 46 45 2 trials (obese, high cholesterol) 4 84 2(+), 5(Ø) Hazelnut 4 109 45 64 1 trials (high cholesterol) 4 54 1(+), 3(Ø) Brazil 1 37 35 0 0 trials 8 5 1(−) Overall 19 481 45 50 3/19 trials (16%) with CVD comorbidities 4 49.5 3(+), 12(Ø), 4(−) All trials Overall 61 2582 45 50 22/61 trials (36%) with CVD comorbidities 4 56 26(+), 29(Ø), 6(−) Open in a separate window 1 Total cholesterol and LDL cholesterol were measured as outcomes in 61 trials; HDL cholesterol in 60 trials; triglycerides in 59 trials; apolipoprotein A1 and apolipoprotein B in 23 and 20 trials, respectively; blood pressure in 21 trials; C-reactive protein in 12 trials; and apolipoprotein B100 in 5 trials ( 19 – 80 ). Descriptive information for individual studies is given in Supplemental Table 1. For a summary of the number of studies and effect sizes by outcome, see Table 2 . Outcomes included total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apolipoprotein A1, apolipoprotein B, apolipoprotein B100, systolic blood pressure, diastolic blood pressure, and C-reactive protein. CVD, cardiovascular disease; MetS, metabolic syndrome. 2 CVD comorbidities refers to trials of patients with diabetes or those that enrolled at least some participants with high cholesterol, metabolic syndrome, or overweight/obesity. Other conditions are specified. Participants were either not receiving medication for CVD comorbidities, or medication use was not specified in the trial. 3 For meta-analysis, nut dose (g/d) was standardized to 1 serving (28.4 g) of nuts/d. 4 A quality control checklist comprising 14 questions on relevance and validity was used to award studies a positive (+), neutral (Ø), or negative score (−). Further details on the questions and scoring system are given in the Supplemental Appendix . Most trials examined walnuts ( n = 21) or almonds ( n = 16); others examined pistachios ( n = 7), hazelnuts ( n = 6), macadamia nuts ( n = 4), pecans ( n = 2), cashews ( n = 2), mixed tree nuts ( n = 2), and Brazil nuts ( n = 1). The dose of nuts varied from 5 to 100 g/d (median: 56 g/d), and the duration of intervention was from 3 to 26 wk (median: 4 wk). Participants had existing disease conditions in 45% (19/42) of randomized trials and 16% (3/19) of nonrandomized trials; these were most commonly hypertension, hyperlipidemia, and metabolic syndrome ( Table 1 ). In 14 trials, participants received detailed advice to maintain total energy constant between intervention arms; in the remaining 47 trials, participants were provided nuts on top of a common background diet. The most common background diet (i.e., recommended to both intervention and control arms) was habitual diet ( n = 30 trials); other background diets included American Heart Association, low-fat, high-fat, and Mediterranean-type diets. Most trials obtained a positive ( n = 26) or neutral ( n = 29) quality score; 6 trials had a negative score. Main outcomes Compared with control, consumption of tree nuts significantly lowered concentrations (mg/dL) of total cholesterol (weighted mean difference per 28 g serving/d: −4.7; 95% CI: −5.3, −4.0), LDL cholesterol (−4.8; 95% CI: −5.5, −4.2), ApoB (−3.7; 95% CI: −5.2, −2.3), and triglycerides (−2.2; 95% CI: −3.8, −0.5) ( Table 2 ). Reductions in total cholesterol were seen in both randomized trials (−3.6; 95% CI: −4.4, −2.9) and nonrandomized trials (−6.7; 95% CI: −7.8, −5.6); effects in the latter were significantly larger ( P -interaction < 0.001) ( Supplemental Figure 1 ). Similar findings were seen for LDL cholesterol: randomized trials, −4.2 (95% CI: −5.0, −3.4); nonrandomized trials, −6.0 (95% CI: −7.1, −4.9); P -interaction = 0.01 ( Figure 2 ). For ApoB, no significant differences in effects were observed in randomized trials (−4.2; 95% CI: −5.7, −2.6) vs. nonrandomized trials (−1.1; 95% CI: −5.1, 3.0) ( P -interaction = 0.17) ( Supplemental Figure 2 ). Effects on triglycerides were also not statistically significant in nonrandomized trials (−4.6; 95% CI: −8.4, −0.8) vs. randomized trials (−1.6; 95% CI: −3.5, 0.24) ( P -interaction = 0.16) ( Supplemental Figure 3 ). TABLE 2 WMDs in lipids/apolipoproteins, blood pressure, and CRP per 1 serving of tree nuts/d (28.4 g/d) in randomized and nonrandomized controlled trials ( 19 – 80 ) 1 Randomized controlled trials Nonrandomized trials All trials Outcome Trials, n WMD (95% CI) I 2 Trials, n WMD (95% CI) I 2 Trials, n WMD (95% CI) P value 2 Total cholesterol 38 −3.6 (−4.4, −2.9) 53.8 23 −6.7 (−7.8, −5.6) 76.8 61 −4.7 (−5.3, −4.0) 0.001 LDL cholesterol 38 −4.2 (−5.0, −3.4) 38.2 23 −6.0 (−7.1, −4.9) 62.9 61 −4.8 (−5.5, −4.2) 0.01 HDL cholesterol 38 −0.04 (−0.8, 0.7) 0 22 −0.7 (−1.7, 0.4) 35.9 60 −0.3 (−0.9, 0.4) 0.33 TG 37 −1.6 (−3.5, 0.24) 0 22 −4.6 (−8.4, −0.8) 0 59 −2.2 (−3.8, −0.5) 0.16 ApoA1 15 −0.8 (−2.1, 0.6) 12.8 8 1.0 (−2.7, 4.7) 0 23 −0.6 (−1.9, 0.7) 0.38 ApoB 13 −4.2 (−5.7, −2.6) 20.3 7 −1.1 (−5.1, 3.0) 0 20 −3.7 (−5.2, −2.3) 0.17 ApoB100 3 −1.5 (−5.8, 2.8) 0 2 −5.2 (11.0, 0.6) 0 5 −2.8 (−6.2, 0.7) 0.31 SBP 17 1.3 (−0.03, 2.6) 0 4 −3.3 (−5.7, 0.9) 0 21 0.3 (−0.8, 1.4) 0.001 DBP 17 0.6 (−0.7, 1.8) 0 3 −1.6 (−5.8, 2.5) 0 20 0.4 (−0.8, 1.6) 0.32 CRP 8 0.2 (−1.7, 2.0) 0 4 −0.4 (−5.7, 4.8) 0 12 0.1 (−1.6, 1.8) 0.84 Open in a separate window 1 Values for lipids/apolipoproteins and CRP are presented in mg/dL; blood pressure is presented in mmHg. The WMD represents the amount by which the tree nut intervention changed the outcome on average compared with the control group or period. Estimates were pooled by using fixed-effects, inverse-variance meta-analysis. Outcomes included total cholesterol, LDL cholesterol, HDL cholesterol, TG, ApoA1, ApoB, ApoB100, SBP, DBP, and CRP. The I 2 index indicates the percentage of total variability in the effect sizes due to between-study heterogeneity, with I 2 > 30% considered at least moderate heterogeneity. ApoA1, apolipoprotein A1; ApoB, apolipoprotein B; ApoB100, apolipoprotein B100; CRP, C-reactive protein; DBP, diastolic blood pressure; SBP, systolic blood pressure; TG, triglycerides; WMD, weighted mean difference. 2 P -heterogeneity between WMD of randomized controlled trials and nonrandomized trials is shown. Open in a separate window FIGURE 2 WMD in LDL cholesterol (mg/dL) per 1 serving of nuts/d (28.4 g/d) in randomized and nonrandomized controlled trials, pooled by using fixed-effects meta-analysis ( 19 – 80 ). To convert mg/dL to mmol/L, multiply by 0.0259. WMD, weighted mean difference. No significant effects of tree nut consumption were identified for HDL cholesterol, apolipoprotein A1, apolipoprotein B100, systolic or diastolic blood pressure, or CRP ( Supplemental Figures 4–9 ). These findings were similar when randomized and nonrandomized trials were separately evaluated. Dose-responses between nut intake and outcomes When we evaluated dose-responses, tree nut intake lowered total cholesterol and LDL cholesterol in a nonlinear fashion ( P -nonlinearity < 0.001); stronger effects were observed in trials providing doses of ≥60 g nuts/d ( Figure 3 ). In contrast, there was little evidence for nonlinear dose-response relations between nut intake and ApoB or triglycerides ( P -nonlinearity > 0.05 each). Open in a separate window FIGURE 3 Dose-response relations between tree nut intake (g/d) and absolute (unstandardized) mean difference (mg/dL) in total cholesterol ( n = 61 trials) (A), LDL cholesterol ( n = 61 trials) (B), apolipoprotein B ( n = 19 trials) (C), and triglycerides ( n = 59 trials) (D) ( 19 – 80 ). Nut intake lowers total cholesterol and LDL cholesterol in a nonlinear fashion ( P -nonlinearity = 0.001 for both), with stronger effects observed above a nut dose of ∼60 g nuts/d. Linear dose-response relations were observed between nut intake and apolipoprotein B ( r = −0.12) and triglycerides ( r = −0.16). The 95% CI is depicted in the shaded regions. Heterogeneity Heterogeneity was at least moderate ( I 2 > 30%) among trials of total cholesterol and LDL cholesterol and nonrandomized trials of triglycerides and HDL cholesterol, as well as low ( I 2 < 30%) among trials of apolipoproteins, blood pressure, and CRP ( Table 2 ). No significant differences in effects by nut type were observed ( Supplemental Table 2 ), although relatively few trials were available for certain nut types. Heterogeneity by quality score, with greater effect sizes found in lower quality trials, was observed for total cholesterol and LDL cholesterol ( P -heterogeneity = 0.09 and 0.005, respectively); however, these differences were no longer statistically significant in analyses including only randomized controlled trials ( Supplemental Table 3 ). Visual inspection of funnel plots suggested that nonrandomized trials more frequently reported larger effect sizes for total cholesterol and LDL cholesterol ( Supplemental Figure 10 ). For ApoB, significant heterogeneity by comorbidity was found, with stronger effects observed in studies including participants with type 2 diabetes (weighted mean difference: −11.5; 95% CI: −16.2, −6.8) than among healthy populations (−2.5; 95% CI: −4.7, −0.3) ( P -heterogeneity = 0.015) (Supplemental Tables 2 and 3). No significant heterogeneity by other disease conditions, age, sex, background diet, baseline outcome level, or intervention duration was observed. Evaluation of publication bias Visual inspection of funnel plots did not suggest publication bias. Statistical evidence of publication bias was also not detected by using Egger’s or Begg’s tests ( Supplemental Table 4 ). DISCUSSION In this systematic review and meta-analysis of controlled trials including 2582 participants, nut consumption lowered total cholesterol, LDL cholesterol, and its primary apolipoprotein, ApoB. Effects on total cholesterol and LDL cholesterol were generally larger in nonrandomized vs. randomized trials but statistically evident in each. For ApoB, stronger effects were also observed in populations with type 2 diabetes. These benefits were not significantly different across diverse types of tree nuts or when added to a variety of background diets. Nut consumption also lowered triglyceride concentrations, although effects were small in magnitude and only statistically significant in nonrandomized trials. Significant effects of nut consumption on HDL cholesterol, ApoA, blood pressure, or CRP were not identified. This meta-analysis provides the most comprehensive estimates to date of the effects of tree nut intake on major cardiovascular disease risk factors, including dose-response relations and presentation of effects by different nut types. Accumulating evidence indicates that nut intake lowers risk of CVD events, including consistent findings from prospective observational studies ( 1 , 81 ) and the Prevención con Dieta Mediterránea trial ( 2 ). Our findings showing that nut intake significantly improves the lipid profile, lowering LDL cholesterol, ApoB, and triglycerides, provide critical mechanistic evidence to support a causal link between nut intake and lowered CVD risk. In dose-response analyses, the relations between tree nut intake and total cholesterol and LDL cholesterol were nonlinear, with stronger effects at consumption amounts at ≥60 g (about 2 oz, or 2 servings) per day. Trials providing 100 g nuts/d lowered concentrations of LDL cholesterol by up to 35 mg/dL, an effect size comparable to some statin regimens ( 82 ). As a point of caution, only 5 trials (4 nonrandomized, 1 randomized) provided nuts in this quantity, however, and additional trials comparing the effects of multiple nut doses on LDL cholesterol within the same study, particularly at high amounts (e.g., 100 g nuts/d) are needed. In comparison, effects of nuts on ApoB appeared more linear, which could relate to differential effects of tree nuts on LDL cholesterol particle size vs. particle number at different doses, a smaller number of studies of high-dose nut consumption and ApoB, or chance. Further randomized studies of high-dose nut consumption will help clarify whether benefits on blood lipids and apolipoproteins are nonlinear. We did not observe significant heterogeneity in outcomes across different types of tree nuts. In addition, our meta-regression demonstrated that the major determinant of cholesterol lowering appears to be the total dose of tree nut consumption rather than nut type. Significant heterogeneity in effects was also not observed for most other factors, including age, sex, background diet, baseline outcome level, and intervention duration; an exception was that tree nut intake lowered ApoB to a 3- to 4-fold greater degree in trials of diabetic populations in comparison to trials including only nondiabetic participants. In diabetic patients, ApoB provides more accurate information about atherogenic particles than LDL cholesterol concentrations ( 83 ). These findings suggest that nut consumption may be particularly important for lowering CVD risk in patients with diabetes. On the basis of the magnitude of effects of nut intake on lowering LDL cholesterol and ApoB observed in this meta-analysis, together with the established relation between LDL cholesterol and ApoB and CVD events ( 84 ), we calculated the predicted changes in risk of CVD events if one daily serving of nuts was incorporated into the diet. For an LDL cholesterol reduction of 4.2 mg/dL and an ApoB reduction of 4.1 mg/dL per daily serving of nuts observed in randomized trials of this meta-analysis, a 4% (HR: 0.96; 95% CI: 0.93, 0.99) and a 6% lower risk of coronary events are predicted, respectively. These calculated effects are smaller than associations between nut intake and CVD events observed in both prospective cohorts ( 81 , 85 ) and the Prevención con Dieta Mediterránea trial ( 2 ). For instance, in prospective observational studies ( 85 ), a daily serving (28.4 g) of nuts was associated with 29% lower risk of CVD (HR: 0.71; 95% CI: 0.59, 0.85), whereas in the Prevención con Dieta Mediterránea trial, a Mediterranean diet supplemented with one daily serving (30 g) of mixed nuts reduced CVD events by 28% (HR: 0.72; 95% CI: 0.54, 0.96) over 4.8 y of follow-up ( 2 ). These consistent effect sizes in prospective studies and controlled clinical trials suggest that tree nuts have additional cardiovascular benefits beyond LDL cholesterol and ApoB lowering, for example, improving blood glucose and endothelial function ( 59 ). Similarly, specific constituents in tree nuts, such as polyunsaturated fats, are thought to influence CVD risk through both lipid and nonlipid mechanisms ( 86 – 88 ). Our study has several strengths. Our systematic search makes it unlikely that large reports were missed, and error and bias were minimized by independent, duplicate decisions on study inclusion and data extraction. Effect sizes were standardized to a common dose, avoiding combining of heterogeneous comparisons (e.g., “high vs. low” intake) and, importantly, allowing quantitative assessment of dose-response relations. The duration of trials was adequate to achieve changes and stabilization of lipid values ( 12 ). We evaluated multiple cardiovascular disease risk factors, including apolipoproteins; separately evaluated different types of tree nuts; and assessed several sources of heterogeneity. The identified trial populations were relatively diverse, including differences in age, sex, disease status, and background diet, increasing generalizability of our findings. Potential limitations should be considered. Compliance was often assessed by self-report, and low compliance would cause underestimation of effects. Greater effect sizes were observed in lower quality, nonrandomized trials, yet significant effects on total cholesterol, LDL cholesterol, and ApoB were still seen in high-quality, randomized trials. The relatively few trials in some subgroups examined in heterogeneity analyses limited statistical power to detect potential interaction; for example, few estimates ( n ≤ 2) were available for some nut types, such as Brazil nuts, cashews, and pecans. Although larger effects on lowering LDL cholesterol were observed at higher nut doses in our study, we did not examine the effects of nuts on weight change. A recent meta-analysis of controlled trials on this topic ( 11 ) found that nut intake had nonsignificant, inverse effects on adiposity, but doses in most included trials were modest (<56 g/d, or 2 servings, of nuts). Furthermore, nut intake was associated with less weight gain over time in US cohorts of male and female health professionals ( 89 , 90 ). Taken together, the inverse associations with weight gain observed in both controlled trials and free-living populations suggest that nut intake might augment satiety and displace other, less healthful foods in the diet, potentially resulting in less weight gain over time. In conclusion, this systematic review and meta-analysis of controlled trials demonstrates that tree nut consumption lowers total cholesterol, LDL cholesterol, ApoB, and triglycerides. Our findings also highlight the need for additional investigation of potentially stronger effects at high doses of nuts and among diabetic populations. Acknowledgments The authors’ responsibilities were as follows—LCDG, MCF, RF, and KL: conducted research; LCDG: analyzed data and performed statistical analysis; LCDG and DM: wrote the manuscript; LCDG: had primary responsibility for final content; and all authors: designed research and read and approved the final manuscript. DM reports ad hoc honoraria from Bunge, Pollock Institute, and Quaker Oats; ad hoc consulting for Foodminds, Nutrition Impact, Amarin, Astra Zeneca, Winston, and Strawn LLP; membership, Unilever North America Scientific Advisory Board; and chapter royalties from UpToDate. LCDG and DM received modest ad hoc consulting fees from the Life Sciences Research Organization (LSRO) in Bethesda, MD, to support this study. 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+Relaxation Techniques - StatPearls - NCBI Bookshelf Warning: The NCBI web site requires JavaScript to function. more... An official website of the United States government Here's how you know The .gov means it's official. Federal government websites often end in .gov or .mil. Before
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Search term Relaxation Techniques Samantha K. Norelli ; Ashley Long ; Jeffrey M. Krepps . Author Information and Affiliations Authors Samantha K. Norelli 1 ; Ashley Long 2 ; Jeffrey M. Krepps 3 . Affiliations 1 Campbell University School of OM 2 Nova Southeastern University KPCOM 3 Campbell University, School of OM Last Update: August 28, 2023 . Continuing Education Activity Relaxation techniques are therapeutic exercises designed to assist individuals by decreasing tension and anxiety. Relaxation therapy has been a part of psychotherapy for ages; however, these techniques can be expanded to include diverse environments as complementary therapies to treat stress, anxiety, depression, and pain. In addition to its psychological impact, stress can cause physiological responses such as increased heart rate, palpitations, diaphoresis, shortness of breath, and muscle tension. Relaxation techniques can aid in the reduction of these unpleasant responses. Many variations of relaxation strategies exist and can be facilitated by a variety of health professionals or learned via self-help modalities. This activity describes the benefits of relaxation techniques in individuals undergoing stress and highlights the role of the interprofessional team in encouraging these practices to improve the lives of their patients. Objectives: Identify the indications for relaxation techniques. Describe the types of relaxation techniques. Outline the clinical benefits of relaxation. Summarize interprofessional team strategies for enhancing care coordination and communication to advance the utilization of relaxation techniques to improve outcomes. Access free multiple choice questions on this topic. Introduction Relaxation techniques are therapeutic exercises designed to assist individuals with decreasing tension and anxiety, physically and psychologically. Strategies to assist patients with relaxation have long been a hallmark component of psychotherapy; however, they can be utilized throughout healthcare environments as complementary therapies to treat patients experiencing various types of distress, including but not limited to anxiety, depression, pain, and stress [1] . Relaxation techniques encompass an array of strategies to increase feelings of calm and decrease feelings of stress. Feelings of stress can include physiological responses such as increased heart rate, shortness of breath, and muscle tension, along with the subjective emotional experience; and relaxation techniques can aid in the reduction of these symptoms [2] . Many variations of relaxation strategies exist and can be facilitated by a variety of health professionals and learned via self-help. Indications Relaxation techniques are therapeutic exercises indicated to assist patients in decreasing physical and psychological tension and anxiety. Preparation The following are step-by-step examples of relaxation techniques that can be relayed to patients by health professionals. It is helpful to know a variety of relaxation techniques to offer to patients as different strategies work for different patients. Relaxation techniques have been shown to reduce cortisol levels in patients, leading to a decrease in somatic and subjective experiences of stress [3] . Like all beneficial, healthy activities, each relaxation technique should be practiced over time and implemented regularly for optimal stress reduction. Technique or Treatment Box Breathing While there are many different forms of deep breathing exercises, box breathing can be particularly helpful with relaxation. Box breathing is a breathing exercise to assist patients with stress management and can be implemented before, during, and/or after stressful experiences. Box breathing uses four simple steps. Its title is intended to help the patient visualize a box with four equal sides as they perform the exercise. This exercise can be implemented in a variety of circumstances and does not require a calm environment to be effective. Step One: Breathe in through the nose for a count of 4. Step Two: Hold breath for a count of 4. Step Three: Breath out for a count of 4. Step Four: Hold breath for a count of 4. Repeat Note: The length of the steps can be adjusted to accommodate the individual (e.g., 2 seconds instead of 4 seconds for each step). Guided Imagery Guided imagery is a relaxation exercise intended to assist patients with visualizing a calming environment. Visualization of tranquil settings assists patients with managing stress via distraction from intrusive thoughts. Cognitive behavioral theory suggests that emotions are derived from thoughts, therefore, if intrusive thoughts can be managed, the emotional consequence is more manageable. Imagery employs all five senses to create a deeper sense of relaxation. Guided imagery can be practiced individually or with the support of a narrator. Step One: Sit or lie down comfortably. Ideally, the space will have minimal distractions. Step Two: Visualize a relaxing environment by either recalling one from memory or created one through imagination (e.g., a day at the beach). Elicit elements of the environment using each of the five senses using the following prompts: What do you see? (e.g., deep, blue color of the water) What do you hear? (e.g., waves crashing along the shore) What do you smell? (e.g., fruity aromas from sunscreen) What do you taste? (e.g., salty sea air) What do you feel? (e.g., warmth of the sun) Step Three: Sustain the visualization as long as needed or able, focusing on taking slow, deep breaths throughout the exercise. Focus on the feelings of calm associated with being in a relaxing environment. Progressive Muscle Relaxation Progressive Muscle Relaxation (PMR) is a relaxation technique targeting the symptom of tension associated with anxiety. The exercise involves tensing and releasing muscles, progressing throughout the body, with the focus on the release of the muscle as the relaxation phase. Progressive muscle relaxation can be practiced individually or with the support of a narrator. Step One: Sit or lie down comfortably. Ideally, the space will have minimal distractions. Step Two: Starting at the feet, curl the toes under and tense the muscles in the foot. Hold for 5 seconds, then slowly release for 10 seconds. During the release, focus attention on the alleviation of tension and the experience of relaxation. Step Three: Tense the muscles in the lower legs. Hold for 5 seconds, then slowly release for 10 seconds. During the release, focus attention on the alleviation of tension and the experience of relaxation. Step Four: Tense the muscles in the hips and buttocks. Hold for 5 seconds, then slowly release for 10 seconds. During the release, focus attention on the alleviation of tension and the experience of relaxation. Step Five: Tense the muscles in the stomach and chest. Hold for 5 seconds, then slowly release for 10 seconds. During the release, focus attention on the alleviation of tension and the experience of relaxation. Step Six: Tense the muscles in the shoulders. Hold for 5 seconds, then slowly release for 10 seconds. During the release, focus attention on the alleviation of tension and the experience of relaxation. Step Seven: Tense the muscles in the face (e.g., squeezing eyes shut). Hold for 5 seconds, then slowly release for 10 seconds. During the release, focus attention on the alleviation of tension and the experience of relaxation. Step Eight: Tense the muscles in the hand, creating a fist. Hold for 5 seconds, then slowly release for 10 seconds. During the release, focus attention on the alleviation of tension and the experience of relaxation. Note: Be careful not to tense to the point of physical pain, and be mindful to take slow, deep breaths throughout the exercise. Clinical Significance Relaxation strategies are used as therapeutic interventions for patients experiencing stress. It is widely accepted that high stress, particularly sustained rates of high stress, have negative effects on physical and mental health. Chronic stress in childhood and adulthood can lead to increased blood pressure and mental health issues among other health concerns [4] . Additionally, chronic stress has been shown to affect brain development, specifically the amygdala which is essential for emotion regulation and the pre-frontal cortex which is necessary for executive functioning and decision-making; therefore, it is useful to have relaxation strategies as coping tools to share with patients to decrease stress. [5] [6] [7] [8] Enhancing Healthcare Team Outcomes The healthcare profession is stressful for physicians, nurses, pharmacists and other related professionals. Burnout from stress is common. Thus, many types of relaxation techniques have been developed to help ease the tension and relieve the stress. There is literature to show that stress free individuals are more efficient and effective compared to stressed individuals. [9] Review Questions Access free multiple choice questions on this topic. Comment on this article. References 1. Parás-Bravo P, Alonso-Blanco C, Paz-Zulueta M, Palacios-Ceña D, Sarabia-Cobo CM, Herrero-Montes M, Boixadera-Planas E, Fernández-de-Las-Peñas C. Does Jacobson's relaxation technique reduce consumption of psychotropic and analgesic drugs in cancer patients? A multicenter pre-post intervention study. BMC Complement Altern Med. 2018 May 02; 18 (1):139. [ PMC free article : PMC5930442 ] [ PubMed : 29720148 ] 2. Volpato E, Banfi P, Nicolini A, Pagnini F. A quick relaxation exercise for people with chronic obstructive pulmonary disease: explorative randomized controlled trial. Multidiscip Respir Med. 2018; 13 :13. [ PMC free article : PMC5932751 ] [ PubMed : 29744054 ] 3. Dawson MA, Hamson-Utley JJ, Hansen R, Olpin M. Examining the effectiveness of psychological strategies on physiologic markers: evidence-based suggestions for holistic care of the athlete. J Athl Train. 2014 May-Jun; 49 (3):331-7. [ PMC free article : PMC4080595 ] [ PubMed : 24490842 ] 4. Brenhouse HC, Danese A, Grassi-Oliveira R. Neuroimmune Impacts of Early-Life Stress on Development and Psychopathology. Curr Top Behav Neurosci. 2019; 43 :423-447. [ PubMed : 30003509 ] 5. Kuloor A, Kumari S, Metri K. Impact of yoga on psychopathologies and quality of life in persons with HIV: A randomized controlled study. J Bodyw Mov Ther. 2019 Apr; 23 (2):278-283. [ PubMed : 31103108 ] 6. Garland SN, Xie SX, DuHamel K, Bao T, Li Q, Barg FK, Song S, Kantoff P, Gehrman P, Mao JJ. Acupuncture Versus Cognitive Behavioral Therapy for Insomnia in Cancer Survivors: A Randomized Clinical Trial. J Natl Cancer Inst. 2019 Dec 01; 111 (12):1323-1331. [ PMC free article : PMC6910189 ] [ PubMed : 31081899 ] 7. Huang AJ, Grady D, Mendes WB, Hernandez C, Schembri M, Subak LL. A Randomized Controlled Trial of Device Guided, Slow-Paced Respiration in Women with Overactive Bladder Syndrome. J Urol. 2019 Oct; 202 (4):787-794. [ PMC free article : PMC6842393 ] [ PubMed : 31075059 ] 8. Lopez-Lopez L, Valenza MC, Rodriguez-Torres J, Torres-Sanchez I, Granados-Santiago M, Valenza-Demet G. Results on health-related quality of life and functionality of a patient-centered self-management program in hospitalized COPD: a randomized control trial. Disabil Rehabil. 2020 Dec; 42 (25):3687-3695. [ PubMed : 31074660 ] 9. Anderson KGC, Langley J, O'Brien K, Paul S, Graves K. Examining the artist-patient relationship in palliative care. A thematic analysis of artist reflections on encounters with palliative patients. Arts Health. 2019 Feb; 11 (1):67-78. [ PMC free article : PMC6494112 ] [ PubMed : 31038040 ] Disclosure: Samantha Norelli declares no relevant financial relationships with ineligible companies. Disclosure: Ashley Long declares no relevant financial relationships with ineligible companies. Disclosure: Jeffrey Krepps declares no relevant financial relationships with ineligible companies. Copyright © 2024, StatPearls Publishing LLC. This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
+( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal. Bookshelf ID: NBK513238 PMID: 30020610 Share Views PubReader Print View Cite this Page Norelli SK, Long A, Krepps JM. Relaxation Techniques. [Updated 2023 Aug 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. In this Page Continuing Education Activity Introduction Indications Preparation Technique or Treatment Clinical Significance Enhancing Healthcare Team Outcomes Review Questions References Bulk Download Bulk download StatPearls data from FTP Related information PMC PubMed Central citations PubMed Links to PubMed Similar articles in PubMed Behavioural modification interventions for medically unexplained symptoms in primary care: systematic reviews and economic evaluation. [Health Technol Assess. 2020] Behavioural modification interventions for medically unexplained symptoms in primary care: systematic reviews and economic evaluation. Leaviss J, Davis S, Ren S, Hamilton J, Scope A, Booth A, Sutton A, Parry G, Buszewicz M, Moss-Morris R, et al. Health Technol Assess. 2020 Sep; 24(46):1-490. Florida Domestic Violence. [StatPearls. 2024] Florida Domestic Violence. Houseman B, Semien G. StatPearls. 2024 Jan Evaluating telehealth lifestyle therapy versus telehealth psychotherapy for reducing depression in adults with COVID-19 related distress: the curbing anxiety and depression using lifestyle medicine (CALM) randomised non-inferiority trial protocol. [BMC Psychiatry. 2022] Evaluating telehealth lifestyle therapy versus telehealth psychotherapy for reducing depression in adults with COVID-19 related distress: the curbing anxiety and depression using lifestyle medicine (CALM) randomised non-inferiority trial protocol. Young LM, Moylan S, John T, Turner M, Opie R, Hockey M, Saunders D, Bruscella C, Jacka F, Teychenne M, et al. BMC Psychiatry. 2022 Mar 27; 22(1):219. Epub 2022 Mar 27. Review Stretch-based relaxation training. [Patient Educ Couns. 1994] Review Stretch-based relaxation training. Carlson CR, Curran SL. Patient Educ Couns. 1994 Apr; 23(1):5-12. Review Breathlessness with pulmonary metastases: a multimodal approach. [J Adv Pract Oncol. 2013] Review Breathlessness with pulmonary metastases: a multimodal approach. Brant JM. J Adv Pract Oncol. 2013 Nov; 4(6):415-22. See reviews... See all... Recent Activity Clear Turn Off Turn On Relaxation Techniques - StatPearls Relaxation Techniques - StatPearls Your browsing activity is empty. Activity recording is turned off. Turn recording back on See more... Follow NCBI Twitter Facebook LinkedIn GitHub NCBI Insights Blog Connect with NLM Twitter Facebook Youtube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov

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+What are the effects of psychological stress and physical work on blood lipid profiles? - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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+            and transmitted securely. Log in Show account info Close Account Logged in as: username Dashboard Publications Account settings Log out Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now . Search PMC Full-Text Archive Search in PMC Advanced Search User Guide Journal List Medicine (Baltimore) v.96(18); 2017 May PMC5419930 Other Formats PDF (190K) Actions Cite Collections Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than  characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Share Permalink Copy RESOURCES Similar articles Cited by other articles Links to NCBI Databases Journal List Medicine (Baltimore) v.96(18); 2017 May PMC5419930 As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with,
+    the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Medicine (Baltimore). 2017 May; 96(18): e6816. Published online 2017 May 5. doi: 10.1097/MD.0000000000006816 PMCID: PMC5419930 PMID: 28471984 What are the effects of psychological stress and physical work on blood lipid profiles? Seyedeh Negar Assadi , MD ∗ Monitoring Editor: Yung-Hsiang Chen. Author information Article notes Copyright and License information PMC Disclaimer Department of Occupational Health Engineering, School of Health, Social Determinants of Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. ∗ Correspondence: Seyedeh Negar Assadi, Department of Occupational Health Engineering, School of Health, Social Determinants of Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran (e-mail: ri.ca.smum@nidassa ). Received 2016 Oct 6; Revised 2017 Mar 15; Accepted 2017 Apr 13. Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0 Abstract Blood lipids disorders are prevalent in the world. Some of their risk factors are modifiable such as mental and physical stress which existed in some places such as work environment. Objective of this study was to determine the effects of psychological and physical stress on the lipid profiles. It was a historical cohort study. The people who were employed as general worker were participated. The study was conducted with flexible interview for getting history, lipid profile examination, and a checklist including occupational and nonoccupational risk factors and using the health issues. According to the type of stress exposures, the study population was divided into 5 groups. Groups were followed for lipid profiles. These groups were exposed to psychological stress, physical stress or both of them; mild psychological stress (group 1), mild physical work without psychological stress (group 2), mild psychological stress and mild physical work (group 3), moderate physical work without psychological stress (group 4), and heavy physical work without psychological stress (group 5). Data were analyzed with SPSS 16. ANOVA, χ 2 , and exact test were calculated with considering P < .05 as significant level. Relative risks were calculated with confidence interval 95%. The means of lipid profiles were in normal ranges. The relative risks for triglycerides more than 200 mg/dL was 1.57 (1.02–2.42) and low density lipoprotein (LDL) more than 130 mg/dL was 14.54 (3.54–59.65) in group 1. The relative risks for high density lipoprotein (HDL) less than 45 mg/dL was 14.61 (8.31–25.68) in group 1 and 16.00 (8.30–30.83) in group 3. After multinomial logistic regression they had significant differences. Psychological stress was a risk factor for lipid disorders, and suitable physical activity was protective in this situation. Keywords: lipid disorder, physical activity, stress, work 1. Introduction Lipid disorders are prevalent in the world. [ 1 ] Some of their risk factors are modifiable such as mental and physical stresses in some situations like workplaces. The main etiology of lipid disorders is genetic factor and family history that is not changeable. In recent decade researchers have worked on risk factors for lipid disorders. [ 1 ] Hypertriglyceridemia, hypercholesterolemia, and related lipid disorders are very common, their prevalence are between 20% and 50% in different populations. [ 1 ] There are a few studies that showed the role of environmental risk factors for dyslipidemia besides nutritional conditions. [ 1 , 2 ] Psychological stress had effects on human body especially on some specific organs and parameters and physiological parameters too, lipid profile was one of them. Physical stresses caused by physical works could be affected lipid profiles too. Night shift work could be a risk factor for hyperlipidemia but the background of well-being is important in this situation. [ 2 , 3 ] Researchers reported lipid disorders; related to job stress in professional drivers. Their study showed the effects of stress on triglycerides, low density lipoprotein (LDL), and high density lipoprotein (HDL). [ 4 ] Scientists showed the relationship between job stress and dyslipidemia including total cholesterol and LDL and decreased HDL. [ 5 ] Researchers studied the association between the occupational stress and hypertension, type 2 diabetes mellitus, lipid disorders. [ 6 ] Other researcher showed the cardiovascular disease and its risk factors in law enforcement personnel. [ 7 ] Another study demonstrated the association between job stress and combined dyslipidemia among workers. [ 8 ] There are also some studies about the dyslipidemias in female law enforcement officers and railway workers, and male aircrew personnel. [ 9 – 11 ] Some studies showed lipid disorders in people with jobs that had psychological stress. [ 12 – 14 ] Researchers demonstrated the effectiveness of wellbeing, preventive methods, and treatment on lipid disorders. [ 15 – 17 ] Night shift work was reported as a risk factor for cardiovascular disorders in different jobs, [ 18 – 20 ] which are common in the society. [ 21 , 22 ] Chemicals such as carbon disulfide was also introduced as a cardiovascular risk factor. [ 23 , 24 ] All together some studies have showed the effects of work stress on health and wellbeing. [ 25 – 28 ] Objective of this study was to determine the effects of psychological and physical stress on lipid profiles. 2. Materials and methods Study design and target population; it was a historical cohort study, which was performed on people who were employed as general workers during 2005 to 2016. The main aim was to compare the effects of psychological and physical stress on participants’ lipid profiles. Data were collected with flexible interview, physical examination, and a checklist including history, measurement of lipid profile and risk factors and using the data from health issues. According to type of exposures the study population was divided into 5 groups. Groups were followed for lipid profiles. These industries had not another risk factor for lipid profile changes. They were not used carbon disulfide, they had low to moderate fat in nutrition. All of them had shift work. Simple random sampling method was used with α = 0.05, power = 90, P1 = 25%, and P2 = 50%, the calculated study population was 1000 for each group (5 groups), and 5000 in total. The inclusion criteria were people who worked in general working with at least 5 years work experience in the same work. The exclusion criteria were having the hyperlipidemia and related diseases before beginning this job and having the positive family history in lipid profile disorders and anxiety disorders. The validity and reliability of checklist were checked with specialists’ opinions and also with performing a pilot study with correlation coefficient 90%. The participants were interviewed by author using a checklist. The results of blood examinations in periodic examination were taken and body mass index (BMI) was calculated. The level of cholesterol in total and ingredients (LDL and HDL) and triglyceride were important for researcher. These values were high risk; BMI was equal and more than 30 kg/m 2 , triglycerides was equal and more than 200 mg/dL, total cholesterol was equal and more than 200 mg/dL, LDL was equal and more than 130 mg/dL, and HDL was equal and more than 45 mg/dL. 2.1. Exposure assessment Two types of physical and psychological stress were assessed in this study and 5 groups with different exposures were evaluated: mild psychological stress (group 1), mild physical work without psychological stress (group 2), mild psychological stress and mild physical work (group 3), moderate physical work without psychological stress (group 4), and heavy physical work without psychological stress (group 5). Group 1: workers with more than 1% to 25% of total grade in work environmental scale and modified standard stress scale. Group 2: workers with mild physical work without psychological stress. Group 3: workers with more than 1% to 25% of total grade in work environmental scale and modified standard stress scale and mild physical work. Group 4: workers moderate physical work without psychological stress. Group 5: workers with heavy physical work without psychological stress. Job stress was assessed with work environmental scale and modified standard stress scale; there were 10 items with 0 to 10 grades. Items were in organizational (change, coworkers, supervisor relationships), career development (achievement, improvement), role (ambiguity, conflict), task (under or over load), and environmental fields. Stress were recognized with more than 1% to 25% of total grades as mild level, and the severity of physical work was assessed with standards aerobic tests (McArdle step test) and calculated metabolic equivalent tasks or metabolic equivalent of tasks (METs) with according to VO 2 max (mL/kg/m) at the preplacement of participants; preplacement examinations results were used for physical stress determination. METs less than or equal to 3 indicates mild activity, between 3 and 6 shows moderate activity and more than 6 declares a heavy work. Other work exposures were kept in the standard levels. The researcher determined the stress level according to work environmental scale and modified standard stress scale. By using of blood examinations were done in periodic examinations the relation between the job risks and lipid profiles were showed. For statistical analysis, data were analyzed with SPSS 16. χ 2 , exact test, ANOVA, and regression were used to compare qualitative and quantitative variables, P -value less than .05 was considered for significant levels and relative risks were calculated with confidence interval 95%. 2.2. Ethical consideration This study, involving human participants, was done in accordance with the ethical standards and with the 1964 Helsinki declaration and comparable ethical standards and was implemented by getting consent that was obtained from all the participants. The researcher used from preplacement for physical tests and periodic examinations for lipid profiles in the industries. 3. Results The study participants were divided into 5 groups based on exposure to physical or psychological stresses. The age, work duration, total cholesterol, and HDL showed significant differences between study groups ( P < .05). They were male workers and had not smoking. They had rotating shift work and low to moderate fat food. Participants in group 4 (moderate physical work) had the highest age, work duration and BMI. Triglycerides, LDL were the most in group 5 (heavy physical work) and HDL was the least in this group too. Total cholesterol had the highest level in group 3 (mild psychological stress and mild physical work). The results of blood test are demonstrated in Table ​ Table1 1 ( P < .05). Table 1 Means of risk factors amounts and comparison between 5 groups ( P < .05). Open in a separate window The highest number of persons with BMI more than 30 and total cholesterol more than 200 was in group 4. The highest number of workers with triglycerides more than 200 and HDL less than 45 was found in group 5. The most number of participants with LDL more than 130 were in groups 5. These items are demonstrated in Table ​ Table2 2 ( P < .05). Table 2 Frequencies of risk factors and comparison between 5 groups ( P < .05). Open in a separate window After deleting the effect of BMI and age with regression, the relative risks for triglycerides more than 200 mg/dL was 1.57 (1.02–2.42) and for LDL more than 130 mg/dL was 14.54 (3.54–59.65) in group 1 (mild psychological stress). The relative risks for HDL less than 45 mg/dL were 14.61 (8.31–25.68) in group 1 and 16.00 (8.30–30.83) in group 3. In groups 2 and 4 the relative risks of LDL more than130 mg/dL and HDL less than 45 mg/dL were below one. The relative risks in group 5 was below one; 0.62 (0.387–1.00), 0.150 (0.104–0.215). Table ​ Table3 3 shows the relative risks in different groups. Table 3 The relative risks of lipid disorders in 5 groups ( P < .05). Open in a separate window 4. Discussion According to our findings, psychological stress was a risk factor for increasing triglycerides, and LDL and for decreasing HDL. After multinomial logistic regression they had significant differences. Stressful situations are hazards for lipid profiles. These hazards include physical and psychological stress such as night shift work. [ 18 , 19 ] Psychological stress had effects on different part of human body especially some organs and physiological parameters, lipid profiles are one of these parameters. Physical stresses induced by heavy physical works could affects lipid profiles too. It seems that psychological stresses that were mentioned in many studies were more prominent in relation to dyslipidemias. In this study researcher showed that at the beginning of the study mean of triglycerides in group 5, and total cholesterol and LDL in group 3 were more than other groups. The least HDL was found in group 5. The means of lipid profiles were in the normal ranges. The highest mean related to age and BMI were observed in group 4 and 5. Other studies had demonstrated the effectiveness of wellbeing and preventive methods on lipid profiles. [ 15 , 16 ] The older workers had dyslipidemias, they were in group 4 and 5 more than other groups. Lipid disorders were more prevalent by aging. The highest numbers of people with BMI equal and more than 30 kg/m 2 were in group 4 and 5 too. Obesity was a risk factor for lipid disorders. [ 2 , 3 , 11 ] The number of people with triglycerides more 200 mg/dL was more in group 5. With regard to cholesterol concentration, the number of people with total cholesterol more 200 was highest in group 4, the highest amount of LDL were observed in group 4 and 5, and the least amount of HDL was found in group 5. The effects of lifestyle on blood lipid profiles had been demonstrated in other studies. [ 11 ] After deleting the effects of BMI and age, the risk of increased triglycerides, and LDL were observed in group 1 that had mild psychological stress. The risk of decrease in HDL was also discovered in group 1 and 3. The group 3 had mild psychological stress with mild physical work or mild physical stress. It seems that psychological stress had more prominent effects on the lipid profiles. With moderate to heavy physical work the risk of lipid disorders were reduced. The risk of dyslipidemias could be reduced with proper nutrition and wellbeing. Psychological stress must be assessed in all the situations especially in work environment. There were some studies that evaluated psychological stresses. [ 26 ] According to the results of this study, researcher believes that job analysis and determining the risk factors for different jobs specially in works with psychological stress are necessary. Researcher demonstrated the effects of Job stress on cardiovascular risk factors in male workers. [ 29 ] In other studies were worked on some specific jobs with physical and psychological risks for example shift workers and their effects on risk factors of cardiovascular disorders. [ 30 – 32 ] In this study after deleting BMI effect or obesity and age with regression, the risks of dyslipidemias were observed in group 1 and 3; the participants who had mild psychological stress and those with mild psychological stress with mild physical activity. Another scientist studied about the burnout syndrome that could be a predictor of hyperlipidemia among employees. [ 33 ] Burnout syndrome was an occupational psychological stress. Job stress could be seen in various forms which varied in different occupations. [ 34 ] Working in the environment with psychological stress without a proper physical health and normal activity could be caused some disorders specially cardiovascular disorders. [ 35 ] Author found that the psychological stress was an important risk factor for dyslipidemia especially in people who have worked. The modification of psychological stresses are not always possible but person's nutrition and physical activity could be modified to prevent dyslipidemias and cardiovascular disorders. Other studies had also showed the risk factors for dyslipidemias such as obesity. [ 36 ] Suitable physical activity help to reduce weight and BMI resulted to improving dyslipidemias. Psychological stress is a strong risk factor for dyslipidemias. Changing this situation in daily environment and work place is necessary. One study demonstrated the effect of prevention on improving dyslipidemias. [ 37 ] In other study was demonstrated the emotional effects on wellbeing of office workers. [ 38 ] In this research there were not have exact job analysis for other occupational hazards and it was a limitation for this study. The author of this article recommended to the people with psychological stress to have a regular physical activity in the daily program and modifying the psychological stress by consultation with a psychologist. Job stress or chronic stress had unsuitable effects on workers’ health and occupational medicine specialist must be had attention to this. [ 39 , 40 ] Psychological stress could be resulted from personal conflict, social and family problems, and working. Considering the importance of mental health on wellbeing, the author recommends the job modification in working situations. 5. Conclusions Psychological stress was a risk factor for lipid disorders, and proper physical activity was protective in this situation. One of the physical activities is work activity; work activity without stress could be harmless and useful. However, psychological stress could be eliminated in the workplace. Acknowledgments The author appreciated the supports of Mashhad University of Medical Sciences. 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Epub 2020 Jan 9. The effect of psyllium consumption on weight, body mass index, lipid profile, and glucose metabolism in diabetic patients: A systematic review and dose-response meta-analysis of randomized controlled trials Zhifang Xiao 1 , Hui Chen 2 , Yu Zhang 3 , Hui Deng 4 , KunWei Wang 5 , Akshaya Srikanth Bhagavathula 6 , Shamma Jauaan Almuhairi 7 , Paul M Ryan 8 , Jamal Rahmani 9 , Minyan Dang 10 , Vasileios Kontogiannis 11 , Andrew Vick 12 , Yuhe Wei 13 Affiliations Expand Affiliations 1 Department of Endocrinology, Affiliated Nanhua Hospital, University of South China, Hengyang, China. 2 Medical Group Office, Northern Jiangsu People's Hospital, Yangzhou, China. 3 Department of Endocrinology, Xinchang People's Hospital, Xinchang County, China. 4 Prehospital Aid Station, Danyang People's Hospital, Danyang, China. 5 Department of Endocrinology, Tianyou Hospital Affiliated to Tongji University, Shanghai, China. 6 Department of Internal Medicine, College of Medicine and Health Sciences, UAE University, Al Ain, UAE. 7 Family Medicine Department, Tawam Hospital, Al Ain, Abu Dhabi, UAE. 8 School of Medicine, University College Cork, Cork, Ireland. 9 Department of Community Nutrition, Student Research Committee, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 10 Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, China. 11 Institute of Health & Society, Newcastle University, Newcastle upon Tyne, UK. 12 Department of Nursing and Public Health, Capella University, Minneapolis, Minnesota. 13 Department of Endocrinology, Affiliated Wujin Hospital, Jiangsu University, Changzhou, China. PMID: 31919936 DOI: 10.1002/ptr.6609 Item in Clipboard Meta-Analysis The effect of psyllium consumption on weight, body mass index, lipid profile, and glucose metabolism in diabetic patients: A systematic review and dose-response meta-analysis of randomized controlled trials Zhifang Xiao et al. Phytother Res . 2020 Jun . Show details Display options Display options Format Abstract PubMed PMID Phytother Res Actions Search in PubMed Search in NLM Catalog Add to Search . 2020 Jun;34(6):1237-1247. doi: 10.1002/ptr.6609. Epub 2020 Jan 9. Authors Zhifang Xiao 1 , Hui Chen 2 , Yu Zhang 3 , Hui Deng 4 , KunWei Wang 5 , Akshaya Srikanth Bhagavathula 6 , Shamma Jauaan Almuhairi 7 , Paul M Ryan 8 , Jamal Rahmani 9 , Minyan Dang 10 , Vasileios Kontogiannis 11 , Andrew Vick 12 , Yuhe Wei 13 Affiliations 1 Department of Endocrinology, Affiliated Nanhua Hospital, University of South China, Hengyang, China. 2 Medical Group Office, Northern Jiangsu People's Hospital, Yangzhou, China. 3 Department of Endocrinology, Xinchang People's Hospital, Xinchang County, China. 4 Prehospital Aid Station, Danyang People's Hospital, Danyang, China. 5 Department of Endocrinology, Tianyou Hospital Affiliated to Tongji University, Shanghai, China. 6 Department of Internal Medicine, College of Medicine and Health Sciences, UAE University, Al Ain, UAE. 7 Family Medicine Department, Tawam Hospital, Al Ain, Abu Dhabi, UAE. 8 School of Medicine, University College Cork, Cork, Ireland. 9 Department of Community Nutrition, Student Research Committee, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 10 Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, China. 11 Institute of Health & Society, Newcastle University, Newcastle upon Tyne, UK. 12 Department of Nursing and Public Health, Capella University, Minneapolis, Minnesota. 13 Department of Endocrinology, Affiliated Wujin Hospital, Jiangsu University, Changzhou, China. PMID: 31919936 DOI: 10.1002/ptr.6609 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Water-soluble dietary fibers have been shown to improve lipid profile and glucose metabolism in diabetes. The aim of this study was to review the effects of psyllium consumption on weight, body mass index, lipid profiles, and glucose metabolism in diabetic patients in randomized controlled trials. A comprehensive systematic search was performed in PubMed/MEDLINE, Web of Sciences, Cochrane, and Scopus by two independent researchers up to August 2019 without any time and language restrictions. The DerSimonian and Laird random-effects model method performed to calculate the pooled results. Inclusion criteria were randomized controlled trial design, adult subjects, and studies reporting the mean differences with the 95% confidence interval for outcome. Eight studies containing nine arms with 395 participants were identified and included in final analysis. Combined results found a significant reduction in triglycerides, low-density lipoprotein, fasting blood sugar, and hemoglobin A1c following psyllium consumption (weighted mean differences [WMD]: -19.18 mg/dl, 95% CI [-31.76, -6.60], I 2 = 98%), (WMD: -8.96 mg/dl, 95% CI [-13.39, -4.52], I 2 = 97%), (WMD: -31.71 ml/dl, 95% CI [-50.04, -13.38], I 2 = 97%), and (WMD: -0.91%, 95% CI [-1.31, -0.51], I 2 = 99%), respectively. There was no significant change in high-density lipoprotein, body mass index, cholesterol, and weight. In conclusion, the results demonstrated a significant reduction in triglycerides, low-density lipoprotein, fasting blood sugar, and hemoglobin A1c by psyllium intervention among diabetic patients. Keywords: body weight; cholesterol; fasting blood sugar; psyllium; triglyceride. © 2020 John Wiley & Sons, Ltd. PubMed Disclaimer Similar articles Effects of psyllium vs. placebo on constipation, weight, glycemia, and lipids: A randomized trial in patients with type 2 diabetes and chronic constipation. Noureddin S, Mohsen J, Payman A. Noureddin S, et al. Complement Ther Med. 2018 Oct;40:1-7. doi: 10.1016/j.ctim.2018.07.004. Epub 2018 Jul 10. Complement Ther Med. 2018. PMID: 30219432 Clinical Trial. Effect of glucomannan on plasma lipid and glucose concentrations, body weight, and blood pressure: systematic review and meta-analysis. Sood N, Baker WL, Coleman CI. Sood N, et al. Am J Clin Nutr. 2008 Oct;88(4):1167-75. doi: 10.1093/ajcn/88.4.1167. Am J Clin Nutr. 2008. PMID: 18842808 Review. The effects of psyllium supplementation on body weight, body mass index and waist circumference in adults: A systematic review and dose-response meta-analysis of randomized controlled trials. Darooghegi Mofrad M, Mozaffari H, Mousavi SM, Sheikhi A, Milajerdi A. Darooghegi Mofrad M, et al. 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See all "Cited by" articles References REFERENCES Abutair, A. S., Naser, I. A., & Hamed, A. T. (2016). Soluble fibers from psyllium improve glycemic response and body weight among diabetes type 2 patients (randomized control trial). Nutrition Journal, 15(1), 86. https://doi.org/10.1186/s12937-016-0207-4 Abutair, A. S., Naser, I. A., & Hamed, A. T. (2018). The effect of soluble fiber supplementation on metabolic syndrome profile among newly diagnosed type 2 diabetes patients. Clin Nutr Res, 7(1), 31-39. https://doi.org/10.7762/cnr.2018.7.1.31 Anderson, J. W., Allgood, L. D., Lawrence, A., Altringer, L. A., Jerdack, G. R., Hengehold, D. A., & Morel, J. G. (2000). Cholesterol-lowering effects of psyllium intake adjunctive to diet therapy in men and women with hypercholesterolemia: Meta-analysis of 8 controlled trials. The American Journal of Clinical Nutrition, 71(2), 472-479. https://doi.org/10.1093/ajcn/71.2.472 Anderson, J. W., Allgood, L. D., Turner, J., Oeltgen, P. R., & Daggy, B. 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Annals of Internal Medicine, 163(6), 437. https://doi.org/10.7326/M15-0452 Show all 43 references Publication types Meta-Analysis Actions Search in PubMed Search in MeSH Add to Search Systematic Review Actions Search in PubMed Search in MeSH Add to Search MeSH terms Adult Actions Search in PubMed Search in MeSH Add to Search Blood Glucose / drug effects* Actions Search in PubMed Search in MeSH Add to Search Blood Glucose / metabolism Actions Search in PubMed Search in MeSH Add to Search Body Mass Index* Actions Search in PubMed Search in MeSH Add to Search Body Weight / drug effects* Actions Search in PubMed Search in MeSH Add to Search Diabetes Mellitus / drug therapy* Actions Search in PubMed Search in MeSH Add to Search Humans Actions Search in PubMed Search in MeSH Add to Search Lipids / blood* Actions Search in PubMed Search in MeSH Add to Search Male Actions Search in PubMed Search in MeSH Add to Search Psyllium / therapeutic use* Actions Search in PubMed Search in MeSH Add to Search Randomized Controlled Trials as Topic Actions Search in PubMed Search in MeSH Add to Search Substances Blood Glucose Actions Search in PubMed Search in MeSH Add to Search Lipids Actions Search in PubMed Search in MeSH Add to Search Psyllium Actions Search in PubMed Search in MeSH Add to Search Related information PubChem Compound (MeSH Keyword) LinkOut - more resources Full Text Sources Ovid Technologies, Inc. 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+Soy isoflavone: The multipurpose phytochemical (Review) - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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+    the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Biomed Rep. 2013 Sep; 1(5): 697–701. Published online 2013 Jun 3. doi: 10.3892/br.2013.129 PMCID: PMC3916987 PMID: 24649012 Soy isoflavone: The multipurpose phytochemical (Review) QINGLU WANG , 1 XIAOYUE GE , 1 XUEWEN TIAN , 2 YUJUN ZHANG , 1 JIE ZHANG , 1 and PINGPING ZHANG 1 QINGLU WANG 1 Key Laboratory of Biomedical Engineering and Technology of Shandong High School, Shandong Wanjie Medical College, Zibo, Shandong 255213, P.R. China Find articles by QINGLU WANG XIAOYUE GE 1 Key Laboratory of Biomedical Engineering and Technology of Shandong High School, Shandong Wanjie Medical College, Zibo, Shandong 255213, P.R. China Find articles by XIAOYUE GE XUEWEN TIAN 2 Shandong Research Center of Sports Science, Jinan, Shandong 250102, P.R. China Find articles by XUEWEN TIAN YUJUN ZHANG 1 Key Laboratory of Biomedical Engineering and Technology of Shandong High School, Shandong Wanjie Medical College, Zibo, Shandong 255213, P.R. China Find articles by YUJUN ZHANG JIE ZHANG 1 Key Laboratory of Biomedical Engineering and Technology of Shandong High School, Shandong Wanjie Medical College, Zibo, Shandong 255213, P.R. China Find articles by JIE ZHANG PINGPING ZHANG 1 Key Laboratory of Biomedical Engineering and Technology of Shandong High School, Shandong Wanjie Medical College, Zibo, Shandong 255213, P.R. China Find articles by PINGPING ZHANG Author information Article notes Copyright and License information PMC Disclaimer 1 Key Laboratory of Biomedical Engineering and Technology of Shandong High School, Shandong Wanjie Medical College, Zibo, Shandong 255213, P.R. China 2 Shandong Research Center of Sports Science, Jinan, Shandong 250102, P.R. China Correspondence to: Dr Qinglu Wang, Key Laboratory of Biomedical Engineering and Technology of Shandong High School, Shandong Wanjie Medical College, Boshan Economic Development Zone, Zibo, Shandong 255213, P.R. China, E-mail: moc.liamg@qczlqw Received 2013 Apr 10; Accepted 2013 May 21. Copyright © 2013, Spandidos Publications Abstract Soy isoflavones are compounds found in soybean and soybean products. They have been reported to possess numerous physiological properties, such as antitumor, anti-menopausal (female) osteoporosis and anti-aging. They have also been reported to improve learning and memory skills in menopausal women and aid in the prevention and treatment of heart disease, diabetes and Kawasaki disease (KD). In this review, the effects of soy isoflavones on various diseases were analyzed. Based on the analysis, it was hypothesized that the function of soybean isoflavones in the prevention and treatment of various diseases results from their phytoestrogen and antioxidant properties. However, due to their phytoestrogen properties, it is recommended that the risks of soy isoflavone intake as food and/or medical treatment be further evaluated. Keywords: soy isoflavone, phytochemical, disease, phytoestrogen, antioxidant ability 1. Introduction Asian populations have consumed foods made from soy beans for centuries, whereas in the West, certain subpopulations, specifically Seventh-day Adventists and vegetarians, have used soyfoods for ~100 years, although the quintessential soyfood tofu was first introduced on a large scale to the general US population in the early 1970s. Health-conscious and ecologically-minded consumers were particularly attracted to soy at that time since it was perceived as a source of high quality protein, low in saturated fat, that was more efficiently produced compared to animal sources of protein. A significant increase in soyfood consumption occurred during the last decade of the 20th century, mainly due to the belief among many consumers that soyfoods may offer health benefits, independent of their nutrient content. This increased interest is best viewed in the context of the general recognition that plants contain large quantities of potentially beneficial, non-nutritive, biologically active components, commonly referred to as phytochemicals. This knowledge led to the concept of functional foods [initially referred to as designer foods by the National Cancer Institute (NCI)] and to soy being one of the first foods widely acknowledged to fall into this category ( 1 ). Soy isoflavones contain 12 different isoforms that are divided into four chemical forms: aglycone (daidzein, genistein and glycitein), glucoside (daidzin, genistin and glycitin), acetylglucoside (acetyldaidzin, acetylgenistin and acetylglycitin) and malonylglucoside (malonyldaidzin, malonylgenistin and malonylglycitin). Soy isoflavones were demonstrated to possess numerous biological functions, such as antioxidant ( 2 ), inhibitory on cancer cell proliferation ( 3 ), anti-inflammatory ( 4 ) and preventive of coronary heart disease ( 5 ) and osteoporosis ( 6 ). Over the last 22 years, there has been a considerable amount of research on the health effects of soy consumption, which may be largely attributed to the presence of isoflavones in the soybean. Isoflavones first came to the attention of the scientific community in the 1940s, as a result of fertility problems observed in sheep grazing on a type of isoflavone-rich clover ( 1 ). In the 1950s, due to their estrogenic effects in rodents, isoflavones were investigated for use as possible growth promoters by the animal feed industry, although shortly thereafter it was demonstrated that isoflavones may also act as antiestrogens ( 1 ). Despite this early study, it was not until the 1990s, mainly due to research sponsored by the US NCI, that the role of soyfoods in disease prevention started to attract significant attention. Subsequently, isoflavones and soyfoods were investigated on their ability to alleviate hot flashes and inhibit bone loss in postmenopausal women. In 1995, soy protein attracted worldwide attention for its ability to lower cholesterol levels ( 1 ). At that same time, isoflavones started to be widely discussed as potential alternatives to conventional hormone replacement therapy ( 1 ). In 2002, it was hypothesized that individuals harbouring intestinal bacteria capable of converting the soybean isoflavone daidzein into the isoflavan equol were more likely to benefit from soy intake ( 1 ). More recently, in vitro and animal studies have raised questions regarding the safety of exposure to isoflavones for certain subsets of the population, although human data are largely inconsistent with these concerns ( 1 ). 2. Effects of soy isoflavones on cancer Melanoma and breast tumor cells are capable of degrading the extracellular matrix via a proteolytic cascade that includes urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs). At non-cytotoxic concentrations (0.1–50 μM), genistein dose-dependently promoted spindle-cell morphology and significantly reduced motility in the two cell lines. Genistein inhibited uPA secreted by F3II cell monolayers, while inducing an increase in the proteolytic activity of B16 cells. By contrast, the compound did not modify the MMP-9 and −2 secretion by tumor cells. These data suggest that tumor cell migration and proteolysis are associated with the antitumor and antiangiogenic activity of the soy isoflavone genistein ( 7 ). Recent studies have demonstrated that soy and isoflavone intake exerts a protective effect against postmenopausal breast cancer ( 8 – 10 ). The overexpression of HER2 promotes the malignant transformation of breast epithelial cells. Genistein enhanced the cytotoxic effect of adriamycin (ADR) at low doses (less than IC 50 ) against the human breast cancer cell. This enhancing effect was mainly attributed to the increase of necrotic-like, rather than apoptotic, cell death. In conjugation with this event, significant inactivation of HER2 and Akt in the breast cancer cell was caused by the combination of genistein and ADR. These results suggest that genistein enhances the necrotic-like cell death of breast cancer cells through the inactivation of the HER2 receptor and Akt in combination with ADR ( 11 ). Statistical data demonstrated that high isoflavone intake (combined RR/OR=0.68, 95% CI: 0.52–0.89) may be associated with reduced breast cancer risk in Asian populations, particularly in postmenopausal women. However, results of studies conducted on Western populations indicated no significant differences, which may be due to the low intake of isoflavone ( 12 ). A previous study by Akaza et al ( 13 ) was the first to confirm that there is an association between prostate cancer and isoflavone intake. In a later study, Kurahashi et al ( 14 ) demonstrated that isoflavone intake was associated with a decreased risk of localized prostate cancer. However, a study by Perabo et al ( 15 ) reported no convincing clinical proof or evidence that genistein may be beneficial in prostate cancer therapy. Between 2008 and 2012, five out of six studies reported a significant association of isoflavones with a decreased risk of prostate cancer ( 16 ), two of which consistently demonstrated that daidzein converted to equol by intestinal bacteria leads to a significantly reduced risk of prostate cancer ( 16 ). 3. Osteoporosis and soy isoflavones The first clinical trial in this area to report a benefit was published in 2001 ( 17 ). The prevalence of age-related bone loss is higher in women compared to men and in 25–30% of aging women this loss results in major orthopedic problems ( 18 ). Natural or surgical menopause results in an initial phase of rapid bone loss followed by a period of slower skeletal deterioration ( 19 ). This rapid phase of bone loss occurs within the first 10 years following the cessation of menses or surgical removal of the ovaries ( 20 ). The ovarian hormone deficiency associated with menopause results in an increased rate of bone turnover and leads to an imbalance between resorption and formation, thereby accelerating bone loss ( 21 ). A previous meta-analysis reported that soy isoflavones significantly increased the bone mineral density by 54% and decreased the bone resorption marker urinary deoxypyridinoline by 23% compared to baseline in women. A sensitivity analysis indicated that the effect of soy isoflavones on bone mineral density and deoxypyridinoline was significant. Postmenopausal women experience a sharp decrease in estrogen concentration, leading to an increased rate of bone remodeling, which is associated with decreased bone mineral density and increased risk of fractures ( 20 , 22 , 23 ). 4. Effects of soy isoflavones on learning and memory A previous study indicated that estrogen use increases the performance on certain tests of cognition, particularly in postmenopausal women ( 20 ). Short-term high-dose soy bean intake altered the levels of total plasma testosterone and improved spatial cognition in women ( 24 ). Isoflavone supplementation exerted a favorable effect on cognitive function, particularly verbal memory, in postmenopausal women ( 25 ). Consumption of dietary phytoestrogens resulting in high plasma isoflavone levels may significantly affect sexually dimorphic brain regions, anxiety, learning and memory ( 26 ). Dietary soy-derived phytoestrogens may affect learning and memory and alter the expression of proteins involved in neural protection and inflammation in rats ( 27 ). Soy isoflavones may also affect the cholinergic system of the brain and reduce age-related neuronal loss and cognition decline in male rats ( 28 ). There are proposed mechanisms for the neuroprotective effects of isoflavones. Genistein protects cells from H 2 O 2 -induced toxicity ( 29 ). H 2 O 2 is a reactive oxygen species (ROS) that may cause neuron damage ( 30 – 33 ). Genistein, a phytoestrogen capable of crossing the blood-brain barrier, has been reported to exert an antioxidant effect against the insults of ultraviolet (UV) radiation and chemicals ( 34 ). This antioxidant effect of soy may protect against neurodegenerative diseases. Previous findings suggested that the mechanisms by which phytoestrogens, particularly genistein, protect neuronal cells include its antioxidant activity, as well as the activation of estrogen receptors (ERs) and upregulation of brain-derived neurotrophic factors ( 34 ). This improvement in cognitive ability in phytoestrogen-treated females may be due in part to the increased presence of choline acetyltransferase mRNA in the frontal cortex, which was associated with protection and enhancement of cognitive function ( 35 ). Furthermore, phytoestrogens significantly affect the brain calcium-binding protein calbindin (CALB), which acts as a buffer by binding intracellular calcium and plays an important role in mediating cell proliferation, programmed cell death (apoptosis) and neurotoxicity ( 27 , 36 ). Soy isoflavones were shown to improve learning and memory function in menopausal women and it was recently reported that they may improve learning and memory impairment induced by Aβ1–42 in rats, maintain Aβ homeostasis in the brain, regulate the disordered expression of RAGE/LRP-1, and restrain RAGE-related NF-κB and inflammatory cytokine activation in neurovascular structures ( 27 , 36 ). These results suggested that soy isoflavones may protect Aβ-impaired learning and memory in rats and the mechanism of action may be associated with the regulation of vascular Aβ transportation and vascular inflammatory reaction. 5. Effects of soy isoflavones on coronary heart disease Soy protein-containing foods are a rich source of isoflavone phytoestrogens, such as genistein and daidzein. There is growing interest in these substances, since a high dietary intake of soy-containing foods has been associated with lower rates of chronic diseases, including coronary heart disease ( 37 ). Soy phytoestrogens bind weakly to the estrogen receptor (ER) and some bind more strongly to ER-β compared to ER-α. A previous meta-analysis indicated that isoflavone phytoestrogens decreased plasma cholesterol concentrations in subjects with initially elevated levels, but had little effect on subjects with normal serum cholesterol concentrations ( 37 ). These substances may also exert beneficial effects on arterial endothelial function, which was also confirmed by Beavers et al ( 38 ). In addition to these potentially antiatherogenic effects, numerous laboratories are investigating other possible mechanisms, including the antioxidant and antiproliferative properties of these substances ( 39 ). A previous study by Tikkanen and Adlercreutz ( 37 ) demonstrated that dietary supplementation with soy-derived isoflavones reduced the in vitro oxidation susceptibility of low-density lipoprotein (LDL). It was hypothesized that lipophilic phytoestrogen derivatives may be incorporated into LDLs, increasing their oxidation resistance and antiproliferative efficacy ex vivo , which theoretically are antiatherogenic effects. Another study by Chan et al ( 40 ) demonstrated that a 12-week isoflavone treatment reduced the serum levels of high-sensitivity C-reactive protein and improved brachial flow-mediated dilatation in patients with clinically manifest atherosclerosis, thus reversing their endothelial dysfunction status. The authors of that study suggested that their findings may have important implications regarding the use of isoflavones as secondary prevention in patients with cardiovascular disease, in addition to conventional interventions. 6. Effects of soy isoflavones on diabetes Type 2 diabetes is a result of chronic insulin resistance and loss of functional pancreatic β-cell mass. Over the past 10 years, numerous studies demonstrated that genistein possesses antidiabetic properties, such as direct effects on β-cell proliferation, glucose-stimulated insulin secretion and protection against apoptosis, independent of its functions as an estrogen receptor agonist, antioxidant, or tyrosine kinase inhibitor ( 41 ). Its effects are structure-specific and not common to all flavonoids ( 42 ). While there are limited data available on the effects of genistein consumption in diabetic humans, there are several animal and cell-culture studies that demonstrated a direct effect of genistein on β-cells at physiologically relevant concentrations (<10 μM) ( 41 ). The effects appear to involve cAMP/PKA signaling and a previous study suggested an effect of gene expression on epigenetic regulation ( 41 ). Genistein was shown to relieve diabetic peripheral painful neuropathy, revert proinflammatory cytokine and ROS overproduction and restore the nerve growth factor (NGF) content of the diabetic sciatic nerve. Genistein was also shown to restore the glutathione (GSH) content and the ratio of reduced to oxidized glutathione (GSH/GSSG), improve the antioxidant enzyme activities, decrease ROS and lipoperoxide levels in the brain and liver and restore the inducible and endothelial nitric oxide synthase (iNOS and eNOS, respectively) content and superoxide dismutase activity in the thoracic aorta. Hyperglycaemia and weight loss were not affected. Genistein was able to reverse diabetic allodynia, oxidative stress and inflammation, as well as ameliorate NGF content and vascular dysfunction, thus suggesting its possible therapeutic use for diabetes complications ( 43 ). 7. Anti-photoaging effects of soy isoflavones A previous study demonstrated that the protective effects of soy isoflavones against UVB radiation may be related to their antioxidant activities ( 44 ). Moreover, the soy isoflavone extract inhibited UVB-induced keratinocyte death and suppressed UVB-induced intracellular H 2 O 2 release, which reduced oxidative stress. Furthermore, it decreased epidermal thickness and inhibited COX-2 and proliferating cell nuclear antigen expression. The activation of p38, c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2 (ERK1/2) were triggered by UVB and counteracted by treatment with soy isoflavone extract ( 44 – 46 ). 8. Kawasaki disease and soy isoflavones Kawasaki disease (KD) is a diffuse vasculitis occurring in children, with a predilection for the coronary arteries. Recent data from a genetic study emphasized the role of specific immune receptors in the pathogenesis of KD. The functions of the Fcγ receptors (FcγRs) are modulated by soy isoflavones, genistein in particular. Epidemiological data from Hawaiian populations suggested an association between soy consumption and KD. These observations form the basis of the hypothesis that isoflavones are involved in KD pathogenesis by modulating the function of the FcGRs and disrupting the balance between the activation and inhibition of the inflammatory response ( 47 ). 9. Risks of soy isoflavones Despite the considerable enthusiasm regarding the potential health benefits of soyfoods and isoflavones, there is also growing concern regarding their safety, based largely on their estrogen-like properties. Isoflavones are classified as phytoestrogens and mixed estrogen agonists/antagonists as well as endocrine disruptors ( 48 – 50 ). Evaluations of isoflavone safety have been conducted by governmental and quasi-governmental agencies in several European countries, Japan and Israel and the European Food Safety Authority is currently conducting another evaluation ( 1 ). These concerns are based almost exclusively on in vitro and animal studies (human studies, including clinical and epidemiological data, are supportive of safety) and the most notable among these is that isoflavone-containing products pose a risk to estrogen-sensitive breast cancer patients and women at high-risk of developing this disease and that isoflavone exposure via the consumption of soy-based infant formula may negatively affect the long-term development of infants ( 51 – 52 ). 10. Conclusions In this study, the properties and role of soybean isoflavones in the prevention and treatment of several diseases were presented, which comprise antitumor, antimenopausal (female) osteoporosis and antiaging properties, improvement of learning and memory skills of menopausal women, prevention and treatment of heart disease, diabetes and KD. Based on the assessment of these diseases under the effect of isoflavones, it was concluded that the function of soybean isoflavones in the prevention and treatment of various diseases largely results from their phytoestrogen and antioxidant properties. Although soybean isoflavones have been demonstrated to exert beneficial effects on the prevention and treatment of several diseases, possible adverse reactions have recently become the focus of attention. Therefore, more clinical trials are required to evaluate the effects of isoflavones on the prevention of disease development and their role in the treatment of various diseases, either alone or in combination with conventional therapeutic methods. Acknowledgements This study was supported by grants from the Program of Science and Technology Development of Shandong (2011YD19005; 2011YD21022) and Natural Scientific Foundation of Chinese Shandong Province (ZR2010CQ031). References 1. Messina M. 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+Zinc toxicity - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Zinc toxicity G J Fosmire 1 Affiliations Expand Affiliation 1 Department of Nutrition, College of Health and Human Development, Penn State University, University Park 16802. PMID: 2407097 DOI: 10.1093/ajcn/51.2.225 Item in Clipboard Review Zinc toxicity G J Fosmire . Am J Clin Nutr . 1990 Feb . Show details Display options Display options Format Abstract PubMed PMID Am J Clin Nutr Actions Search in PubMed Search in NLM Catalog Add to Search . 1990 Feb;51(2):225-7. doi: 10.1093/ajcn/51.2.225. Author G J Fosmire 1 Affiliation 1 Department of Nutrition, College of Health and Human Development, Penn State University, University Park 16802. PMID: 2407097 DOI: 10.1093/ajcn/51.2.225 Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID Abstract Although consequences of zinc deficiency have been recognized for many years, it is only recently that attention has been directed to the potential consequences of excessive zinc intake. This is a review of the literature on manifestations of toxicity at several levels of zinc intake. Zinc is considered to be relatively nontoxic, particularly if taken orally. However, manifestations of overt toxicity symptoms (nausea, vomiting, epigastric pain, lethargy, and fatigue) will occur with extremely high zinc intakes. At low intakes, but at amounts well in excess of the Recommended Dietary Allowance (RDA) (100-300 mg Zn/d vs an RDA of 15 mg Zn/d), evidence of induced copper deficiency with attendant symptoms of anemia and neutropenia, as well as impaired immune function and adverse effects on the ratio of low-density-lipoprotein to high-density-lipoprotein (LDL/HDL) cholesterol have been reported. Even lower levels of zinc supplementation, closer in amount to the RDA, have been suggested to interfere with the utilization of copper and iron and to adversely affect HDL cholesterol concentrations. Individuals using zinc supplements should be aware of the possible complications attendant to their use. PubMed Disclaimer Similar articles Effect of dietary zinc deficiency on rat lipid concentrations. Khoja SM, Marzouki ZM, Ashry KM, Hamdi SA. Khoja SM, et al. Saudi Med J. 2002 Jan;23(1):82-6. Saudi Med J. 2002. PMID: 11938370 Zinc supplements and serum lipids in young adult white males. Black MR, Medeiros DM, Brunett E, Welke R. Black MR, et al. Am J Clin Nutr. 1988 Jun;47(6):970-5. doi: 10.1093/ajcn/47.6.970. Am J Clin Nutr. 1988. PMID: 3163879 Clinical Trial. Relationship between the nutritional status of zinc and cholesterol concentration of serum lipoproteins in adult male rats. Koo SI, Williams DA. Koo SI, et al. Am J Clin Nutr. 1981 Nov;34(11):2376-81. doi: 10.1093/ajcn/34.11.2376. Am J Clin Nutr. 1981. PMID: 6946704 Requirements and toxicity of essential trace elements, illustrated by zinc and copper. Sandstead HH. Sandstead HH. Am J Clin Nutr. 1995 Mar;61(3 Suppl):621S-624S. doi: 10.1093/ajcn/61.3.621S. Am J Clin Nutr. 1995. PMID: 7879727 Review. Zinc requirements and the risks and benefits of zinc supplementation. Maret W, Sandstead HH. Maret W, et al. J Trace Elem Med Biol. 2006;20(1):3-18. doi: 10.1016/j.jtemb.2006.01.006. Epub 2006 Feb 21. J Trace Elem Med Biol. 2006. PMID: 16632171 Review. See all similar articles Cited by Differential Protective Effect of Zinc and Magnesium for the Hepatic and Renal Toxicity Induced by Acetaminophen and Potentiated with Ciprofloxacin in Rats. Ciocan Moraru A, Ciubotariu D, Ghiciuc CM, Hurmuzache ME, Lupușoru CE, Crișan-Dabija R. Ciocan Moraru A, et al. Medicina (Kaunas). 2024 Apr 8;60(4):611. doi: 10.3390/medicina60040611. Medicina (Kaunas). 2024. PMID: 38674257 Free PMC article. Zinc Supplementation Trial in Pediatric Chronic Kidney Disease: Effects on Circulating FGF-23 and Klotho. Belostotsky V, Atkinson SA, Filler G. Belostotsky V, et al. Can J Kidney Health Dis. 2024 Mar 13;11:20543581241234723. doi: 10.1177/20543581241234723. eCollection 2024. Can J Kidney Health Dis. 2024. PMID: 38487751 Free PMC article. Study protocol for a zinc intervention in the elderly for prevention of pneumonia, a randomized, placebo-controlled, double-blind clinical pilot trial. Ortega EF, Wu D, Guo W, Meydani SN, Panda A. Ortega EF, et al. Front Nutr. 2024 Feb 21;11:1356594. doi: 10.3389/fnut.2024.1356594. eCollection 2024. Front Nutr. 2024. PMID: 38450236 Free PMC article. Biochar as Alternative Material for Heavy Metal Adsorption from Groundwaters: Lab-Scale (Column) Experiment Review. Viotti P, Marzeddu S, Antonucci A, Décima MA, Lovascio P, Tatti F, Boni MR. Viotti P, et al. Materials (Basel). 2024 Feb 7;17(4):809. doi: 10.3390/ma17040809. Materials (Basel). 2024. PMID: 38399060 Free PMC article. Review. Ratiometric Detection of Zn 2+ Using DNAzyme-Based Bioluminescence Resonance Energy Transfer Sensors. Wu Y, Lewis W, Wai JL, Xiong M, Zheng J, Yang Z, Gordon C, Lu Y, New SY, Zhang XB, Lu Y. Wu Y, et al. Chemistry (Basel). 2023 Sep;5(3):1745-1759. doi: 10.3390/chemistry5030119. Epub 2023 Aug 8. Chemistry (Basel). 2023. PMID: 38371491 Free PMC article. 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+Cigarette smoking and diabetes - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Cigarette smoking and diabetes Björn Eliasson 1 Affiliations Expand Affiliation 1 Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, Göteborg, Sweden. bjorn.eliasson@medic.gu.se PMID: 12704597 DOI: 10.1053/pcad.2003.00103 Item in Clipboard Review Cigarette smoking and diabetes Björn Eliasson . Prog Cardiovasc Dis . 2003 Mar-Apr . Show details Display options Display options Format Abstract PubMed PMID Prog Cardiovasc Dis Actions Search in PubMed Search in NLM Catalog Add to Search . 2003 Mar-Apr;45(5):405-13. doi: 10.1053/pcad.2003.00103. Author Björn Eliasson 1 Affiliation 1 Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, Göteborg, Sweden. bjorn.eliasson@medic.gu.se PMID: 12704597 DOI: 10.1053/pcad.2003.00103 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Smokers are insulin resistant, exhibit several aspects of the insulin resistance syndrome, and are at an increased risk for type 2 diabetes. Prospectively, the increased risk for diabetes in smoking men and women is around 50%. Many patients with type 1 and type 2 diabetes mellitus are at risk for micro- and macrovascular complications. Cigarette smoking increases this risk for diabetic nephropathy, retinopathy, and neuropathy, probably via its metabolic effects in combination with increased inflammation and endothelial dysfunction. This association is strongest in type 1 diabetic patients. The increased risk for macrovascular complications, coronary heart disease (CHD), stroke, and peripheral vascular disease, is most pronounced in type 2 diabetic patients. The development of type 2 diabetes is another possible consequence of cigarette smoking, besides the better-known increased risk for cardiovascular disease. In diabetes care, smoking cessation is of utmost importance to facilitate glycemic control and limit the development of diabetic complications. Copyright 2003, Elsevier Science (USA). All rights reserved. PubMed Disclaimer Similar articles Increased prevalence of microvascular complications in type 2 diabetes patients with the metabolic syndrome. Abdul-Ghani M, Nawaf G, Nawaf F, Itzhak B, Minuchin O, Vardi P. Abdul-Ghani M, et al. Isr Med Assoc J. 2006 Jun;8(6):378-82. Isr Med Assoc J. 2006. PMID: 16833164 [Smoking and diabetes mellitus]. Christiansen E, Madsbad S. Christiansen E, et al. Ugeskr Laeger. 1989 Nov 13;151(46):3050-3. Ugeskr Laeger. 1989. PMID: 2688232 Review. Danish. Prevalence of vascular complications and their risk factors in type 2 diabetes. Ramachandran A, Snehalatha C, Satyavani K, Latha E, Sasikala R, Vijay V. Ramachandran A, et al. J Assoc Physicians India. 1999 Dec;47(12):1152-6. J Assoc Physicians India. 1999. PMID: 11225214 Diabetes care and complications in a remote primary health care setting. Maple-Brown LJ, Brimblecombe J, Chisholm D, O'Dea K. Maple-Brown LJ, et al. Diabetes Res Clin Pract. 2004 May;64(2):77-83. doi: 10.1016/j.diabres.2003.10.008. Diabetes Res Clin Pract. 2004. PMID: 15063599 Cigarette smoking, smoking cessation, and diabetes. Tonstad S. Tonstad S. Diabetes Res Clin Pract. 2009 Jul;85(1):4-13. doi: 10.1016/j.diabres.2009.04.013. Epub 2009 May 7. Diabetes Res Clin Pract. 2009. PMID: 19427049 Review. See all similar articles Cited by Impact of brief smoking cessation intervention on quitting rate and glycemic control in patients with diabetes: a randomized controlled trial. Ibrahim AKA, Syed Sulaiman SA, Awaisu A, Shafie AA. Ibrahim AKA, et al. J Int Med Res. 2023 Oct;51(10):3000605231208598. doi: 10.1177/03000605231208598. J Int Med Res. 2023. PMID: 37890143 Free PMC article. Clinical Trial. Evaluation of the Prevalence and Risk Factors of Drug-Related Problems in Hypertension and Type 2 Diabetes Mellitus Patients at a Tertiary Care Hospital: A Cross-Sectional Study. Reddy Peddi D, Pallekonda H, Reddy V. Reddy Peddi D, et al. Cureus. 2023 Jul 31;15(7):e42775. doi: 10.7759/cureus.42775. eCollection 2023 Jul. Cureus. 2023. PMID: 37663988 Free PMC article. Diabetic retinopathy as the leading cause of blindness and early predictor of cascading complications-risks and mitigation. Kropp M, Golubnitschaja O, Mazurakova A, Koklesova L, Sargheini N, Vo TKS, de Clerck E, Polivka J Jr, Potuznik P, Polivka J, Stetkarova I, Kubatka P, Thumann G. Kropp M, et al. EPMA J. 2023 Feb 13;14(1):21-42. doi: 10.1007/s13167-023-00314-8. eCollection 2023 Mar. EPMA J. 2023. PMID: 36866156 Free PMC article. Review. Oklahoma Tobacco Helpline Utilization and Outcomes by Diabetes Status. Martinez SA, Hasan A, Boeckman LM, Beebe LA. Martinez SA, et al. J Public Health Manag Pract. 2023 Mar-Apr 01;29(2):142-150. doi: 10.1097/PHH.0000000000001690. Epub 2022 Dec 6. J Public Health Manag Pract. 2023. PMID: 36715593 Free PMC article. Relation Between Diabetes and Psychiatric Disorders. Akhaury K, Chaware S. Akhaury K, et al. Cureus. 2022 Oct 26;14(10):e30733. doi: 10.7759/cureus.30733. eCollection 2022 Oct. Cureus. 2022. PMID: 36447711 Free PMC article. Review. See all "Cited by" articles Publication types Review Actions Search in PubMed Search in MeSH Add to Search MeSH terms Diabetes Complications Actions Search in PubMed Search in MeSH Add to Search Diabetes Mellitus / etiology* Actions Search in PubMed Search in MeSH Add to Search Diabetes Mellitus / metabolism Actions Search in PubMed Search in MeSH Add to Search Diabetes Mellitus / physiopathology* Actions Search in PubMed Search in MeSH Add to Search Diabetic Angiopathies / etiology Actions Search in PubMed Search in MeSH Add to Search Diabetic Nephropathies / etiology Actions Search in PubMed Search in MeSH Add to Search Diabetic Neuropathies / etiology Actions Search in PubMed Search in MeSH Add to Search Female Actions Search in PubMed Search in MeSH Add to Search Humans Actions Search in PubMed Search in MeSH Add to Search Insulin Resistance Actions Search in PubMed Search in MeSH Add to Search Male Actions Search in PubMed Search in MeSH Add to Search Microcirculation / drug effects Actions Search in PubMed Search in MeSH Add to Search Nicotine / adverse effects* Actions Search in PubMed Search in MeSH Add to Search Nicotinic Agonists / adverse effects* Actions Search in PubMed Search in MeSH Add to Search Risk Factors Actions Search in PubMed Search in MeSH Add to Search Smoking / adverse effects* Actions Search in PubMed Search in MeSH Add to Search Substances Nicotinic Agonists Actions Search in PubMed Search in MeSH Add to Search Nicotine Actions Search in PubMed Search in MeSH Add to Search Related information Cited in Books PubChem Compound PubChem Compound (MeSH Keyword) PubChem Substance LinkOut - more resources Full Text Sources Elsevier Science Medical Genetic Alliance MedlinePlus Health Information Full text links [x] Elsevier Science [x] Cite Copy Download .nbib .nbib Format: AMA APA MLA NLM Send To Clipboard Email Save My Bibliography Collections Citation Manager [x] NCBI Literature Resources MeSH PMC Bookshelf Disclaimer The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). 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+L-carnitine treatment of insulin resistance: A systematic review and meta-analysis - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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L-carnitine treatment of insulin resistance: A systematic review and meta-analysis Ying Xu 1 , Wenjie Jiang 2 , Guochang Chen 1 , Wenjiao Zhu 3 , Weiliang Ding 3 , Zhijun Ge 4 , Yongfei Tan 5 , Tieliang Ma 3 , Guoxing Cui 1 Affiliations Expand Affiliations 1 Department of Gastroenterology, the Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, China. 2 Department of Anesthesiology, the Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, China. 3 Central Laboratory, the Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, China. 4 Department of Critical Care Medicine, the Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, China. 5 Department of Cardiac & Thoracic Surgery, the Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, China. PMID: 28791854 DOI: 10.17219/acem/61609 Free article Item in Clipboard Review L-carnitine treatment of insulin resistance: A systematic review and meta-analysis Ying Xu et al. Adv Clin Exp Med . 2017 Mar-Apr . Free article Show details Display options Display options Format Abstract PubMed PMID Adv Clin Exp Med Actions Search in PubMed Search in NLM Catalog Add to Search . 2017 Mar-Apr;26(2):333-338. doi: 10.17219/acem/61609. Authors Ying Xu 1 , Wenjie Jiang 2 , Guochang Chen 1 , Wenjiao Zhu 3 , Weiliang Ding 3 , Zhijun Ge 4 , Yongfei Tan 5 , Tieliang Ma 3 , Guoxing Cui 1 Affiliations 1 Department of Gastroenterology, the Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, China. 2 Department of Anesthesiology, the Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, China. 3 Central Laboratory, the Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, China. 4 Department of Critical Care Medicine, the Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, China. 5 Department of Cardiac & Thoracic Surgery, the Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, China. PMID: 28791854 DOI: 10.17219/acem/61609 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Background: L-carnitine has been used for several years as an adjuvant therapy in oxidative stress, blood sugar, high-sensitivity C-reactive protein (CRP), anemia, etc. However, the efficacy of L-carnitine treating insulin resistance (IR) remains controversial. Homeostasis model assessment of Insulin Resistance (HOMA-IR) is widely used in the clinical evaluation of patients with IR. Objectives: A meta-analysis, including randomized controlled trials (RCTs), was performed to assess the effect of L-carnitine on HOMA-IR patients. Material and methods: The Cochrane Library, PubMed, and EMBASE databases were systematically searched to identify RCTs which evaluated the effects of L-carnitine on HOMA-IR patients. We screened relevant studies according to predefined inclusion and exclusion criteria. In the selected articles, we extracted the data: study design, sample size, age, L-carnitine dose and regimen, body mass index (BMI) of patients, mode of administration, study duration and study outcomes. Results: A total of 5 studies were included for the meta-analysis. The result showed L-carnitine was useful in the treatment of IR (WMD -0.724, CI -0.959 -0.488, p < 0.0001). Evaluation at 3, 6, 9, 12 months, the p-values were 0.875, 0.165, 0.031, 0, 007, respectively. Conclusions: L-carnitine was useful in treating patients with IR. L-carnitine can treat IR more effectively with prolonging the medication time. However, more RCTs with long-term L-carnitine treatment of IR are needed to confirm the viewpoint. Keywords: L-carnitine; insulin resistance; meta-analysis. PubMed Disclaimer Similar articles A meta-analysis of the effect of angiotensin receptor blockers and calcium channel blockers on blood pressure, glycemia and the HOMA-IR index in non-diabetic patients. Yang Y, Wei RB, Xing Y, Tang L, Zheng XY, Wang ZC, Gao YW, Li MX, Chen XM. Yang Y, et al. Metabolism. 2013 Dec;62(12):1858-66. doi: 10.1016/j.metabol.2013.08.008. Epub 2013 Sep 16. Metabolism. 2013. PMID: 24050270 Review. The effects of L-carnitine supplementation on glycemic control: a systematic review and meta-analysis of randomized controlled trials. Fathizadeh H, Milajerdi A, Reiner Ž, Kolahdooz F, Asemi Z. Fathizadeh H, et al. EXCLI J. 2019 Aug 19;18:631-643. doi: 10.17179/excli2019-1447. eCollection 2019. EXCLI J. 2019. PMID: 31611746 Free PMC article. The effects of L-carnitine supplementation on glycemic markers in adults: A systematic review and dose-response meta-analysis. Zamani M, Pahlavani N, Nikbaf-Shandiz M, Rasaei N, Ghaffarian-Ensaf R, Asbaghi O, Shiraseb F, Rastgoo S. Zamani M, et al. Front Nutr. 2023 Jan 10;9:1082097. doi: 10.3389/fnut.2022.1082097. eCollection 2022. Front Nutr. 2023. PMID: 36704801 Free PMC article. Effect of programmed exercise on insulin sensitivity in postmenopausal women: a systematic review and meta-analysis of randomized controlled trials. Bueno-Notivol J, Calvo-Latorre J, Alonso-Ventura V, Pasupuleti V, Hernandez AV, Pérez-López FR; Health Outcomes and Systematic Analyses (HOUSSAY) Project. Bueno-Notivol J, et al. Menopause. 2017 Dec;24(12):1404-1413. doi: 10.1097/GME.0000000000000936. Menopause. 2017. PMID: 28654627 Review. Caloric restriction and L-carnitine administration improves insulin sensitivity in patients with impaired glucose metabolism. Molfino A, Cascino A, Conte C, Ramaccini C, Rossi Fanelli F, Laviano A. Molfino A, et al. JPEN J Parenter Enteral Nutr. 2010 May-Jun;34(3):295-9. doi: 10.1177/0148607109353440. JPEN J Parenter Enteral Nutr. 2010. PMID: 20467011 Clinical Trial. See all similar articles Cited by High-throughput metabolomics identifies new biomarkers for cervical cancer. Li X, Zhang L, Huang X, Peng Q, Zhang S, Tang J, Wang J, Gui D, Zeng F. Li X, et al. Discov Oncol. 2024 Mar 29;15(1):90. doi: 10.1007/s12672-024-00948-8. Discov Oncol. 2024. PMID: 38551775 Free PMC article. Acetyllevocarnitine Hydrochloride for the Treatment of Diabetic Peripheral Neuropathy: A Phase 3 Randomized Clinical Trial in China. Guo L, Pan Q, Cheng Z, Li Z, Jiang H, Zhang F, Li Y, Qiu W, Lu S, Tian J, Fu Y, Li F, Li D. Guo L, et al. Diabetes. 2024 May 1;73(5):797-805. doi: 10.2337/db23-0377. Diabetes. 2024. PMID: 38320260 Free PMC article. Clinical Trial. Combined Exercise Training and Nutritional Interventions or Pharmacological Treatments to Improve Exercise Capacity and Body Composition in Chronic Obstructive Pulmonary Disease: A Narrative Review. Brauwers B, Machado FVC, Beijers RJHCG, Spruit MA, Franssen FME. Brauwers B, et al. Nutrients. 2023 Dec 18;15(24):5136. doi: 10.3390/nu15245136. Nutrients. 2023. PMID: 38140395 Free PMC article. Review. Ameliorating effects of L-carnitine and synbiotic co-supplementation on anthropometric measures and cardiometabolic traits in women with obesity: a randomized controlled clinical trial. Fallah F, Mahdavi R. Fallah F, et al. Front Endocrinol (Lausanne). 2023 Oct 18;14:1237882. doi: 10.3389/fendo.2023.1237882. eCollection 2023. Front Endocrinol (Lausanne). 2023. PMID: 37929031 Free PMC article. Clinical Trial. Assessing the In Vitro and In Vivo Performance of L-Carnitine-Loaded Nanoparticles in Combating Obesity. Uner B, Ergin AD, Ansari IA, Macit-Celebi MS, Ansari SA, Kahtani HMA. Uner B, et al. Molecules. 2023 Oct 16;28(20):7115. doi: 10.3390/molecules28207115. Molecules. 2023. PMID: 37894594 Free PMC article. 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+Effects of coenzyme Q10 on cardiovascular and metabolic biomarkers in overweight and obese patients with type 2 diabetes mellitus: a pooled analysis - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Published online 2018 Nov 29. doi: 10.2147/DMSO.S184301 PMCID: PMC6276825 PMID: 30568475 Effects of coenzyme Q 10 on cardiovascular and metabolic biomarkers in overweight and obese patients with type 2 diabetes mellitus: a pooled analysis Haohai Huang , 1 Honggang Chi , 2 Dan Liao , 3 and Ying Zou 2, 4 Haohai Huang 1 Department of Clinical Pharmacy, Dongguan Third People’s Hospital, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, Dongguan, Guangdong, China Find articles by Haohai Huang Honggang Chi 2 Department of Traditional Chinese Medicine, Scientific Research Platform, The Second Clinical Medical College, Guangdong Medical University, Dongguan, China, moc.liamtoh@8611ralos Find articles by Honggang Chi Dan Liao 3 Department of Gynaecology & Obstetrics, Dongguan Third People’s Hospital, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, Dongguan, Guangdong, China, moc.qq@62521362 Find articles by Dan Liao Ying Zou 2 Department of Traditional Chinese Medicine, Scientific Research Platform, The Second Clinical Medical College, Guangdong Medical University, Dongguan, China, moc.liamtoh@8611ralos 4 Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Guangdong Medical University, Dongguan, Guangdong, China, moc.liamtoh@8611ralos Find articles by Ying Zou Author information Copyright and License information PMC Disclaimer 1 Department of Clinical Pharmacy, Dongguan Third People’s Hospital, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, Dongguan, Guangdong, China 2 Department of Traditional Chinese Medicine, Scientific Research Platform, The Second Clinical Medical College, Guangdong Medical University, Dongguan, China, moc.liamtoh@8611ralos 3 Department of Gynaecology & Obstetrics, Dongguan Third People’s Hospital, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, Dongguan, Guangdong, China, moc.qq@62521362 4 Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Guangdong Medical University, Dongguan, Guangdong, China, moc.liamtoh@8611ralos Correspondence: Dan Liao, Department of Gynaecology and Obstetrics, Dongguan Third People’s Hospital, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, No.1, Huangzhou Xianglong Road of Shilong Town, Dongguan, Guangdong 523326, China, Tel +86 769 8136 8280, Email moc.qq@62521362 Ying Zou, Department of Traditional Chinese Medicine, Scientific Research Platform, Guangdong Medical University, No.1, Xincheng Road of Songshan Lake Science and Technology Industry Park, Dongguan, Guangdong Province 523808, China, Tel +86 769 2289 6403, Email moc.liamtoh@8611ralos Copyright © 2018 Huang et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/ ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Abstract Background The potential effects of coenzyme Q10 (CoQ 10 ) supplementation in overweight/obese patients with type 2 diabetes mellitus are not fully established. In this article, we aimed to perform a pooled analysis to investigate the effects of CoQ 10 intervention on cardiovascular disease (CVD) risk factors in overweight/obese patients with type 2 diabetes mellitus (T2DM). Methods MEDLINE, Embase, and Cochrane databases were searched for randomized controlled trials that evaluated the changes in CVD risk factors among overweight and obese patients with T2DM following CoQ 10 supplementation. Two investigators independently assessed articles for inclusion, extracted data, and assessed risk of bias. Major endpoints were synthesized as weighted mean differences (WMDs) with 95% CIs. Subgroup analyses were performed to check the consistency of effect sizes across groups. Publication bias and sensitivity analysis were also performed. Results Fourteen eligible trials with 693 overweight/obese diabetic subjects were included for pooling. CoQ 10 interventions significantly reduced fasting blood glucose (FBG; −0.59 mmol/L; 95% CI, −1.05 to −0.12; P =0.01), hemoglobin A1c (HbA1c; –0.28%; 95% CI−0.53 to −0.03; P =0.03), and triglyceride (TG) levels (0.17 mmol/L; 95% CI, −0.32 to −0.03; P =0.02). Subgroup analysis also showed that low-dose consumption of CoQ 10 (<200 mg/d) effectively reduces the values of FBG, HbA1c, fasting blood insulin, homeostatic model assessment of insulin resistance, and TG. CoQ 10 treatment was well tolerated, and no drug-related adverse reactions were reported. Conclusion Our findings provide substantial evidence that daily CoQ 10 supplementation has beneficial effects on glucose control and lipid management in overweight and obese patients with T2DM. Keywords: coenzyme Q10, type 2 diabetes mellitus, cardiovascular risk factors, lipids, glucose, obesity Introduction Diabetes is a chronic disease with high rates of disability and mortality. In 2013, it was estimated that globally there were 382 million diabetic adults and is expected to increase to almost 592 million by 2035. 1 Early onset of diabetes leads to longer lifetime exposure to hyperglycemia and consequently a greater propensity to long-term complications. 2 Poor glycemic control causes long-term adverse outcomes in subjects with diabetes, including microvascular and macrovascular complications. 3 , 4 Some researchers have suggested that up to two of every three cases of type 2 diabetes mellitus (T2DM) can be attributed to obesity. 5 Being overweight and obese increases the risks of diabetes and cardiovascular disease (CVD). 6 Obesity accentuates the metabolic and CVD complications in patients with T2DM by increasing insulin resistance, causing a progressive decline of β-cell functions, and subsequently increasing the difficulty in achieving the glycemic targets. 7 , 8 The management of diabetes and its CVD-related complications impose enormous medical and economic burdens. Therefore, primary and secondary prevention of diabetes and delaying the onset or progression of diabetes-related complications have become a public health imperative. Treatment strategies for patients with T2DM who are obese should focus equally on glycemic control, weight loss, and the comprehensive management of CVD comorbidities or risk factors. In recent decades, large meta-analyses of randomized controlled trials (RCTs) have suggested that lifestyle modifications, such as dietary micro-nutrients or functional food supplementations, are generally used to improve glycemic management and clinically relevant metabolic biomarkers in patients with diabetes. 9 – 11 Accumulating evidence indicates that mitochondrial dysfunction, inflammation, and oxidative stress contribute to the pathogenesis of diabetes and associated complications. 12 , 13 Coenzyme Q10 (CoQ 10 ; also called ubiquinone), a lipid-soluble benzoquinone with 10 isoprenyl units in the side chain, can be synthesized endogenously or obtained naturally from the diet. In clinical applications, oral CoQ 10 treatment is a frequent mitochondrial energizer and antioxidant strategy in many diseases that may provide a significant symptomatic benefit. CoQ 10 has been used to prevent and treat a wide range of diseases, including primary and secondary CoQ 10 deficiencies, mitochondrial diseases, fibromyalgia, CVD, neurodegenerative diseases, cancer, diabetes mellitus, hypertension, and periodontal disease. 14 – 16 The plasma levels of CoQ 10 in patients with diabetes are significantly lower when compared with the healthy individuals. 17 , 18 The deficiency of CoQ 10 may further impair the body’s defensive mechanisms against oxidative stress induced by hyperglycemia in diabetes. 19 Several studies have demonstrated that the restoration of CoQ 10 levels in patients with diabetes by the supplemental use of exogenous CoQ 10 could potentially preserve mitochondrial function, alleviate oxidative stress, and eventually lead to improvement of glycemic control. 20 – 24 However, the results of whether the supplementation of CoQ 10 helps to improve glucose and insulin levels, to modify lipid profiles, and to reduce blood pressure in overweight diabetic patients are inconsistent and have not been fully understood. Therefore, we undertook a comprehensive meta-analysis of RCTs to investigate the effects and safety of CoQ 10 supplementation on multiple markers of cardiovascular health in overweight and obese patients with established T2DM. Materials and methods Search strategy The protocol for this pooled analysis was conducted following PRISMA guidelines. 25 Two independent investigators performed an electronic literature search of MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) from their inception to December 31, 2017, restricting the search to publications in English and clinical trials that investigated the effects of CoQ 10 intervention in patients with established T2DM. We used the following search terms: “Coenzyme Q10” OR “Co-enzyme Q10” OR “CoQ 10 ” OR “ubiquinone” OR “ubiquinol” and combined with “diabetes mellitus” OR “type 2 diabetes” OR “type 2 diabetes mellitus” OR “diabetes” OR “noninsulin-dependent diabetics” OR “NIDDM” OR “T2DM”. To identify any other missing eligible trials, we also performed a manual search of reference citations in relevant review articles and original articles that were selected for full-text retrieval. Study inclusion criteria To be included, an original study had to meet the following criteria: 1) population: target population (adults aged ≥18 years) with a body mass index (BMI) of ≥25 kg/m 2 and diagnosed with T2DM; 2) intervention: the patients ingested a determined amount of CoQ 10 or ubiquinol intervention for ≥4 weeks; 3) comparison: placebo or conventional antidiabetic agents were used; 4) outcomes of interest: an assessment of at least one of the following outcome markers, namely fasting blood glucose (FBG), hemoglobin A1c (HbA1c), homeostatic model assessment of insulin resistance (HOMA-IR), fasting blood insulin (FBI), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), SBP, DBP, and BMI; and 5) study design: study was an RCT conducted in human subjects with either a parallel or crossover design. Data extraction Data extraction included information regarding study characteristics (first author’s name, year of publication, sample size, details of the study design, and length of follow-up), basic characteristics of participants (such as age, percentage male, duration of diabetes, baseline of BMI, and FBG), and intervention characteristics (such as type of intervention, dose, and type of control) and reported the outcomes of interest. Assessing the quality of the methodology used Two of the investigators independently used the Cochrane Collaboration bias risk analysis tool to assess the quality of the trials included. 26 Randomization sequence generation, allocation concealment, blinding of participants and study personnel, blinding of outcome assessors, incomplete outcome data, selective reporting, and other biases (defined as baseline imbalance in our present study) were classified as high, low, or unclear for each domain of the studies included. Grading quality of evidence The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to rate the quality of evidence and generate absolute estimates of the effect of CoQ 10 for the primary and secondary outcomes. 27 Statistical analyses We used STATA software (version 12; StataCorp LP, College Station, TX, USA) to combine the individual study results for all outcomes studied. For each marker, we calculated the effect sizes as a weighted mean difference (WMD) and a 95% CI between the CoQ 10 intervention and control groups using a random-effects model. We used the I 2 statistic to assess the degree of statistical heterogeneity among studies, with a value of <25%, 26%–50%, and >50% being considered as a low, moderate, and high levels of heterogeneity, respectively. 28 To evaluate the robustness of our findings, sensitivity analyses were performed by removing one study each time and repeating the analysis (the “leave-one-out” approach). To explore the influence of various factors on the cardiovascular risk factors of CoQ 10 intervention, a priori subgroup analyses were then carried out according to the mean age of the patients, the duration of T2DM, the baseline level of BMI, CoQ 10 dose, and intervention duration. We investigated the possibility of publication bias using funnel plot asymmetry and Egger’s weighted regression test. 29 A P -value of <0.05 was considered to be statistically significant. Meta-regression In the present study, we applied a restricted maximum likelihood (REML)-based random-effects meta-regression analysis to explore whether the potential confounders of treatment response, such as the dose (mg/d) and duration (number of weeks) of supplementation with CoQ 10 , were associated with the source of heterogeneity. 30 Results Search results and trial flow A PRISMA study flow chart of the selected trials is shown in Figure S1 . We initially identified 375 potential records from the original literature search, of which 44 were duplicate articles. Three hundred thirty-one potentially relevant articles were screened based on their titles and abstracts, and then 45 articles were selected for detailed evaluation. After full-text assessment, 31 of these studies were excluded, most of them due to CoQ 10 being mixed with other components (n=3); reported from the same population (n=2); the outcomes of interest not being reported (n=3); duplicate data (n=2); not being an RCT study (n=4); letters, reviews, or meta-analysis (n=6); mixed patients (n=5); subjects being younger than 18 years (n=3); and participants with a BMI< 25 kg/m 2 (n=3). Overall, a total of 14 studies with 693 participants were finally selected for the meta-analysis. 20 – 24 , 31 – 39 Study and participant characteristics Detailed characteristics of the resulting 14 trials are listed in Table 1 . Most studies included were single-center studies published between 1999 and 2018. The mean baseline BMI of the T2DM patients varied from 25.0 to 30.4 kg/m 2 . The population sizes included in these studies ranged from 23 to 80 subjects. Overall, 730 subjects were randomly assigned in these trials, while 693 (94.9%) subjects completed the studies. Of the 14 trials used in the meta-analysis, 10 trials included both men and women, 20 – 22 , 24 , 31 , 33 – 36 , 39 one included only women, 38 and three did not indicate the sex composition of the sample. 23 , 32 , 37 The dose of CoQ 10 varied from 100 to 400 mg/d (median, 185.7 mg/d). The follow-up duration of CoQ 10 intervention was 8, 12, or 24 weeks (median, 12.86 weeks). The mean age of the participants ranged from 47 to 68 years (median, 55.78 years). The mean baseline FBG ranged from 7.15 to 11.5 mmol/L (median, 8.88 mmol/L). All trials were randomized, with 92.8% (13 trials) utilizing a parallel design and 7.2% (one trials) utilizing a crossover design. Among the studies included, 11 of the 14 studies included subjects with only T2DM. Of the remaining three trials, one was performed on subjects with T2DM and dyslipidemia, one was conducted on T2DM subjects with left ventricular diastolic dysfunction, and one was conducted on T2DM subjects with coronary heart disease. Table 1 Characteristics of the included studies Reference (years) Study design Location Enrollment/no. completed Population Male (%) Duration of DM (years) Mean age (years) BMI (s) Baseline of FBG DM criteria Intervention Dose (mg/d) Duration (weeks) Main outcomes Treatment group Control group Chew et al 31 (2008) R, DB, P Australia 36/36 T2DM subjects with LVDD 75.0 4.3±4.0 61.8±7.63 30.4±4.81 7.4±1.7 ADA CoQ 10 Placebo 200 24 FBG, HbA1c, TC, TG, LDL-C, HDL-C Eriksson et al 23 (1999) R, DB, P Denmark 23/23 Patients with T2DM NR NR 64.5±6 29.4±3.86 11.5±2.47 NR CoQ 10 Placebo 200 24 FBG, HbA1c, TC, TG, HDL-C, SBP, DBP, BMI Akbari Fakhrabadi et al 39 (2014) R, DB, P Iran 74/62 Patients with T2DM 25.8 16.2±7.25 55.7±6.55 29.1±3.70 9.16±2.78 ADA CoQ 10 Placebo 100 12 FBG, HbA1c, FBI, HOMA-IR, TC, LDL-C, HDL-C Hamilton et al 32 (2009) R, DB, C Australia 23/23 Statin-treated T2DM patients NR 8.0 68.0±6 29.0±4 NR NR CoQ 10 Placebo 200 12 HbA1c, LDL-C, SBP, DBP Hernández-Ojeda et al 33 (2012) R, DB, P Mexico 56/49 Patients with T2DM 22.4 10.7±8.74 56.1±8.66 29.3±6.35 11.6±5.06 ADA Ubiquinone Placebo 400 12 FBG, HbA1c, TC, LDL-C, HDL-C, TG Hosseinzadeh-Attar et al 34 (2015) R, DB, P Iran 64/64 Patients with T2DM 57.8 5.3±3.4 46.1±7.97 29.5±3.04 8.83±1.74 ADA CoQ 10 Placebo 200 12 FBG, HbA1c, TC, TG, LDL-C, HDL-C, BMI Lim et al 35 (2008) R, DB, P Singapore 80/80 Patients with T2DM 50 NR 53.5±9 25.0±4.81 7.75±2.0 NR CoQ 10 Placebo 200 12 FBG, HbA1c, SBP, DBP Moazen et al 21 (2015) R, SB, P Iran 52/52 Patients with T2DM 53.8 4.6±3.91 51.7±7.36 25.3±2.27 9.75±4.00 NR CoQ 10 Placebo 200 8 FBG, HbA1c, BMI Mohammed-Jawad et al 20 (2014) R, NB, P Iraq 38/38 Patients with T2DM 47.4 4.4±3.48 50.5±7.55 28.8±4.19 10.56±3.09 ADA CoQ 10 Sulfonylurea and metformin 150 8 FBG, HbA1c, TC, LDL-C, HDL-C Mehrdadi et al 22 (2017) R, DB, P Iran 64/56 Overweight/obese T2DM subjects 57.1 5.2±3.5 47.0±8 29.5±3.10 8.88±1.75 NR CoQ 10 Placebo 200 12 FBG, HbA1c, FBI, HOMA-IR Playford et al 36 (2003) R, DB, P Australia 40/40 Patients with T2DM and dyslipidemia 82.5 NR 53.7±1.85 30.4±0.89 7.75±0.53 NR CoQ 10 Placebo 200 12 HbA1c, TC, LDL-C, HDL-C, TG, SBP Raygan et al 37 (2016) R, DB, P Iran 60/60 Overweight or obese and T2DM patients with CHD NR NR 62.9±12.81 29.4±5.58 7.15±2.47 ADA CoQ 10 Placebo 100 8 FBG, FBI, HbA1c, TC, LDL-C, HDL-C, TG Zahedi et al 24 (2014) R, DB, P Iran 40/40 Patients with T2DM 47.5 7.6±6.09 56.1±9.65 25.9±3.02 7.34±2.07 NR CoQ 10 Placebo 150 12 FBG, HbA1c, FBI, HOMA-IR, TC, LDL-C, HDL-C, TG Gholami et al 38 (2018) R, DB, P Iran 80/70 Women with T2DM 0 4.75±2.60 53.3±6.45 28.9±3.33 7.78±2.90 WHO CoQ 10 Placebo (cellulose acetate) 100 12 FBG, HbA1c, FBI, HOMA-IR, TC, LDL-C, HDL-C, TG, SBP, DBP, BMI Open in a separate window Abbreviations: ADA, American Diabetes Association; BMI, body mass index; C, crossover; CoQ10, coenzyme Q10; CHD, coronary heart disease; DB, double blind; DM, diabetes mellitus; FBG, fasting blood glucose; FBI, fasting blood insulin; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model assessment of insulin resistance; LDL-C, low-density lipoprotein cholesterol; LVDD, left ventricular diastolic dysfunction; NR, not reported; P, parallel; R, randomized; TC, total cholesterol; TG, triglyceride; T2DM, type 2 diabetes mellitus. Assessment of quality and potential bias A detailed risk-of-bias summary is shown in Figure 1 . Among the 14 studies included, only seven studies reported random sequence generation. 21 , 22 , 33 – 35 , 37 , 39 Two trials did not describe whether the blind method was adopted and were categorized as at high risk of bias. 20 , 21 Overall, six trials were considered as at low risk of bias, 22 , 33 – 35 , 37 , 39 two as at a high risk of bias, 20 , 21 and six as unclear. 23 , 24 , 31 , 32 , 36 , 37 Open in a separate window Figure 1 Quality assessment of the included studies. Note: Labeling an item as “question mark” indicated a unclear or unknown risk of bias; labeling an item as “negative sign” indicated a high risk of bias; and labeling an item as “positive sign” indicated a low risk of bias. Changes in glycemic control, insulin levels, and sensitivity Overall, the pooled result showed that the consumption of CoQ10 significantly decreased the FBG (12 studies; WMD=−0.59 mmol/L; 95% CI=−1.05 to −0.12; P =0.01) and HbA1c levels (13 studies; WMD=−0.28%; 95% CI=−0.53 to −0.03; P =0.03) in overweight and obese patients with T2DM. Heterogeneity tests results of these outcomes were 37% and 33%, respectively. However, FBI (five studies; WMD=−1.87 μIU/mL; 95% CI=4.51 to 0.77; P =0.17; I 2 =71%) and HOMA-IR (five studies; WMD=−1.03; 95% CI=−2.06 to −0.00; P =0.05; I 2 =71%) levels did not change significantly with the consumption of CoQ 10 . Forest plots for each measured parameter are shown in Figure 2 . Open in a separate window Figure 2 Forest plot detailing WMD and 95% CIs for the impact of CoQ 10 supplementation on FBG ( A ), HbA1c ( B ), FBI ( C ), and HOMA-IR ( D ) in overweight and obese patients with established T2DM. Abbreviations: CoQ 10 , coenzyme Q10; FBG, fasting blood glucose; FBI, fasting blood insulin; HbA1c, hemoglobin A1c; HOMA-IR, homeostatic model assessment of insulin resistance; T2DM, type 2 diabetes mellitus; WMD, weighted mean difference. Changes in lipid concentrations, blood pressure, and BMI As shown in Figure 3 , the consumption of CoQ 10 by overweight and obese patients with T2DM caused a significant reduction in TG concentrations compared with the control (eight studies; WMD=−0.17 mmol/L; 95% CI=−0.32 to −0.03; P =0.02; I 2 =0%). However, no significant changes were found in the concentrations of TC (10 studies; WMD=−0.18 mmol/L; 95% CI=−0.33 to 0.16; P =0.50; I 2 =40%), LDL-C (10 studies; WMD=0.05 mmol/L; 95% CI=−0.30 to 0.20; P =0.69; I 2 =77%), and HDL-C (10 studies; WMD=0.03 mmol/L; 95% CI=−0.01 to 0.08; P =0.17; I 2 =29%) values of the diabetic participants. Open in a separate window Figure 3 Forest plot detailing WMD and 95% CIs for the impact of CoQ10 supplementation on TC ( A ), LDL-C ( B ), HDL-C ( C ), and TG ( D ) in overweight and obese patients with established T2DM. Abbreviations: CoQ10, coenzyme Q10; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride; T2DM, type 2 diabetes mellitus; WMD, weighted mean difference. Six studies investigated the impact of CoQ 10 on BP in overweight and obese patients with T2DM. CoQ 10 supplementation did not result in a significant reduction in SBP (six studies; WMD=1.84 mmHg; 95% CI=−5.60 to 1.92; P =0.34; I 2 =21%) and DBP levels (five studies; WMD=−1.38 mmHg; 95% CI=−5.48 to 2.72; P =0.51; I 2 =80%). Similarly, no significant difference was seen in BMI with CoQ 10 intake in the three studies that evaluated this outcome (WMD=−0.35 kg/m 2 ; 95% CI=−1.58 to 0.88; P =0.58; I 2 =0%). Meta-regression analyses The results from the univariate weighted random-effects meta-regression analysis demonstrate that the duration of CoQ 10 supplementation was not a source of heterogeneity of FBG (coefficient=0.068; 95% CI=−0.069 to 0.206; P =0.294) and HbA1c levels (coefficient=−0.034; 95% CI=−0.038 to 0.106; P =0.294; Figure S2 ). Similarly, as shown in Figure S3 , the amount of CoQ 10 consumed per day was also not a source of heterogeneity of FBG (coefficient=0.002; 95% CI=−0.006 to 0.010; P =0.626) and HbA1c levels (coefficient=−0.0003; 95% CI=−0.005 to 0.004; P =0.877). Subgroup analysis and sensitivity analysis The subgroup analysis results based on the CoQ 10 dose demonstrated that CoQ 10 consumption significantly decreased the levels of FBG ( P =0.006), HbA1c ( P =0.005), FBI ( P =0.01), HOMA-IR ( P =0.0001), and TG ( P =0.02) in the low-dose CoQ10 supplementation group (<200 mg/d). In the subgroup analysis based on the baseline patient BMI, the pooled result showed that CoQ 10 supplementation significantly decreased FBG, HbA1c, and TG levels of overweight and obese patients with diabetes mellitus by 0.67 mmol/L, 0.36%, and 0.16 mmol/L, respectively. We layered the trials according to mean age (<55.7 or ≥55.7 years), and a significant change in FBG ( P =0.02) and HbA1c levels ( P =0.01) was observed in subjects with a mean age of <55.7 years, whereas a significant change in FBI ( P =0.001) and HOMA-IR levels ( P =0.03) was observed in subjects with mean age of ≥55.7 years. A post hoc subgroup analysis was also performed to examine the effect of intervention duration on the overall effects of CoQ 10 on CVD risk factors in overweight and obese patients with T2DM. The post hoc subgroup analysis suggested that CoQ 10 consumption significantly decreased the levels of FBG ( P =0.01), HbA1c ( P =0.02), and TG ( P =0.04) at supplemental duration of ≤12 weeks. There were no statistically significant differences in the pooled effects of CoQ 10 on CVD risk markers in the subgroups stratified by the duration of diabetes. Complete results of subgroup analysis are shown in Table S1 . The sensitivity analysis results show that the exclusion of any single study each time did not influence the significance of our pooled effect size for either outcome (data not shown). Publication bias No obvious publication bias was found in the visual inspection of funnel plots. Figure 4 shows the funnel plots of these study outcomes. Similarly, Egger’s tests showed that no statistical evidence of publication bias was observed in relation to levels of FBG ( P =0.275), HbA1c ( P =2.53), FBI ( P =0.836), HOMA-IR ( P =0.618), TC ( P =0.518), LDL-C ( P =0.560), HDL-C ( P =0.627), TG ( P =0.069), SBP ( P =0.977), DBP ( P =0.896), or BMI ( P =0.093). Open in a separate window Figure 4 Funnel plot detailing publication bias in the studies reporting the impact of CoQ10 on glucose control, insulin sensitivity, and blood lipid. Abbreviations: CoQ10, coenzyme Q10; FBG, fasting blood glucose; FBI, fasting blood insulin; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; HOMAIR, homeostatic model assessment of insulin resistance; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride; WMD, weighted mean difference. GRADE profile evidence evaluation GRADE evidence profiles for the primary and secondary outcomes are shown in Table S2 . There were 11 outcomes regarding efficacy in this meta-analysis. The GRADE Working Group grade levels of evidence are of high quality for levels of TG, SBP and BMI; of moderate quality for levels of FBG, HbA1c, and HDL-C; and low quality for levels of HOMA-IR, FBI, TC, LDL-C, and DBP. Discussion Summary of main results The results from our pooled analysis demonstrate that CoQ 10 interventions significantly reduced the levels of FBG, HbA1c, and TG by 0.59 mmol/L, 0.28%, and 0.17 mmol/L, respectively. These changes varied substantially depending on the treatment dose of CoQ 10 , the intervention duration, the mean age of the subjects, and the initial level of BMI. Subgroup analysis also demonstrated that consumption of lower dose of CoQ 10 (<200 mg/d) caused a significant reduction in levels of FBG, HbA1c, FBI, HOMA-IR, and TG in overweight and obese individuals with T2DM. Agreements and disagreements with other studies The impact of CoQ 10 supplementation for improving glucose and insulin responses, various lipid parameters, and blood pressure in patients with diabetes have been inconsistent. Therefore, there is not yet sufficient synthesis regarding the efficacy and risks for clinicians to make evidence-based decisions regarding the supplementation of CoQ 10 in the management of diabetes, especially in overweight and obese patients with diabetes mellitus. Two meta-analyses regarding this topic have been published. 40 , 41 A previous meta-analysis that included seven trials involving 356 patients pointed out that CoQ 10 supplementation has no beneficial effects on glycemic control, lipid profile, or blood pressure in patients with diabetes. However, TG levels may be reduced with CoQ 10 ingestion. 41 A further meta-analysis based on 14 eligible studies regarding the effects of CoQ 10 supplementation on diabetes biomarkers in healthy (healthy subjects without diabetes mellitus) and unhealthy subjects by Moradi et al 40 concluded that CoQ 10 supplementation slightly but significantly reduced FBG levels, but not fasting insulin and HbA1c levels in the overall analysis. A subgroup analysis based on the type of disease was also performed in this study, with no beneficial effects of CoQ 10 on FBG and HbA1c levels being found in patients with diabetes. However, the primary outcomes included were the change in HbA1c, FBI, and FPG levels, while CVD risk factors, such as levels of HOMA-IR, lipid profile and BP, were not determined in this study. In our present study, nine studies included were overlapped with the two previous meta-analyses. By using the previous meta-analysis as a base, we included five other recent RCTs, giving a greater power to identify and quantify the effects of CoQ 10 on cardiovascular and metabolic biomarkers in overweight and obese patients with established T2DM. Furthermore, several strengths of our study should be noted: first, our meta-analysis paid attention to only overweight and obese patients with established T2DM and included 14 clinical RCTs totaling 693 patients, which was highly homogeneous and selective. Second, largely due to lenient inclusion criteria, there is indirectness of evidence in terms of the differences in population and the differences in intervention and inconsistency in the effect and effect size across studies. To evaluate the strength of the available evidence and make more objective decisions regarding the results, subgroup analyses according to putative moderators, such as baseline BMI, CoQ 10 dose, mean age, and intervention duration, were performed to distinguish the influence of different factors on treatment efficacy. Third, our current meta-analysis was the latest and the most comprehensive one, which generally redefined and reinforces earlier results of previous meta-analyses. We examined the dose response and time response of CoQ 10 consumption by using linear meta-regression. Publication bias and sensitivity analysis were also performed to test the robustness of our findings. Furthermore, the GRADE methodology was used to rate the level of evidence. Finally, we further summarized the reported side effects of CoQ 10 consumption in the eligible trials, which had not been investigated in previous reviews. Potential explanation of findings The exact mechanisms responsible for the glycemic control and lipid-lowering effects of CoQ 10 in diabetes are not yet completely understood. Increasing evidence suggests that oxidative stress contributes to and also results from hyperglycemia, insulin resistance, and malfunction of β-cell function. 42 , 43 The β-cell function as well as glucose and fatty acid metabolism in the liver may be deteriorated as a result of CoQ 10 deficiency resulting in impaired insulin action and hyperinsulinemia. Supplemental use of CoQ 10 improves insulin sensitivity and hyperglycemia- or hyperinsulinemia-associated metabolic disorders by modulating insulin and adiponectin receptors, as well as tyrosine kinase (TK), phosphatidylinositol 3 kinase (PI3K), and glucose transporters 2 (GLUT2), while improving the lipid profile, redox system, soluble receptor of advanced glycated end products (sRAGEs), and adipocytokines (eg, adiponectin and visfatin). 44 Our results also show that participants with established diabetes receiving CoQ 10 had statistically significantly lower levels of TG level after treatment compared with control individuals. This positive effect was supported by in vivo mechanistic study finding, in which CoQ 10 has been shown to increase fatty acid oxidation through AMP-activated protein kinase (AMPK)-mediated peroxisome proliferator-activated receptor alpha (PPARα) induction. 45 Moreover, CoQ 10 increased the lipolysis of TGs by decreasing the oxidative stresses and endothelial metabolism of the participants. 46 Supplementation with CoQ 10 could also improve hypertension and coronary artery disease. Some investigators found that CoQ 10 consumption can decrease BP in subjects with uncontrolled or poorly controlled hypertension. 47 , 48 The primary mode of action of CoQ 10 in clinical hypertension is vasodilatation, via a direct effect on the endothelium and vascular smooth muscle. 47 CoQ 10 may also reduce BP by reducing peripheral resistance through the preservation of nitric oxide. 49 In addition, CoQ 10 is beneficial in improving prostaglandin prostacyclin production, promoting vasodilation and inhibiting platelet aggregation. 50 The effect of CoQ 10 on the change of BP in diabetes has not yet been systematically examined. Therefore, we further assessed the effect of CoQ 10 consumption on SBP and DBP outcomes, but failed to find any significant effects. Safety concerns Some adverse events reported to be associated with CoQ 10 were gastrointestinal effects (ie, abdominal discomfort, nausea, vomiting, diarrhea, and anorexia), allergic rash, headache, and the risk of bleeding. 51 In our pooled analysis, CoQ 10 treatment was well tolerated, and no drug-related adverse reactions were reported among the eligible trials during the follow-up period. Implications for clinical practice The persistence of excess adiposity in children and adults can lead to metabolic abnormality. Insulin resistance and progressive β-cell dysfunction are regarded as the key pathophysiologic mechanisms of T2DM development, and most T2DM patients who are overweight or obese also have CVD comorbidities/risk factors such as hypertension, dyslipidemia, and hypercoagulability. 52 , 53 Our findings may have major clinical implications, given that the metabolic biomarkers evaluated in our present study are clinically relevant for monitoring the treatment and progression of diabetes across multiple organ systems. Glycemic control is fundamental to the management of diabetes. The pooled estimates suggest that CoQ 10 significantly affected the FBG level. FBG level is considered a key variable in the diagnosis of diabetes and is also adopted by the Food and Drug Administration (FDA) to evaluate the efficacy of dietary supplements and glycemic-lowering drugs. Moreover, our results show a significant benefit for HbA1c levels in overweight and obese individuals with T2DM. Large clinical trials have firmly established that a reduction in HbA1c level, a long-term indicator of glycemic control, is associated with a decreased risk for multiple diabetic complications and death. 3 Patients with T2DM also have an increased prevalence of lipid abnormalities in visceral organs and ectopic fat depots that contribute to higher rates of CVD outcomes. Lipid management has been shown to reduce macrovascular disease and mortality in patients with T2DM, particularly in those who have had prior cardiovascular events. 54 Our pooled result also shows that CoQ 10 intervention significantly lowered TG levels. Therefore, our study provided evidence for clinicians and researchers to incorporate CoQ 10 treatment into the management of T2DM in overweight and obese patients. Limitations Our present meta-analysis has some limitations in interpreting the current results. First, our search was limited to studies published in English, and non-English or unpublished reports may exist. Second, despite the numerous subgroup and sensitivity analyses that were carried out, there was unavoidable heterogeneity in many of the reported outcomes, indicating variation between the studies in the estimates of the effect of CoQ 10 on the measured outcomes. Moreover, due to the lack of information in most of the existing studies, influences of other covariates such as the smoking habits could not be fully determined. Therefore, we hardly considered this point in the subgroup analysis and ruled out heterogeneity thoroughly. Third, our pooled result was obtained with unadjusted estimates, and the precise effect of CoQ 10 on CVD biomarkers in overweight and obese patients with T2DM could have been impacted by other confounders (ie, other lifestyle interventions, alcohol consumption). The synergistic effects of other coexisting substances on the clinical outcomes should be excluded during the study period. Finally, since we performed multiple comparisons in this meta-analysis, the Bonferroni method, which controls false-positive error rate, was used to adjust for multiple comparisons. The threshold for significance was set at a P -value of <0.015. After Bonferroni correction, no significant effect was observed for the HbA1c and TG outcomes. Conclusion The present pooled analysis provides evidence for the beneficial effects of daily CoQ 10 supplementation on concentrations of FBG, HbA1c, and TG levels in overweight and obese patients with established T2DM. In a subgroup analysis, CoQ 10 effectively reduced the values of FBG, HbA1c, FBI, HOMA-IR, and TG in the low-dose of CoQ 10 (<200 mg/d) consumption group. CoQ 10 was well tolerated, and drug-related adverse reactions were not reported among the eligible trials during the follow-up period. 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+The psychological benefits of moderate alcohol consumption: a review of the literature - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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The psychological benefits of moderate alcohol consumption: a review of the literature C Baum-Baicker PMID: 4053968 DOI: 10.1016/0376-8716(85)90008-0 Item in Clipboard The psychological benefits of moderate alcohol consumption: a review of the literature C Baum-Baicker . Drug Alcohol Depend . 1985 Aug . Show details Display options Display options Format Abstract PubMed PMID Drug Alcohol Depend Actions Search in PubMed Search in NLM Catalog Add to Search . 1985 Aug;15(4):305-22. doi: 10.1016/0376-8716(85)90008-0. Author C Baum-Baicker PMID: 4053968 DOI: 10.1016/0376-8716(85)90008-0 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract A review of the literature on the positive psychological benefits of light and moderate alcohol consumption suggests the following: (1) Alcohol in moderate amounts is effective in reducing stress. This has been found in both physiologic and self-report measures. (2) Low and moderate doses of alcohol have been reported to increase overall affective expression, happiness, euphoria, conviviality and pleasant and carefree feelings. Tension, depression and self-consciousness have been reported to decrease with equal doses. (3) Low alcohol doses have been found to improve certain types of cognitive performance. Included here are problem-solving and short-term memory. (4) Heavy drinkers and abstainers have higher rates of clinical depression than do regular moderate drinkers. (5) Alcohol in low and moderate doses has been effective in the treatment of geropsychiatric problems. As indicated in the text, results from many of the studies reviewed suggest that light or moderate drinking may be beneficial to psychological well-being. Liber (N. Engl. J. Med., 310(13) (1984) 846) has commented that the subject of control of alcohol intake evokes strong emotional responses, which can overshadow a logical assessment of whether or not to include 'healthy' drinking in a dietary plan. It is hoped that this review of data from available research can help provide a basis for making such an assessment. PubMed Disclaimer Similar articles Does a moderate dose of alcohol reinforce feelings of pleasure, well-being, happiness and joy? A brief communication. Gustafson R. Gustafson R. Psychol Rep. 1991 Aug;69(1):220-2. doi: 10.2466/pr0.1991.69.1.220. Psychol Rep. 1991. PMID: 1961796 Reinforcing mood effects of alcohol in coping and enhancement motivated drinkers. Wilkie H, Stewart SH. Wilkie H, et al. Alcohol Clin Exp Res. 2005 May;29(5):829-36. doi: 10.1097/01.alc.0000163498.21044.cb. Alcohol Clin Exp Res. 2005. PMID: 15897728 Clinical Trial. Role of impulsivity in the relationship between depression and alcohol problems among emerging adult college drinkers. Gonzalez VM, Reynolds B, Skewes MC. Gonzalez VM, et al. Exp Clin Psychopharmacol. 2011 Aug;19(4):303-13. doi: 10.1037/a0022720. Exp Clin Psychopharmacol. 2011. PMID: 21480733 Exploring psychological benefits associated with moderate alcohol use: a necessary corrective to assessments of drinking outcomes? Peele S, Brodsky A. Peele S, et al. Drug Alcohol Depend. 2000 Nov 1;60(3):221-47. doi: 10.1016/s0376-8716(00)00112-5. Drug Alcohol Depend. 2000. PMID: 11053757 Review. Cognitive functioning in sober social drinkers: a review of the research since 1986. Parsons OA, Nixon SJ. Parsons OA, et al. J Stud Alcohol. 1998 Mar;59(2):180-90. doi: 10.15288/jsa.1998.59.180. J Stud Alcohol. 1998. PMID: 9500305 Review. See all similar articles Cited by Data-driven lifestyle patterns and risk of dementia in older Australian women. Dingle SE, Bowe SJ, Bujtor M, Milte CM, Daly RM, Byles J, Cavenagh D, Torres SJ. Dingle SE, et al. Alzheimers Dement. 2024 Feb;20(2):798-808. doi: 10.1002/alz.13467. Epub 2023 Oct 1. Alzheimers Dement. 2024. PMID: 37777990 Free PMC article. The changing relationship between health risk behaviors and depression among birth cohorts of Canadians 65+, 1994-2014. Yang G, D'Arcy C. Yang G, et al. Front Psychiatry. 2022 Dec 21;13:1078161. doi: 10.3389/fpsyt.2022.1078161. eCollection 2022. Front Psychiatry. 2022. PMID: 36620694 Free PMC article. Early historical report of alcohol hepatotoxicity in Minooye Kherad , a Pahlavi manuscript in Ancient Persia, 6 th century CE. Hamdi H, Soleymani S, Zargaran A. Hamdi H, et al. Caspian J Intern Med. 2022 Spring;13(2):431-435. doi: 10.22088/cjim.13.2.431. Caspian J Intern Med. 2022. PMID: 35919642 Free PMC article. Is There a Novel Biosynthetic Pathway in Mice That Converts Alcohol to Dopamine, Norepinephrine and Epinephrine? Fitzgerald PJ. Fitzgerald PJ. Molecules. 2022 Apr 23;27(9):2726. doi: 10.3390/molecules27092726. Molecules. 2022. PMID: 35566075 Free PMC article. Toxic Effects of Methamphetamine on Perivascular Health: Co-morbid Effects of Stress and Alcohol Use Disorders. Rodriguez EA, Yamamoto BK. Rodriguez EA, et al. Curr Neuropharmacol. 2021;19(12):2092-2107. doi: 10.2174/1570159X19666210803150023. Curr Neuropharmacol. 2021. PMID: 34344290 Free PMC article. Review. See all "Cited by" articles MeSH terms Adaptation, Psychological / drug effects* Actions Search in PubMed Search in MeSH Add to Search Affect / drug effects Actions Search in PubMed Search in MeSH Add to Search Alcohol Drinking* Actions Search in PubMed Search in MeSH Add to Search Alcoholic Intoxication / psychology Actions Search in PubMed Search in MeSH Add to Search Alcoholism / psychology Actions Search in PubMed Search in MeSH Add to Search Cognition / drug effects Actions Search in PubMed Search in MeSH Add to Search Dose-Response Relationship, Drug Actions Search in PubMed Search in MeSH Add to Search Ethanol / blood Actions Search in PubMed Search in MeSH Add to Search Humans Actions Search in PubMed Search in MeSH Add to Search Life Change Events Actions Search in PubMed Search in MeSH Add to Search Stress, Psychological / complications Actions Search in PubMed Search in MeSH Add to Search Substances Ethanol Actions Search in PubMed Search in MeSH Add to Search Related information Cited in Books PubChem Compound (MeSH Keyword) LinkOut - more resources Full Text Sources Elsevier Science Medical MedlinePlus Health Information Research Materials NCI CPTC Antibody Characterization Program Full text links [x] Elsevier Science [x] Cite Copy Download .nbib .nbib Format: AMA APA MLA NLM Send To Clipboard Email Save My Bibliography Collections Citation Manager [x] NCBI Literature Resources MeSH PMC Bookshelf Disclaimer The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). 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+Water and Electrolytes - Recommended Dietary Allowances - NCBI Bookshelf Warning: The NCBI web site requires JavaScript to function. more... An official website of the United States government Here's how you know The .gov means it's official. Federal government websites often end in .gov or .mil. Before
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+							and transmitted securely. Log in Show account info Close Account Logged in as: username Dashboard Publications Account settings Log out Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Bookshelf Search database Books All Databases Assembly Biocollections BioProject BioSample Books ClinVar Conserved Domains dbGaP dbVar Gene Genome GEO DataSets GEO Profiles GTR Identical Protein Groups MedGen MeSH NLM Catalog Nucleotide OMIM PMC PopSet Protein Protein Clusters Protein Family Models PubChem BioAssay PubChem Compound PubChem Substance PubMed SNP SRA Structure Taxonomy ToolKit ToolKitAll ToolKitBookgh Search term Search Browse Titles Advanced Help Disclaimer NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health. National Research Council (US) Subcommittee on the Tenth Edition of the Recommended Dietary Allowances. Recommended Dietary Allowances: 10th Edition. Washington (DC): National Academies Press (US); 1989. Recommended Dietary Allowances: 10th Edition. Show details National Research Council (US) Subcommittee on the Tenth Edition of the Recommended Dietary Allowances. Washington (DC): National Academies Press (US) ; 1989. Contents Hardcopy Version at National Academies Press Search term < Prev Next > 11 Water and Electrolytes Although water and the principal electrolytes (sodium, potassium, and chloride) are often excluded from lists of nutrients, these substances are essential dietary components, in that they must be acquired from the diet either exclusively or—in the case of water—in amounts well in excess of that produced by metabolism in the body. Concerns about possible overconsumption (sodium and chloride) or underconsumption (potassium) of these substances in the United States are comparatively recent (NRC, 1989; Tobian, 1979). WATER Water is the most abundant constituent of the human body, accounting for one-half to four-fifths of body weight, depending mainly on body fat content. Accordingly, body water, as a percentage of body mass, is higher in men than in women and tends to fall with age in both. Figure 11-1 shows the routes and approximate magnitudes of water intake and loss in an environment cool enough to prevent sweating. The normal daily turnover of water via these routes is approximately 4% of total body weight in adults and much higher, 15% of total body weight, in infants. As Figure 11-1 shows, even in the absence of visible perspiration, approximately one-half of the turnover occurs through what is called insensible water loss, i.e., water lost from the lungs and skin. These insensible losses can all be increased under certain conditions, including high temperatures, high altitude, and dry air. Exertion under any of these conditions can cause up to a 10-fold increase in water loss from skin and lungs. Diarrhea can increase intestinal loss dramatically. FIGURE 11-1 Routes and approximate magnitude of water intake and outgo without sweating. From NRC, 1980b. M is minimal urine volume at maximal solute concentration. Ox is water of oxidation. Figure 11-1 includes an estimate of minimal urine volume required when urinary solute concentration is maximal (about 1,400 mosmol/ liter in the healthy adult and 700 mosmol/liter in the infant). Because the kidney must excrete waste products, the solute load—composed of the nitrogen-containing breakdown products of protein metabolism (principally urea), sulfates, phosphates, and other electrolytes—determines the minimal volume of water required for urine formation. Normally functioning kidneys can adjust urine osmolarity from 40 to 1,400 mosmol/liter, depending both on water intake and on dietary solute load. Despite the kidney's ability to compensate, its limitations require the effective use of the thirst sensation to maintain water balance. If the sensation of thirst is not met by water consumption, or if the thirst mechanism is inoperative because of intense, sustained exertion, especially at a high altitude (Buskirk and Mendez, 1967), dehydration will eventually result. This can become life threatening when more than 10% of body weight is lost. Sources Although water, consumed as water, is a major source of liquid in some parts of the world, much of the water consumed in the United States is taken in the form of other beverages. Median daily intake of water as such among respondents in the 1977–1978 Nationwide Food Consumption Survey was 2.8 cups (USDA, 1984). In 1981, daily per capita milk consumption was approximately one and one-third cups, per capita coffee and tea consumption was about one and one-half cups, and soft drink consumption was one and three-fourths cups per capita. In addition, many solid foods, especially fruits and vegetables, contain from 85 to 95% water. Estimate of Requirements The primary determinant of maintenance water requirement appears to be metabolic (Holliday and Segar, 1957), but the actual estimation of water requirement is highly variable and quite complex. Because the water requirement is the amount necessary to balance the insensible losses (which can vary markedly) and maintain a tolerable solute load for the kidneys (which may vary with dietary composition and other factors), it is impossible to set a general water requirement. Adults For practical purposes, 1 ml/kcal of energy expenditure can be recommended as the water requirement for adults under average conditions of energy expenditure and environmental exposure. However, there is so seldom a risk of water intoxication that the specified requirement for water is often increased to 1.5 ml/kcal to cover variations in activity level, sweating, and solute load. Special attention must be given to the water needs of the elderly whose thirst sensation may be blunted. Even though these people may be less physically active, they may still have a high water requirement, especially during the summer. If uncorrected, water depletion with heat exhaustion, resulting from inadequate replacement of fluid losses, can eventually cause a loss of consciousness and heat stroke (NRC, 1980b). Pregnancy and Lactation Pregnancy is associated with an increased need for water because of the expanded extracellular fluid space, the needs of the fetus, and the amniotic fluid. However, calculations indicate that the increment amounts to only about 30 ml/ day. A lactating woman, on the other hand, requires an increased volume of water to match that secreted in the milk. Since milk is 87% water and average milk secretion is 750 ml/day for the first 6 months, the extra fluid required would be less than 1,000 ml/day. Infants and Children Infants must be treated as a separate category for several reasons: their large surface area per unit of body weight, their higher percentage of body water and its high rate of turnover, the limited capacity of their kidneys for handling the solute load from high protein intakes required for growth, and their susceptibility to severe dehydration due in part to their inability to express thirst. It is prudent, therefore, to recommend an average water intake of 1.5 ml/kcal of energy expenditure for infants. This figure corresponds to the water-to-energy ratio in human milk and common formulas and has been well established as a satisfactory level for the growing infant. Excessive Intakes and Toxicity Toxicity results from the ingestion of water at a rate beyond the capacity of the kidneys to excrete the extra load, resulting in hyposmolarity. Such a condition is rarely observed in a normal healthy adult. The manifestations usually include a gradual mental dulling, confusion, coma, convulsion, and even death. SODIUM Sodium, the principal cation of extracellular fluid, is the primary regulator of extracellular fluid volume. Both the body content of sodium and its concentration in body fluids are under homeostatic control, and the volume of extracellular fluid is thus normally determined by its sodium content. In addition to its role in regulating extracellular fluid volume, sodium is important in the regulation of osmolarity, acid-base balance, and the membrane potential of cells. Sodium is also involved in active transport across cell membranes and must be pumped out in exchange for potassium in order to maintain an appropriate intracellular milieu—a process that requires an appreciable fraction of the energy required in the basal metabolic state. Sodium homeostasis is maintained over a wide range of environmental and dietary circumstances, primarily through the action of the hormone aldosterone on the renal tubules of the kidney. When sodium intake is high, the aldosterone level decreases and urinary sodium increases. When dietary sodium intake is low, the aldosterone level increases and urinary excretion of sodium rapidly falls almost to zero. Although the kidney can thus conserve sodium, there is some obligatory loss via feces and sweat. Sodium deficiency resulting from low dietary intake thus does not normally occur, even among those existing on very low sodium diets (Page, 1976, 1979). Even relatively heavy sweating does not normally create a need to provide salt supplements (Conn, 1949). The body may be depleted of sodium under extreme conditions of heavy and persistent sweating, or where trauma, chronic diarrhea, or renal disease produce an inability to retain sodium (Gothberg et al., 1983). These latter conditions require medical attention. Dietary Sources and Usual Intakes Foods and beverages containing sodium chloride (39% sodium by weight) are the primary sources of sodium. Sources other than table salt—e.g., sodium bicarbonate and monosodium glutamate���are believed to account for less than 10% of total dietary sodium intake (Sanchez-Castillo, 1987a). Water from community systems usually contains less than 20 mg of sodium per liter, and it has been estimated that water contributes less than 10% of daily sodium intake (NRC, 1977). By using a lithium chloride marker to trace the use of salt in cooking and at the table, Sanchez-Castillo et al. (1987a, 1987b) found that only 10% of the salt came from the natural salt content of foods, 15% from salt added during cooking and at the table, and fully 75% from salt added during processing and manufacturing. Because of the high proportion of dietary sodium accounted for by processing, the highest salt intakes are normally associated with a diet high in processed foods and the lowest intakes are associated with diets emphasizing fresh fruits, vegetables, and legumes. In the first National Health and Nutrition Examination Survey (Abraham and Carroll, 1981), 32% of the sodium chloride consumed came from baked goods and cereals, approximately 21% came from meats, and 14% from dairy products. The FDA's Total Diet Study, in which a very different methodology was used, showed similar results (Pennington et al., 1984). Usual levels of sodium consumption have been estimated in dietary surveys by assessing salt intake and by measuring urinary sodium. Reported dietary intakes of sodium range from 1.8 g/day to 5 g/day in various studies, depending on the methods of assessment used (Abraham and Carroll, 1981; Dahl, 1960; Pennington et al., 1984) and on whether or not discretionary sodium use is assessed. The discretionary intake of sodium is quite variable and can be quite large. In one 28-day study, males were found to add about 5.5 g of sodium chloride (2.2 g of sodium) to their food per day (Mickelson et al., 1977). Because of the difficulty of assessing sodium use from dietary recall, dietary surveys probably underestimate total sodium intake, even when contributions of water and other marginal sources are included. From data on daily urinary sodium excretion over 24 hours, Dahl and Love (1957) calculated the average daily adult intake of salt to be 10 g/day (4 g of sodium per day). Dahl subsequently reported a mean sodium chloride intake of 10.3 g (range, 4 to 24 g) for 71 working men in New York. Coatney et al. (1958) reported that a 5-month sodium excretion in a military population corresponded to an intake of 11 g of salt per day. Sanchez-Castillo et al. (1987a, b) found sodium chloride excretion over a 12-day period to be 10.6 ± 0.55 g in men and 7.4 ± 2.9 g in women. Estimate of Requirements Calculations of sodium requirements (shown in Table 11-1 ) are based on estimates of what is needed for growth and for replacement of obligatory losses. The amount needed to support growth depends on the rate at which extracellular fluid volume is expanded, a rate that varies with age and reproductive status. Adults In a temperate climate, the healthy adult can maintain sodium balance with a very low intake of sodium (Kempner, 1948). Dole et al. (1950) have estimated obligatory urinary and fecal losses by adults to be 23 mg (1 mEq) a per day. The other source of loss is sweat, which normally averages a sodium concentration of 25 mEq/ liter (Consolazio et al., 1963). Sanchez-Castillo et al. (1987a) found that sweat and fecal excretion contributed only 2 to 5% of the sodium lost by British men and women. Obligatory dermal losses have been assumed to range from 46 to 92 mg (2 to 4 mEq) per day (Fregley, 1984). Thus, a minimum average requirement for adults can be estimated under conditions of maximal adaptation and without active sweating as no more than 5 mEq/day, which corresponds to 115 mg of sodium or approximately 300 mg of sodium chloride per day. In consideration of the wide variation of patterns of physical activity and climatic exposure, a safe minimum intake might be set at 500 mg/day. Such an intake is substantially exceeded by usual diets in the United States, even in the absence of added sodium chloride. Although no optimal range of salt intake has been established, there is no known advantage in consuming large amounts of sodium, and clear disadvantages for those susceptible to hypertension. From this and other considerations, a Food and Nutrition Board committee recently recommended that daily intakes of sodium chloride be limited to 6 g (2.4 g of sodium) or less (NRC, 1989). Pregnancy and Lactation During pregnancy, there is an increased need for sodium because of the increased extracellular fluid volume in the mother, the requirements of the fetus, and the level of sodium in the amniotic fluid. This need is normally met in part by physiological responses of the renin-angiotensin-aldosterone systems (Pike and Smiciklas, 1972). Given a pregnancy weight gain of 11 kg (70% of which is extracellular water containing 150 mEq of sodium per liter), the average total sodium requirement for the duration of pregnancy is 3 mEq (69 mg) per day in addition to the normal requirement. Since the average intake is, as has been noted, considerably above that, the sodium requirement for pregnancy is met by usual salt intake. Lactation increases sodium requirements considerably. Since human milk contains about 7.8 mEq of sodium (180 mg) per liter (AAP, 1985), and the average milk secretion when established is about 750 ml, lactation would add about 6 mEq (135 mg) per day to the usual adult requirement. This increase is easily met by the usual dietary sodium intake. Infants and Children The sodium requirement is obviously highest in infants and young children in whom extracellular fluid volume is rapidly expanding. Forbes (1952) calculated that from birth to 3 months of age, 0.5 mEq/kg (11.5 mg/kg) daily is needed for growth, or approximately 2 mEq (46 mg) per day for the reference infant. At 6 months of age, the daily requirement for growth is approximately 0.2 mEq (4.6 mg)/kg. According to calculations by Cooke et al. (1950), daily losses of sodium from the skin range from 0.4 to 0.7 mEq/kg (9 to 16 mg/kg). Because sodium losses from the kidney can be regulated precisely when intakes are not excessive, the convenient value of 1 mEq/kg (23 mg/kg) daily is considered more than satisfactory for the healthy infant and young child residing in a temperate climate. Human milk contains 7 mEq of sodium per liter (range, 3 to 19 mEq/liter) (Gross, 1983; Macy, 1949). Consumed at a rate of 750 ml/day, this provides the reference infant with an average of 120 mg/day, which corresponds to 1.16 mEq/kg (27 mg/kg) daily from birth through 2 months of age and 0.8 mEq/kg (18 mg/kg) daily from 3 through 5 months of age. Except for the premature infant, in whom hyponatremia can occur (Roy et al., 1976), human milk certainly provides adequate sodium for the growing infant. Formula-fed infants consuming 750 ml/day now receive a minimum of 100 mg/day and a maximum of 300 mg/day (AAP, 1985). The American Academy of Pediatrics has estimated that there is a threefold increase in dietary sodium between 2 and 12 months of age (AAP, 1981). Excessive Intakes and Toxicity Acute excessive intake of sodium chloride leads to an increase in the extracellular space as water is pulled from cells to maintain sodium concentration. The end result is edema and hypertension. Such acute toxicity from dietary sodium is not a concern, however, since as long as water needs can be met, the kidney can excrete the excess sodium. Sustained overconsumption of sodium, particularly as salt, has been related to development of hypertension in sensitive individuals (NRC, 1989; Tobian, 1979). POTASSIUM Potassium is the principal intracellular cation, occurring in cell water at a concentration of 145 mEq/liter, b more than 30 times the concentration at which it is found in plasma and interstitial fluid (3.8 to 5.0 mEq/liter). This small percentage of extracellular potassium is, however, of great physiological importance, contributing to the transmission of nerve impulses, to the control of skeletal muscle contractility, and to the maintenance of normal blood pressure. More than 90% of ingested potassium is absorbed from the gastrointestinal tract, but higher or lower intakes are not reflected in fluctuations in plasma potassium concentrations because the kidney can regulate potassium balance. Potassium is lost from the body in the urine and, to a lesser extent, in gastrointestinal secretions, whereas only minimal amounts are excreted in sweat. Under normal circumstances, dietary deficiency of potassium does not occur. The most important cause of potassium deficiency is excessive losses, usually through the alimentary tract or the kidneys. Large alimentary potassium losses may occur through prolonged vomiting, chronic diarrhea, or laxative abuse. The most common cause of excessive renal loss is the use of diuretic agents, especially for the treatment of hypertension. Some forms of chronic renal disease and metabolic disturbances (e.g., diabetic acidosis) can also lead to severe potassium loss. Deficiency symptoms include weakness, anorexia, nausea, listlessness, apprehension, drowsiness, and irrational behavior. Severe hypokalemia may result in cardiac dysrhythmias that can be fatal. Dietary Sources and Usual Intakes Potassium is widely distributed in foods, since it is an essential constituent of all living cells. Animal tissue concentration of potassium is fairly constant, but varies inversely with the amount of fat. Some potassium is also added in food processing, but the overall effect of processing on the food supply has been to increase the sodium and decrease the potassium (NRC, 1989). Thus, the richest dietary sources are unprocessed foods, especially fruits, many vegetables, and fresh meats. The contribution of drinking water to potassium intake is negligible. The mean concentration in household tap water was reported to be 2.15 mg/liter (range, 0.72 to 8.3 mg/liter) (Greathouse and Crown, 1979; NRC, 1980a). Potassium intakes vary considerably, depending on food selection. People who eat large amounts of fruits and vegetables have a high potassium intake, on the order of 8 to 11 g/day (NRC, 1989). In the FDA's Total Diet Study, mean potassium intake in the United States during 1981–1982 was found to be 1,500 mg/day for 6-month-old infants, 1,800 mg/day for 2-year-old children, and 3,400 mg/day for 15- to 20-year olds (Pennington et al., 1984). Urban whites eat about 2,500 mg/day (Khaw and Barrett-Connor, 1987); low intakes of about 1,000 mg/day have been reported in blacks (Grim et al., 1980; Langford, 1985). Human milk contains about 500 mg (12.8 mEq) of potassium per liter, and therefore provides the reference infant consuming 750 ml daily with 375 mg/day. Infant formulas contain slightly more potassium than human milk on the average, and cow's milk contains almost 3 times as much, 1,365 mg (35 mEq) per liter. Estimate of Requirements Adults Potassium requirements have been evaluated in only a few studies. Although losses on a low or “minimum” potassium diet are small, potassium is less well conserved than sodium (see Table 11-1 ). Fecal losses are less than 400 mg (10 mEq) per day, and renal losses may approach 200 to 400 mg (5 to 10 mEq) per day (Squires and Huth, 1959). Other losses (e.g., in sweat) are negligible. On intakes of about 20 mEq/day, metabolic balance is achieved at the expense of reduced body potassium stores (up to 250 mEq) and in some cases with reduced plasma levels (<4 mEq/liter). To maintain normal body stores and a normal concentration in plasma and interstitial fluid, an intake of about 40 mEq/day may be needed (Sebastian et al., 1971). Therefore, it would appear that the minimum requirement is approximately 1,600 to 2,000 mg (40 to 50 mEq) per day. There is considerable evidence that dietary potassium exerts a beneficial effect in hypertension, and recommendations for increased intake of fruits and vegetables (NRC, 1989) would raise potassium intake of adults to about 3,500 mg (90 mEq) per day. TABLE 11-1 Estimated Sodium, Chloride, and Potassium Minimum Requirements of Healthy Persons. Pregnancy and Lactation There is no evidence that potassium requirements are appreciably increased during pregnancy, except for the increment needed to build new tissue, which is easily satisfied by the usual ingestion of potassium. Since maternal milk contains about 500 mg (12.8 mEq) per liter, this increased loss must be considered during lactation, but is supplied by usual intakes. Infants and Children Since potassium is a necessary constituent of each body cell, an increase in lean body mass is a major determinant of potassium needs. From 60 to 80 mEq are required for each kilogram of weight gained. Using growth rates for infants and children calculated from the reference weight data reported by Hammill et al. (1979), and assuming that 70 mEq of potassium are required for each kg of body weight, one may estimate that the potassium requirement for growth averages 65 mg/day for infants, 15 to 20 mg/ day for 1- to 10-year-old children, and 35 mg/day for adolescents. To allow for obligatory urinary, cutaneous, and fecal losses, dietary intake must, of course, be higher than the amount required at the tissue level. Holliday and Segar (1957) have estimated that in general, 78 mg (2 mEq) per 100 kcal should maintain potassium balance in children of all ages as long as there is no preexisting potassium deficit or ongoing excessive loss. This is in keeping with data on potassium intake in infants and children showing that average potassium intake (from milk and solid foods) ranges from about 780 mg/day at 2 months of age to about 1,600 mg/day at the end of the first year of life (AAP, 1981). Excessive Intakes and Toxicity In the absence of markedly increased losses of potassium from the body, acute intoxication (hyperkalemia) will result from sudden enteral or parenteral increases in potassium intake to levels about 12.0 g/m 2 (250 to 300 mEq/m 2 ) of surface area per day—about 18 g for an adult (NRC, 1980b). Although urinary excretion provides some protection, acute hyperkalemia can prove fatal because it can cause cardiac arrest. CHLORIDE Chloride, the principal inorganic anion in the extracellular fluid compartment, is essential in maintaining fluid and electrolyte balance, and is a necessary component of gastric juice. It occurs in plasma in concentrations of 96 to 106 mEq/liter, c and in a more concentrated form in cerebrospinal fluid and gastrointestinal secretions. Its concentration in most cells is low. Under normal circumstances, dietary deficiency of chloride does not occur. The only known instance of diet-related chloride depletion occurred in healthy infants inadvertently fed diets containing 1 to 2 mEq/liter (Grossman et al., 1980; Rodriguez-Soriano et al., 1983; Roy and Arant, 1981) rather than the minimum of 10.4 mEq/liter now recommended (AAP, 1985). Chloride loss tends to parallel losses of sodium; hence, conditions associated with sodium depletion (e.g., heavy, persistent sweating, chronic diarrhea or vomiting, trauma, or renal disease) will also cause chloride loss, resulting in hypochloremic metabolic alkalosis. Dietary Sources and Usual Intakes Dietary chloride comes almost entirely from sodium chloride. Much smaller amounts are supplied from potassium chloride. Therefore, dietary sources of chloride are essentially the same as those described for sodium, and processed foods are the major source. Although chloride is also found in almost all natural waters, estimates by the Environmental Protection Agency (EPA, 1975) suggest a daily contribution of 42 mg/day. This is insignificant compared to the roughly 6 g of chloride a day contributed by added salt. Estimate of Requirements Because both the intake of chloride from food and its losses from the body under normal conditions parallel those of sodium, the requirements specified for all age and sex groups except infants parallel those of sodium on a mEq basis (see Table 11-1 ). Human milk contains 11 mEq of chloride per liter, which makes the chloride level higher than the sodium level on a mEq basis. The American Academy of Pediatrics has suggested a similar level (10.4 mEq/liter) for infant formulas on the grounds that a 1.5–2.0 ratio of sodium plus potassium to chloride maintained good acid-base regulation in infants (AAP, 1985). Excessive Intakes and Toxicity The toxicity of salts containing the chloride ion depends mainly on the characteristics of the cation. The only known dietary cause of hyperchloremia is water-deficiency dehydration. Sustained ingestion of high levels of chloride (as salt) has been associated with elevated blood pressure in sensitive individuals and animal models (Kurtz et al., 1987; Whitescarver et al., 1986). REFERENCES AAP (American Academy of Pediatrics). 1981. Sodium intake of infants in the United States . Pediatrics 68: 444–445. [ PubMed : 7279479 ] AAP (American Academy of Pediatrics). 1985. Pediatric Nutrition Handbook , 2nd Ed. 
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+Washington, D.C. Gothberg, G., S. Lundin, M. Aurell, and B. Folkow. 1983. Responses to slow graded bleeding in salt-depleted rats . J. Hypertens . Suppl. 2: 24–26. [ PubMed : 6599490 ] Greathouse, D.G., and G.F. Crown. 1979. Cardiovascular disease study—occurrence of inorganics in household tap water and relationships to cardiovascular mortality rates . Pp. 31–39 in D.D. Hemphill, editor. , ed. Trace Substances in Environmental Health-XII . Proceedings of the 12th Annual Conference, 1978, 
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+1983. Growth and biochemical response of preterm infants fed milk or modified infant formula . N. Engl. J. Med. 308: 237. [ PubMed : 6848932 ] Grossman, H., E. Duggan, S. McCamman, E. Welchert, and S. Hellerstein. 1980. The dietary chloride deficiency syndrome . Pediatrics 66: 366–374. [ PubMed : 6932641 ] Hamill, P.V.V., T.A. Drizd, C.L. Johnson, R.B. Reed, A.F. Roche, and W.M. Moore. 1979. Physical growth . National Center for Health Statistics Percentiles. Am. J. Clin. Nutr. 32: 607–629. [ PubMed : 420153 ] Holliday, M.A., and W.E. Segar. 1957. The maintenance need for water in parental fluid therapy . Pediatrics 19: 823. [ PubMed : 13431307 ] Kempner, W.
+1948. Treatment of hypertension vascular disease with rice diet . Am. J. Med. 4: 545. [ PubMed : 18909456 ] Khaw, K.T., and E. Barrett-Connor. 1987. Dietary potassium and stroke-associated mortality . A 12-year prospective population study. N. Engl. J. Med. 316: 235–240. [ PubMed : 3796701 ] Kurtz, T.W., H.A. Al-Bander, and R.C. Morris. 1987. ‘Salt sensitive' essential hypertension in men . N. Engl. J. Med. 317: 1043–1048. [ PubMed : 3309653 ] Langford, H.G.
+1985. Dietary potassium and hypertension . Pp. 147–153 in M.J. Horan, editor; , M. Blaustein, editor; , J.B. Dunbar, editor; , W. Kachadorian, editor; , N.M. Kaplan, editor; , and A.P. Simopoulos, editor. , eds. NIH Workshop on Nutrition and Hypertension: Proceedings from a Symposium . 
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+1949. Compositon of human colostrum and milk . Am. J. Dis. Child. 78: 589. [ PubMed : 18141078 ] Mickelson, O., D. Makdani, J.L. Gill, and R.L. Frank. 1977. Sodium and potassium intakes and excretions of normal men consuming sodium chloride or a 1:1 mixture of sodium and potassium chloride . Am. J. Clin. Nutr. 30: 2033. [ PubMed : 930873 ] NRC (National Research Council). 1977. Drinking Water and Health . Report of the Safe Drinking Water Committee, Advisory Center on Toxicology, Assembly of Life Sciences. 
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+Washington, D.C. 939 pp. NRC (National Research Council). 1980. a. Drinking Water and Health , Vol. 3. Report of the Safe Drinking Water Committee, Board on Toxicology and Environmental Health Hazards, Assembly of Life Sciences. 
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+Washington, D.C. 415 pp. NRC (National Research Council). 1980. b. Recommended Dietary Allowances , 9th Revised Ed. Committeee on Dietary Allowances, Food and Nutrition Board, Division of Biological Sciences, Assembly of Life Sciences . 
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+Washington, D.C. 185 pp. NRC (National Research Council), 1989. Diet and Health: Implications for Reducing Chronic Disease Risk . Report of the Committee on Diet and Health, Fovod and Nutrition Board. 
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+Washington, D.C. 750 pp. [ PubMed : 25032333 ] Page, L.B.
+1976. Epidemiologic evidence on the etiology of human hypertension and its possible prevention . Am. Heart J. 91: 527–534. [ PubMed : 769520 ] Page, L.B.
+1979. Hypertension and atherosclerosis in primitive and acculturating societies . Pp. 1–12 in J.C. Hunt, editor. , ed. Hypertension Update , Vol; 1. 
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+Lyndhurst, N.J. Pennington, J.A.T., D.B. Wilson, R.F. Newell, B.F. Harland, R.D. Johnson, and J.E. Vanderveen. 1984. Selected minerals in food surveys, 1974 to 1981/82 . J. Am. Diet. Assoc. 84: 771–780. [ PubMed : 6736504 ] Pike, R.L., and H.A. Smiciklas. 1972. A reappraisal of sodium restriction during pregnancy . Int. J. Gynecol. Obstet. 10: 1–8. Rodriguez-Soriano, J., A. Vallo, G. Castillo, R. Oiveros, J.M. Cea, and M.J. Balzategui. 1983. Biochemical features of dietary chloride deficiency syndrome: a comparative study of 30 cases . J. Pediatr. 103: 209–214. [ PubMed : 6875710 ] Roy, S., and B.S. Arant. 1981. Hypokalemic metabolic alkalosis in normotensive infants with elevated plasma renin activity and hyperaldosteronism: role of dietary chloride deficiency . Pediatrics 67: 423–429. [ PubMed : 7017580 ] Roy, R.N., G.W. Chance, I.C. Radde, D.E. Hill, D.M. Willis, and J. Sheepers. 1976. Late hyponatremia in very low birthweight infants less than 1.3 kilograms . Pediatr. Res. 10: 526–531. [ PubMed : 934723 ] Sanchez-Castillo, C.P., S. Warrender, T.P. Whitehead, and W.P. James. 1987. a. An assessment of the sources of dietary salt in a British population . Clin. Sci. 72: 95–102. [ PubMed : 3802726 ] Sanchez-Castillo, C.P., W.J. Branch, and W.P. James. 1987. b. A test of the validity of the lithium-marker technique for monitoring dietary sources of salt in men . Clin. Sci. 72: 87–94. [ PubMed : 3802725 ] Sebastian, A., E. McSherry, and R.C. Morris, Jr.
+1971. Renal potassium wasting in renal tubular acidosis (RTA): its occurrence in Types 1 and 2 RTA despite sustained correction of systemic acidosis . J. Clin. Invest. 50: 667–678. [ PMC free article : PMC291975 ] [ PubMed : 5101785 ] Squires, R.D., and E.J. Huth. 1959. Experimental potassium depletion in normal human subjects. I . Relation of ionic intakes to the renal conservation of potassium. J. Clin. Invest. 38: 1134–1148. [ PMC free article : PMC293261 ] [ PubMed : 13664789 ] Tobian, L., Jr.
+1979. The relationship of salt to hypertension . Am. J. Clin. Nutr. 32: 2739–2748. [ PubMed : 389029 ] USDA (U.S. Department of Agriculture). 1984. Nationwide Food Consumption Survey . Nutrient Intakes: Individuals in 48 States, Year 1977–78 . Report No. 1-2. 
+Consumer Nutrition Division, Human Nutrition Information Service, U.S. Department of Agriculture, 
+Hyattsville, Md. 439 pp. Whitescarver, S.A., B.J. Holtzclaw, J.H. Downs, O.H. Co, J.R. Sowers, and T.A. Kotchen. 1986. Effect of dietary chloride on salt-sensitive and renin-dependent hypertension . Hypertension 8: 56–61. [ PubMed : 3510973 ] Footnotes a 1 mEq of sodium is 23 mg, and 1 mmol of sodium chloride is 58.5 mg. b 1 mEq of potassium is 39 mg. c 1 mEq of chloride is 35.5 mg. Copyright © 1989 by the National Academy of Sciences. Bookshelf ID: NBK234935 Contents < Prev Next > Share Views PubReader Print View Cite this Page National Research Council (US) Subcommittee on the Tenth Edition of the Recommended Dietary Allowances. Recommended Dietary Allowances: 10th Edition. Washington (DC): National Academies Press (US); 1989.  11, Water and Electrolytes. PDF version of this title (1.9M) In this Page WATER SODIUM POTASSIUM CHLORIDE REFERENCES Other titles in this collection The National Academies Collection: Reports funded by National Institutes of Health Related information PMC PubMed Central citations PubMed Links to PubMed Recent Activity Clear Turn Off Turn On Water and Electrolytes - Recommended Dietary Allowances Water and Electrolytes - Recommended Dietary Allowances Your browsing activity is empty. Activity recording is turned off. Turn recording back on See more... Follow NCBI Twitter Facebook LinkedIn GitHub NCBI Insights Blog Connect with NLM Twitter Facebook Youtube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov

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+Significance of HbA1c Test in Diagnosis and Prognosis of Diabetic Patients - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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+    the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Biomark Insights. 2016; 11: 95–104. Published online 2016 Jul 3. doi: 10.4137/BMI.S38440 PMCID: PMC4933534 PMID: 27398023 Significance of HbA1c Test in Diagnosis and Prognosis of Diabetic Patients Shariq I. Sherwani , 1 Haseeb A. Khan , 2 Aishah Ekhzaimy , 3 Afshan Masood , 4 and Meena K. Sakharkar 5 Shariq I. Sherwani 1 Department of Internal Medicine, Division of Pulmonary Medicine, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH, USA. Find articles by Shariq I. Sherwani Haseeb A. Khan 2 Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia. Find articles by Haseeb A. Khan Aishah Ekhzaimy 3 Division of Endocrinology, Department of Medicine, King Khalid University Hospital, Riyadh, Saudi Arabia. Find articles by Aishah Ekhzaimy Afshan Masood 4 Obesity Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia. Find articles by Afshan Masood Meena K. Sakharkar 5 Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Canada. Find articles by Meena K. Sakharkar Author information Article notes Copyright and License information PMC Disclaimer 1 Department of Internal Medicine, Division of Pulmonary Medicine, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH, USA. 2 Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia. 3 Division of Endocrinology, Department of Medicine, King Khalid University Hospital, Riyadh, Saudi Arabia. 4 Obesity Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia. 5 Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Canada. CORRESPONDENCE: moc.oohay@beesah_nahk ; as.ude.usk@beesah Received 2016 Feb 5; Revised 2016 Jun 9; Accepted 2016 Jun 9. Copyright © 2016 the author(s), publisher and licensee Libertas Academica Ltd. This is an open-access article distributed under the terms of the Creative Commons CC-BY-NC 3.0 License. Abstract Diabetes is a global endemic with rapidly increasing prevalence in both developing and developed countries. The American Diabetes Association has recommended glycated hemoglobin (HbA1c) as a possible substitute to fasting blood glucose for diagnosis of diabetes. HbA1c is an important indicator of long-term glycemic control with the ability to reflect the cumulative glycemic history of the preceding two to three months. HbA1c not only provides a reliable measure of chronic hyperglycemia but also correlates well with the risk of long-term diabetes complications. Elevated HbA1c has also been regarded as an independent risk factor for coronary heart disease and stroke in subjects with or without diabetes. The valuable information provided by a single HbA1c test has rendered it as a reliable biomarker for the diagnosis and prognosis of diabetes. This review highlights the role of HbA1c in diagnosis and prognosis of diabetes patients. KEYWORDS: diabetes, HbA1c, diagnosis, prognosis, blood test Introduction Analysis of glycated hemoglobin (HbA1c) in blood provides evidence about an individual’s average blood glucose levels during the previous two to three months, which is the predicted half-life of red blood cells (RBCs). 1 The HbA1c is now recommended as a standard of care (SOC) for testing and monitoring diabetes, specifically the type 2 diabetes. 2 Historically, HbA1c was first isolated by Huisman et al. 3 in 1958 and characterized by Bookchin and Gallop 4 in 1968, as a glycoprotein. The elevated levels of HbA1c in diabetic patients were reported by Rahbar et al. 5 in 1969. Bunn et al. 6 identified the pathway leading to the formation of HbA1c in 1975. Using the HbA1c as a biomarker for monitoring the levels of glucose among diabetic patients was first proposed by Koenig et al. 7 in 1976. Proteins are frequently glycated during various enzymatic reactions when the conditions are physiologically favorable. However, in the case of hemoglobin, the glycation occurs by the nonenzymatic reaction between the glucose and the N-terminal end of the β-chain, which forms a Schiff base. 8 , 9 During the rearrangement, the Schiff base is converted into Amadori products, of which the best known is HbA1c ( Fig. 1 ). In the primary step of glycated hemoglobin formation, hemoglobin and the blood glucose interact to form aldimine in a reversible reaction. In the secondary step, which is irreversible, aldimine is gradually converted into the stable ketoamine form. 10 The major sites of hemoglobin glycosylation, in the order of prevalence, are β-Val-1, β-Lys-66, and α-Lys-61. Normal adult hemoglobin consists predominantly of HbA (α2β2), HbA2 (α2δ2), and HbF (α2γ2) in the composition of 97%, 2.5%, and 0.5%, respectively. About 6% of total HbA is termed HbA1, which in turn is made up of HbA1a1, HbA1a2, HbA1b, and HbA1c fractions, defined by their electrophoretic and chromatographic properties. HbA1c is the most abundant of these fractions and in health comprises approximately 5% of the total HbA fraction. As mentioned above, glucose in the open chain format binds to the N-terminal to form an aldimine before undergoing an Amadori rearrangement to form a more stable ketoamine. This is a nonenzymatic process that occurs continuously in vivo . The formation of the glycated hemoglobin is a normal part of the physiologic function cycle. However, as the average plasma glucose increases, so does the amount of glycated hemoglobin in the plasma. This specific characteristic of the hemoglobin biomarker is utilized for estimating the average blood glucose levels over the previous two to three months. 11 In this review, we have described the current trends in diabetes prevalence, diagnostic and prognostic potential of HbA1c, analytical aspects in HbA1c assays, and physiological changes due to hemoglobin glycation. Open in a separate window Figure 1 Formation of glycated hemoglobin (HbA1c) from the binding of glucose to hemoglobin. Diabetes – a Silent Killer According to the 2014 release of the American Diabetes Association (ADA), as of 2012, 29.1 million Americans, or 9.3% of the total US population, had diabetes. 12 Type 1 diabetes is prevalent among approximately 1.25 million American children and adults. A large percentage of Americans (about 28%) were undiagnosed diabetes cases from among the 29.1 million cases (21.0 million diagnosed and 8.1 million undiagnosed). The Americans aged 65 and older (senior citizens) are at a much higher risk (25.9% or 11.8 million, diagnosed and undiagnosed combined). Even though the incidence of new diabetes cases is astounding, the trajectory appeared to have slowed momentarily, with 1.7 million new diagnoses per year as reported in 2012 as compared to 1.9 million in 2010, reflecting fewer cases diagnosed in 2012 than in 2010. This raises the question – is this really a downward trend or have many diabetes cases gone unreported and undiagnosed due to various confounding factors? The prediabetes cases have been on an upward swing with 86 million Americans, aged 20 years or older, having been reported as being prone to diabetes (pre-diabetes) as of 2012, which is higher than the 2010 estimates (79 million). Based on race and ethnicity, diabetes affects 7.6% of non-Hispanic whites, 9.0% of Asian Americans, 12.8% of Hispanics, 13.2% of non-Hispanic blacks, and 15.9% of American Indians/Alaskan Natives, among the US population. Diabetes is the seventh leading cause of death in the US. According to the ADA, 69,071 death certificates listed diabetes as the underlying cause of death in 2010. A total of 234,051 death certificates listed diabetes as an underlying or contributing cause of death. According to the latest statistics available, the total costs of diagnosed diabetes in the US as of 2012 was $245 billion, of which, $176 billion was spent toward direct medical costs and $69 billion costs were associated with reduced productivity. So, it is easy to see how detrimental diabetes is to the overall health of the population and the economy of the United States. Diabetes – a Global Epidemic The worldwide picture of diabetes is not much better either, with 387 million people with confirmed diabetes according to the latest census. 13 According to the 2014 estimate, the prevalence of diabetes in the world was 9%, among adults aged 18 years or older. It is projected that by the year 2035, those affected by diabetes will be around 592 million. The population with type 2 diabetes continues to increase worldwide. Among the total diabetes patients, 77% live in low- and middle-income countries and 40–49-year olds have the largest number of people of any group. It is estimated that as many as 179 million people remain undiagnosed, for various reasons, but may be affected by diabetes. Every seven seconds, dia betes causes the death of an individual worldwide, and in 2014 alone, 4.9 million deaths were attributed to diabetes with 80% of deaths related to diabetes reported from low- and middle-income countries. In 2014, the overall health expenditure, as a result of diabetes, was estimated as $612 billion, which is approximately 11% of the total spending on adults. In 2013, type 1 diabetes was reported in more than 79,000 children. Gestational diabetes was responsible for more than 21 million live births, affecting both the mother and the newborn, in one way or the other, in 2013. 13 The North America and Caribbean region spends the most amount of money on diabetes health care than any other region of the world and still has more than 39 million diabetes patients, and this number is projected to increase to 50 million by 2035, as shown in Figure 2 . The prediction for the South and Central America region does not look good with 2035 projections predicting the diabetes to increase by 60%. In the Middle East and North Africa (MENA) region, 10% of the population (more than 37 million cases) has diabetes, which is predicted to increase to 68 million by 2035, with many prediabetes and undiagnosed cases. Saudi Arabia, representing the MENA region, has reported 3.8 million confirmed cases of diabetes as of 2014, with still many unreported and/or undiagnosed cases. According to the 2014 data, more than 20% (3,806.4 million diabetics out of the total population of 18,546 million) of the Saudi Arabian adult population (aged 20 years and older) has diabetes. The total number of deaths due to diabetes in Saudi Arabia was reported as 25,527 in 2014 and the cost per person with diabetes is estimated to be $1,067.30. And, the total number of undiagnosed cases of diabetes among adults is apprized as more than 1.5 million. The projected trajectory for diabetes in Saudi Arabia is alarming, particularly among the 40–49 age group, as reflected in Figure 2 . 13 The increase in the incidence of diabetes in Saudi Arabia has been attributed to significant changes in cultural and socioeconomic factors, such as increase in affluence, which unmasks an increase in the genetic or ethnic propensity for diabetes, in addition to physical inactivity and changes in dietary habits with the substitution of animal products and refined foods. 14 – 16 Open in a separate window Figure 2 Prevalence of diabetes in ( A ) USA and ( b ) Saudi Arabia versus the entire world. Source: https://www.idf.org/membership/mena/saudi-arabia . Abbreviations: NAC, North America and Caribbean; MENA, Middle East and North Africa. Southeast Asia region remains the biggest challenge with approximately half of the diabetic population, which may still be undiagnosed. Among the Western Pacific region (China, Australia, New Zealand, Malaysia, Mongolia, Philippines, etc.), an estimated 138 million adult individuals have diabetes, which is the highest among any region in the world. In China, diabetes has acquired epidemic proportions and continues to develop at an unprecedented rate. China has overtaken the United States in the prevalence of diagnosed cases of diabetes, with 11.6% of Chinese adults affected by confirmed cases of diabetes. 13 The Chinese diabetes population (approximately 114 million) alone is one-third of the entire diabetes population in the world, and the growing number of cases will continue to put enormous strain on China’s health-care system and the overall economy. Representing the South Asia region of the world, India is home to approximately 67 million (66,847.9 million) cases of diabetes, which is about 8.6% of the total adult population (20–79 years) and continues to grow at an alarming rate (2010 estimates: 50.8 million). 13 Obesity, associated with diabetes, has reached epidemic proportions among middle-class children and adolescents due to their exposure to fast food diets and lack of exercise and physical activity. In Russia, 6.2% of the entire adult population (20–79 years old) is suffering from diabetes with more than 6.7 million cases of diabetes. 13 It is estimated that there may be as many as 2.3 million cases of undiagnosed diabetes among the adults. Regionally, Africa region remains at the forefront with majority of the deaths occurring as a result of diabetes and its complication are confined in people younger than 60 years old. Presently, there are approximately 2 million cases of diabetes in South Africa. 13 The total number of people with diabetes may be even higher due to many undiagnosed and unreported cases, which is quite common in many developing countries. As of 2014, more than 11.6 million (8.7% adults) Brazilians had diabetes, which continues to grow with approximately 33 million reporting high blood pressure. More than 80,000 deaths per year are attributed to diabetes in Brazil. The prevalenceof type 1 diabetes is the highest in the Europe (EUR) region. The EUR region has a total of 52 million diabetes patients, and this number is expected to increase to 69 million by 2035. Representing the EUR region, Germany had over 7.2 million cases of diabetes as of 2014. 13 Diagnostic Potentials of HbA1c The ADA has recently recommended HbA1c with a cut-point ≥6.5% for diagnosing diabetes as an alternative to fasting plasma glucose (FPG ≥7.0 mmol/L)-based criteria. 17 The levels of HbA1c are strongly correlated with FPG ( Fig. 3 ). 18 FPG, 2-hour post-glucose load plasma glucose, and oral glucose tolerance tests are recommended for the diagnosis of diabetes only if HbA1c testing is not possible due to unavailability of the assay, patient factors that preclude its interpretation, and during pregnancy. 19 HbA1c provides a reliable measure of chronic glycemia and correlates well with the risk of long-term diabetes complications, so that it is currently considered the test of choice for monitoring and chronic management of diabetes. However, the cut-point of HbA1c from the diagnostic point of view is still controversial. Among diabetics, the blood glucose levels increase in the blood and the glucose attaches to the hemoglobin molecule in a concentration-dependent manner. The glucose-bound (glycated) hemoglobin or HbA1c provides the average glucose levels in an individual’s blood as it becomes glycated with the hemoglobin. It is important to note that the HbA1c levels are directly proportional to the blood glucose levels. A simple blood glucose test such as a fasting glucose test (FGT) is a measure of glucose concentration present in an individual’s blood at a given point of time. 20 The blood used for the FGT may be obtained through a needlestick of a finger or directly from the arm. A new techno logy, continuous glucose monitoring, has arrived in the market, which allows for non-prick readings. 21 – 23 A small chip is implanted under the skin, which provides continuous glucose monitoring readings to the sensor kept outside, and if the glucose levels are higher or lower, it sends a special signal to the sensor, thus alerting the patient and/or the health-care provider for intervention. 22 , 23 The FGT is an excellent test for “in the moment” glucose levels, but it does not provide detailed information about the time course trend of the glucose levels. The HbA1c test, however, is a marker of the average glucose levels spread over a two- to three-month period. Contrary to popular belief, along with the type 2 diabetes, the HbA1c is also used to diagnose, manage, and monitor the type 1 diabetes as well. 24 In a series of 12,785 male diabetic patients, Khan et al. 11 have shown that the HbA1c cut-point of 6.5% was associated with 3.78% false-negative predictions ( Fig. 4 ), while majority of the false-negative patients had borderline FPG (7.0–8.0 mmol/L) and HbA1c (6.0%–6.5%), and therefore belonged to at-risk category on the basis of HbA1c alone criteria. These findings suggest that the status of individuals with HbA1c between 6.0% and 6.5% should be verified by combined FPG and HbA1c criteria. 11 Recently, Khan et al. 25 have provided regression equations for interconversions between the levels of FGT and HbA1c for predicting their expected values in diabetic patients. Open in a separate window Figure 3 Correlation between HbA1c and FBG in type 2 diabetic patients. Clinical and Experimental Medicine, Association between glycaemic control and serum lipids profile in type 2 diabetic patients: HbA1c predicts dyslipidaemia. Volume 7, 2007, 24–29, Khan HA, Sobki SH, Khan SA. (Copyright © 2007, Springer-Verlag Italia) Reused with permission of Springer. Open in a separate window Figure 4 Diagnostic potential of HbA1c. Notes: The histogram is showing the frequency of patients versus HbA1c. The vertical reference line shows the cutoff value of 6.5% HbA1c. Reprinted from Khan et al. 11 with permission from Taylor and Francis, www.tandfonline.com . Not requiring fasting and also not being bound by the time of the day on the part of the patient, the HbA1c is a very convenient test to administer and evaluate. 26 Diabetes, the silent killer, can be detected earlier, and an appropriate treatment regimen can be implemented sooner than later among people. The blood glucose data available from HbA1c are used in prescribing and monitoring the medicines for diabetes and prediabetes, along with exercise and diet. The accuracy of this test has continued to evolve over the last several years and is becoming the go-to option for SOC for detecting blood glucose values among patients in clinics. According to the National Glycohemoglobin Standardization Program (NGSP), which developed the A1C tests, the accuracy has continued to evolve and got more precise over time. 27 The HbA1c is recommended to be performed at least twice a year in diabetes patients with stable blood glucose levels. 28 Still, there is no substitute for the daily (several times a day) monitoring of the blood glucose, particularly those on insulin regimen as the readings dictate the amount of insulin that a patient must take before each meal. The estimated average glucose can also be calculated from the actual HbA1c levels to help individuals with diabetes to correlate these levels with the daily monitoring of glucose levels. 29 , 30 The HbA1c levels differ for different diabetes patients, depending on their history of diabetes and whether they are on tablets or long-term and/or short-term insulin dosage. 29 Type 2 diabetes mellitus (DM) manifests itself in terms of hyperglycemia due to compromised insulin production (no production or nonavailability). 31 The significance of the HbA1c test lies in the diagnosis and the prognosis of the diabetes patients, which lends it to a detailed understanding of insulin and insulin resistance. There is a direct correlation between HbA1c and insulin resistance, where HbA1c has been shown to be more strongly associated with the insulin sensitivity in healthy subjects with normal glucose tolerance. 32 The HbA1c test has revealed mini mal overlap in values between normal glucose tolerance in subjects with type 2 diabetes while comparing the glycemic spectrum for insulin resistance. As a result, HbA1c is a reliable biomarker and an excellent indicator of insulin resistance for testing individuals for diabetes and prediabetes. 33 Kwon et al. 34 evaluated the clinical usefulness of HbA1c in diagnosing gestational diabetes mellitus (GDM) and predicting the risk of future type 2 DM development among GDM patients. HbA1c showed high sensitivity with relatively low specificity for diagnosis of GDM in pregnant women but was a potential predictor of postpartum DM. The prognostic value of HbA1c for postpartum DM was evaluated by receiver-operating characteristic curve analysis, with a sensitivity of 78.6% and a specificity of 72.5% at a cut-off value of 5.55%. 34 A retrospective cohort study on women who delivered and had an early screening HbA1c test performed at ≤20 weeks of gestation showed that nearly one-third of those patients in the HbA1c 5.7%–6.4% group (27.3%) experienced the development of GDM compared with only 8.7% in the HbA1c <5.7% group. 35 Thus, women with HbA1c 5.7%–6.4% have a significantly higher risk of progression to GDM compared with women with normal HgbA1c values and should be considered for closer GDM surveillance and possible intervention. Although paired values of blood glucose and serum fructosamine were also reported for the screening of GDM, there were significant fluctuations during several antenatal visits. 36 , 37 Prognostic Potentials of HbA1c HbA1c is not only a useful biomarker of long-term glycemic control but also a good predictor of lipid profile; thus, monitoring of glycemic control using HbA1c could have additional benefits of identifying diabetes patients who are at a greater risk of cardiovascular complications. 18 Thus, a single HbA1c test provides valuable information that can be used for the management of chronic diseases. In a series of 1,011 type 2 diabetic patients, HbA1c exhibited direct correlations with cholesterol, triglycerides, and low density lipoprotein cholesterol and inverse correlation with high-density lipoprotein cholesterol. There was a linear relationship between HbA1c and dyslipidemia as the levels of serum cholesterol and triglycerides were significantly higher and that of high-density lipo-protein cholesterol were significantly lower in patients with worse glycemic control as compared to patients with good glycemic control ( Fig. 5 ). 18 Open in a separate window Figure 5 Prognostic potential of HbA1c. Impact of HbA1c on various parameters. The patients were categorized into three groups according to HbA1c levels: group 1 (HbA1c ≤6%), group 2 (HbA1c >6%–9%), and group 3 (HbA1c >9%). Notes: * P < 0.05, ** P < 0.01, and *** P < 0.001 group 1 versus group 2; # P < 0.05 and ### P < 0.001 group 2 versus group 3. Clinical and Experimental Medicine, Association between glycaemic control and serum lipids profile in type 2 diabetic patients: HbA1c predicts dyslipidaemia. Volume 7, 2007, 24–29, Khan HA, Sobki SH, Khan SA. (Copyright © 2007, Springer-Verlag Italia) Reused with permission of Springer. Elevated level of HbA1c has been identified as a significant risk factor for cardiovascular diseases and stroke in subjects who may have diabetes. 38 A community-based population study on 11,092 nondiabetic patients found that elevated HbA1c level was strongly associated with the risk of cardiovascular disease and mortality. 39 High levels of HbA1c were associated with an increased risk of recurrence of atrial tachyarrhythmia in patients with type 2 DM and paroxysmal atrial fibrillation undergoing catheter ablation. 40 Even an increase of 1% in HbA1c concentration was associated with about 30% increase in all-cause mortality and 40% increase in cardiovascular or ischemic heart disease mortality, among individuals with diabetes. 41 Whereas reducing the HbA1c level by 0.2% could lower the mortality by 10%. 41 Vaag 42 has suggested that improving glycemic control in patients with type 2 diabetes may be more important than treating dyslipidemia for the prevention of both microvascular and macrovascular complications. Cicek et al. 43 determined the effect of HbA1c on the outcomes of primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). They observed that in-hospital mortality and major adverse cardiac events were significantly higher in patients with HbA1c ≥6.5% (11%) compared with the group of patients with HbA1c between 5.7% and 6.4% (2.8%) or HbA1c ≤5.6% (0.9%). Out of the total 374 patients, 196 (63.6%) patients without a history of DM had elevated HbA1c ≥5.7%, with 31 (10.1%) of them having HbA1c ≥6.5%. 43 On the basis of 12-month follow-up of 1,433 patients with stable angina who underwent coronary angiography, it was concluded that high level of baseline HbA1c appeared to be an independent predictor for the severity of coronary artery disease and poor outcome in patients with stable coronary artery disease. 44 As the levels of HbA1c increased, patients were more likely to have prior cardiovascular disease and a more unfavorable baseline cardiovascular risk profile in a cohort of AMI patients. 45 Although the admission glucose levels may represent a marker for increased risk in the acute and subacute setting after AMI, HbA1c, being a surrogate for more chronic dysglycemia, is clearly a more useful marker of patients with greater long-term risk of death. 45 However, in an observational multicenter study on 608 patients with STEMI who underwent primary PCI, the admission level of HbA1c was not found to be an independent prognostic marker for short-term outcomes in STEMI patients treated with primary PCI. 46 A prospective cohort of 2,519 nondiabetic patients undergoing elective coronary angiography for suspected stable angina pectoris did not show any association between HbA1c levels and prognosis, questioning an independent role of glycemia in the pathogenesis of atherosclerotic complications in nondiabetic patients. 47 Recently, Wang et al. 48 have shown that HbA1c level is not a significant and independent marker for the severity of angiography (stenosis) in ACS patients. Kompoti et al. 49 investigated the clinical significance of HbA1c levels on admission in the intensive care unit as a prognostic marker for morbidity and mortality in critically ill patients. The findings showed that HbA1c is a useful tool for the diagnosis of a previously undiagnosed DM in critically ill patients, and HbA1c at admission is significantly associated with intensive care unit mortality. Pimentel et al. 50 have shown that HbA1c ≥6.5% is not enough to be used alone in the diagnosis of post-transplantation DM in renal transplant patients. However, the combined use of HbA1c cut-off points of ≤5.8% and ≥6.2% would reduce the number of oral glucose tolerance tests by 85% and the use of an algorithm with HbA1c in combination with FPG proved to be the most efficient strategy to diagnose or rule out post-transplantation DM. 50 Poor glycemic control (HbA1c ≥8%) has been associated with decreased survival in the general population of diabetic patients on maintenance hemodialysis, suggesting that moderate hyperglycemia increases the risk for all-cause mortality of diabetic maintenance hemodialysis patients in Han Chinese population. 51 Helminen et al. 52 assessed the utility of HbA1c levels in predicting the clinical disease in genetically predisposed children with multiple autoantibodies. They observed that a 10% increase in HbA1c levels in samples obtained 3–12 months apart predicted the diagnosis of clinical disease, suggesting the usefulness of HbA1c as a marker for predicting the time to diagnosis of type 1 diabetes in children with multiple autoantibodies. HbA1c Test Units As is usually the case with most of the units, the United States and European Union and other countries do not agree with the units of HbA1c measurements. 53 In the US, the HbA1c levels are expressed in terms of percentage of the Diabetes Control and Complications Trial units. 54 , 55 The United Kingdom, New Zealand, and Australia, along with many other European and Asian countries, however, express the HbA1c levels as millimoles per mole, keeping in reference with the recommendations of the International Federation of Clinical Chemistry (IFCC). 56 , 57 The International HbA1c Consensus Committee has recommended that the HbA1c levels must be reported in terms of System International (SI) units (millimoles per mole, with no decimal places), which relate better scientifically to a valid measure of HbA1c. The NGSP still recommends using the units in terms of the percentage with one decimal place, for example, an HbA1c level below 5.7% is considered as normal. The SI units allow for avoiding any confusion between the reported HbA1c levels and the traditional fasting glucose levels expressed as millimoles per liter. All of these units can be easily converted using one of the online calculators and the values are interchangeable including those expressed as mg/dL and also allow for calculating the estimated average glucose results. 55 It is important to note that the HbA1c levels, expressed in millimoles per mole, must not be confused with blood glucose levels, which are expressed in millimoles per liter, and provide an average long-term trend. The following equation will help to obtain the SI units from the HbA1c expressed in terms of the percentage: HbA1c SI unit (mmol/mol) (HbA1c NGSP unit in % ×10.93) − 23.50. For example, if the HbA1c is 5.7% (Diabetes Control and Complications Trial), then the HbA1c SI unit (mmol/mol) (IFCC) can be calculated as HbA1c SI unit (mmol/mol) (5.7 × 10.93) − 23.50 = 38.8 mmol/mol (IFCC). 56 , 57 The values, based upon different units, are illustrated in Table 1 . Table 1 HbA1c as an indicator of diabetes control. BLOOD GLUCOSE STATUS HbA1c mmol/L mg/dL % mmol/mol 5.4 97 Normal 5 31 7.0 126 6 42 8.6 155 Pre-Diabetes 7 53 10.2 184 Diabetes 8 64 11.8 212 Diabetes 9 75 13.4 241 10 86 14.9 268 Diabetes 11 97 16.5 297 12 108 Open in a separate window HbA1c Range Nondiabetes usually falls within the 4.0%–5.6% HbA1c range. The prediabetes usually has the HbA1c levels as 5.7%–6.4%, while those with 6.4% or higher HbA1c levels have diabetes. 12 , 28 Since diabetes is associated with several comorbidities, the recommendations for individuals with diabetes include a healthy lifestyle (diet and exercise) and maintaining the HbA1c levels below 7.0%. Diabetes-related complications are directly proportional to the levels of HbA1c – the increase in the HbA1c levels also increases the risk of such complications. Using HbA1c as a SOC test also provides some complications for the health-care providers and the patients alike. For example, in anemic (low hemoglobin) patients or those with shorter RBC lifespan (glucose-6-phosphate dehydrogenase deficiency, sickle-cell disease, etc.), the HbA1c levels may be compromised indicating a false “good” result. 58 The excessive use of vitamin C, B, and E supplements and increased levels of cholesterol, liver, and kidney diseases can also present abnormally high levels of HbA1c. 59 , 60 Dyslipidemia, which is an imbalance of lipids and fats circulating in the blood stream, is another debilitating disease associated with diabetes. 61 , 62 However, maintaining healthy glucose levels for type 2 diabetics is of paramount importance and may help in preventing micro- and macrovascular complications. 63 The HbA1c is also used routinely for testing gestational diabetes among pregnant women. 64 Other researchers have utilized the serum fructosamine and blood glucose for the screening of GDM. 36 , 37 Both these tests allow the health-care providers to establish whether the pregnant women, with associated risk facts, had developed diabetes before the pregnancy, which may have gone undiagnosed. If the HbA1c levels are not monitored closely to establish acceptable glycemic control, the higher levels of HbA1c may cause the long-axis cardiac dysfunction in the developing fetus. 65 , 66 There is a direct correlation between reduced HbA1c levels and reduced percentage of mortality. Maintaining healthy levels of the HbA1c significantly ameliorates the risk of cardiovascular diseases among individuals with diabetes. 67 Methods for HbA1c Analysis The HbA1c analysis methods can be divided into two categories: methods based on the charge differences and methods based on the structural differences. Ion-exchange chromatography and capillary electrophoresis belong to the first category, while immunoassay, enzymatic assay, and affinity chromatography belong to the second category. Thus, the routine determination of HbA1c can be achieved by methods based on different principles such as immunoturbidimetry, boronate affinity chromatography, ion-exchange high-performance liquid chromatography (HPLC), and enzymatic assay. 68 – 70 Özçelik et al. 71 measured HbA1c in blood from 120 patients with prediabetes and diabetes using three different methods including turbidimetric inhibition immunoassay (TINIA), particle-enhanced immunoturbidimetric assay (PEITT), and HPLC. Although the average HbA1c measured by HPLC (7.52% ± 1.40%) was significantly higher than the other methods, including TINIA (7.12% ± 1.66%) and PEITT (7.26% ± 1.39%), there was good concordance between results of PEITT and HPLC methods ( r = 0.9401). The measured total time spent on 120 samples was 45 minutes for TINIA, 39 minutes for PEITT, and 384 minutes for HPLC. 71 Recently, capillary 2-FP analyzer has been found to be suitable for HbA1c measurement, and sometimes, it showed some advantages with respect to the HPLC analyzers tested, especially when Hb variants are present. 72 Since the HbA1c test is now recommended for diagnosing diabetes and minimal variation of the concentration affects the clinical therapy, it is very important that the results are reliable and interference free. One must become more stringent that any unacceptable results are detected, not reported and each method is evaluated for Hb variant interference. 73 There are at least 30 different laboratory methods commercially available to measure the proportion of HbA1c in blood. 74 Studies have also reported significant bias among analytical methods to measure HbA1c levels. 75 Therefore, standardization and comparability of HbA1c results with different methods appear to be an important issue. In 1995, the IFCC established a Working Group (IFCC WG-HbA1c) to achieve international standardization of HbA1c measurement. 76 A reference measurement procedure for HbA1c was developed based on the proteolytic digestion of red cell hemoglobins followed by quantitative peptide mapping by HPLC-mass spectrometry or HPLC-capillary electrophoresis. 77 The reliability of HbA1c measurement depends on bias (related to proper calibration) and precision (related to the reproducibility of the method). Quality goals can be derived from biological variation, clinical needs, or the state of the art. For HbA1c, a generally accepted rule of thumb is that clinicians interpret a difference of 5 mmol/mol (0.5%) between successive patient samples as a significant change in glycemic control. 78 Accessibility to HbA1c Testing for Diagnosis Although most laboratories in tertiary care hospitals are well equipped with modern instrumentation including HPLC, many of the primary care centers in low- and middle-income countries do not have access to HPLC, some are still struggling with outdated methods or doubtful point-of-care devices that may not be reliable to monitor diabetes. For accurate results, small clinics and health centers have to be dependent on accredited clinical laboratories for HbA1c analysis. However, this strategy becomes more expensive due to the additional cost of sample transportation. Recently, Fokkema et al. 79 evaluated the feasibility of HbA1c measurements from dried blood spots collected on filter paper and compared the HbA1c from filter paper (capillary blood) with HbA1c measured in venous blood. HbA1c on filter paper was highly correlated with routine HbA1c ( r = 0.987) while the evaluation of samples collected at home showed comparable HbA1c values by filter paper and routine sampling methods. Most of the participants (83%) said that they would like the filter method to be brought into practice, suggesting that HbA1c sampling on filter paper is an acceptable sampling alternative for analysis of HbA1c. 79 It is anticipated that a finger prick sample collection on a filter paper would be more convenient for remote and rural health-care centers to send the samples of HbA1c analysis to dedicated laboratories. Moreover, the good relationship and concordance between the immunoturbidimetric and HPLC methods may support the reliability of properly standardized immunoturbidimetric methods for preliminary screening of diabetes in remote areas. 71 , 80 – 82 Physiological Changes due to Hemoglobin Glycosylation An increase in HbA1c as observed in conditions of poor diabetic control has been associated with increased blood viscosity. 83 Glycosylation of hemoglobin and increased glucose levels tends to affect RBC properties, lowering the RBC flexibility and increasing their aggregation tendency, leading to increased blood viscosity. 84 Glycosylation of hemoglobin may also affect membrane lipid protein interactions in RBCs, altering their internal viscosity, modifying viscoelastic properties of erythrocyte membranes, and impairing RBC deformability. 85 There is also evidence that glycosylation of hemoglobin impairs nitric oxide (NO)-related relaxation of human mesenteric vessels. 86 Hemoglobin glycosylation is also reported to alter NO binding with thiols resulting in lowered NO bioavailability and impaired vasodilatation in rabbit aortic rings. 87 Another mechanism by which glycosylation of hemoglobin is proposed to be vasoactive is via the formation of reactive oxygen species. 88 Glycosylation of hemoglobin also lowers oxygen-carrying capacity, thereby promoting hypoxia and its related systemic vascular vasodilatory adaptations and responses. 89 Glycosylation of hemoglobin appeared to lead to blood pressure reduction in type 2 diabetic patients untreated for hypertension. 90 Since 8%–10% HbA1c is considered to be a threshold beyond which the effects of hemoglobin glycosylation become significant, these investigators determined mean arterial blood pressure for patients not treated for hypertension below and above 9% HbA1c and found significant reduction in mean arterial blood pressure below the threshold (86.2 ± 3.9 mmHg) as compared to above the threshold (93.1 ± 12.5 mmHg). 90 Conclusion The HbA1c is an accurate and easy-to-administer test with on-the-spot results availability and can be an effective tool in establishing the diagnosis of diabetes, especially in low- and middle-income countries and hard-to-reach populations. Even though HbA1c has been endorsed for diagnosis of diabetes, in most of the countries worldwide, some testing strategies and cutoff ranges are still being debated. However, combination of FGT and HbA1c significantly enhances the diagnostic accuracy of these individual tests. The prognostic potential of HbA1c lies in its unique ability of assessing retrospective glycemic control as well as predicting the lipid profile in diabetic patients. As the epidemic of diabetes continues to grow worldwide, HbA1c test may continue to be implemented as part of the diagnostic and prognostic tool, leading to better patient care and successful clinical outcomes. Footnotes ACADEMIC EDITOR: Karen Pulford, Editor in Chief PEER REVIEW: Four peer reviewers contributed to the peer review report. Reviewers’ reports totaled 694 words, excluding any confidential comments to the academic editor. FUNDING: Authors disclose no external funding sources. COMPETING INTERESTS: Authors disclose no potential conflicts of interest. Paper subject to independent expert blind peer review. All editorial decisions made by independent academic editor. Upon submission manuscript was subject to anti-plagiarism scanning. Prior to publication all authors have given signed confirmation of agreement to article publication and compliance with all applicable ethical and legal requirements, including the accuracy of author and contributor information, disclosure of competing interests and funding sources, compliance with ethical requirements relating to human and animal study participants, and compliance with any copyright requirements of third parties. This journal is a member of the Committee on Publication Ethics (COPE). Provenance: the authors were invited to submit this paper. Author Contributions Conceived and designed the experiments: HAK, SIS. Analyzed the data: HAK, SIS, AE. Wrote the first draft of the manuscript: SIS, HAK. 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Epub 2020 Oct 30. Comprehensive Investigation of Circulating Biomarkers and Their Causal Role in Atherosclerosis-Related Risk Factors and Clinical Events Daniela Zanetti 1 2 3 , Stefan Gustafsson 4 , Themistocles L Assimes 1 2 , Erik Ingelsson 1 2 3 Affiliations Expand Affiliations 1 Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, CA (D.Z., T.L.A., E.I.). 2 Stanford Cardiovascular Institute (D.Z., T.L.A., E.I.), Stanford University, CA. 3 Stanford Diabetes Research Center (D.Z., E.I.), Stanford University, CA. 4 Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Sweden (S.G.). PMID: 33125266 PMCID: PMC8202726 DOI: 10.1161/CIRCGEN.120.002996 Item in Clipboard Comprehensive Investigation of Circulating Biomarkers and Their Causal Role in Atherosclerosis-Related Risk Factors and Clinical Events Daniela Zanetti et al. Circ Genom Precis Med . 2020 Dec . Show details Display options Display options Format Abstract PubMed PMID Circ Genom Precis Med Actions Search in PubMed Search in NLM Catalog Add to Search . 2020 Dec;13(6):e002996. doi: 10.1161/CIRCGEN.120.002996. Epub 2020 Oct 30. Authors Daniela Zanetti 1 2 3 , Stefan Gustafsson 4 , Themistocles L Assimes 1 2 , Erik Ingelsson 1 2 3 Affiliations 1 Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, CA (D.Z., T.L.A., E.I.). 2 Stanford Cardiovascular Institute (D.Z., T.L.A., E.I.), Stanford University, CA. 3 Stanford Diabetes Research Center (D.Z., E.I.), Stanford University, CA. 4 Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Sweden (S.G.). PMID: 33125266 PMCID: PMC8202726 DOI: 10.1161/CIRCGEN.120.002996 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Background: Circulating biomarkers have been previously associated with atherosclerosis-related risk factors, but the nature of these associations is incompletely understood. Methods: We performed multivariable-adjusted regressions and 2-sample Mendelian randomization analyses to assess observational and causal associations of 27 circulating biomarkers with 7 cardiovascular traits in up to 451 933 participants of the UK Biobank. Results: After multiple-testing correction (alpha=1.3×10 -4 ), we found a total of 15, 9, 21, 22, 26, 24, and 26 biomarkers strongly associated with coronary artery disease, ischemic stroke, atrial fibrillation, type 2 diabetes, systolic blood pressure, body mass index, and waist-to-hip ratio; respectively. The Mendelian randomization analyses confirmed strong evidence of previously suggested causal associations for several glucose- and lipid-related biomarkers with type 2 diabetes and coronary artery disease. Particularly interesting findings included a protective role of IGF-1 (insulin-like growth factor 1) in systolic blood pressure, and the strong causal association of lipoprotein(a) in coronary artery disease development (β, -0.13; per SD change in exposure and outcome and odds ratio, 1.28; P =2.6×10 -4 and P =7.4×10 -35 , respectively). In addition, our results indicated a causal role of increased ALT (alanine aminotransferase) in the development of type 2 diabetes and hypertension (odds ratio, 1.59 and β, 0.06, per SD change in exposure and outcome; P =4.8×10 -11 and P =6.0×10 -5 ). Our results suggest that it is unlikely that CRP (C-reactive protein) and vitamin D play causal roles of any meaningful magnitude in development of cardiometabolic disease. Conclusions: We confirmed and extended known associations and reported several novel causal associations providing important insights about the cause of these diseases, which can help accelerate new prevention strategies. Keywords: blood pressure; cardiovascular disease; coronary artery disease; diabetes mellitus, type 2; risk factors. PubMed Disclaimer Figures Figure 1. Causal and observational associations of… Figure 1. Causal and observational associations of circulating biomarkers with coronary artery disease, ischemic stroke,… Figure 1. Causal and observational associations of circulating biomarkers with coronary artery disease, ischemic stroke, atrial fibrillation, type 2 diabetes, systolic blood pressure, body mass index, and waist-to-hip ratio in UK Biobank. The plots represent observational and Mendelian randomization significant results: * P-values significant after Bonferroni correction (p≤1.3*10 −4 ); ** P-values significant after Bonferroni correction using all three outcome definitions (External GWAS+UKB; External GWAS only; UKB only). The hazard and odds ratios are given per SD change in circulating biomarker. The betas from linear regression represent SD change in outcome variable per SD change in circulating biomarker. Observational models were adjusted for age, sex, region of the UK Biobank assessment center, ethnicity, smoking, Townsend index, fasting time, blood pressure, body mass index, type 2 diabetes, hypertensive and cholesterol-lowering medications, high-density lipoprotein cholesterol, low-density lipoprotein direct and glucose. Mendelian randomization effect from the inverse-variance weighted method (IVW) removing outliers, if needed (based on MR-PRESSO). HR, hazard ratio; OR, odds ratio; P, p value; ; HbA1c, hemoglobin A1c; Gluc, glucose; IGF-1, insulin-like growth factor 1; CRP, C-reactive protein; RF, rheumatoid factor; Ca, calcium; Cre, creatinine; CysC, cystatin C; Phos, phosphate, UA, urate; VitD, vitamin D; APOA1, apolipoprotein A; APOB, apolipoprotein B; HDL-C, high-density lipoprotein cholesterol; Lp(a), lipoprotein A; LDL-C, low-density lipoprotein direct; TC, total cholesterol; TG, triglycerides; ALT, alanine aminotransferase; Alb, albumin; ALP, alkaline phosphatase; AST, aspartate aminotransferase; BilD, direct bilirubin; BilT, total bilirubin; GGT, gamma glutamyltransferase; Prot, total protein. See this image and copyright information in PMC Similar articles Urinary Albumin, Sodium, and Potassium and Cardiovascular Outcomes in the UK Biobank: Observational and Mendelian Randomization Analyses. Zanetti D, Bergman H, Burgess S, Assimes TL, Bhalla V, Ingelsson E. Zanetti D, et al. Hypertension. 2020 Mar;75(3):714-722. doi: 10.1161/HYPERTENSIONAHA.119.14028. Epub 2020 Feb 3. Hypertension. 2020. PMID: 32008434 Free PMC article. Association of Body Mass Index With Cardiometabolic Disease in the UK Biobank: A Mendelian Randomization Study. Lyall DM, Celis-Morales C, Ward J, Iliodromiti S, Anderson JJ, Gill JMR, Smith DJ, Ntuk UE, Mackay DF, Holmes MV, Sattar N, Pell JP. Lyall DM, et al. JAMA Cardiol. 2017 Aug 1;2(8):882-889. doi: 10.1001/jamacardio.2016.5804. JAMA Cardiol. 2017. PMID: 28678979 Free PMC article. Birthweight, Type 2 Diabetes Mellitus, and Cardiovascular Disease: Addressing the Barker Hypothesis With Mendelian Randomization. Zanetti D, Tikkanen E, Gustafsson S, Priest JR, Burgess S, Ingelsson E. Zanetti D, et al. Circ Genom Precis Med. 2018 Jun;11(6):e002054. doi: 10.1161/CIRCGEN.117.002054. Circ Genom Precis Med. 2018. PMID: 29875125 Free PMC article. Identification of Circulating Proteins Associated With Blood Pressure Using Mendelian Randomization. Thériault S, Sjaarda J, Chong M, Hess S, Gerstein H, Paré G. Thériault S, et al. Circ Genom Precis Med. 2020 Feb;13(1):e002605. doi: 10.1161/CIRCGEN.119.002605. Epub 2020 Jan 12. Circ Genom Precis Med. 2020. PMID: 31928076 The Role of Emerging Risk Factors in Cardiovascular Outcomes. Lacey B, Herrington WG, Preiss D, Lewington S, Armitage J. Lacey B, et al. Curr Atheroscler Rep. 2017 Jun;19(6):28. doi: 10.1007/s11883-017-0661-2. Curr Atheroscler Rep. 2017. PMID: 28477314 Free PMC article. Review. See all similar articles Cited by Multiplex proteomics identifies inflammation-related plasma biomarkers for aging and cardio-metabolic disorders. Wu S, Li Y, Zhao X, Shi FD, Chen J. Wu S, et al. Clin Proteomics. 2024 Apr 22;21(1):30. doi: 10.1186/s12014-024-09480-x. Clin Proteomics. 2024. PMID: 38649851 Free PMC article. Vitamin D and human health: evidence from Mendelian randomization studies. Fang A, Zhao Y, Yang P, Zhang X, Giovannucci EL. Fang A, et al. Eur J Epidemiol. 2024 Jan 12. doi: 10.1007/s10654-023-01075-4. Online ahead of print. Eur J Epidemiol. 2024. PMID: 38214845 Review. Mendelian randomization provides evidence for a causal effect of serum insulin-like growth factor family concentration on risk of atrial fibrillation. Lin S, Tang J, Li X, Wu G, Lin YF, Li YF. Lin S, et al. World J Clin Cases. 2023 Dec 26;11(36):8475-8485. doi: 10.12998/wjcc.v11.i36.8475. World J Clin Cases. 2023. PMID: 38188205 Free PMC article. Major lipids and lipoprotein levels and risk of blood pressure elevation: a Mendelian Randomisation study. Liu W, Yang C, Lei F, Huang X, Cai J, Chen S, She ZG, Li H. Liu W, et al. EBioMedicine. 2024 Feb;100:104964. doi: 10.1016/j.ebiom.2023.104964. Epub 2024 Jan 5. EBioMedicine. 2024. PMID: 38181703 Free PMC article. Appraising the Causal Role of Risk Factors in Coronary Artery Disease and Stroke: A Systematic Review of Mendelian Randomization Studies. Georgiou AN, Zagkos L, Markozannes G, Chalitsios CV, Asimakopoulos AG, Xu W, Wang L, Mesa-Eguiagaray I, Zhou X, Loizidou EM, Kretsavos N, Theodoratou E, Gill D, Burgess S, Evangelou E, Tsilidis KK, Tzoulaki I. Georgiou AN, et al. J Am Heart Assoc. 2023 Oct 17;12(20):e029040. doi: 10.1161/JAHA.122.029040. Epub 2023 Oct 7. J Am Heart Assoc. 2023. PMID: 37804188 Free PMC article. See all "Cited by" articles References Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1459–1544.
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+The clinical relevance of an isolated increase in the number of circulating hyperchromic red blood cells - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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+    the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice J Clin Pathol. 2002 Nov; 55(11): 841–844. doi: 10.1136/jcp.55.11.841 PMCID: PMC1769790 PMID: 12401822 The clinical relevance of an isolated increase in the number of circulating hyperchromic red blood cells A M Conway , A J Vora , and R F Hinchliffe A M Conway Department of Paediatric Haematology, Sheffield Children’s Hospital NHS Trust, Sheffield S10 2TH, UK Find articles by A M Conway A J Vora Department of Paediatric Haematology, Sheffield Children’s Hospital NHS Trust, Sheffield S10 2TH, UK Find articles by A J Vora R F Hinchliffe Department of Paediatric Haematology, Sheffield Children’s Hospital NHS Trust, Sheffield S10 2TH, UK Find articles by R F Hinchliffe Author information Article notes Copyright and License information PMC Disclaimer Department of Paediatric Haematology, Sheffield Children’s Hospital NHS Trust, Sheffield S10 2TH, UK Correspondence to: Dr A Vora, Department of Paediatric Haematology, Sheffield Children’s Hospital NHS Trust, Sheffield S10 2TH, UK; ku.shn.hcs@arov.yaja Accepted 2002 May 30. Copyright © Copyright 2002 Journal of Clinical Pathology Abstract Aims: To search for laboratory evidence of hereditary spherocytosis (HS) among apparently healthy children with the chance finding of an isolated increase in hyperchromic red cells (cells with intracellular haemoglobin concentration > 410 g/litre). Methods: Blood and reticulocyte counts and Pink tests were performed on successive children found on routine counts to have > 4% hyperchromic red cells, and compared with age and mean cell haemoglobin concentration (MCHC) matched controls and children known to have HS. Results: Thirty four patients with > 4% hyperchromic red cells had significantly higher absolute numbers of such cells (p < 0.0001) and higher reticulocyte counts (p < 0.01) than age matched controls, together with higher MCHC (p < 0.0001) and haemoglobin distribution width (p < 0.0001) values and lower mean cell volume (p < 0.02) values. Significant differences were also found among hyperchromic red blood cell, reticulocyte, and haemoglobin distribution width values when subjects were compared with MCHC matched controls. Pink test values were higher in children with increased hyperchromic red blood cells, but not significantly so. In patients with HS, most variables measured were significantly different both from those of children with > 4% hyperchromic cells and controls. Despite the differences found, few MCHC, HDW, reticulocyte, or Pink test values were outside of the normal limits, and only one child with increased hyperchromic cells had both a mild reticulocytosis and a slightly raised Pink test value. Conclusions: Subjects with an isolated increase in hyperchromic red blood cells have a profile of red blood cell changes similar to that of patients with HS, but to a lesser degree. They may carry a recessive form of the disease but lack the laboratory features of clinically manifest HS. Keywords: hereditary spherocytosis, hyperchromic red blood cells, paediatrics, reticulocytes As a result of advances in automated red blood cell analysis, an increase in the proportion of hyperchromic red blood cells (cells with haemoglobin concentration > 410 g/litre) has become a consistent finding in subjects with hereditary spherocytosis (HS). The finding is of diagnostic value and can be of use in assessing the severity of the disorder. 1– 3 Red blood cells in HS are normally shaped when young but become progressively thicker with age. Mean cell volume (MCV) decreases slightly and mean cell haemoglobin (MCHC) increases as they acquire the spherocytic and hyperchromic appearances typical of the disorder. Normal red blood cell morphology may be found transiently in HS when the red cell population is shifted to a younger age—for example, after a period of aplasia. 4 A much smaller proportion of hyperchromic cells is found in normal subjects and probably represents the dense cells formed as a result of red blood cell aging. “Red blood cells in hereditary spherocytosis are normally shaped when young but become progressively thicker with age” We have noted increases in hyperchromic red cells in a small proportion of apparently healthy children in the UK, and carried out our present study to determine whether such children have other laboratory evidence of HS. METHODS Blood count data (Technicon H1; Bayer, Newbury, UK) were obtained from children whose samples gave a hyperchromia flag, indicating the presence of ≥ 4% hyperchromic red blood cells. In addition, the following tests were performed on each sample: flow cytometric reticulocyte count (Facscan; Becton Dickinson, Oxford, UK), modified glycerol lysis Pink test, 5 direct antihuman globulin test, and haemoglobin (Hb) electrophoresis on cellulose acetate membrane at pH 6.8. The Pink test is a modification of the acidified glycerol lysis test in which 10 μl of blood is suspended in a buffered sodium chloride/glycerol reagent for 30 minutes, after which the degree of haemolysis is measured. Absolute numbers of hyperchromic red blood cells and reticulocytes were calculated from percentage values and the automated red blood cell count. The same investigations were carried out on two groups of controls, one matched for age (within six months for children > 2 years of age, within 3 months for those < 2 years) and the other for MCHC (within ± 2 g/litre). Subjects and controls were essentially healthy children attending hospital for minor illnesses or planned surgery and, apart from hyperchromia flags in the test population, all had normal blood counts. The same panel of tests was also performed on children known to have HS. Each child was tested on one occasion only. All tests were performed on skin puncture blood samples: blood counts were performed within one hour of collection and Pink tests within three hours. The additional tests required < 0.2 ml of blood in total and no child had extra blood taken for the purpose of our study. Results were compared using the Wilcoxon signed rank test. Laboratory records of subjects and controls were studied to determine the incidence of a hyperchromia flag in blood count samples analysed before and after the one on which the above tests were performed. RESULTS Samples from 34 consecutive children with a hyperchromia flag and sufficient remaining sample to perform the full range of tests were studied over a period of 12 months, during 1996 and 1997. Their ages ranged from 1 to 14.5 years, with a median of 6. Thirty four age matched controls were also studied and controls matched for MCHC were found for the 21 subjects with MCHC values < 352 g/litre. We were unable to find MCHC matched controls with higher values than this because there was always an associated hyperchromia flag. Fourteen children with HS aged 0.5 to 11 years, median 6, were also studied. None had been splenectomised. All subjects, controls, and children with HS had a negative direct antihuman globulin test and a normal Hb electrophoresis. Proportions of hyperchromic red blood cells were 0.3–3.9% in controls, 4.0–13.0% in the subject group, and 4.0–53.3% in children with HS. Subjects had significantly higher numbers of hyperchromic red blood cells and reticulocytes than age matched controls, together with significantly higher values for MCHC and haemoglobin distribution width (HDW; a measure of anisochromia) and lower MCV values (table 1 ​ 1). ). They also had higher Pink test values than controls, although the difference was not significant. Table 1 Mean values (SD) and significance of differences between variables in age matched subjects and controls, and patients with HS Variable Subjects (n=34) Controls (n=34) HS patients (n=14) p Value (subjects/controls) p Value (HS/controls) p Value (subjects/HS patients) Hb (g/l) 131 (12) 127 (7) 112 (14) NS <0.0001 <0.001 MCV (fl) 79.3 (2.0) 82.0 (5.8) 78.3 (3.5) <0.02 <0.05 NS MCH (pg) 27.9 (1.3) 27.8 (2.0) 28.5 (1.6) NS NS NS MCHC (g/l) 351 (1.0) 339 (0.9) 366 (1.6) <0.0001 <0.001 <0.01 RDW (%) 12.7 (0.6) 13.0 (1.0) 18.4 (3.9) NS <0.001 <0.0001 HDW (g/l) 29.8 (1.8) 25.6 (2.7) 41.5 (7.2) <0.0001 <0.0001 <0.0001 Hyperchromic RBC (×10 9 /l) 329 (245) 51.8 (47) 1193 (579) <0.0001 <0.0001 <0.0001 Reticulocytes (×10 9 /l) 102.8 (44.8) 76.0 (32.6) 445.7 (131.2) <0.01 <0.0001 <0.0001 Haemolysis (%) 18.4 (11.0) 14.3 (10.3) 81.9 (15.2) NS <0.0001 <0.0001 Open in a separate window Hb, haemoglobin; HDW, haemoglobin distribution width; HS, hereditary spherocytosis; MCH, mean cell heamoglobin; MCHC, mean cell haemoglobin concentration; MCV, mean cell volume; NS, not significant; RBC, red blood cells; RDW, red blood cell distribution width. Significantly higher numbers of hyperchromic red blood cells and reticulocytes, and higher HDW values were also found among the 21 subjects matched for MCHC with a control group (table 2 ​ 2 ). Table 2 Mean values (SD) and significance of differences between variables in subjects and controls matched for MCHC Variable Subjects (n=21) Controls (n=21) p Value Hb (g/l) 131 (10) 126 (2) NS MCV (fl) 80.0 (2.5) 80.4 (5.8) NS MCH (pg) 27.7 (0.9) 27.8 (1.9) NS RDW (%) 12.6 (0.6) 13.0 (0.9) NS HDW (g/l) 29.6 (2.1) 26.4 (2.0) <0.01 Hyperchromic RBC (×10 9 /l) 249 (106) 99 (100) <0.01 Reticulocytes (×10 9 /l) 122 (51) 74 (32) <0.01 Haemolysis (%) 19.3 (10.3) 13.7 (9.2) NS Open in a separate window Hb, haemoglobin; HDW, haemoglobin distribution width; MCH, mean cell haemoglobin; MCHC, mean cell haemoglobin concentration; MCV, mean cell volume; NS, not significant; RBC, red blood cells; RDW, red cell distribution width. As expected, the HS group showed highly significant differences compared with both the subject and control groups for most variables tested (table 1 ​ 1 ). Four subjects (11.8%) had evidence of increased red blood cell turnover, defined as a reticulocyte count greater than the mean + 2 SD value of the control group; one also had a raised Pink test value. Two other children had raised Pink test values alone. Twenty four of the 34 subjects studied had at least one blood count performed on another occasion. Of the 14 who had counts within six months of the date of the study sample, eight gave a hyperchromia flag on at least one other occasion, whereas six did not. Among the remaining 10, one gave a flag on only one of nine samples analysed over a four year period, whereas two others gave flags on each of three samples analysed over three years and each of five analysed over 2.5 years, respectively. No hyperchromia flags were found in the blood count records of children comprising the control groups. DISCUSSION Increased numbers of hyperchromic red blood cells are found in a variety of red blood cell disorders other than HS, including immune haemolytic states, in association with HbC, 6 (interaction of this common variant with the inner aspect of the red cell membrane leads to cellular dehyctration and increased MCHC values), and in disorders of red blood cell fragmentation. The children in our subject group were free of such disorders and a mild form of HS seemed a possible cause of their blood count findings, therefore prompting further investigation. The observation of significantly higher MCHC values and hyperchromic red blood cell numbers by comparison with the control group was to be expected from the study design. However, taken together with the significantly higher reticulocyte numbers and HDW values, these findings produce a profile of changes very similar to that found in patients with HS, albeit to a lesser degree (table 1 ​ 1). ). For instance, the reticulocyte counts and HDW values of children with HS were consistently raised above normal limits and MCHC values frequently so, whereas in the subject group most such values were within the ranges found in the control group. This was also the case with the Pink test, where we found, as have others, 7 that values of normal subjects and patients with HS overlap at haemolysis values around 40–45%. There were three such borderline results among the subjects and one in both the control and HS groups. The red blood cell distribution width (RDW) is typically raised in HS, and together with a raised MCHC is highly predictive of this disorder. 8 Our findings in patients with HS support this conclusion, although in our study group RDW values were almost identical to those of the controls (tables 1,2 ​ 1,2 ​ ). It might be argued that the higher reticulocyte counts of the subject group are a compensatory feature secondary to their higher MCHC values, based on the premise that higher MCHCs are a marker of less deformable red cells, which are likely to have a reduced life span. We found no evidence for this, because significantly higher numbers of hyperchromic red blood cells and reticulocytes and higher HDW values persisted in the 21 subjects with less high MCHC values for whom MCHC matched controls could be found (table 2 ​ 2 ). The proportion of hyperchromic red blood cells in our subjects ranged from 4.0% to 13.0%, a very similar range to that reported by Pilar Ricard and Gilsanz 3 in patients with mild and moderate forms of HS. Whereas all their subjects also had increased reticulocyte numbers and positive osmotic fragility tests, only three of our subjects had a reticulocytosis, two had a borderline positive Pink test, and one had both findings. Although some subjects with very mild HS may give negative findings with the osmotic fragility group of tests, 9 only one child, a 14.5 year old boy with a reticulocyte count of 169 × 10 9 /litre and a Pink test value of 41.6%, might be considered to have a mild form of the disorder. “Our findings confirm the earlier reports based on osmotic fragility tests that about 1% of North European subjects have laboratory findings indicative of a continuum between normal subjects and those with clinically manifest hereditary spherocytosis” The laboratory records of the subject group were studied to assess the likelihood that an increase in hyperchromic red blood cells was a transient phenomenon. Eight of 14 subjects gave at least one additional hyperchromia flag in blood counts analysed within six months of the date of the study sample. A further two subjects showed the continued presence of the abnormality over periods of 2.5 and three years, respectively. These findings indicate that in many children the abnormality is persistent, a conclusion supported by the associated higher reticulocyte counts and HDW values. Failure to demonstrate a small increase in hyperchromic cells consistently may be caused by mild physiological fluctuations within an essentially stable red blood cell population, sufficient to activate the analyser flag on some occasions but not on others. Take home messages Subjects with an isolated increase in hyperchromic red blood cells have a profile of red blood cell changes similar to that seen in patients with hereditary spherocytosis (HS), including significantly higher numbers of hyperchromic red blood cells and reticulocytes, and significantly higher values for mean cell haemoglobin concentration and haemoglobin distribution width, and lower mean cell volume values, although these were seen to a lesser degree than is present in HS About 1% of North European subjects have laboratory findings indicative of a continuum between normal subjects and those with clinically manifest HS These individuals may carry a recessive form of the disease but lack the laboratory features of clinically manifest HS Earlier searches for evidence of mild HS among 1008 Norwegian and 1464 German blood donors using the osmotic fragility and acidified glycerol lysis tests, respectively, 10, 11 produced positive findings in about 1% of those tested. Some of these subjects also had a mild reticulocytosis. We estimate the incidence of an increase in hyperchromic red blood cells in our population also to be around 1%, giving an incidence of an abnormal Pink test of about 0.1%, based on our finding of a borderline positive result in three of the 34 children studied. The reason for this approximate tenfold difference is unclear, although the number of children we tested is too small for meaningful comparison. Our findings, using sensitive methods of red blood cell analysis and precise automated reticulocyte counts, confirm the earlier reports based on osmotic fragility tests that about 1% of North European subjects have laboratory findings indicative of a continuum between normal subjects and those with clinically manifest HS. Carrier status for a recessive form of HS might be the molecular basis for the clinically unimportant red blood cell changes in these individuals. Acknowledgments The authors thank L Anderson for assistance with statistical analysis. Abbreviations Hb, haemoglobin HDW, haemoglobin distribution width HS, hereditary spherocytosis MCHC, mean cell haemoglobin concentration MCV, mean cell volume RDW, red blood cell distribution width REFERENCES 1. Pati , AR, Patton, WN, Harris, RI. The use of the Technicon H1 in the diagnosis of hereditary spherocytosis. Clin Lab Haematol 1989; 11 :27–30. [ PubMed ] [ Google Scholar ] 2. Ialongo P , Vignetti M, Cigliano G, et al . Flow cytometric measurement (H-1 Technicon) of microcytic and hyperchromic red cell populations in pediatric patients affected by hereditary spherocytosis (HS). Haematologica 1989; 74 :547–53. [ PubMed ] [ Google Scholar ] 3. Pilar Ricard M , Gilsanz, F. Assessment of the severity of hereditary spherocytosis using routine haematological data obtained with dual angle laser scattering cytometry. Clin Lab Haematol 1996; 18 :75–8. [ PubMed ] [ Google Scholar ] 4. 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[ PubMed ] [ Google Scholar ] Articles from Journal of Clinical Pathology are provided here courtesy of BMJ Publishing Group Other Formats PDF (180K) Actions Cite Collections Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than  characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Share Permalink Copy RESOURCES Similar articles Cited by other articles Links to NCBI Databases [x] Cite Copy Download .nbib .nbib Format: AMA APA MLA NLM Follow NCBI Twitter Facebook LinkedIn GitHub Connect with NLM SM-Twitter SM-Facebook SM-Youtube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov

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+Muscular exercise can cause highly pathological liver function tests in healthy men - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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+            and transmitted securely. Log in Show account info Close Account Logged in as: username Dashboard Publications Account settings Log out Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now . Search PMC Full-Text Archive Search in PMC Advanced Search User Guide Journal List Br J Clin Pharmacol v.65(2); 2008 Feb PMC2291230 Other Formats PDF (1.2M) Actions Cite Collections Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than  characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Share Permalink Copy RESOURCES Similar articles Cited by other articles Links to NCBI Databases Journal List Br J Clin Pharmacol v.65(2); 2008 Feb PMC2291230 As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with,
+    the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Br J Clin Pharmacol. 2008 Feb; 65(2): 253–259. Published online 2007 Aug 31. doi: 10.1111/j.1365-2125.2007.03001.x PMCID: PMC2291230 PMID: 17764474 Muscular exercise can cause highly pathological liver function tests in healthy men Jonas Pettersson , Ulf Hindorf , Paula Persson , Thomas Bengtsson , Ulf Malmqvist , 1 Viktoria Werkström , 1 and Mats Ekelund 2 Ulf Malmqvist 1 Department of Clinical Pharmacology, Lund University Hospital, Lund, Mölndal, Sweden Find articles by Ulf Malmqvist Viktoria Werkström 1 Department of Clinical Pharmacology, Lund University Hospital, Lund, Mölndal, Sweden Find articles by Viktoria Werkström Mats Ekelund 2 AstraZeneca R&D Mölndal, Mölndal, Sweden Find articles by Mats Ekelund Author information Article notes Copyright and License information PMC Disclaimer AstraZeneca R&D Lund, Lund University Hospital, Lund, Mölndal, Sweden 1 Department of Clinical Pharmacology, Lund University Hospital, Lund, Mölndal, Sweden 2 AstraZeneca R&D Mölndal, Mölndal, Sweden Correspondence Ulf Hindorf, Medical Science, AstraZeneca R&D Lund, SE-221 87 Lund, Sweden. Tel: + 46 4633 7143 Fax: + 46 4633 7576 E-mail: es.ul.dem@frodnih.flu Received 2007 Apr 13; Accepted 2007 May 31. Copyright © 2007 The Authors Journal compilation © 2007 Blackwell Publishing Ltd Abstract Aim To investigate the effect of intensive muscular exercise (weightlifting) on clinical chemistry parameters reflecting liver function in healthy men. Methods Fifteen healthy men, used to moderate physical activity not including weightlifting, performed an 1 h long weightlifting programme. Blood was sampled for clinical chemistry parameters [aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LD), gamma-glutamyl transferase (γGT), alkaline phosphatase (ALP), bilirubin, creatine kinase (CK) and myoglobin] at repeated intervals during 7 days postexercise and at a follow-up examination 10–12 days postexercise. Results Five out of eight studied clinical chemistry parameters (AST, ALT, LD, CK and myoglobin) increased significantly after exercise ( P < 0.01) and remained increased for at least 7 days postexercise. Bilirubin, γGT and ALP remained within the normal range. Conclusion The liver function parameters, AST and ALT, were significantly increased for at least 7 days after the exercise. In addition, LD and, in particular, CK and myoglobin showed highly elevated levels. These findings highlight the importance of imposing restrictions on weightlifting prior to and during clinical studies. Intensive muscular exercise, e.g. weightlifting, should also be considered as a cause of asymptomatic elevations of liver function tests in daily clinical practice. What is already known about this subject The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the leading cause of postmarketing warnings and withdrawals. Physical exercise can result in transient elevations of liver function tests. There is no consensus in the literature on which forms of exercise may cause changes in liver function tests and to what extent. What this study adds Weightlifting results in profound increases in liver function tests in healthy men used to moderate physical activity, not including weightlifting. Liver function tests are significantly increased for at least 7 days after weightlifting. It is important to impose relevant restrictions on heavy muscular exercise prior to and during clinical studies. Keywords: clinical trials, liver function tests, physical exercise Introduction The liver is the main organ for conversion of one chemical species to another and this interconversion is the main route for preparing drugs for excretion from the body. The metabolism of drugs can lead to the formation of chemically reactive intermediates that may play a significant role in the induction of hepatic injury. It is important that potentially hepatotoxic effects of new drugs are recognized early during drug development. Therefore, in Phase I clinical trials, monitoring of liver function parameters is mandatory. The occurrence of asymptomatic elevations in liver function tests is a problem during all phases of drug development. An asymptomatic elevation of, for example, liver transaminases during clinical trials could be drug related, but other factors, such as exercise [ 1 ] and diet [ 2 ], may also have had this effect. It has long been known that physical exercise results in transient elevations of liver function tests [ 3 , 4 ]. Subjects studied in Phase I clinical trials are often young healthy volunteers who in their normal life perform some kind of recreational exercise, and during outpatient trials the volunteers usually continue with their normal life, including exercise. We have observed that healthy subjects performing intensive weightlifting during clinical trials may exhibit altered liver function tests [elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT)], but the influence of weightlifting on clinical chemistry parameters is poorly described. There is no consensus on what forms of exercise can cause changes in clinical chemistry parameters, which parameters may be affected, or to what extent. Several studies have described enzyme elevations in response to running [ 5 , 6 ], whereas only a few have dealt with the effects of weightlifting [ 7 , 8 ]. The effects of muscular exercise on clinical chemistry parameters may also vary depending on gender and on the fitness level of the individual [ 9 ]. However, no study to our knowledge has examined the possible effect of weightlifting on clinical chemistry parameters, commonly used to evaluate liver function, and the duration of such an effect. The primary objective of the present study was to investigate the effect of intensive muscular exercise (weightlifting) on a single occasion on clinical chemistry parameters, reflecting liver function in healthy men not used to performing weightlifting on a regular basis. A secondary objective was to investigate the effect of a single occasion of intensive muscular exercise (weightlifting) on clinical chemistry parameters reflecting muscle damage, i.e creatine kinase (CK) and myoglobin. Methods Study design This was an open study consisting of five separate visits to one centre (AstraZeneca Clinical Pharmacology Unit, Lund, Sweden); screening and weightlifting ‘test’ (visits 1 and 2), baseline blood sampling before weightlifting (visit 3), weightlifting with blood sampling at repeated intervals up to 1 week post exercise (visit 4), and follow-up (visit 5). Visit 1 was to be performed within 21 days of visit 3, and visit 2 was to take place at least 10 days before visit 3. Visit 5 was to be performed within 10–12 days after the weightlifting exercise at visit 4. The study involved 15 healthy men aged 18–45 years with a body mass index (BMI) between 18 and 30 and a minimum weight of 60 kg. They were all used to moderate physical exercise, but not used to performing weightlifting on a regular basis. The subjects were not allowed to perform strenuous physical exercise within 2 weeks of visit 1 and they had to abstain from physical exercise during the study, other than study-specific exercise. They were not allowed to have any clinically relevant abnormalities in physical examination, clinical chemistry parameters, human immunodeficiency virus (HIV) and/or hepatitis B/C serology, haematology, urinalysis, ECG or vital signs. All subjects were required to have AST, ALT, alkaline phosphatase (ALP), CK, gamma glutamyl transferase (γGT), lactate dehydrogenase (LD), myoglobin and bilirubin within the appropriate reference ranges at visit 3. They were not allowed to use any medication (except for occasional intake of paracetamol) within 2 weeks of visit 1 and they had to maintain a normal diet and constant weight during the study. In addition, they had to abstain from alcohol consumption for 48 h before each visit, between visits 2 and 3, and during visits, for as long as blood sampling for clinical chemistry parameters were being performed. Weightlifting programme At visit 2, subjects tested the weightlifting equipment and the maximum weight possible for each exercise and subject was estimated. At visit 4, subjects used 70% of the obtained maximum weight in each exercise. Before starting the programme at visit 4, subjects warmed up by cycling at moderate speed for 5 min. They conducted an approximately 1 h long weightlifting programme going through the major muscle groups in the body ( Table 1 ). Every part of the programme was performed in three sets, with approximately a 1-min pause between sets, to a maximum number of repetitions per set with the aim of reaching 12 repetitions. If 12 repetitions were not reached during a set, the weight had to be adjusted before the start of the next (not applicable for push-ups, sit-ups and back-raises). If 12 repetitions were easily reached, the weight was increased. Table 1 Weightlifting programme Weightlifting exercise Muscle groups Lat pull down behind neck Trapezius, teres major, latissimus dorsi, rhomboideus, brachioradialis, brachialis, biceps brachii Cable machine seated row Trapezius, rhomboideus major, latissimus dorsi, teres major, deltoideus, erector spinae, brachioradialis Back raise * Gluteus maximus, semitendinosus Sit-ups Rectus abdominus Push-ups Pectoralis major and minor, triceps brachii, deltoideus Reversed curls with barbell Biceps brachii, brachialis Machine side shoulder raise Deltoideus Seated leg extension Quadriceps femoris Hamstring curl Biceps femoris, semitendinosus, semimembranosus Leg press Gluteus maximus, quadriceps femoris, biceps femoris Open in a separate window * With or without a weight. After the programme was completed, the subjects had to stretch the major muscles. Laboratory analysis At visit 1, blood samples for haematology (haemoglobin, leucocyte count, leucocyte differential count, platelets), clinical chemistry (AST, ALT, ALP, γGT, creatinine, albumin, glucose, C-reactive protein, potassium, calcium, sodium) and HIV and hepatitis B and C serology were taken. A mid-stream urine sample for urinalysis and a drugs of abuse screen (RapidTest d.a.u.® 10 kit; Syva Co., Marburg, Germany) was also performed. At visit 2, after at least 10 h fasting, a blood sample for plasma bilirubin was taken to exclude subjects with Gilbert's syndrome. Blood samples were taken for clinical chemistry parameters in plasma (AST, ALT, ALP, CK, γGT, LD, bilirubin) and in serum (myoglobin) at visits 3–5. At visit 3 baseline values were obtained. At visit 4, blood sampling for these clinical chemistry parameters was performed immediately before, immediately after and at 1, 3, 6, 24, 48, 72, 96, 120, 144 and 168 h after the weightlifting programme. If the enzyme levels were normalized before 168 h, blood sampling was interrupted. Follow-up blood sampling was performed at visit 5, 10–12 days after the weightlifting programme. Alcohol breath tests were performed at visits 2, 3 and 4. Ethics Before the study, approval was obtained by the Ethics Committee of Lund University, Sweden. The study was performed in accordance with the ethical principles of the Declaration of Helsinki and all subjects gave their written informed consent before participation. Statistics The study was explorative in nature and not powered with respect to any prespecified difference of interest. Primary data were analysed using descriptive statistics and graphical illustrations. Changes from baseline to different time points after exercise were assessed using Wilcoxon's signed rank sum test. All hypothesis testing was done using two-sided alternative hypotheses. P -values < 5% were considered to be statistically significant. The statistical analysis was done using Gauss from Aptech Systems Inc. (Black Diamond, WA, USA). Results A total of 35 subjects were enrolled at one centre. Twenty subjects were excluded because eligibility criteria were not met ( n = 7) or for other reasons ( n = 13). The 15 subjects included were all men with a mean age of 24.5 years and a mean BMI of 22.8 kg m −2 . The mean exercise duration was 73.1 min and the mean total workload was 10.5 tonnes. One subject (no. 14) withdrew 1 day after performing the weightlifting programme due to personal circumstances. In total, 14 subjects were used for the statistical analysis (all except subject 14). Changes in AST and ALT The individual value curves for AST and ALT are illustrated in Figures 1 and ​ and2. 2 . On day 1 postexercise, six subjects showed AST above the upper reference limit, whereas none of the subjects showed increased ALT. On day 2 post exercise, five subjects showed an increased ALT. All 14 subjects had AST above the upper reference limit 3, 4 and 5 days post exercise. The increase was higher for AST; the highest value obtained was 16.0 µkat l −1 in two subjects (nos. 1 and 12) as shown in Table 2 . The maximum increase in ALT was 4.1 µkat l −1 (subjects 11 and 15). Seven days postexercise, AST and ALT were still significantly increased compared with the pre-exercise levels ( P ≤ 0.01). Open in a separate window Figure 1 Individual changes over time for aspartate aminotransferase (µkat l −1 ). 1, (○); 2, (□); 3, (▵); 4, (+); 5, (◊); 6, (▿); 7, (×); 8, (•); 9, (▪); 10, (▴); 11, ( + ); 12, (♦); 13, (▾); 15 ( × ) Open in a separate window Figure 2 Individual changes over time for alanine aminotransferase (µkat l −1 ). 1, (○); 2, (□); 3, (▵); 4, (+); 5, (◊); 6, (▿); 7, (×); 8, (•); 9, (▪); 10, (▴); 11, ( + ); 12, (♦); 13, (▾); 15 ( × ) Table 2 Individual responders (above upper reference limit) by parameter Maximum value (if responder) * Subject ALT (µkat l −1 ) AST (µkat l −1 ) γGT (µkat l −1 ) ALP (µkat l −1 ) LD (µkat l −1 ) CK (µkat l −1 ) Bilirubin (µmol l −1 ) Myoglobin (µg l −1 ) 1 3.3 16.0 26.0 857.0 24 >2999 † 2 2.9 7.6 12.0 377.0 2874 3 1.3 5.5 2.1 7.7 233.0 1385 4 1.3 4.3 5.9 152.0 742 5 0.7 1.7 3.8 50.4 415 6 1.0 3.7 37.3 193 7 0.7 1.9 3.7 57.4 607 8 0.8 2.3 4.5 94.0 585 9 2.6 13.0 31.0 822.0 >2999 † 10 0.7 1.8 3.9 62.2 532 11 4.1 15.0 14.0 891.0 >2999 † 12 3.7 16.0 23.0 812.0 >2999 † 13 2.3 9.9 12.0 392.0 1954 15 4.1 14.0 10.0 507.0 >2999 † Open in a separate window * Only results from subjects with values above local upper reference limit are shown; alanine aminotransferase (ALT) (>0.7 µkat l −1 ), aspartate aminotransferase (AST) (>0.7 µkat l −1 ), gamma-glutamyl transferase (γGT) (>0.6 µkat l −1 ), alkaline phosphatase (ALP) (>1.8 µkat l −1 ), lactate dehydrogenase (LD) (>3.5 µkat l −1 ), creatine kinase (CK) (>3.3 µkat l −1 ), bilirubin (>20 µmol l −1 ), and myoglobin (>72 µg l −1 ). † The upper detection limit for myoglobin with method used was 2999 µg l −1 . The AST/ALT ratio was >1.0 in all subjects from 6 h to 7 days post exercise. At the follow-up visit, the mean value curve for ALT showed higher values than for AST and 12 of the subjects had a ratio < 1.0. The highest AST/ALT ratio was 6.2, observed in subject 1 on day 2 post exercise. The lowest ratio was 0.36 in subject 2 at follow-up ( Figure 3 ). Open in a separate window Figure 3 The aspartate aminotransferase/alanine aminotransferase ratio during the study period. Each box shows the median and the interquartile range values; lines show the total range Changes in LD The individual changes in LD are illustrated in Figure 4 . All subjects showed an increased LD at some time point during the assessment period and the highest value obtained was 31.0 µkat l −1 (subject 9; Table 2 ). On day 7, LD was still significantly increased compared with the pre-exercise levels ( P ≤ 0.01). Open in a separate window Figure 4 Individual changes over time for lactate dehydrogenase (µkat l −1 ). 1, (○); 2, (□); 3, (▵); 4, (+); 5, (◊); 6, (▿); 7, (×); 8, (•); 9, (▪); 10, (▴); 11, ( + ); 12, (♦); 13, (▾); 15 ( × ) Changes in ALP, γGT and bilirubin Bilirubin, γGT and ALP were almost unaltered during the 7-day measurement period. The maximum values for individual responders are given in Table 2 . There was one responder for ALP (subject 3; 2.1 µkat l −1 ) and one for bilirubin (subject 1; 24 µmol l −1 ). There were no responders for γGT. Changes in CK and myoglobin Creatine kinase and myoglobin showed significantly increased values during the full measurement period ( Figures 5 and ​ and6). 6 ). On day 2, both CK and myoglobin were above the reference limit in all 14 subjects. Four subjects had CK levels >800 µkat l −1 and five subjects had myoglobin levels above the maximum detectable level of 2999 µg l −1 . Open in a separate window Figure 5 Individual changes over time for creatine kinase (µkat l −1 ). 1, (○); 2, (□); 3, (▵); 4, (+); 5, (◊); 6, (▿); 7, (×); 8, (•); 9, (▪); 10, (▴); 11, ( + ); 12, (♦); 13, (▾); 15 ( × ) Open in a separate window Figure 6 Individual changes over time for myoglobin (µg l −1 ). 1, (○); 2, (□); 3, (▵); 4, (+); 5, (◊); 6, (▿); 7, (×); 8, (•); 9, (▪); 10, (▴); 11, ( + ); 12, (♦); 13, (▾); 15 ( × ) On day 7, these two parameters were still significantly increased compared with pre-exercise levels ( P < 0.01). The maximum values for individual responders are given in Table 2 . Time pattern of changes in clinical chemistry parameters The time to reach t max , time to first passage above upper local reference limit and time of renormalization [last passage below upper local reference limit or defined as day 8 (192 h) if still increased on day 7] was calculated for five of the studied clinical chemistry parameters ( Table 3 ). Myoglobin had the shortest t max (0.08 h) and ALT the longest t max and time to first passage above upper local reference limit, whereas LD had the shortest time to first passage below upper local reference limit. Except for LD, >50% of the subjects had values above the upper local reference limit on day 7. Table 3 Median time to response Median times (decimal hours) Parameter ALT AST LD CK Myoglobin t max 120 96 78 96 60 Above ref. limit 59 28 26 2.0 0.08 Below ref. limit * 192 192 142 192 192 Open in a separate window * If above reference limit on day 7, day 8 (192 h) was used as estimate. ALT, Alanine aminotransferase; AST, aspartate aminotransferase; LD, lactate dehydrogenase; CK, creatine kinase. Discussion The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the leading cause of postmarketing warnings and withdrawals [ 10 ]. Asymptomatic elevations of liver function tests during clinical trials could be drug-related, but other factors, such as strenuous exercise, have resulted in increased serum transaminase levels [ 11 ]. As we had observed that healthy subjects performing intensive weightlifting during clinical trials exhibited altered liver function tests (elevations of AST, ALT; unpublished observations), we conducted a study to clarify the effects of weightlifting on liver function tests. The effects of weightlifting on CK and myoglobin levels have been thoroughly described [ 8 , 12 ], but there is no information regarding the effect on clinicalchemistry parameters commonly used to evaluate liver function. However, other types of strenuous physical exercise, such as marathon running, are known to affect liver function tests [ 13 ]. In this study, it has been shown that weightlifting resulted in profound increases in the liver function parameters, AST and ALT, as well as in LD, CK and myoglobin levels. Furthermore, we have been able to show that this effect was prolonged and that most subjects still had increased enzyme concentrations 1 week after performing the weightlifting programme. The duration of increased markers for muscle damage (myoglobin, CK, AST, ALT and LD) was in line with a recent study using strenuous one-arm exercise, in which all markers of muscle damage were significantly increased for up to 10 days after exercise [ 14 ]. There was, however, considerable variability in the extent of response to the heavy muscular exercise. One possible explanation for this could be that the subjects were used to varying amounts of physical activity in daily life. Other factors, e.g. ethnicity and diet, could also have contributed to this variability. These findings highlight the importance of imposing relevant restrictions on weightlifting prior to and during clinical studies, and illustrate the need to consider weightlifting and probably other forms of intense muscular activity as possible causes of asymptomatic elevations of liver function tests in daily clinical practice. The weightlifting programme used in this study resulted in CK values consistent with exercise-induced rhabdomyolysis in most of the subjects. Eight subjects (57%) had maximum CK levels >167 µkat l −1 (10 000 U l −1 ), a threshold commonly used to diagnose severe rhabdomyolysis [ 15 ]. Furthermore, seven out of these eight subjects had CK levels >250 µkat l −1 (15 000 U l −1 ), which have been associated with an increased risk of renal failure due to rhabdomyolysis [ 16 ]. Although renal function was not monitored during the study, none of the subjects had an affected renal function at follow-up. Our findings are in accordance with previous studies [ 14 , 17 ], and clinicians shouldbe aware of these observations when evaluating patients who have performed a heavy work-out such as weightlifting. Bilirubin, γGT and ALP were almost unaltered during the 7-day measurement period. This finding was expected, as these enzymes are not present in muscle tissue, and is also in accordance with a previous study [ 18 ]. The time pattern of changes in clinical chemistry parameters after the weightlifting programme were also investigated. Myoglobin has the shortest t max and time to first passage above upper reference limit, followed by LD, CK and AST, whereas ALT has the longest t max and time to first passage above upper reference limit. The myoglobin peaked 36 h before the CK, a finding consistent with results from a cohort of critically ill patients with rhabdomyolysis treated at an intensive care unit [ 19 ]. The AST/ALT ratio was >1 in almost all subjects during 7 days post exercise. However, at the follow-up (10–12 days post exercise) the majority of subjects had an AST/ALT ratio < 1 and ALT concentrations above the upper reference range. This could be explained by the longer half-life of ALT (47 h) compared with AST (17 h) [ 20 , 21 ]. If liver fuction tests are performed at that time point, a misleading picture may result, suggesting mild liver disease. The time pattern of enzyme activity following exercise compared with following acute myocardial infarction (AMI) has been reported previously [ 22 ]. It is considered that a distinguishing characteristic of LD activity post exercise is that this enzyme peaks at least 40 h sooner than maximal LD activity following AMI. This was not true for our results, where t max for LD was 78 h postexercise compared with t max for LD following an AMI, which is about 48 h. One reason for the discrepancy between our results and those of the previous study [ 22 ] may be that the type of exercise was different in the respective studies – a weightlifting programme and a 6–10-mile run, respectively. One similarity, however, between these studies was that LD peaked about 16 h earlier than CK in both studies. Conclusion Liver function tests are significantly increased for at least 7 days after weightlifting among men used to moderate physical activity, but not used to performing weightlifting on a regular basis. In accordance with these results, and in order to exclude potential exercise-related effects on liver function tests, it is important to impose training restrictions on weightlifting for at least 1 week before the start of clinical trials. 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The effects of near maximum exercise on serum enzymes: the exercise profile versus the cardiac profile. Clin Chim Acta. 1977; 81 :145–52. [ PubMed ] [ Google Scholar ] Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society Other Formats PDF (1.2M) Actions Cite Collections Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than  characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Share Permalink Copy RESOURCES Similar articles Cited by other articles Links to NCBI Databases [x] Cite Copy Download .nbib .nbib Format: AMA APA MLA NLM Follow NCBI Twitter Facebook LinkedIn GitHub Connect with NLM SM-Twitter SM-Facebook SM-Youtube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov

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+Serum Enzyme Profiles Differentiate Five Types of Muscular Dystrophy - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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+    the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Dis Markers. 2015; 2015: 543282. Published online 2015 Apr 29. doi: 10.1155/2015/543282 PMCID: PMC4429213 PMID: 26063958 Serum Enzyme Profiles Differentiate Five Types of Muscular Dystrophy Yuling Zhu , 1 Huili Zhang , 2 Yiming Sun , 3 Yaqin Li , 2 Langhui Deng , 4 Xingxuan Wen , 5 Huaqiao Wang , 1
+, * and Cheng Zhang 2
+, * Yuling Zhu 1 Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, China Find articles by Yuling Zhu Huili Zhang 2 Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, China Find articles by Huili Zhang Yiming Sun 3 Department of Healthcare Clinic, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, China Find articles by Yiming Sun Yaqin Li 2 Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, China Find articles by Yaqin Li Langhui Deng 4 Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, China Find articles by Langhui Deng Xingxuan Wen 5 Department of Epidemiology and Health Statistics, School of Public Health, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, China Find articles by Xingxuan Wen Huaqiao Wang 1 Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, China Find articles by Huaqiao Wang Cheng Zhang 2 Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, China Find articles by Cheng Zhang Author information Article notes Copyright and License information PMC Disclaimer 1 Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, China 2 Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, China 3 Department of Healthcare Clinic, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, China 4 Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, China 5 Department of Epidemiology and Health Statistics, School of Public Health, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, China *Huaqiao Wang: nc.ude.usys.liam@qhgnaw and *Cheng Zhang: moc.liamtoh@001gnahzgnehc Academic Editor: Donald H. Chace Received 2015 Feb 16; Revised 2015 Apr 9; Accepted 2015 Apr 15. Copyright © 2015 Yuling Zhu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background. Differentiation among types of muscular dystrophy (MD) has remained challenging. In this retrospective study, we sought to develop a methodology for differentiation of MD types using analysis of serum enzyme profiles. Methods. The serum levels of enzymes from 232 patients, including 120 with DMD, 36 with BMD, 36 with FSHD, 46 with LGMD, and 11 with EDMD, were evaluated. Results. The characteristic profiles of serum enzymes facilitated differentiation of these five types of MD. DMD was characterized by simultaneous elevation of ALT, AST, LDH, and ALP; BMD and LGMD were characterized by elevation of ALT, AST, and LDH; and FSHD and EDMD were characterized by a lack of abnormal serum enzyme levels. We further developed discriminant functions to distinguish BMD and LGMD. For LGMD, LGMD2B patients had significantly higher ALP levels than non-LGMD2B patients (98 ± 59 U/L versus 45 ± 9 U/L, resp., p < 0.05). Conclusions. Our approach enabled the determination of MD subtypes using serum enzyme profiles prior to genetic testing, which will increase the chance a mutation will be found in the first gene analyzed. 1. Introduction Muscular dystrophies (MDs) are a heterogeneous group of inherited myopathies that share similar clinical features and dystrophic changes on muscle biopsies [ 1 ]. Despite the well-known disease symptoms, the diagnosis of MD continues to be challenging in the general pediatric settings and in pediatric neurology units [ 2 , 3 ], potentially because unsuspected myopathy in children with hypertransaminasemia can be erroneously attributed to liver disease [ 4 – 11 ]. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and lactic dehydrogenase (LDH) are components of routine or comprehensive blood panels and collectively demonstrate liver function. Consequently, in apparently healthy children, analysis of these liver enzymes is performed more frequently than analysis of creatine kinase (CK), a more specific marker of muscle disease [ 12 ]. Particularly in rural or underdeveloped areas, a child with isolated hypertransaminasemia, labeled as being affected by cryptogenic hepatopathy, could be monitored only with liver function tests for a long time before serum CK is analyzed or before a muscular disease becomes clinically obvious, thus delaying diagnosis and treatment [ 13 ]. With advancements in diagnostic methodologies, such as magnetic resonance imaging (MRI), muscle biopsy, and genetic screening, more types of MD can be categorized accurately. However, because not all hospitals have access to these advanced techniques, the diagnosis of MD can still be challenging. CK values may facilitate differential diagnosis to some extent [ 13 ], but measurement of CK alone is not as comprehensive as measurement of other serum enzymes. Thus, the development of additional tools for serum enzymes tests may facilitate differential diagnosis of subtypes of MD. Therefore, in this study, we retrospectively reviewed the clinical records of hundreds of Chinese patients with MD, in order to examine changes in enzyme profiles in different types of MD. Our results emphasize that a diagnosis of occult muscle disease should be considered when confronted with an unexplained elevation of serum enzymes. 2. Patients and Methods 2.1. Patients Clinical data from Chinese patients with MD who visited the Department of Neurology at the First Affiliated Hospital of Sun Yat-sen University were collected between June 2012 and October 2013. Patients were excluded if they had any coexisting medical diseases according to medical records. This study was approved by the Local Ethical Committee at Sun Yat-sen University (China) and was conducted in accordance with the recommendations of the Declaration of Helsinki. Adult patients and parents of affected children provided written informed consent. Patients had been diagnosed with one of the following five pathologies: (1) Duchenne muscular dystrophy, (2) Becker's muscular dystrophy (BMD), (3) facioscapulohumeral dystrophy (FSHD), (4) limb girdle muscular dystrophy (LGMD), or (5) Emery-Dreifuss muscular dystrophy (EDMD). For DMD/BMD, patients were diagnosed by dystrophin gene analysis or immunohistochemistry and western blotting for dystrophin on muscular biopsy specimen. FSHD was confirmed by two neurologists on the basis of clinical manifestation. LGMD was identified according to traditional clinical, electrophysiological, and histological criteria, and diagnoses of DMD/BMD, FSHD, polymyositis, and myotonic dystrophy were excluded simultaneously. Some cases of LGMD were confirmed by gene analysis. EDMD was diagnosed according to previously published criteria [ 14 ], and some of cases were confirmed by gene analysis. 2.2. Laboratory Measurements Serum enzymes, including ALT, AST, ALP, LDH, and CK, were measured using an Abbott Aeroset fully automatic biochemical analyzer (Abbott Laboratories, USA). The levels of serum enzymes were assayed according to the instructions provided with the corresponding enzymatic kits. The upper limits of normal for ALT, AST, ALP, LHD, and CK were 40, 37, 110, 240, and 250 U/L, respectively. 2.3. Statistical Analysis Statistical analysis was performed using SPSS, Version 20.0 (IBM SPSS Statistics 20.0). Due to the differences in the normal ranges of different enzymes, new variables were adopted appropriately for analysis; variables ALTn, ASTn, ALPn, and LDHn were defined as the value of the enzyme divided by the upper limit of normal (ULN) for that enzyme. The normal distributions of the variables were tested with the Kolmogorov-Smirnov test ( n > 50) or Shapiro-Wilk test ( n ≤ 50). Variables (distributed normally) were reported as the mean and standard deviation (mean ± SD) or as the median and the 25th and 75th percentiles. Since not all variables were distributed normally, Mann-Whitney rank sum tests and Bonferroni tests ( a ′ = 0.005) were applied to compare the enzyme values of one group with another. We then performed one-sample t -tests or rank sum tests to determine magnitude of changes in enzyme levels. To distinguish between the BMD and LGMD groups, discrimination analysis was performed to develop discriminant functions derived from the Fisher principle. ALT, AST, ALP, LDH, CK, age, and gender were regarded as independent variables, and category of diagnosis (BMD or LGMD) was regarded as the dependent variable. All tests were two-tailed, and differences with p values of less than 0.05 were considered statistically significant. 3. Results 3.1. Patient Demographic Characteristics A total of 232 patients were included in this study, of which 120 patients were diagnosed with DMD, 36 patients were diagnosed with BMD, 19 were diagnosed with FSHD, 46 were diagnosed with LGMD, and 11 were diagnosed with EDMD. The mean age of patients with DMD was the lowest of all subtypes (~7 years), while the mean age of patients with FSHD was the highest of all subtypes (~26 years). More than 97% of patients with DMD and BMD had abnormal ALT, AST, and LDH values. The proportion of patients with abnormal ALT and AST values was lowest in patients with EDMD (27.3% and 36.4%, resp.). More than 40% of patients with FSHD and LGMD had abnormal ALT, AST, ALP, and LDH values, with the exception of AST in FSHD, which was abnormal in less than 40% of patients (36.8%). The demographics and frequencies of patients with MD presenting with abnormal serum enzymes are shown in Table 1 . Table 1 The demography and frequency of patients with MD presented with normal or abnormal serum enzymes levels. Category Age (y) Gender n (%) ALTn n (%) ASTn n (%) ALPn n (%) LDHn n (%) CKn n (%) Mean ± SD (range) Male Female Normal Abnormal Normal Abnormal Normal Abnormal Normal Abnormal Normal Abnormal DMD 6.7 ± 3.4 (7 m–24) 120 (100) 0 (0) 3 (2.5) 119 (97.5) 3 (2.5) 119 (97.5) 39 (32) 83 (68) 3 (2.5) 119 (97.5) 0 (0) 122 (100) BMD 13.0 ± 8.5 (2–37) 36 (100) 0 (0) 0 (0) 37 (100) 0 (0) 37 (100) 16 (43.2) 21 (56.8) 0 (0) 37 (100) 0 (0) 37 (100) FSHD 25.8 ± 9.3 (13–50) 13 (68) 6 (32) 5 (26.3) 14 (73.7) 12 (63.2) 7 (36.8) 10 (52.6) 9 (47.4) 11 (57.9) 8 (42.1) 1 (5.3) 18 (94.7) LGMD 22.6 ± 11.4 (3–54) 23 (56) 18 (44) 11 (26.8) 30 (73.2) 9 (22.0) 32 (78.0) 24 (58.5) 17 (41.5) 10 (24.4) 31 (75.6) 1 (2.4) 40 (97.6) EDMD 15.4 ± 9.9 (6–42) 6 (55) 5 (45) 8 (72.7) 3 (27.3) 7 (63.6) 4 (36.4) 4 (36.4) 7 (63.6) 6 (54.5) 5 (45.5) 3 (27.3) 8 (72.7) Open in a separate window MD, muscular dystrophy; DMD, Duchenne muscular dystrophy; BMD, Becker's muscular dystrophy; FSHD, facioscapulohumeral dystrophy; LGMD, limb girdle muscular dystrophy; EDMD, Emery-Dreifuss muscular dystrophy; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; LDH, lactic dehydrogenase; CK, creatine kinase; m, month. 3.2. Serum Enzyme Levels among Five Types of MD For ALT, AST, and LDH levels, patients with DMD had higher serum concentrations than patients with BMD, FSHD, LGMD, and EDMD ( p < 0.05), and patients with BMD had higher serum concentrations than patients with FSHD, LGMD, and EDMD ( p < 0.05). In addition, patients with LGMD had higher ALTn concentrations than patients with EDMD ( p < 0.05). However, ALTn concentrations did not differ between patients with FSHD and LGMD or between patients with FSHD and EDMD. In contrast, patients with FSHD had significantly lower ASTn concentrations than patients with LGMD ( p < 0.05). Similarly, patients with LGMD had higher ALTn concentrations than patients with EDMD ( p < 0.05). However, no differences in LDH concentrations were observed between these groups. Serum ALP profiles were different from those of the other three enzymes (ALT, AST, and LDH). Significant differences were only observed between patients with DMD and FSHD and between patients with DMD and LGMD ( p < 0.05). Additionally, in patients with DMD, BMD, FSDH, and LGMD, the fold changes for ALT, AST, and LDH were greater than that for ALP, while, in patients with EDMD, the fold increases for ALT, AST, and LDH were lower than that for ALP. Serum enzymes concentrations in patients with the five different types of MD are shown in Table 2 . Table 2 Serum enzymes levels among five types of MD. Category ALTn ( P 25 – P 75 ) ASTn ( P 25 – P 75 ) ALPn ( P 25 – P 75 ) LDHn ( P 25 – P 75 ) CKn ( P 25 – P 75 ) DMD 6.55 (4.85–8.18) b,c,d,e 5.32 (3.98–6.68) b,c,d,e 1.1 (0.94–1.25) c,d 4.28 (3.23–5.60) b,c,d,e 44.77 (31.05–56.57) b,c,d,e BMD 2.91 (1.96–4.61) a,c,d,e 2.85 (1.76–4.5) a,c,d,e 1.06 ± 0.48 2.02 (1.49–3.48) a,c,d,e 27.59 (16.64–41.22) a,c,d,e FSHD 1.04 ± 0.48 a,b 1.00 (0.87–1.44) a,b,d 0.60 (0.42–0.92) a 1.02 (0.93–1.44) a,b 3.05 (1.64–3.91) a,b,d LGMD 1.65 (0.74–3.39) a,b,e 1.68 (1.01–2.86) a,b,c,e 0.55 (0.45–1.17) a 1.49 (1.00–2.37) a,b 9.08 (4.50–21.87) a,b,c,e EDMD 0.50 (0.36–0.83) a,b,d 0.73 (0.69–1.04) a,b,d 1.15 ± 0.54 1.09 ± 0.17 a,b 1.64 (0.66–3.51) a,b,d H 92.45 111.09 22.83 112.19 114.01 p value <0.001 <0.001 <0.001 <0.001 <0.001 Open in a separate window MD, muscular dystrophy; DMD, Duchenne muscular dystrophy; BMD, Becker's muscular dystrophy; FSHD, facioscapulohumeral dystrophy; LGMD, limb girdle muscular dystrophy; EDMD, Emery-Dreifuss muscular dystrophy; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; LDH, lactic dehydrogenase; CK, creatine kinase. a Comparing with DMD, p < 0.05. b Comparing with BMD, p < 0.05. c Comparing with FSHD, p < 0.05. d Comparing with LGMD, p < 0.05. e Comparing with EDMD, p < 0.05. 3.3. Profiles of Serum Enzymes in Different Types of MD For patients with different types of MD, only patients with DMD exhibited simultaneous elevation of serum ALT, AST, ALP, and LDH values. ALT levels exhibited the greatest increase, followed by AST, LDH, and ALP ( Table 3 ). Table 3 The serum enzymes profile in five types of MD. Category ALTn ( P 25 – P 75 ) ASTn ( P 25 – P 75 ) ALPn ( P 25 – P 75 ) LDHn ( P 25 – P 75 ) BMD 2.91 (1.96–4.61) (↑) 2.85 (1.76–4.5) (↑) 1.06 ± 0.46 (→) 2.02 (1.49–3.48) (↑) DMD 6.55 (4.85–8.18) (↑) 5.32 (3.98–6.68) (↑) 1.1 (0.94–1.25) (↑) 4.28 (3.23–5.60) (↑) EDMD 0.50 (0.36–0.83) (→) 0.73 (0.69–1.04) (→) 1.15 ± 0.54 (→) 1.06 ± 0.19 (→) FSHD 1.04 ± 0.48 (→) 1.00 (0.87–1.44) (→) 0.60 (0.42–0.92) (→) 1.02 (0.93–1.44) (→) LGMD 1.65 (0.74–3.39) (↑) 1.68 (1.01–2.86) (↑) 0.55 (0.45–1.17) (→) 1.49 (1.00–2.37) (↑) Open in a separate window MD, muscular dystrophy; DMD, Duchenne muscular dystrophy; BMD, Becker's muscular dystrophy; FSHD, facioscapulohumeral dystrophy; LGMD, limb girdle muscular dystrophy; EDMD, Emery-Dreifuss muscular dystrophy; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; LDH, lactic dehydrogenase. “→” represents that patients had similar levels of enzymes comparing with normal people ( p > 0.05). “↑” represents that patients had significantly higher levels of enzymes comparing with normal people ( p < 0.05). Elevated serum ALT, AST, and LDH values were observed in patients with BMD or LGMD ( p < 0.05), while serum ALP values remained within the normal range ( p > 0.05). However, these two MD subtypes could be roughly distinguished by the magnitudes of changes in these enzymes ( Table 4 ). For patients with BMD, ALT and AST levels exceeded 2-fold the ULN. In contrast, in patients with LGMD, ALT and AST levels were about 2-fold the ULN. Since LDH levels in patients with BMD and LGMD were both 2-fold the ULN ( p > 0.05 compared with “2”), we did not detect significant differences in LDH levels between patients with these subtypes. However, patients with BMD tended to have higher serum LDH levels. In patients with BMD, ALTn and ASTn levels exhibited the greatest increase, followed by LDHn and ALPn. In contrast, in patients with LGMD, ALTn, ASTn, and LDHn levels exhibited similar increases, while the increase in ALPn was lower. Table 4 The enzymes profile between patients with BMD and LGMD. Category ALTn ( P 25 – P 75 ) ASTn ( P 25 – P 75 ) ALPn ( P 25 – P 75 ) LDHn ( P 25 – P 75 ) BMD 2.91 (1.96–4.61) (↑) 2.85 (1.76–4.5) (↑) 1.06 ± 0.46 2.02 (1.49–3.48) (→) LGMD 1.65 (0.74–3.39) (→) 1.68 (1.01–2.86) (→) 0.55 (0.45–1.17) 1.49 (1.00–2.37) (→) Open in a separate window BMD, Becker's muscular dystrophy; LGMD, limb girdle muscular dystrophy; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; LDH, lactic dehydrogenase. “→” represents that patients had 2-fold ULN of enzymes levels (compared with “2,” p > 0.05). “↑” represents that patients had exceeded 2-fold ULN of enzymes levels (compared with “2,” p < 0.05). As demonstrated in Table 2 , there was no significant difference of ALP serum levels in patients with BMD and LGMD, so we did not perform further analysis on magnitude of change in ALP serum levels. Patients with FSHD and EDMD exhibited the same profiles for the four liver enzymes, with all values remaining within the normal range ( Table 3 ). Nonetheless, patients with FSHD tended to have higher serum ALT and AST values than patients with EDMD, whereas patients with EDMD tended to have higher serum ALP and LDH values than patients with FSHD ( p > 0.05). 3.4. Discriminant Functions to Identify Patients with BMD and LDMD Because age and gender were correlated with diagnosis, we developed discriminant functions to distinguish between BMD and LGMD more accurately without gene detection or muscle biopsy ( Table 5 ). Once serum enzyme levels (ALT, AST, ALP, and LDH) were measured in patients of known age, we could separately calculate two mathematical values ( Y 1 and Y 2 ), and by comparison of Y 1 and Y 2 , clinicians could make a probable diagnosis of BMD when Y 1 was greater than Y 2 . On the contrary, a probable diagnosis of LGMD could be established when Y 2 was greater than Y 1 . Table 5 Discriminant functions to identify patients with BMD and LGMD. Discriminant functions Y 1 = −19.406 + 0.724 X 1 − 0.003 X 2 + 0.032 X 3 + 0.80 X 4 + 0.001 X 5 + 13.299 X 6 Y 2 = −30.537 + 0.909 X 1 e − 0.007 X 2 + 0.030 X 3 + 0.92 X 4 + 0.002 X 5 + 18.745 X 6 Open in a separate window BMD, Becker's muscular dystrophy; LGMD, limb girdle muscular dystrophy; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; LDH, lactic dehydrogenase. X 1 is age, X 2 is ALT, X 3 is AST, X 4 is ALP, X 5 is LDH, and X 6 is gender, Y 1 represents a diagnosis of BMD, and Y 2 represents a diagnosis of LGMD. 3.5. Serum Enzyme Levels in Patients with LGMD Twenty-six patients with LGMD (over 50%) had genetic tests. Among them, five had duplicate genetic tests (data not shown). Three patients carried CAPN3 gene mutations responsible for LGMD2A, and three patients were negative for the CAPN3 gene mutation. Moreover, eight patients harbored DYSF gene mutations responsible for LGMD2B, and eight patients were negative for the DYSF gene mutation. Since there were few samples from patients with LGMD2A, we could not perform any statistical analysis to detect characteristic profiles of serum enzymes between patients with and without LGMD2A. There were no significant differences in ALT, AST, or LDH levels between patients with and without LGMD2B (data not shown). Additionally, no significant differences in CK levels were observed between patients with and without LGMD2B. However, ALP levels in LGMD2B patients (98 ± 59 U/L) were significantly higher than those in non-LGMD2B patients (45 ± 9 U/L; t = −2.474, p = 0.04). 4. Discussion Here, we presented a retrospective analysis of serum enzyme levels from patients with MD, who were originally diagnosed according to clinical and/or genetic diagnoses. Although serum CK testing is an easy, sensitive, and inexpensive test for muscular diseases, it appears to be underutilized in routine clinical practice. In apparently healthy children, aminotransferase levels are assessed more frequently than CK or aldolase levels [ 15 ]. Economic restrictions may negatively influence the broadening of laboratory tests [ 16 ], and transaminases may be the only targets analyzed before signs of a muscular disease become clinically obvious in patients with incidental elevations in aminotransferase levels. Ciafaloni et al. reported that initial evaluations in children presenting with motor or global developmental delays included CK screening in only 35% of cases [ 3 ]. Hence, routine biochemical assays, such as transaminases, ALP, LDH, and CK analyses, should be evaluated for their predictive ability. In the present study, a high frequency of patients with MD presented with abnormal levels of serum enzymes (including ALT, AST, ALP, and LDH). For instance, all patients with BMD and up to 97% of patients with DMD had elevated ALT, AST, and LDH values. Even in patients with EDMD, for which the frequency was relatively small, the proportion of patients presenting with abnormal ALT, AST, or LDH values was no lower than 25%. Indeed, studies from around the world [ 4 , 6 – 8 , 11 , 15 , 17 ] have reported that patients with muscular diseases are often erroneously labeled as having cryptogenic liver disease. However, most of these studies have analyzed aminotransferases, with few analyses of ALP and LDH. Hence, serum ALP and/or LDH as markers of muscle diseases should also be stressed. The mechanism through which levels of ALP and LDH become abnormal in patients with MD is still unknown. Elevations in ALT and AST levels are common indicators of hepatocellular damage; however, ALT abnormalities are also found in cardiac and skeletal muscle, although ALT activity in skeletal muscle is only one-tenth of that in hepatocytes [ 18 ]. AST is found within the cardiac muscle, skeletal muscle, kidneys, brain, pancreas, lungs, leukocytes, and erythrocytes [ 17 ]. Since serum CK is markedly elevated with breakdown of muscle and is considered a diagnostic marker of MDs [ 19 ], we assumed that leakage of transaminases from muscle membrane would occur along with the leakage of CK under pathological conditions, such as in patients with MD. Serum enzyme levels were elevated to variable degrees among patients with different subtypes of MD. McMillan et al. reported that ALT values are elevated by up to 22.6 times the ULN in patients with DMD [ 20 ], whereas we observed that ALT reached 5–8 times the ULN in patients with DMD. Different methods for detecting enzyme levels or taking blood samples under nonstandardized conditions may account for this discrepancy. Additionally, Zhang et al. reported that disorders can be sequenced (e.g., DMD/BMD > LGMD > FSHD) according to AST or ALT levels [ 21 ], consistent with our results. Regarding LDH, Yasmineh et al. reported that the mean total serum activity in patients with DMD was 3.4-fold that of serum from the control group [ 22 ], which was consistent with the range observed in our current analysis (3.23 to 5.60). Our observations were also consistent with previous reports demonstrating that serum LDH activity in patients with EDMD was within the normal limit or slightly increased [ 14 , 23 ]. As another index, ALP levels have seldom been described in muscular disease. Strikingly, in patients with DMD, BMD, FSDH, and LGMD, the fold increases for ALT, AST, and LDH were greater than that for ALP, while in patients with EDMD, the fold increases for ALT, AST, and LDH were lower than that for ALP. Further research is needed to determine the correlation between EDMD and ALP. To some extent, CK values may facilitate differential diagnosis [ 24 ]. Hence, when advanced diagnostic technology is absent, discrepancies in levels of other enzymes may also be used to provide important clues. Interestingly, each type of MD had a characteristic profile of serum enzymes. Therefore, the distribution of serum enzymes may have additional implications for the differential diagnosis of MD. Moreover, although patients with FSHD and EDMD shared the same serum enzyme profiles, distinguishing between these diseases is relatively simple based on clinical features alone. For example, FSHD is characterized by weakness of the face, upper-arm, and shoulder girdle muscles [ 24 ], whereas EDMD is characterized by slow progressive muscle weakness, early joint contractures, and atrial arrhythmias [ 25 ]. Thus, differential diagnoses should consider as many parameters as possible. Clinical differential diagnosis between BMD and LGMD may be difficult because the clinical phenotype of BMD tends to overlap with other limb girdle syndromes, especially LGMD [ 26 ]. In fact, in our tertiary care center, we continue to observe misdiagnosis of BMD as LGMD and vice versa. Genetic analysis is the gold standard for distinguishing between these disorders. However, it is difficult to perform genetic analysis when first evaluating a patient suspected of LGMD because of the various subtypes of LGMD. Hence, additional methods for distinguishing between BMD and LGMD, as well as subtypes of LGMD, should be developed. As illustrated here, serum enzyme levels were elevated to variable degrees in patients with BMD or LGMD. For the former, ALT or AST levels were more than 2-fold the ULN, and, for the latter, ALT or AST levels were equal to 2-fold the ULN. In addition, we provided discriminant functions to assist clinicians in identification of these subtypes without advanced diagnostic technology as follows: once serum enzyme levels (ALT, AST, ALP, and LDH) are measured in patients of known age, clinicians can make a probable diagnosis of BMD when Y 1 is greater than Y 2 or of LGMD when Y 2 is greater than Y 1 . LGMD is a heterogeneous genetically determined group of skeletal muscle disorders. Because at least 18 genetically distinct subtypes of LGMD have been described, determining the exact subtype of LGMD in a particular patient can be challenging [ 27 ]. In our study, over half of patients with LGMD had genetic tests. However, only three patients were positive for CAPN3 gene mutations, and eight patients were positive for DYSF gene mutations. This low positive rate necessitates the urgent detection of appropriate clinical information to narrow the scope of gene testing. The CK value also serves as an important clue to facilitate the differential diagnosis of subtypes. For example, a marked elevation in CK concentrations has been shown to occur in confirmed cases of LGMD2B [ 28 ]. However, we failed to detect significant differences in CK concentrations between patients with and without LGMD2B, which may be explained by the limited number of cases analyzed here. Moreover, higher ALP levels were observed in patients with LGMD2B, suggesting another parameter for distinguishing LGMD2B from other types of LGMD in clinical practice. Therefore, further studies of LGMD cases confirmed by genetic test are needed to determine the correlations between genotype and serum enzyme levels. Our study had several limitations. First, only 11 cases of EDMD and 19 cases of FSHD were reviewed in the present study. It is likely that the small sample studied is not representative of the general patient population. Second, not all the patients with LGMD were confirmed by genetic testing, and the exact diagnosis of LGMD subtypes was challenging. Third, we did not thoroughly investigate the effects of some medications or food on serum enzyme levels. Marked variability in serum enzymes can occur from day to day [ 29 ]. In summary, we found that a high frequency of patients with MD presented with abnormal serum enzyme levels. The characteristic profiles of serum enzymes facilitated the differentiation of MD subtypes. For example, DMD was characterized by simultaneous elevation of ALT, AST, LDH, and ALP; BMD and LGMD were characterized by elevation of ALT, AST, and LDH; and FSHD and EDMD lacked abnormalities in the serum levels of these four enzymes. To further differentiate BMD from LGMD, discriminant functions were developed for cases in which enzyme levels and age are known. For LGMD, patients with LGMD2B had significantly higher ALP levels than patients with non-LGMD2B subtypes. Thus, our approach makes it possible to determine the subtypes of MD by serum enzyme profiles prior to genetic testing, which will increase the chance that a mutation will be found in the first gene analyzed. Acknowledgments The authors are grateful to the patients and families who participated in the study. This research was supported by funding from the National Nature Science Foundation of China (no. 81271401), Joint Fund of National Nature Science Foundation of China, and Natural Science Foundation of Guangdong Province of China (no. U1032004). Conflict of Interests All authors declare that there is no conflict of interests regarding the publication of this paper. Authors' Contribution Yuling Zhu and Huili Zhang contributed equally to the paper. 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+Does untreated obstructive sleep apnea cause secondary erythrocytosis? - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Epub 2017 Jul 6. Does untreated obstructive sleep apnea cause secondary erythrocytosis? Christopher D Nguyen 1 , Jon-Erik C Holty 2 Affiliations Expand Affiliations 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University, Palo Alto, CA, USA; Stanford Sleep Medicine Center, Department of Psychiatry, Stanford University, Palo Alto, CA, USA. 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University, Palo Alto, CA, USA; Pulmonary, Critical Care and Sleep Medicine Section, VA Palo Alto Health Care System, Palo Alto, CA, USA; Center for Health Policy (CHP/PCOR), Stanford University, Palo Alto, CA, USA. Electronic address: jholty@stanford.edu. PMID: 29206630 DOI: 10.1016/j.rmed.2017.07.003 Free article Item in Clipboard Does untreated obstructive sleep apnea cause secondary erythrocytosis? Christopher D Nguyen et al. Respir Med . 2017 Sep . Free article Show details Display options Display options Format Abstract PubMed PMID Respir Med Actions Search in PubMed Search in NLM Catalog Add to Search . 2017 Sep:130:27-34. doi: 10.1016/j.rmed.2017.07.003. Epub 2017 Jul 6. Authors Christopher D Nguyen 1 , Jon-Erik C Holty 2 Affiliations 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University, Palo Alto, CA, USA; Stanford Sleep Medicine Center, Department of Psychiatry, Stanford University, Palo Alto, CA, USA. 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University, Palo Alto, CA, USA; Pulmonary, Critical Care and Sleep Medicine Section, VA Palo Alto Health Care System, Palo Alto, CA, USA; Center for Health Policy (CHP/PCOR), Stanford University, Palo Alto, CA, USA. Electronic address: jholty@stanford.edu. PMID: 29206630 DOI: 10.1016/j.rmed.2017.07.003 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Background: The current literature suggests a relationship between obstructive sleep apnea (OSA) severity and hematocrit. However, the degree that OSA contributes to clinically significant erythrocytosis is uncertain. The aim of this study is to evaluate this association in a large study sample controlling for multiple confounders. Methods: We evaluated consecutive subjects with suspected untreated OSA using multivariate analysis to test the associations between apnea-hypopnea index (AHI) and hematocrit. Subjects were evaluated with sleep studies, comprehensive sleep questionnaires, and detailed electronic medical record reviews to document their medical comorbidities, and demographic and laboratory information. Results: 1604 consecutive veterans (age 57.6 ± 13.4 years, 92% male) were included in the analysis with 77.4% diagnosed with OSA. However, few included subjects (1.6%) had clinical erythrocytosis. OSA severity defined by AHI was not associated with hematocrit or clinically significant erythrocytosis. Rather, awake oxygen saturation (-0.17 points, p < 0.001) and mean nocturnal oxygen saturation (-0.08 points, p = 0.04) were inversely proportional to hematocrit (per standardized Z-score). Other factors including active tobacco, increased alcohol ingestion and exogenous testosterone therapy were associated with higher hematocrit. Although AHI was not predictive of erythrocytosis, having severe OSA was predictive of nocturnal hypoxemia (adjusted OR 7.4, p < 0.001). Conclusions: Hematocrit levels and presence of erythrocytosis appear not associated with OSA severity, but rather with hypoxemia as measured by awake and to a lesser extent mean nocturnal oxygen saturation. Nocturnal oximetry may provide diagnostic utility in the evaluation of unexplained secondary polycythemia and polysomongraphy may be warranted in those with unexplained nocturnal hypoxemia and erythrocytosis. Keywords: Apnea hypopnea index; Erythrocytosis; Hypoxemia; Obstructive sleep apnea; Polycythemia. Published by Elsevier Ltd. PubMed Disclaimer Similar articles Does obstructive sleep apnea increase hematocrit? Choi JB, Loredo JS, Norman D, Mills PJ, Ancoli-Israel S, Ziegler MG, Dimsdale JE. Choi JB, et al. Sleep Breath. 2006 Sep;10(3):155-60. doi: 10.1007/s11325-006-0064-z. Sleep Breath. 2006. PMID: 16770648 Nocturnal Mean Oxygen Saturation Is Associated with Secondary Polycythemia in Young Adults with Obstructive Sleep Apnea, Especially in Men. Li N, Li HP, Wang P, Yan YR, Li SQ, Li QY. Li N, et al. Nat Sci Sleep. 2019 Dec 5;11:377-386. doi: 10.2147/NSS.S226143. eCollection 2019. Nat Sci Sleep. 2019. PMID: 31824198 Free PMC article. Increased Carbonic Anhydrase Activity is Associated with Sleep Apnea Severity and Related Hypoxemia. Wang T, Eskandari D, Zou D, Grote L, Hedner J. Wang T, et al. Sleep. 2015 Jul 1;38(7):1067-73. doi: 10.5665/sleep.4814. Sleep. 2015. PMID: 25845687 Free PMC article. Sleep Study and Oximetry Parameters for Predicting Postoperative Complications in Patients With OSA. Suen C, Ryan CM, Mubashir T, Ayas NT, Abrahamyan L, Wong J, Mokhlesi B, Chung F. Suen C, et al. Chest. 2019 Apr;155(4):855-867. doi: 10.1016/j.chest.2018.09.030. Epub 2018 Oct 22. Chest. 2019. PMID: 30359618 Free PMC article. Review. Treatment outcomes of supraglottoplasty for pediatric obstructive sleep apnea: A meta-analysis. Lee CF, Hsu WC, Lee CH, Lin MT, Kang KT. Lee CF, et al. Int J Pediatr Otorhinolaryngol. 2016 Aug;87:18-27. doi: 10.1016/j.ijporl.2016.05.015. Epub 2016 May 20. Int J Pediatr Otorhinolaryngol. 2016. PMID: 27368437 Review. See all similar articles Cited by [Analysis of related factors in secondary erythrocytosis of obstructive sleep apnea hypopnea syndrome in Gansu province]. Wang J, Fang J, Xie Y, Ma W, Hui P, Su X, Guo B, Chen X, Wang X, Fan J, Zhao Y. Wang J, et al. Lin Chuang Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2022 May;36(5):338-342. doi: 10.13201/j.issn.2096-7993.2022.05.003. Lin Chuang Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2022. PMID: 35483682 Free PMC article. Chinese. Is obstructive sleep apnea associated with erythrocytosis? A systematic review and meta-analysis. Rha MS, Jeong Y, Kim J, Kim CH, Yoon JH, Cho HJ. Rha MS, et al. Laryngoscope Investig Otolaryngol. 2022 Feb 2;7(2):627-635. doi: 10.1002/lio2.751. eCollection 2022 Apr. Laryngoscope Investig Otolaryngol. 2022. PMID: 35434329 Free PMC article. Review. Obstructive Sleep Apnea is Associated with an Increased Prevalence of Polycythemia in Patients with Chronic Obstructive Pulmonary Disease. Zeng Z, Song Y, He X, Yang H, Yue F, Xiong M, Hu K. Zeng Z, et al. Int J Chron Obstruct Pulmon Dis. 2022 Jan 15;17:195-204. doi: 10.2147/COPD.S338824. eCollection 2022. Int J Chron Obstruct Pulmon Dis. 2022. PMID: 35068930 Free PMC article. Polycythemia is Associated with Lower Incidence of Severe COPD Exacerbations in the SPIROMICS Study. Fawzy A, Woo H, Balasubramanian A, Barjaktarevic I, Barr RG, Bowler RP, Comellas AP, Cooper CB, Couper D, Criner GJ, Dransfield MT, Han MK, Hoffman EA, Kanner RE, Krishnan JA, Martinez FJ, McCormack M, Paine Iii R, Peters S, Wise R, Woodruff PG, Hansel NN, Putcha N. Fawzy A, et al. Chronic Obstr Pulm Dis. 2021 Jul 28;8(3):326-335. doi: 10.15326/jcopdf.2021.0216. Chronic Obstr Pulm Dis. 2021. PMID: 34197703 Free PMC article. Can the complete blood count be used as a reliable screening tool for obstructive sleep apnea? Cummins E, Waseem R, Piyasena D, Wang CY, Suen C, Ryan C, Wong J, Kryger M, Chung F. Cummins E, et al. Sleep Breath. 2022 Jun;26(2):613-620. doi: 10.1007/s11325-021-02383-3. Epub 2021 Jun 29. Sleep Breath. 2022. 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+Congenital and Acquired Polycythemias - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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+            and transmitted securely. Log in Show account info Close Account Logged in as: username Dashboard Publications Account settings Log out Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now . Search PMC Full-Text Archive Search in PMC Advanced Search User Guide Journal List Dtsch Arztebl Int v.105(4); 2008 Jan PMC2696729 Other Formats PDF (226K) Actions Cite Collections Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than  characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Share Permalink Copy RESOURCES Similar articles Cited by other articles Links to NCBI Databases Journal List Dtsch Arztebl Int v.105(4); 2008 Jan PMC2696729 As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with,
+    the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Dtsch Arztebl Int. 2008 Jan; 105(4): 62–68. Published online 2008 Jan 25. doi: 10.3238/arztebl.2008.0062 PMCID: PMC2696729 PMID: 19633771 Congenital and Acquired Polycythemias Fabian P. Siegel *, 1 and Petro E. Petrides , Prof. Dr. med. 1, * Fabian P. Siegel 1 Hematology Oncology Center Munich Find articles by Fabian P. Siegel Petro E. Petrides 1 Hematology Oncology Center Munich Find articles by Petro E. Petrides Author information Article notes Copyright and License information PMC Disclaimer 1 Hematology Oncology Center Munich *Hematology Oncology Center Munich, Zweibrückenstr. 2 80331 Munich, Germany Received 2007 Apr 27; Accepted 2007 Oct 15. PMC Copyright notice See letter " Correspondence (letter to the editor): Radioactive Phosphorus in Polycythemia Vera Therapy " on page 480. See letter " Correspondence (letter to the editor): Key Role of HIF-2α " on page 480. See letter " Correspondence (letter to the editor): Testosterone Induced Polycythemias " on page 480. See letter " Correspondence (reply): In Reply " on page 480. Abstract Introduction Polycythemias are characterized by an increased concentration of red blood cells. Because blood cell counts are a routine investigation, these disorders present to non-hematologic physicians. Polycythemia vera (PV), an acquired stem cell disease, is the most important variant. Methods Selective literature review and the authors’ own clinical experiences. Results and Discussion Erythropoietin, which is produced in the kidneys, and its receptor system in the bone marrow, are of critical importance in polycythemia. Congenital polycythemias are caused by mutations of the Erythropoietin-receptor gene, hemoglobin variants, 2,3-bisphosphoglycerate mutase deficiency or by disturbances of renal oxygen sensing. Acquired polycythemias can occur secondary to hypoxia at high altitudes, or primarily through acquired mutations in the EPO-receptor signaling system (JAK2 mutations). Alternatively they may be caused by pulmonary or renal disease. An artificial erythrocytosis is induced by athletes through doping. Differential diagnosis comprises erythropoietin determination, JAK2 mutation analysis and if necessary hemoglobin electrophoresis. Only PV requires immediate treatment, because of a high thromboembolic risk. Epidemiological studies on polycythemias in German speaking countries are urgently needed. Keywords: polycythemia vera, JAK2 mutation, erythropoietin, doping, aquagenic pruritus At the Olympic Winter Games in 2006, Evi Sachenbacher-Stehle had an elevated hemoglobin reading of 16.4 g/dL in a doping sample and was suspended for five days. In the summer of 2006, more than 50 cyclists were involved in the scandal surrounding the team physician Fuentes in the run-up to the Tour de France ( 1 ). Investigators found stored blood units intended to artificially increase hematocrit and evidence of orders for erythropoietin. Professional cyclist Jörg Raschke recently confirmed that erythropoietin doping is normal practice in the cycling world ( 1 ). Hematocrit can be regarded as a symbol of manipulation in endurance sports: it can be increased legally by high altitude training or illegally with erythropoietin (EPO), androgens, and autologous blood transfusions. But not every elevated hematocrit is attributable to high altitude training or doping. The Finnish cross-country skier Eero Mäntyranta was known since youth to have high hemoglobin levels of above 20 g dL (hematocrit above 60%). Examinations performed on the several times Olympic champion revealed increased sensitivity of erythropoietin precursors in the bone marrow to erythropoietin. Causally responsible is a hereditary point mutation in the erythropoietin receptor gene which leads to permanent activation of the EPO receptor system and thus to erythrocytosis. Unlike congenital forms of erythrocytosis, the commonest form – polycythemia vera (PV) – is acquired. Although the term polycythemia originally denoted "too many" cells in the peripheral blood, it is now used as a synonym for erythrocytosis. In polycythemia vera (PV) not the erythropoietin receptor, but the signal cascade associated with it is changed. A basic distinction can be made between relatively rare congenital and the more common acquired polycythemias. The following overview of polycythemias is based on a selective literature review and the authors’ own clinical experiences. Congenital polycythemias Certain mutations in the alpha and beta chains of hemoglobin can lead to high affinity hemoglobins which release oxygen to a reduced extent in peripheral tissue. At an O 2 partial pressure of 20 mm Hg in the capillaries, for example, 35% oxyhemoglobin is present, whereas with high oxygen affinity hemoglobin Johnstown the oxygenation level is still 60% ( figure 1 ). The resulting decrease in oxygen release in peripheral tissue leads to a compensatory increase in the hemoglobin concentration. In addition, a decrease in the intraerythrocytic 2,3-bisphosphoglycerate level due to 2,3-bisphosphoglycerate mutase deficiency can lead to increased oxygen affinity of hemoglobin. Open in a separate window Figure 1 Oxygen binding curve of high oxygen affinity hemoglobin Johnstown compared to the hemoglobin molecule of a control person; P50 = pressure at which 50% of the hemoglobin is loaded with oxygen Congenital erythropoietin (EPO) receptor mutations result in a decrease in intracellular receptor protein ( 2 ). As a result, negative regulators can no longer bind, resulting in constitutive activation of the receptor. In contrast to PV, the persons affected do not have an increased risk of thrombosis and bleeding, which suggests that erythrocytosis alone is not responsible for this situation. Initially in Eastern Russia and later in Central Europe, a special form of congenital polycythemia was identified which is based on an autosomal recessive inherited mutation in the von Hippel-Lindau (VHL) gene. The VHL protein regulates the breakdown of hypoxia inducible factor (HIF1) in the peritubular fibroblasts of the kidney ( figure 2 ). HIF 1 consists of two subunits alpha and beta and mediates oxygen measurement in the kidneys. In the presence of oxygen the alpha chains are degraded with involvement of the VHL gene product ( 3 ). A homozygotic mutation of the VHL gene results in the formation of a VHL protein with reduced activity, so that the alpha chains are not degraded even in normoxemic conditions. The resulting increase in erythropoietin release leads to a marked increase in the hemoglobin level. The persons affected develop an increased incidence of thromboses and bleeding. Therapeutic bloodletting does not reduce the rate of complications. This suggests the presence of other causes, such as the observed increased production of vascular endothelial growth factor (VEGF) which is also regulated by HIF ( 3 ). Open in a separate window Figure 2 Erythropoiesis feedback system regulated by erythropoietin: when the oxygen supply is reduced, a decrease in oxygen is registered in the kidneys; the breakdown of HIF a is in-hibited by the hypoxia. This inhibition comes about by hydroxylation of HIF a in the peri-tubular fibroblasts by oxygen dependent proline hydrolase. The hydroxylated HIF a is de-graded in binding to the VHL protein. As a result, more erythropoietin is produced, leading to increased erythrocyte production in the bone marrow. The same conditions can be achieved by exogenous supply of erythropoietin. The system is regulated by the resulting negative feedback (PHD, prolyl hydroxylase; HIF, hypoxia inducible factor; VHL, von Hippel-Lindau). Various heart defects associated with cyanosis (such as septal defects, left-right shunt) lead to chronic hypoxemia and thus, via an increase in erythropoietin, to compensatory erythrocytosis. These secondary polycythemias are a physiological response to the developing tissue hypoxia. Bloodletting is therefore only indicated in exceptional cases ( 4 ). Acquired polycythemias Polycythemias secondary to hypoxemia Reactive polycythemia can also develop as a physiological compensatory reaction in persisting hypoxemic states, such as smoker’s polycythemia, chronic obstructive pulmonary disease (COPD) or sleep apnea. While no erythropoietin elevation is generally observed in sleep apnea, it does occur in COPD when oxygen partial pressure falls below 67 mm Hg. Competitive athletes use this fact to their advantage in high altitude training. Polycythemias not caused by hypoxemia Various renal function impairments can also lead to erythrocytosis without hypoxic stimuli. Examples include Wilms’ tumor, polycystic kidney disease, renal cell cancer, and post-transplantation erythrocytosis. The administration of erythropoietin, e.g., for the treatment of malignant or renal anemia, causes an increase in erythrocytes. The level to which hemoglobin should be raised is currently a subject of debate, because in some studies excessive stimulation was found to be associated with a declining survival rate ( 5 ). Polycythemias caused by mutation of a bone marrow stem cell The commonest form is polycythemia vera. Together with primary thrombocythemia ( 6 ) and primary myelofibrosis, it is one of the Philadelphia chromosome negative chronic myeloproliferative diseases. It is associated with an increase in erythrocytes and in some cases granulocytes and/or platelets. The resulting rise in hematocrit increases the risk of thromboembolic complications that can occur throughout the vascular system ( table 1) . Recent findings suggest that the risk of thrombosis is promoted by JAK2-induced changes (of a disease associated mutation) in surface proteins of the PV erythrocytes ( 7 ). In addition, platelet abnormalities can lead to bleeding and thrombosis ( 8 ). More than half of these patients have the clinical symptoms splenomegaly ( 9 ) and frequently severe aquagenic pruritus, i.e. itching induced by contact with water ( 10 ) ( table 2 ) as well as a number of unspecific symptoms ( box 1 ). In Sweden, the incidence of PV is 2.8 per 100 000 population ( 11 ). Unfortunately, no epidemiological data are available for Germany. Extrapolating these values, therefore, 2200 new cases of disease per year are to be expected. The condition is generally diagnosed after the age of 60 years, and nothing is known about the precipitating mutagens. Long-term risks of the disease include transition to acute leukemia or post-polycythemic myelofibrosis ( 12 ). The mean leukemic risk is 7.4%. The risk in-creases from 2.4% (with bloodletting, anagrelide, interferon alpha) to 16.7% in therapy with at least two cytotoxic medications. Table 1 Thromboembolic and bleeding complications in 1638 patients with polycythemia vera ( 25 ) Type Incidence (%) Arterial thromboses 28.7 Transitory ischemic attack Acute myocardial infarction Stroke Peripheral 10.3 8.9 8.9 5.5 Venous thromboses 13.7 Deep vein thromboses Superficial thrombophlebitis Pulmonary embolism 8.2 6.1 2.4 Erythromelalgia (painful reddening of the hands or feet) 5.3 Intermittent claudication 4.7 Hemorrhage 8.1 Open in a separate window Table 2 Complications of polycythemia vera Complication Cause Thrombosis Elevated hematocrit Hemorrhage Platelet dysfunction Hepato/splenomegaly Increased cell production or extramedullary hematopoiesis Aquagenic pruritus Inflammatory mediators and/or elevated hematocrit Hyperuricemia, gout, kidney stones Increased cell turnover Erythromelalgia or visual disorders Thrombocythemia and/or platelet dysfunction Myelofibrosis Reaction to the neoplastic clone Acute leukemia Iatrogenic or clonal evolution Open in a separate window Box 1 Unspecific symptoms Headache Asthenia Tendency to sweating Paresthesias Upper abdominal discomfort Weight loss Lightheadedness Pathogenesis of PV Bone marrow erythrocyte precursors of patients with PV proliferate spontaneously in vitro without addition of erythropoietin. At the same time, the EPO level is lowered in most patients. This suggests acquired mutations in the erythropoietin receptor and the associated signal cascade genes. In 2005, five research groups working independently of each other discovered the JAK2 V617F mutation in exon 14 of the JAK2 gene ( 14 ). JAK2 (Janus kinase 2) is a cytoplasmic tyrosine kinase involved in signal transduction of various cytokines (including at the EPO receptor). The mutation intensifies the activity of JAK2 and thus leads to EPO-independent growth ( figure 3 ). This mutation is acquired because it is not detectable in the germ line. Since erythrocytes no longer have a nucleus, this JAK2 V617F mutation is detected in peripheral blood via granulocyte DNA. Open in a separate window Figure 3 Simplified presentation of the erythropoietin receptor signal cascade via STAT-dependent and STAT-independent signal pathways and their consequences (EPO, erythropoietin; JAK2, Janus kinase 2; STAT, signal transducer and activator of transcription) 95% of all patients with PV have this mutation, and the majority of patients are homozygotic. In the search for mutations in JAK2 V617F negative patients, changes in the JAK2 gene have recently been identified in exon 12 (amino acids 537 to 543) ( figure 3 ). In contrast to the JAK2 V617F mutation, which can also occur in patients with primary thrombocythemia or primary myelofibrosis, however, these mutations are specific for PV ( box 2 ). Patients with exon 12 mutations have higher erythrocyte but lower leukocyte and platelet levels than patients with the exon 14 mutation ( 15 ). Since the mutations in exon 12 and 14 of the JAK2 gene occur in almost 100% of patients with PV, mutation analysis is a useful diagnostic criterion. Box 2 The newly discovered JAK2 mutations JAK2 F537-K539delinsL JAK2 H538QK539L JAK2 N542-E543del JAK2 K539L Differential diagnosis of polycythemia The discovery of the mutations in the exons 12 and 14 of JAK2 kinase has revolutionized the diagnosis of polycythemia. The WHO classification of PV, which is based only on non-molecular principles, is therefore currently being revised and will not be discussed further here. Instead, a diagnostic algorithm is presented ( figure 4 ) which is presently under discussion ( 16 ): at a permanently elevated hematocrit (52% in men, 48% in women) with normal oxygen saturation, an erythropoietin assay and a JAK2 V617F mutation analysis are performed. If the mutation is homozygotically present and the erythropoietin level lowered, the diagnosis of PV is conclusive. Open in a separate window Figure 4 Diagnostic algorithm for polycythemias. A search is first conducted for the more common JAK2 V617F mutation and only if the result is negative for the more rare, newly discovered mutations in exon 12. If the JAK2 V617F mutation is not present and the EPO level lowered, exon 12 should then be examined for mutations. If one of the mutations is detected, PV is also present in this case. If the JAK2 specific mutations are not detected and if the EPO level is normal or elevated, PV is unlikely. In this case a search should be conducted for tumors that can cause EPO elevation and primary polycythemia should be ruled out. In our view, the presence of aquagenic pruritus accompanied by a hematocrit elevation is a definite sign of PV because about 40% of all PV patients already suffer from water-induced itching before or at diagnosis ( 10 ). Treatment Since the congenital polycythemias and secondary polycythemia associated with cyanotic congenital heart diseases rarely require hematological management, only the treatment of PV will be presented below. The goal is to reduce the PV-associated potentially life-threatening thromboembolic and hemorrhagic complications as well as the unspecific symptoms. Reduction of complication rate Phlebotomy – Since blood viscosity and thus the risk of thrombosis greatly increase with rising hematocrit, the primary goal is to permanently reduce hematocrit to <45% in men and <40% in women. However, this goal is frequently not attained because of inconsistent treatment. This goal can be achieved with cytoreductive therapy with phosphorus-32, chlorambucil, busulfan, hydroxyurea, or by phlebotomy. It was shown in the PVSG-01 study that although the now obsolete cytostatic therapy with chlorambucil and phosphorus-32 reduces thrombotic risk to a greater extent than phlebotomy, it is associated with a distinctly higher risk of leukemia ( 17 ). Whether the likelihood of leukemia is also increased with hydroxyurea alone is now being debated. This important question can only be resolved by long-term analyses. Phlebotomy, a method practiced since the time of Hippocrates, is the treatment of choice. Each bloodletting involves aspirating 500 mL of blood into a vacuum bottle. The fluid loss can be compensated by oral or intravenous replacement. Because of the lifetime of erythrocytes of 120 days only these cells are reduced over a prolonged period, while granulocytes and platelets are rapidly regenerated again because of their much shorter lifetime of 8 days. Although phlebotomy can effectively lower blood viscosity, the platelet count can transiently increase due to overcompensation ( 18 ). The removal of iron with the erythrocytes causes secondary iron deficiency which limits erythropoiesis and can result in fatigue and decreased performance. Antiplatelet therapy – Platelets can also be implicated in the development of thromboses in PV patients. The results of the ECLAP study ( 19 ) – a randomized, placebo-controlled double-blind study in 518 patients – showed that patients who take 50 to 100 mg acetylsalicylic acid (ASA) daily have a lower thrombotic risk. The daily intake of 100 mg aspirin is therefore recommended. Critics of the study object that individual patients in this study only required aspirin therapy because their hematocrit was insufficiently lowered ( 20 ). Since individual PV patients have an increased bleeding risk, physicians should be alert for bleeding complications during aspirin therapy. Cytoreductive therapy – Medicinal therapy is only indicated if an adequate hematocrit reduction cannot be achieved by bloodletting or if a thromboembolic complication has occurred despite low-dose aspirin with normalized hematocrit. This may be due to leukocyte and platelet elevations. Further indications include increasing splenomegaly or water-induced pruritus refractory to bloodletting. In some patients, the iron deficiency secondary to regular bloodletting causes fatigue or concentration difficulties, prompting them to request a changeover from iron depleting to cytoreductive therapy. Today, only hydroxyurea and interferon alpha should be used for therapy: with hydroxyurea, erythrocytes, granulocytes, and platelets are reduced (500 to 2500 mg daily). The commonest adverse effects are mucosal irritations and cutaneous tumors (spinocellular carcinoma). Sporadically, marked oscillations in platelet levels are observed. Since a leukemogenic activity has not so far been ruled out, caution is advised during long-term use (>10 years) ( 21 ). Conventional interferon alpha and pegylated interferon alpha (interferon alpha covalently bound to a polyethylene residue) combine high efficacy with an absence of leukemogenic and tumorigenic potential. In a weekly subcutaneous dosage between 3 x 3 and 5 x 5 million IU interferon alpha (or 40 µg pegylated interferon alpha), it reduces erythrocytosis, splenomegaly, and pruritus. In many cases, however, the therapy has to be discontinued due to influenza-like symptoms, alopecia and/or psychiatric side effects ( 22 ). Because of its oral availability, better tolerability, low cost, and regulatory approval, hydroxyurea is generally preferred to interferon alpha. If platelet reduction is the sole concern, anagrelide is the first line medication (mean dosage 2 mg daily). This product acts selectively on megakaryocytes and is non-leukemogenic. Adverse effects may include headache and palpitations ( 23 ) which are generally reversible within four weeks. The platelet level at which a reduction should be considered is uncertain. There is unfortunately a lack of randomized studies on the management of PV with interferon alpha and anagrelide ( table 3 ). Differing therapeutic strategies are employed for the management of hematocrit and thrombocytosis in the USA ( 24 ). Nothing is so far known about the quality of therapy in Germany, which is one of the reasons why a national register is urgently required. The observation that close to 100% of PV patients have a JAK2 mutation is the starting point for the development of JAK2 inhibitors. So far, these agents have only been studied for PV in murine models, while phase 1 studies have already produced encouraging results for myelofibrosis (ASH 12/2007). Table 3 Medicinal treatment options for polycythemia vera (PV) Active substance Undesirable effects Prospective randomized studies Approved in Germany for treatment of PV Hydroxyurea Mucosal intolerance, drug fever, skin tumors (spinocellular cancer), leukemogenic activity not ruled out so far Yes Approved Interferon α Influenza like symptoms, psychiatric side effects or even psychosis No Not approved Anagrelide Palpitations, diarrhea No Not approved Open in a separate window Management of aquagenic pruritus Water-induced itching is the chronic symptom of PV which most severely impairs quality of life. It affects more than 60% of patients and is induced by water of differing quality and temperature, and in some cases even by heavy perspiration or hand washing. Many patients find it impossible to take a bath. Aquagenic pruritus is most effectively treated by consistent management of the PV (bloodletting or cytoreductive therapy). For persisting pruritus, the authors recommend adding bicarbonate or starch to the bath water, although it is uncertain how the effect is produced. If these approaches fail, antihistamines, serotonin reuptake inhibitors (such as fluoxetine, paroxetine), or topical application of a capsaicin cream may be attempted. Severely refractory pruritus may respond to phototherapy, although a carcinogenic potential has not been ruled out for this therapeutic modality ( 10 ). Prognosis of polycythemia vera An Italian retrospective study in 70 under-50-year-old patients estimates mean life expectancy as over 23 years. 73% of these subjects had received pipobroman, which is now no longer recommended because of its leukemogenic risk. The 20-year risk of transition to acute leukemia is 15%, and the earliest onset was observed after 9 years. The use of cytoreductive medications with a leukemogenic risk profile should be avoided especially in young patients. The 20-year risk of transition to postpolycythemic myelofibrosis, i.e., fibrotic degeneration of the bone marrow with increasing diversion of hematopoiesis to the spleen and liver, reached a level of 10% in this study ( 12 ). Pregnancy in PV patients The presence of PV does not preclude pregnancy. Because of the increased thrombotic risk for the patient and the fetus (elevated rate of spontaneous abortions, placental infarction/insufficiency), however, close interdisciplinary management is required which can result in viable newborns in a good 50% of cases. Patient support groups Several patient support groups have been founded in Germany with the aim of improving the care of PV patients ( www.mpd-netzwerk.de , www.cmpe.de , www.polyzythaemie.de ). Acknowledgments Translated from the original German by mt-g. Footnotes Conflict of interest statement Prof. Dr. Petrides has received lecture fees from the companies Shire and AOP. 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PMCID: PMC3562538 PMID: 23482519 Comparison of hematological parameters in untreated and treated subclinical hypothyroidism and primary hypothyroidism patients Haamid Bashir , 1 Mohmmad Hayat Bhat , 2 Rabia Farooq , 3 Sabhiya Majid , 4 Sheikh Shoib , 5 Rabia Hamid , 6 Arshed Ahmad Mattoo , 7 Tabassum Rashid , 8 Arif Akbar Bhat , 9 Hilal Ahmad Wani , 10 and Akbar Masood 11 Haamid Bashir 1 MSc, MPhil, Department of biochemistry, GMC, Srinagar, Kashmir, India. moc.liamg@7bdimaah Find articles by Haamid Bashir Mohmmad Hayat Bhat 2 MD, DM, Consultant endocrinologist, Department of Medicine, SMHS Hospital, GMC Srinagar. moc.liamffider@bmtayah Find articles by Mohmmad Hayat Bhat Rabia Farooq 3 MSc, MPHILL, Department of biochemistry, GMC, Srinagar, Kashmir, India. moc.liamg@uuu4najaibar Find articles by Rabia Farooq Sabhiya Majid 4 PhD, Prof, & Head, Department of Biochemistry, GMC, Srinagar, Kashmir, India Find articles by Sabhiya Majid Sheikh Shoib 5 MD, Department of Psychiatry, GMC, Srinagar, Kashmir, India. moc.oohay@22biohshkiehs Find articles by Sheikh Shoib Rabia Hamid 6 PhD, Sr Asst Prof, Dept of Biochemistry, University of Kashmir. ni.oc.oohay@smayebar Find articles by Rabia Hamid Arshed Ahmad Mattoo 7 MSc, MPhil, Department of biochemistry, GMC, Srinagar, Kashmir, India. moc.liamg@54321sradhmla Find articles by Arshed Ahmad Mattoo Tabassum Rashid 8 PhD, Department of biochemistry, GMC, Srinagar, Kashmir, India. moc.liamg@321.mussabat Find articles by Tabassum Rashid Arif Akbar Bhat 9 MSc, MPHIL, Department of biochemistry, GMC, Srinagar, Kashmir, India. moc.liamg@91tahbfeira Find articles by Arif Akbar Bhat Hilal Ahmad Wani 10 MSc, MPhil, Department of biochemistry, GMC, Srinagar, Kashmir, India. moc.liamg@7002mhcoiblalih Find articles by Hilal Ahmad Wani Akbar Masood 11 PhD, Prof, Dept of Biochemistry, University of Kashmir, Srinagar India. moc.liamtoh@doosamrabka Find articles by Akbar Masood Author information Article notes Copyright and License information PMC Disclaimer 1 MSc, MPhil, Department of biochemistry, GMC, Srinagar, Kashmir, India. moc.liamg@7bdimaah 2 MD, DM, Consultant endocrinologist, Department of Medicine, SMHS Hospital, GMC Srinagar. moc.liamffider@bmtayah 3 MSc, MPHILL, Department of biochemistry, GMC, Srinagar, Kashmir, India. moc.liamg@uuu4najaibar 4 PhD, Prof, & Head, Department of Biochemistry, GMC, Srinagar, Kashmir, India 5 MD, Department of Psychiatry, GMC, Srinagar, Kashmir, India. moc.oohay@22biohshkiehs 6 PhD, Sr Asst Prof, Dept of Biochemistry, University of Kashmir. ni.oc.oohay@smayebar 7 MSc, MPhil, Department of biochemistry, GMC, Srinagar, Kashmir, India. moc.liamg@54321sradhmla 8 PhD, Department of biochemistry, GMC, Srinagar, Kashmir, India. moc.liamg@321.mussabat 9 MSc, MPHIL, Department of biochemistry, GMC, Srinagar, Kashmir, India. moc.liamg@91tahbfeira 10 MSc, MPhil, Department of biochemistry, GMC, Srinagar, Kashmir, India. moc.liamg@7002mhcoiblalih 11 PhD, Prof, Dept of Biochemistry, University of Kashmir, Srinagar India. moc.liamtoh@doosamrabka Corresponding author. Corresponding author: Sabhiya Majid, Department of Biochemistry Govt. Medical College Srinagar, Kashmir, India. Email: moc.oohay@dijamubas Received 2012 Apr 28; Revised 2012 Sep 1; Accepted 2012 Sep 8. Copyright © 2012 Tehran University of Medical Sciences This is an open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0), which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly. Abstract Backgrounds Thyroid hormones play an important physiological role in human metabolism. Erythrocyte abnormalities are frequently associated with thyroid disorder. However, they are rarely investigated and related to the subclinical and primary hypothyroidism in Kashmiri Patients. In this study an attempt was made to study hematological parameters in untreated and treated subclinical hypothyroidism and primary hypothyroidism patients. Methods This retrospective study included 600 subjects, among which were untreated subclinical hypothyroid (n=110), treated subclinical hypothyroid (n=110), untreated primary hypothyroid (n=100), treated primary hypothyroid (n=100) and euthyroid (n=180). This study was carried out at Department of Biochemistry, Government Medical College Srinagar. The hematological parameters and thyroid profile of the subjects were assessed by the Sysmex (Italy) and ECLIA (Germany) 2010 automatic analyzer. Mean, standard deviation (SD), analysis of variance (Two-way ANOVA), and multiple comparisons were used to report our results, with p<0.05 or p<0.01 considered as statistically significant. Results In this study group we compared the hematological parameters in these groups, untreated subclinical hypothyroid, treated subclinical hypothyroid, untreated primary hypothyroid, treated primary hypothyroid and euthyroid. We found that hematological parameters like Hb, RBC, MCV, HCT, RDW,RBC% were significantly increased in untreated subclinical hypothyroidism and untreated primary hypothyroidsm, with the p value being less than 0.05 whereas, in treated SCH & Pr. Hypothyroid, results were insignificant. The results reported in these groups as mean±SD, were statistically tested by ANOVA and multiple comparison tests. In untreated subclinical hypothyroid the values were: Hb (10.83±1.33 g/dl), RBC (4.21±0.66 10 6 /µl), MCV (84.56±6.84 fL), HCT (38.5±2.2%), RDW (17.91±2.37 fL), RBC% (84.36±13.2%) and in untreated primary hypothyroid, Hb (10.73±0.86 g/dl), RBC (4.63±0.51 10 6 /µl), MCV (83.34±6.92 fL), HCT (38.6±2.6%), RDW (14.93±5.47 fL), RBC% (92.63±10.30%) suggesting that these patients were at risk of anemia and other erythrocyte abnormalities. MCV is an inexpensive approach to study the types of anemia and explore related information like production, destruction, loss and morphological changes of RBC'S. Conclusion The thyroid dysfunction is frequently associated with anemia in subclinical hypothyroidism and primary hypothyroidism. Subclinical hypothyroidism (SCH) is associated with serious complications. Substantial numbers of patients with the risk of SCH could be getting converted into primary hypothyroidism. Such conditions should be identified and corrected. On the other hand, their presence could move to a thyroid dysfunction, allowing its early management. Keywords: Subclinical hypothyroidism, Primary hypothyroidism, Blood count, Hemoglobin, Red cell distribution, Mean corpuscular volume Introduction Thyroid hormones are essential for the normal development, differentiation, metabolic balance, and physiological function of virtually all tissues and thyroid function disorders are among the most common endocrine diseases ( 1 ). Hypothyroidism is the most common functional disorder of the thyroid gland. Pathology of the thyroid gland (primary hypothyroidism) accounts for over 99.5% of cases of thyroid gland failure and < 0.5% result from disorders of the pituitary gland or hypothalamus (central hypothyroidism). Overt primary hypothyroidism refers to cases in which the serum thyrotropin (TSH) concentration is elevated and the serum free thyroxine (T4) level is below the reference range, while subclinical hypothyroidism is defined as an elevated serum TSH value associated with a serum free T4 that is still within the reference range. The incidence of overt hypothyroidism has been estimated to be 4.1 cases per 1000 women per year and 0.6 cases per 1000 men per year ( 2 ). The prevalence has been reported to be approximately 1-2% in women and 0.1% in men in large population studies ( 3 – 5 ). The presence of subclinical hypothyroidism is far higher, and reported to be about 4-10% in multiple populations and as high as 18% in the elderly ( 6 – 9 ). In iodine deficient areas such as India the incidence can reach as high as 10-20 times more than non-iodine areas like U.S.A ( 3 , 10 – 11 ). Subclinical hypothyroidism may progress to overt hypothyroidism in approximately 2-5% cases annually. All patients with overt hypothyroidism and subclinical hypothyroidism with TSH >10 mIU/L should be treated ( 12 ). Anemia is a decrease in number of red blood cells (RBC's) or less than the normal quantity of hemoglobin in the blood. Anemia can have several reasons, such as, abnormality of the formation ( 13 ) and reduction on the half life time of the red cells ( 14 ). The size is reflected in mean corpuscular volume (MCV). The prevalence of anemia in patients with hypothyroidism has been shown to be 20-60% ( 15 ). Thyroid hormone is involved in hemoglobin synthesis in adults and maturation of hemoglobin in fetus ( 16 , 17 ) and by affecting hematopoietic process, hypothyroidism results in anemia through slowing the oxygen process ( 18 ). The present study was therefore undertaken to find out the association between hematological parameters in untreated and treated subclinical hypothyroidism and primary hypothyroidism patients of Kashmir valley. Srinagar (Kashmir valley) reported that substantial increase of thyroid dysfunction patients have increased in past few years. Hence further research is needed to address the metabolic diseases and to understand the etiology and to create awareness among people. Methods Subjects and recruitment process This retrospective-hospital based study was conducted at the department of Biochemistry Government Medical College Srinagar from April 2011 to February 2012. All patients were referred from out-patient department (OPD) and Inpatient Department (IPD) of Government Medical College Srinagar and its associated Shri-Mahraja Hari Singh Hospital (SMHS) hospital, a major referral hospital of Kashmir valley (North-India), to the diagnostic Biochemistry and Haematology laboratory of Government Medical College Srinagar for the evaluation of thyroid function and performing complete blood count (CBC). All the patients were examined by an endocrinologist. The study was approved by Departmental ethical committee of Biochemistry, Government Medical College (GMC) Srinagar. Individuals who fulfilled exclusion criteria for both diseases and gave consent to participate in the study were recruited as normal. All the Subjects’ information was kept confidential. Patients and normal subjects recruited for study were selected for age matched and gender matched. A total of 600 subjects were selected for the study. These included the subclinical hypothyroid untreated (n=110), subclinical hypothyroid treated (110), primary untreated hypothyroid (n=100), primary hypothyroid treated (n=100) and normal-controls (n=180). Subclinical hypothyroid patients were treated as SCH, after 3 months of follow up. Exclusion criteria Patients with ischemic heart disease, cerebrovascular and neurological diseases, diabetes mellitus, chronic renal impairment, known psychological illnesses, previous history of thyroid disease or previous thyroxine therapy, asthma and pregnancy. Inclusion criteria Hypothyroid patients, Kashmiri ethnicity and normal patient. Blood Sample collection About 5-6 ml of venous blood was collected, in which 3 ml blood was taken in EDTA vials and remaining 3 ml centrifuged to separate serum from the cells as soon as the clot formed. Measurement of Hematological parameter The 3ml peripheral venous blood was taken in sterilized EDTA vials. The CBC and haemogram comprised of (Hb, TLC, DLC, RBC, PLT, MHC, MCV, MCHC, PDW, RDCV, LYM%, GRA%, HB%, RBC%, Color Index, ESR). Blood samples were processed manually for various hematological indices mainly hemoglobin (Hb), total erythrocyte counts (TEC), total leukocyte count (TLC), mean corpuscular value (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), Red cell width distribution (RDW). The CBC and hemogram were assayed in Sysmex (Italy) hemocytometer analyzer. The Erythrocyte sedimentation rate (ESR) was determined by Wintrobe's method. The Hb%, RBC% and Color Index determined by the formulae (Godkar et al., 2006). Hb%= 100*Hb value/14.5 RBC%= 100* RBC Count/5.0 Color Index= Hb%/RBC% Measurement of thyroid hormone profile Serum aliquots were stored at 4ºC to be run in batches. The samples were allowed to thaw prior to assay, mixed thoroughly. Hemolysed and lipemic samples were rejected. Bi level i.e. high and low control was run with each batch. Thyroid function test (TFT) comprising of T3, T4 and TSH levels was carried out by electrochemi-luminescence Immunoassay method using fully automatic analyzer ECLIA 2010 (Roche Diagnostic Germany). Patients with thyroid hormone evaluation picture of elevated serum TSH levels (>4.3 to ≥10 mIU/ml) with normal levels of serum thyroxine (T 4 ) and triiodothyronine (T 3 ) were categorized as subclinical hypothyroidism (SCH) if similar levels observed in repeated thyroid profile after a lapse of three months. Statistical Analysis Data were extracted and analysed by GraphPad Prism 5.0. The results were expressed as mean ± standard deviation (SD). Differences in variables were analyzed by an analysis of variance (ANOVA), Dunnet's Multiple comparisons test, Bonferroni multiple comparisons, two-way ANOVA and Chi square test. The differences were considered to be significant at p<0.05 or p<0.01. Results In this study, the total of 600 subjects participated in the research among which 64% were females and 36% males, in the age group between 25-60. There were 180 euthyroid (normal), 110 Subclinical hypothyroid (untreated), 110 Subclinical hypothyroid (treated), 100 Primary hypothyroid (untreated) and 100 primary hypothyroid (treated). Median + Standard deviation values of Hb, RBC,WBC, MCV, RDW, Hct, Lym%, Hb% and RBC% with respect to T4 and TSH were assessed and data are presented as F-value and P-value. The value of P<0.05, denotes in results were statistically significant and had association in the thyroid disorder. Results are shown in Table 1 – 3 . Table 1 General characteristics of study population [All reported values are numbers and frequency as percentages (%)] Variables Cases (both SCH and Primary Hypothyroid untreated and treated) N=420 Controls N=180 p-Value Age 25-45 250(59.5%) 100(55.55%) 0.36 45-60 170(40.4%) 80(44.44%) Gender Male 150(35.7%) 70(38.88%) 0.51 Female 270(64.2%) 110(61.11%) Life style Smoker 140(33.3%) 60(33.33%) 1.0 Non-smoker 280(66.6%) 120(66.66%) Diet Vegetarian 100(23.8%) 40(22.22%) 0.67 Non-Vegetarian 320(76.19%) 140(77.77%) Goitrogen intake (Cauliflower turnip etc) Yes 300(71.4%) 50(27.77%) No 120(28.57%) 130(72.22%) <0.001 Iodised food (Fish, meat, egg, milk, salt etc 300(71.4%) 140(77.77%) 0.10 Non –Iodised food 120(28.57%) 40(22.22%) Drinking water facility Boiled 200(47.61%) 120(66.66%) <0.001 Un boiled 220(52.38%) 60(33.33%) Tap water 200(47.61%) 120(66.66%) <0.001 Well water/ River water 220(52.38%) 60(33.33%) Previous Goitre History Residence Yes 20(4.76%) 2(1.1%) 0.02 No 400(95.23%) 178(98.88%) Urban 210(50%) 80(44.44%) Rural 210(50%) 100(55.55%) 0.21 Open in a separate window Table 3 Euthyroid vs cases (using two-way ANOVA and Bonferroni multiple comparisons) Parameters Euthyroid vs Untreated SCH (p value) Euthyroid vs treated SCH (p value) Euthyroid vs Untreated Pr. Hypothyroid (p value) Euthyroid vs treated Pr. Hypothyroid (p value) T3 (ng/dl) p<0.05 p<0.05 p<0.05 p<0.05 T4 (µg/dl) p<0.05 p<0.05 p<0.001 p<0.05 TSH (µIU/ml) p<0.001 p<0.05 p<0.001 p<0.05 Hb (g/dl) p<0.001 p<0.05 p<0.001 p<0.05 RBC (10 6 /µl) p<0.001 p<0.05 p<0.001 p<0.05 WBC (10 3 /µl) p<0.05 p<0.05 p<0.05 p<0.05 HCT (%) p<0.001 p<0.05 p<0.001 p<0.05 MCV (fL) p<0.001 p<0.05 p<0.001 p<0.05 LYM (%) p<0.05 p<0.05 p<0.001 p<0.05 RBC (%) p<0.001 p<0.05 p<0.001 p<0.05 RDW (fL) p<0.001 p<0.05 p<0.001 p<0.05 Open in a separate window * p<0.05 or 0.01 is significant. Table 2 Comparison of hematological parameters and thyroid hormone levels in untreated and treated subclinical hypothyroid and primary hypothyroid patients. Parameters Euthyroid N=180 Subclinical hypothyroid Primary hypothyroid p-value Untreated SCH n=110 Mean±SD Treated SCH n=110 Mean±SD Untreated Pr. Hypothyroid n= 100 Mean±SD Treated Pr. Hypothyroid n=100 Mean±SD Untreated primary hypothyroid vs. treated pr. hypothyroid Untreated SCH vs. treated SCH T3(ng/dl) 1.052±0.17 1.062±0.28(0.0) 1.060±0.28 (0.01) 0.82±0.41(-0.01) 0.82±0.41(-0.00) 0.92 0.99 T4(µg/dl) 7.42±1.63(0.0) 7.52±1.53(0.0) 7.52±1.53(0.0) 5.54±1.53(+2.06) 9.54±2.53(-1.84) <0.0001 <0.0001 TSH(µIU/ml) 2.23±0. 93 19.37±10.54(-12.73) 14.22±8.20(-3.67) 18.67±11.34(-10.82) 15.28±7.30(-5.46) <0.001 <0.001 Hb(g/dl) 14.72±1.77 10.83±1.33 12.01±1.20 10.73±0.86 12.64±1.33 <0.001 <0.001 RBC(10 6 /µl) 5.15±1.59 4.21±0.66 5.14±0.62 4.63±0.51 5.14±0.62 0.04 0.01 WBC(10 3 /µl) 7.4±1.06 6.71±0.91 6.81±1.01 7.25±0.86 6.14±0.96 0.006 0.002 HCT(%) 41.5±2 38.5±2.2 39.4±2.8 38.6±2.6 39.5±2.5 <0.001 <0.001 MCV(fL) 86.34±5.71 84.56±6.84 86.19±6.43 83.34±6.92 85.81±6.22 <0.05 <0.05 LYM (%) 34.63±7.85 31.44±12.55 19.82±11.4 17.85±9.19 28.17±13.6 0.008 0.006 RBC (%) 82.71±12.3 84.36±13.2 82.85±12.4 92.63±10.30 82.71±12.30 0.05 0.04 RDW (fL) - 15.5±1.85 17.91±2.37 14.93±5.47 14.61±3.61 0.089 0.057 Open in a separate window In untreated subclinical hypothyroid the values obtained were: Hb (10.83±1.33 g/dl), RBC (4.21±0.66 10 6 /µl), MCV (84.56±6.84 fL), HCT (38.5±2.2%), RDW (17.91±2.37 fL), RBC% (84.36±13.2%) and in untreated primary hypothyroid, Hb (10.73±0.86 g/dl), RBC (4.63±0.51 10 6 /µl), MCV (83.34±6.92 fL), HCT (38.6±2.6%), RDW (14.93±5.47fL), RBC% (92.63± 10.30%) which supports the fact that these patients are at risk of anemia (Normocytic). And also, patients treated with Thyroxine-therapy show correction in these erythrocyte abnormalities. As compared with patients with euthyroid status for TSH values, the RDW values showed statistically highly significant difference. It was found to be significantly increased in both subclinical hypothyroid and primary hypothyroid untreated patients. MCV values showed statistically significant difference among patients with abnormal thyroid function. MCV values were significantly increased in both overt and SCH. Other parameters like Hb, RBC, WBC, Hct, Lym%, Hb% and RBC% were also significantly increased in the hypothyroid patients. Anemia was classified into three types: Macrocytic anemia (MCV>100), Normocytic anemia (MCV 80-100) and Macrocytic anemia (MCV <80). Also, all patients and controls were interviewed by questionnaires and the information extracted from them. It was found that patients using goitrogen foods in their diet with a poor drinking water facility had significance increased in illness (p<0.001) which might be etiologically important in subclinical and primary hypothyroidism susceptibility. Discussion This retrospective hospital based study conducted at SMHS hospital Srinagar, main referral hospital of Kashmir valley, where witnessing heavy patients rush at routine basis, helped us to understand the problem, simultaneously address the management of this metabolic diseases among the patients. Kashmir valley is a mountainous region demographically, here six month of winter season receives heavy snow fall and rains. The soil contains less amount of iodine mineral, since it is leached out by the snow and rain ( 24 ). The agriculture grown here has less amount of iodine, main mineral necessary for proper thyroid hormone synthesis. That is why substantial increase of patients are at the risk of thyroid dysfunction. Subclinical hypothyroidism (SCH) is associated with serious complications. Substantial number of patients have risk of SCH getting converted into primary hypothyroidism ( 23 ). The prevalence of subclinical hypothyroidism and primary hypothyroidsm is constantly increasing, especially in women. It is now widely recognized that TSH measurement is a sensitive test for detecting both subclinical hypothyroidism and primary hypothyroidism. This measurement is recommended as the first test for diagnosing thyroid disorder in patients ( 18 ). In the present study predominant population with thyroid dysfunction was observed in females. Thyroid diseases are frequently associated with erythrocyte abnormalities ( 19 ). Although it has been reported that thyroid dysfunction might be associated with some forms of anemia, especially in childhood, the prevalence of this association in adults varies widely ( 18 ). Kinetic approach and morphological approach were better studied by low cost assement of MCV in whole blood along with these informations. Hypothyroidism can cause certain forms of anemia on the one hand or hyperproliferation of immature progenitors on the other hand. The anemia is usually macrocytic hypochromic and/ or normocytic anemia with an increased MCV, and hypothyroidism with moderate severity ( 18 , 25 ). The anemia of hypothyroidism has been ascribed to a physiological compensation for the diminished need of tissues for oxygen. The low plasma erythropoietin levels found in hypothyroid anemia is in accord with this hypothesis. An overall increase in the size of the red cells has been observed after thyroidectomy in patients with uncomplicated primary hypothyroidism. Hypothyroidism should always therefore be considered as a possible cause of unexpected and unexplained anemia. An increase in MCV may develop rapidly in association with the evolving hypothyroidism. On replacement therapy with thyroxine the MCV was found to fall progressively, even if the initial value was within the normal range. The cause of the increase in size of the red cells and of the minor degree of anisocytosis in uncomplicated hypothyroidism is unknown ( 20 , 21 ). The present study showed increased MCV values in untreated and treated subclinical hypothyroidism and primary hypothyroidism subjects. Although no definitive mechanism(s) can be suggested to explain the larger prevalence of increased RDW in patients with thyroid dysfunction, results of this retrospective cross-sectional analysis suggest that abnormal levels of thyroid hormones might substantially influence the size variability of circulating RBCs ( 22 ). The present study also showed increased RDW, HB, HCT and RBC in untreated SCH and primary hypothyroid as compared to treated SCH and primary hypothyroid patients. On the basis of assessment of MCV, we found patients were at the risk of normocytic anemia. Conclusion Thyroid hormones (T3 and T4) have a significant influence on erythropoiesis. In view of this present study among 600 subjects, we found increased levels of haematological parameters like Hb, RBC, MCV, HCT, RBC% and RDW in thyroid dysfunction patients of kashmir valley, which suggests that abnormal levels of thyroid hormones might substantially influence the size variability of circulating RBC's, predisposing patient to normocytic anemia. There might be some limitation with this study like, insufficient data, and small sample size. Since this was retrospective-hospital based study, further investigation is needed in studying the role of all types of anemias, erythrocyte abnormalities with increased sample size in thyroid dysfunction patients at district levels of state. Mass screening of thyroid hormone profile and TSH value greater than 10 mIU/ml required intervention and proper follow-up. Substantial numbers of patients have risk of SCH which could be converted into primary hypothyroidism and psychiatric problems. These abnormalities should be investigated and corrected and their presence could steer towards thyroid dysfunction allowing its early management. We suggest those people with thyroid disorder should have routine screening of haematological, biochemical and hormonal profile assay and simultenously proper management of this metabolic disease should be provided base on American endocrinologists guidline etc. There is no need to fear from this disease, only locally or externally available foods high in iodine mineral are good source and supplement. Acknowledgements We thank lab staff of department of biochemistry and pathology at GMC, especially Mr Zahoor Ahmad, Mr Javaid, Ms Fizalah, Ms Ishrat and Ms Sumaira for the technical assistance. We specially are thankful to reviewers who helped us in the necessary correction of this manuscript. References 1. Yen PM. 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+12 Ways To Naturally Increase Endorphins + New Research - SelfHacked Skip to content drugs labs resources supplements health Home Posts Substances Testing Science Conditions Healthy Living About Get SelfDecode Evidence Based This post has 93 references 4.2 /5 31 12 Ways To Naturally Increase Endorphins + New Research Written by Joe Cohen, BS | Last updated: December 15, 2022 SelfHacked has the strictest sourcing guidelines in the health industry and we almost exclusively link to medically peer-reviewed studies, usually on PubMed. We believe that the most accurate information is found directly in the scientific source. We are dedicated to providing the most scientifically valid, unbiased, and comprehensive information on any given topic. Our team comprises of trained MDs, PhDs, pharmacists, qualified scientists, and certified health and wellness specialists. All of our content is written by scientists and people with a strong science background. 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The term endorphins was created by combining the two words: endo genous m orphin e. These compounds trigger a natural high in our brains which encourages us to repeat the experience that produced it. Addictive drugs like heroin hijack this process to create dependency, but plenty of natural and healthy experiences, supplements, and foods act on this system to make us feel pretty good.This post will discuss ways that you can either increase endorphins or activate the body’s opioid system. An Intro To Your Brain’s Opioid System The brain opioid systems play an important role in motivation , emotion, attachment behavior, the response to stress and pain , and the control of food intake [ 1 ]. There are four opioid receptors in our brain: mu-opioid (MOR), kappa-opioid (KOR), delta-opioid (DOR) and nociceptin (NOP). Activating these receptors or increasing the molecules that bind to them will produce an opioid high. Mu-Opioid Receptors Activation of the mu receptor by a substance such as morphine causes sedation, euphoria and decreased respiration [ 2 , 3 ]. Although morphine increases sedation, it decreases the total amount of deep sleep and rapid eye movement sleep in humans [ 4 ]. Individual differences in the function of the mu-receptor system predict personality traits that confer vulnerability to or resiliency against risky behaviors such as the predisposition to develop substance use disorders [ 5 ]. Delta-Opioid Receptors Molecules that bind to delta opioid receptors show robust evidence of both antidepressant effects and also increase of BDNF production in the brain in animal models of depression [ 6 ]. They also protect against heart damage from strokes by preconditioning our heart [ 7 ]. DORs are neuroprotective as well and work in part by reducing TNF [ 8 ]. Activation of delta receptors produces some pain relief, although less than that of mu-opioid activators [ 9 ]. Kappa-Opioid Receptors Kappa activation actually produces a bad mood (dysphoria), some pain relief (analgesic), and increased urination (diuretic). In high doses, kappa opioid activators may produce hallucinations [ 9 , 10 ]. Activation of the KOR opposes many of the effects of the MOR and can prevent addiction to morphine, alcohol, and cocaine . It can cause an appetite increase and is activated by stress [ 11 ]. KOR activation causes a release of prolactin , a hormone known for its important role in learning, neuronal plasticity, and myelination [ 12 ]. A Natural, Drug-Free High? These are among the factors that are currently under investigation for their potential to release endorphins, activate opioid receptors, or re-sensitize the brain after addiction or trauma. Many of these are limited to animal studies, meaning that there is no clinical evidence to support using or taking them to activate your opioid receptors. In the next sections, we’ll discuss many of them in more detail. Talk to your doctor before making significant changes to your diet, exercise, or supplement regimen. Cold [ 13 ] High-intensity exercise [ 14 , 15 ] Sleep [ 16 ] Sun /UVB [ 17 , 18 ] Warm showers [ 13 ] Social interaction [ 19 ] Massages [ 20 ] Palatable foods [ 21 , 22 ] Acupuncture [ 23 ] Magnesium [ 24 , 25 ] Butyrate [ 26 ] Capsaicin /Chilli [ 27 ] Acidophilus [ 28 ] Melatonin [ 29 ] LLLT [ 30 ] Low dose naltrexone ’s [ 31 ] Nicotine [ 32 ] Marijuana – THC / CBD [ 33 ] Poppy Seeds (though rare, poppy seed tea consumption can be fatal . It also has the potential to be abused or lead to opiate dependence ) [ 34 , 35 , 36 , 37 ] Pregnenolone [ 38 ] Kratom [ 39 ] tDCS [ 40 ] Alcohol [ 41 ] Stress [ 13 ] Top Strategies (Likely Effective) These strategies have been investigated in clinical trials, but the evidence is not considered strong enough to determine effectiveness. Talk to your doctor before making significant changes to your diet, lifestyle, or supplement regimen. 1) Exercise Physical exertion can release opioids to produce a mental state famously called the “runner’s high” [ 14 ]. Researchers have found that light-to-moderate weight training or cardiovascular exercise doesn’t produce endorphins for roughly the first hour, or until the body crosses from aerobic to anaerobic exercise. Power-based heavy weights or training that incorporates sprinting or other anaerobic exertion are required to quickly produce endorphins [ 42 ]. When your body crosses over from an aerobic state to an anaerobic state, it has to operate without enough oxygen to satisfy the muscles and cells screaming out for it. This is when the “runner’s high” occurs [ 42 ]. 2) The Love Hormone Oxytocin (not to be confused with oxycodone) is a significant love and pleasure molecule and it increases prosocial behavior. Oxytocin is often referred to as the “love hormone” because it facilitates trust and attachment between individuals [ 43 ]. According to some studies in animals, oxytocin could potentially inhibit the development of tolerance to various addictive drugs (opiates, cocaine, alcohol) and reduce withdrawal symptoms [ 44 , 45 ]. In rats, oxytocin activated the opioid system to a degree, especially the mu- and the kappa-receptors in the brain [ 46 ]. Positive Social Interaction There are several factors which have been associated with increased oxytocin release. High levels of plasma oxytocin have been correlated with romantic attachment, for example. Oxytocin is also released in large amounts when parents are bonding with their newborn infant [ 47 , 48 ]. It turns out that some of the circuitry responsible for drug addiction in the brain is also responsible for positive social interactions and the formation of new romantic bonds – this is likely to be part of its original purpose, while addictive compounds hijack and misuse the same mechanisms. Some researchers even go so far as to say that falling in love is biologically similar to becoming addicted to your new romantic attachment [ 49 ]! A 2011 study found that stimulation of mu-opioid receptors in the nucleus accumbens is an important neural mechanism for the attribution of positive value to social interactions in adolescent rats [ 19 ]. Massage In a study of 95 adults, blood oxytocin increased after only 15 minutes of upper back massage. Likewise, a 10-minute foot massage increased blood oxytocin in 40 adult men. In this second study, participants’ oxytocin levels increased more dramatically when the massage was delivered by hand rather than by machine [ 50 ]. 3) Tasty Foods Studies have shown previously that stimulation of mu-opiate receptors within the ventral striatum increases the intake of palatable food. The over-consumption of readily available and highly palatable foods likely contributes to the growing rates of obesity worldwide. Palatable food is thought to work via the opioid system to create these addictions [ 21 , 22 ]. Eating a nice juicy steak gives you a good feeling, without the addictive properties. Stick with whole foods and you should be alright [ 22 ]. Chocolate We all are familiar with the feel-good sensations we get from chocolate. Epicatechins in chocolate acts mainly via delta-opioid receptors [ 51 ]. Foods with Morphine-Like Characteristics Casomorphin (from casein found in the milk of mammals, including cows) [ 52 ] Gluten exorphin (from gluten found in wheat, rye, barley) [ 53 ] Soymorphin-5 (from soybean) [ 54 ] Rubiscolin (from spinach) [ 55 ] Menthol – Found in numerous species of mint, (including peppermint, spearmint, and watermint), the naturally-occurring compound menthol activates the kappa opioid receptor [ 56 ] Poppy Seeds Though rare, poppy seed tea consumption can be fatal . It also has the potential to be abused or lead to opiate dependence [ 35 , 36 , 37 ]. Poppy Seeds have morphine and codeine in them [ 57 ]. According to international data, poppy seeds have a maximum of 62 mg/100g morphine and 5.7 mg/100g codeine [ 58 ]. Morphine effectively kills pain starting at a dosage of around 10-15mg. It is therefore unsurprising that eating poppy seeds can make a person test positive for opioids in the urine [ 58 , 59 , 57 ]. Be very cautious about consuming poppy seeds if you are taking opioid medication or if you have a bowel obstruction [ 35 , 60 ]. Chili/Cayenne Capsaicin , the chemical that makes cayenne and chili taste spicy, increases endorphin release and activates opioid receptors in rats. Some people report feeling a “high” after eating very spicy food, but there is little research on this phenomenon [ 61 , 62 ]. Sugar Most drugs of abuse increase dopamine in the nucleus accumbens. Under select dietary circumstances, sugar can have effects similar to a drug of abuse [ 22 ]. Repeated and excessive intake of sugar mimicked the effect on neurotransmitters in a similar manner to morphine or nicotine [ 63 , 64 ]. Rats show signs of dopamine sensitization and opioid dependence when given intermittent access to sucrose, such as alterations in dopamine and mu-opioid receptors [ 22 ]. When these animals then fasted, they had the same chemical changes as withdrawal effects from addictive drugs, suggesting that the rats had become sugar-dependent. Specifically, acetylcholine was higher and dopamine was lower in the nucleus accumbens, which causes anxiety and cravings [ 63 , 64 ]. Sugar-dependent animals have a delayed satiation response (acetylcholine release is delayed), drink more sugar, and release more dopamine than normal rats [ 22 ]. Fiber & Resistant Starch Hi-maize sure does give you a high, but it takes the next day to hit. To really feel good you need 120g of this stuff or 30g taken 4 times a day. Resistant starch digests in your large intestine to produce butyrate. Butyrate increases mu-opioid receptors [ 26 ]. One study found that resistant starch consistently produces more butyrate than other types of dietary fiber [ 65 ]. Butyrate is an HDAC inhibitor, meaning that it “uncoils” DNA and allows for increased gene expression [ 66 ]. HDAC Inhibitors have had mood stabilizing, anti-epileptic, and anti-inflammatory effects in animal models [ 67 , 68 , 69 ]. Good supplementary sources include Jo’s Resistant Starch . 4) Alcohol in Moderation Drinking alcohol induces opioid release in the nucleus accumbens and orbitofrontal cortex, areas of the brain implicated in reward valuation [ 41 ]. In excess, alcohol is damaging to our health; alcohol in moderation is more of a controversial topic, with some studies finding cardiovascular benefits of moderate alcohol consumption and others finding associations with cancer. Whatever your choice, we recommend strongly against drinking in excess [ 70 , 71 ]. 5) Magnesium In 60 patients who had just had surgery, magnesium amplified the analgesic effect of low-dose morphine in conditions of sustained pain. This early clinical trial confirmed the results of earlier rat studies. In each of these cases, however, magnesium did not itself activate the opioid receptors or release endorphins; rather, it potentiated the effect of another compound that did [ 24 , 25 ]. It certainly wouldn’t hurt to make sure you eat magnesium-rich foods. The best sources of magnesium are nuts, leafy greens, and whole grains [ 72 ]. 6) Mild Stress In both humans and animals, short-term stress triggers the release of pain-killing endorphins. This is the same mechanism by which exercise triggers endorphin release [ 73 , 74 , 13 , 75 , 76 ]. In the longer term, however, stress triggers the release of dynorphins, which produce bad feelings and aversive behaviors – that is, they make both humans and animals avoid the circumstances that preceded their release. Some researchers suspect that dynorphins play a role in the feelings of dysphoria and hopelessness associated with major depression [ 77 , 78 ]. Limiting and controlling stress is one of the most important skills for a healthy lifestyle. Cold Intermittent swimming in cold water induced opioid-receptor-mediated pain relief in rats [ 13 ]. Cold exposure also increased “heat shock inducible factor” (which increases opioid receptor expression) in experimental rats. Specifically, mu and delta opioid receptors – the same receptors that heroin and morphine work on – are upregulated by heat shock inducible factor [ 79 , 80 ]. 7) Acupuncture People undergoing acupuncture have higher pain thresholds than normal, an effect that many researchers attribute to endorphin release and opioid receptor activation [ 81 ]. Acupuncture activated the opioid system of experimental rats. Therapy increased both the release and synthesis of opioids and the function and expression of their receptors [ 23 ]. Potential Strategies (Lacking Evidence) No clinical evidence supports the approaches listed below to combat X. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit. 8) High-Quality Sleep Sleep deprivation decreases mu and delta opioid receptor binding in the rat limbic system, which controls emotions to increase feelings of pleasure [ 16 ]. Light & Dark Cycles Mu-opioid receptors are activated in a pattern that aligns with the circadian rhythm . When we disrupt this rhythm chronically, other systems (including the opioid receptors) get disrupted as well and don’t function the way they’re supposed to [ 82 ]. Experimental animals exposed to constant white fluorescent light had a significant decrease in tissue content of opioids (enkephalins, which bind to delta opioid receptors) during the dark phase of the 24-h circadian rhythm [ 83 ]. Melatonin Melatonin exerts its analgesic actions by increasing the release of beta-endorphins [ 29 ]. 9) Some Probiotics The gut flora and brain interact in complex ways that we don’t fully understand. One of the stranger mechanisms by which the bacteria in the human gut affect our brains is through oxytocin release [ 84 , 85 ]. L reuteri is among the bacterial species that has been observed to increase oxytocin in mice and rats. This effect has not yet been studied in humans [ 85 , 86 ]. Acidophilus is capable of increasing the expression of mu-opioid and cannabinoid receptors in the intestines and has morphine-like effects [ 28 ]. 10) Moderate Sun Exposure Some clinical reports suggest that sun tanning could be genuinely addictive, much in the same way that drugs of abuse are. In a rat study, even low-dose UV light exposure increased endorphins in the skin and blood [ 17 , 18 ]. Therefore, moderate sun exposure could potentially increase endorphins, but excessive exposure has been associated with addictive behavior [ 17 , 18 ]. 11) Hot Shower/Bath Many people turn to hot baths or showers to relieve stress and feel better. Mice that took a short swim in warm water were found to have increased beta-endorphins and pain relief, suggesting a mechanism for this suspected benefit [ 13 ]. 12) LLLT In rats, low-level laser therapy ( LLLT ) relieved pain, possibly by increasing natural opioids. This effect has not been investigated in humans [ 30 ]. Controversial Drugs The drugs discussed in this section are heavily regulated and controversial. We include them here because they are the subject of a great deal of current research into their potential to increase opioid receptor activation with fewer side effects than conventional opioid painkillers. However, we strongly advise against using them without a doctor’s supervision. Low Dose Naltrexone Low dose naltrexone (LDN) is a controversial topic in current research. Naltrexone decreases opioid receptor binding and is typically used to treat opioid dependence. More recently, researchers have begun exploring the idea that a tenth of the conventional naltrexone dose (hence, low dose naltrexone) could actually have a positive effect on people with chronic pain [ 87 , 88 ]. The mechanism by which LDN could help in chronic pain is unclear. However, some researchers believe that when opioid receptors are down-regulated, the body might compensate by increasing the production of endorphins and enkephalins . If these increased levels of endogenous opioids persist after the naltrexone has been eliminated from the body, they would then be available to bind to the newly freed up receptors [ 87 , 88 ]. If you have chronic pain, you may want to talk to your doctor about trying LDN. Naltrexone is a powerful pharmaceutical drug. Do not use naltrexone without a doctor’s prescription and supervision. Cannabis Marijuana (or cannabis) produces positive feelings in most users. It acts primarily on cannabinoid receptors, but the two most active ingredients in cannabis, THC and CBD , both activate mu and delta opioid receptors as well [ 89 , 33 ]. Cannabis is still a highly controversial subject among doctors and researchers. Many studies and reviews have emerged in recent months and years discussing the potential of cannabis as an alternative to opioids in chronic pain. There is no consensus on whether it is effective against pain on its own or whether it can be used to wean patients off of opioids [ 90 , 91 , 92 ]. Cannabis is classified as a schedule I drug in the United States, making it illegal to use and very difficult to study [ 93 ]. About the Author Joe Cohen, BS Joe Cohen flipped the script on conventional and alternative medicine…and it worked.
+
+Growing up, he suffered from inflammation, brain fog, fatigue, digestive problems, insomnia, anxiety, and other issues that were poorly understood in traditional healthcare.
+
+Frustrated by the lack of good information and tools, Joe decided to embark on a learning journey to decode his DNA and track his biomarkers in search of better health.
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+Through this personalized approach, he discovered his genetic weaknesses and was able to optimize his health 10X better than he ever thought was possible.
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+Based on his own health success, he went on to found SelfDecode, the world’s first direct-to-consumer DNA analyzer & precision health tool that utilizes AI-driven polygenic risk scoring to produce accurate insights and health recommendations. Today, SelfDecode has helped over 100,000 people understand how to get healthier using their DNA and labs. Joe is a thriving entrepreneur, with a mission of empowering people to take advantage of the precision health revolution and uncover insights from their DNA and biomarkers so that we can all feel great all of the time. RATE THIS ARTICLE ( 12 votes, average: 4.17 out of 5) Loading... FDA Compliance The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition. Leave a Reply Cancel reply Your email address will not be published. Required fields are marked * Comment * Name * Email * Website Save my name, email, and website in this browser for the next time I comment. Contents An Intro To Your Brain’s Opioid System Mu-Opioid Receptors Delta-Opioid Receptors Kappa-Opioid Receptors A Natural, Drug-Free High? Top Strategies (Likely Effective) 1) Exercise 2) The Love Hormone 3) Tasty Foods 4) Alcohol in Moderation 5) Magnesium 6) Mild Stress 7) Acupuncture Potential Strategies (Lacking Evidence) 8) High-Quality Sleep 9) Some Probiotics 10) Moderate Sun Exposure 11) Hot Shower/Bath 12) LLLT Controversial Drugs Low Dose Naltrexone Cannabis Joe Cohen, CEO About Joe Joe Cohen flipped the script on conventional and alternative medicine… and it worked. Frustrated by the lack of good information and tools, Joe decided to embark on a learning journey to decode his DNA and track his biomarkers in search of better health. Read More Related Articles View All 11 min read Brain 17 Mycoplasma Roles in Disease + Treatment, Prevention 10 min read Conditions Ketoacidosis: Treatment,  Prevention & Complications 1 min read Thyroid Hashimoto’s Thyroiditis Genetic Factors What do your genes tell you about your health? Align your health hacks with your genes for optimal health & cognitive function. Check out SelfDecode Now SelfDecode is a personalized health report service,
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+Body Mass Index (BMI)  | Healthy Weight, Nutrition, and Physical Activity | CDC Skip directly to site content Skip directly to search Español | Other Languages Centers for Disease Control and Prevention. CDC twenty four seven. Saving Lives, Protecting People Centers for Disease Control and Prevention. CDC twenty four seven. Saving Lives, Protecting People Search Submit Healthy Weight, Nutrition, and Physical Activity Body Mass Index (BMI) Español (Spanish) Print Minus Related Pages Food Assistance and Food Systems Resources Calculate Your BMI Adult BMI Calculator Child and Teen BMI Calculator Body Mass Index (BMI) is a person’s weight in kilograms divided by the square of height in meters. A high BMI can indicate high body fatness. BMI screens for weight categories that may lead to health problems, but it does not diagnose the body fatness or health of an individual. How Do I Interpret Body Mass Index Information? About BMI for Adults Information about BMI and interpreting this number for adults. About BMI for Children and Teens Information about BMI and interpreting the BMI percentile for children and teens. Other Helpful BMI Tools Adult Body Mass Index Calculator Widget Add this widget to your website to let anyone calculate their BMI. BMI is a reliable indicator of body fatness for most people. It is used to screen for weight categories that may lead to health problems. This calculator provides BMI and the corresponding weight category. Use this calculator for adults, 20 years old and older. CDC Child and Teen BMI Calculator Widget Add this widget to your website. This calculator provides BMI and the corresponding BMI-for-age percentile on a CDC BMI-for-age growth chart. Use this calculator for children and teens, aged 2 through 19 years old. The Children’s BMI Tool for Schools School staff, child care leaders, and other professionals can use this spreadsheet to compute BMI for as many as 2,000 children. Also see safeguards for BMI measurement in schools . Connect with Nutrition, Physical Activity, and Obesity Last Reviewed: March 14, 2024 Source: Division of Nutrition, Physical Activity, and Obesity , National Center for Chronic Disease Prevention and Health Promotion Facebook Twitter LinkedIn Syndicate home Healthy Weight, Nutrition, and Physical Activity Assessing Your Weight plus icon Body Mass Index (BMI) About Adult BMI Adult BMI Calculator plus icon Metric Version About Child & Teen BMI plus icon Measuring Children’s Height and Weight Accurately At Home Child & Teen BMI Calculator Children’s BMI Tool for Schools Finding a Balance Losing Weight plus icon Improving Your Eating Habits Keeping It Off Healthy Eating for a Healthy Weight plus icon Water and Healthier Drinks plus icon Rethink Your Drink Know Your Limits for Added Sugars Planning Meals and Snacks Cutting Calories plus icon Using Fruits & Vegetables to Manage Your Weight Physical Activity for a Healthy Weight plus icon Getting Started Tips for Parents Health Effects of Overweight & Obesity External Resources  email_03 Get Email Updates To receive email updates about this topic, enter your email address. Email Address What's this? Submit Division of Nutrition, Physical Activity, and Obesity About Us Nutrition Physical Activity Overweight & Obesity Healthy Weight, Nutrition, and Physical Activity Breastfeeding Micronutrient Malnutrition State and Local Programs Salt Related Topics Prevent Type 2 Diabetes Prevent Heart Disease Healthy Schools – Promoting Healthy Behaviors Obesity Among People with Disabilities About CDC Contact Us 800-232-4636 Facebook Twitter Instagram LinkedIn Youtube Pinterest Snapchat CONTACT CDC Contact Us Call 800-232-4636 Email Us ABOUT CDC About CDC Jobs Funding POLICIES Accessibility External Links Privacy Policies No Fear Act FOIA OIG Nondiscrimination Vulnerability Disclosure Policy CONNECT WITH US Facebook Twitter Instagram LinkedIn Youtube Pinterest Snapchat Email LANGUAGES Español 繁體中文 Tiếng Việt 한국어 Tagalog Русский العربية Kreyòl Ayisyen Français Polski Português Italiano Deutsch 日本語 فارسی English U.S. Department of Health & Human Services Accessibility External Links Privacy Policies No Fear Act FOIA Nondiscrimination OIG Vulnerability Disclosure Policy USA.gov SAS stats Exit Notification / Disclaimer Policy Close Links with this icon indicate that you are leaving the CDC website. The Centers for Disease Control and Prevention (CDC) cannot attest to the accuracy of a non-federal website. Linking to a non-federal website does not constitute an endorsement by CDC or any of its employees of the sponsors or the information and products presented on the website. You will be subject to the destination website's privacy policy when you follow the link. CDC is not responsible for Section 508 compliance (accessibility) on other federal or private website. For more information on CDC's web notification policies, see Website Disclaimers . Cancel Continue

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+The Health Effects of Passive Smoking: An Overview of Systematic Reviews Based on Observational Epidemiological Evidence - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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+    the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice PLoS One. 2015; 10(10): e0139907. Published online 2015 Oct 6. doi: 10.1371/journal.pone.0139907 PMCID: PMC4595077 PMID: 26440943 The Health Effects of Passive Smoking: An Overview of Systematic Reviews Based on Observational Epidemiological Evidence Shiyi Cao , Chen Yang , Yong Gan , and Zuxun Lu * Shiyi Cao School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Find articles by Shiyi Cao Chen Yang School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Find articles by Chen Yang Yong Gan School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Find articles by Yong Gan Zuxun Lu School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Find articles by Zuxun Lu Yan Li, Editor Author information Article notes Copyright and License information PMC Disclaimer School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Shanghai Institute of Hypertension, CHINA Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: ZL. Performed the experiments: SC CY. Analyzed the data: SC YG. Contributed reagents/materials/analysis tools: CY. Wrote the paper: SC. * E-mail: moc.oohay@ulnuxuz Received 2015 Apr 23; Accepted 2015 Sep 19. Copyright © 2015 Cao et al This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. Associated Data Supplementary Materials S1 PRISMA Checklist: (DOC) pone.0139907.s001.doc (65K) GUID: 9F4D2058-3FA3-4ACB-B4C6-DAC6B3293405 Data Availability Statement All relevant data are within the paper and its Supporting Information files. Abstract Purpose We aim to systematically summarize the available epidemiological evidence to identify the impact of environmental tobacco smoke on health. Methods A systematic literature search of PubMed, Embase, Web of Science, and Scopus for meta-analyses was conducted through January 2015. We included systematic reviews that investigated the association between passive smoking and certain diseases. Quantitative outcomes of association between passive smoking and the risk of certain diseases were summarized. Results Sixteen meta-analyses covering 130 cohort studies, 159 case-control studies, and 161 cross-sectional studies and involving 25 diseases or health problems were reviewed. Passive smoking appears not to be significantly associated with eight diseases or health problems, but significantly elevates the risk for eleven specific diseases or health problems, including invasive meningococcal disease in children (OR 2.18; 95% CI 1.63–2.92), cervical cancer (OR 1.73; 95% CI 1.35–2.21), Neisseria meningitidis carriage (OR 1.68; 95% CI 1.19–2.36), Streptococcus pneumoniae carriage (OR 1.66; 95% CI 1.33–2.07), lower respiratory infections in infancy (OR 1.42; 95% CI 1.33–1.51), food allergy (OR 1.43; 95% CI 1.12–1.83), and so on. Conclusions Our overview of systematic reviews of observational epidemiological evidence suggests that passive smoking is significantly associated with an increasing risk of many diseases or health problems, especially diseases in children and cancers. Introduction Smoking is a major public health problem worldwide. There have been thousands of studies investigating the impact of active smoking on health, and the overall toxic effects of active smoking are generally recognized [ 1 ]. In comparison, the effects of passive smoking on health are not fully understood. Existing studies suggest that passive smoking and active smoking might equally increase the risk of certain diseases, such as female breast cancer [ 2 ], allergic rhinitis, allergic dermatitis, and food allergy [ 3 ]. As early as 1928, Schonherr suspected that inhalation of husbands’ smoke could cause lung cancer among non-smoking wives [ 4 ]. Since then a substantial body of research about environmental tobacco smoke and health has appeared [ 5 ]. But the impact of passive smoking on health remains largely inconclusive and has not been systematically summarized. Due to the relative small health risks associated with exposure to passive smoking, investigation of this issue requires large study sizes. Difficulties in measuring passive smoking and controlling various confounding factors further add to the uncertainty in any investigation of the effects of passive smoking. Consequently, a meta-analysis, pooling together individual original studies quantitatively, has played an important part in establishing the evidence about the health effects of passive smoking [ 5 ]. Since Zmirou evaluated the respiratory risk of passive smoking by a meta-analysis in the early 1990s, many meta-analyses of observational epidemiological studies have been published to identify the impact of passive smoking on health. Recognizing that the evidence is accumulating constantly worldwide, we conducted an overview of systematic reviews that have summarized the evidence from observational epidemiological studies on the health effects of passive smoking. Methods No protocol exists for this overview of systematic reviews. Ethics Data for this research was acquired from previously published papers. Written consent and ethical approval were not required. Literature search strategy We attempted to conduct this overview of systematic reviews in accordance with the rationale and guideline recommended by Cochrane handbook 5.1.0 [ 6 ] ( S1 Checklist ). A systematic literature search of PubMed, Embase, Web of Science, and Scopus was conducted in January 2015 using the following search terms with no restrictions: passive smoking, secondhand smoking, environmental tobacco smoke, involuntary smoking, and tobacco smoke pollution. The reference lists of the retrieved articles were also reviewed. We did not contact authors of the primary studies for additional information. Selection of relevant systematic reviews Systematic reviews meeting the following criteria were regarded as eligible: (1) the design was meta-analysis, (2) passive smoking was an exposure variable and the outcome was the incidence of certain diseases or health problems, (3) the included original studies were cross-sectional, case-control, or/and cohort study design, (4) the literature search was international or worldwide, and (5) the pooled relative risk (RR) or odds ratio (OR) and the corresponding 95% confidence interval (CI) of specific diseases relating to exposure to passive smoking were reported or could be calculated from the data provided. Systematic reviews in which all included original studies were conducted in one country or region were excluded. We also excluded the meta-analyses that investigated the association between maternal smoking in pregnancy and the health risk of offspring. All potential meta-analyses were independently screened by two authors (SC and CY), who reviewed the titles or/abstracts first and then conducted a full-text assessment. Disagreements between the two reviewers were resolved through discussion with the third investigator (ZL). Data extraction The following information was extracted from the studies by two investigators (SC and CY): first author, publication year, country, number and design of the included original studies, and main quantitative estimates of the association of interest. Quality appraisal We appraised all the included meta-analyses using the Assessment of Multiple Systematic Reviews (AMSTAR) standard, an 11-item assessment tool designed to appraise the methodological quality of systematic reviews [ 7 ]. The maximum score is 11, and 0–4, 5–8, and 9–11 respectively indicates low, moderate, and high quality [ 8 ]. Disagreements on assessment scores were resolved by discussion among the authors. Synthesis of the evidence There may be more than one meta-analysis published regarding the association between passive smoking and risk of a specific disease. We only included the latest meta-analysis and excluded all the previous ones. For each included meta-analysis, we summarized the number and design of the included original studies, the main quantitative estimates of association of interest, heterogeneity between original studies, and so on. In any included meta-analyses, when estimates of association between passive smoking and certain diseases were reported separately for subgroups, we combined the results of the subgroups and calculated common estimates using a fixed-effects model if appropriate. Results Literature search Fig 1 shows the process of study identification and inclusion. Initially, we retrieved 2,079 articles from Pubmed, Emabse, Web of Science, and Scopus. After 1,105 duplicates were excluded, 974 articles were screened through titles and abstracts, of which 858 were excluded mainly because they were original studies or irrelevant reviews. After full-text review of the remaining 116 articles, 100 were further excluded because they did not report the outcomes of interest or their findings were already updated by newer systematic reviews. Finally, 16 meta-analyses were included [ 3 , 9 – 23 ]. Open in a separate window Fig 1 Identification of relevant meta-analyses. Characteristics and quality of the included systematic reviews The main characteristics of the sixteen meta-analyses were summarized in Table 1 . These meta-analyses covered a total of 130 cohort studies, 159 case-control studies, and 161 cross-sectional studies. They were published between 1998 and 2014. The quality scores of these meta-analyses appraised using AMSTAR ranged from 3 to 10. The numbers of meta-analyses with high quality, middle quality, and low quality were 5, 9, and 2 respectively (see Table 2 ). Table 1 Main characteristics of the included systematic reviews. Author Year Diseases Number and design of included studies Pooled odds ratio (95% confidence interval) Lee CC 2010 pediatric invasive bacterial disease and bacterial carriage 30 case-control studies for invasive bacterial disease invasive bacterial disease: 12 cross-sectional studies for bacterial carriage 1.21 (95% CI 0.69–2.14) for invasive pneumococcal disease 1.22 (95% CI 0.93–1.62) for invasive Hib disease. pharyngeal carriage: 1.68 (95% CI, 1.19–2.36) for Neisseria. meningitidies 1.66 (95% CI 1.33–2.07) for Streptococcus. pneumoniae 0.96 (95% CI 0.48–1.95) for Hib. Van Hemelrijck MJ, 2009 bladder cancer 8 studies 0.99 (95% CI 0.86–1.14) 3 cohort 1.19 (95% CI 0.88–1.62) for childhood passive smoking 5 case-control 0.90 (95% CI 0.79–1.02) for adulthood passive smoking Jones DT 2008 inflammatory bowel disease 13 case-control studies 1.10 (95% CI 0.92–1.30) for Crohn's disease 1.01 (95% CI 0.85–1.20) for ulcerative colitis Jones LL 2011 lower respiratory infections in infancy 60 studies 1.22 (95% CI 1.10–1.35) for paternal smoking 32 cohort 1.62 (95% CI 1.38–1.89) for both parents smoking 15 case-control 1.54 (95% CI 1.40–1.69) for any household member smoking. 13 cross-sectional Zeng XT 2012 cervical cancer 11 case-control studies 1.73 (95% CI 1.35–2.21) Strachan DP 1998 middle ear disease in children 28 studies 1.48 (95% CI 1.08–2.04) for recurrent otitis media, 11 cohort 1.38 (95% CI 1.23–1.55) for middle ear effusion 13 case-control 1.21 (95% CI 0.95–1.53) for glue ear. 4 cross-sectional Murray RL 2012 invasive meningococcal disease in children 18 studies 2.18 (95% CI 1.63–2.92) 2 cohort 2.48 (95% CI 1.51–4.09) in children under 5 years. 16 case-control 2.26 (95% CI 1.54–3.31) for maternal smoking after birth Zhou J 2012 pancreatic cancer 10 studies 1.12 (95% CI 0.89–1.43) during childhood. 7 cohort 1.23 (95% CI 0.86–1.77) during adulthood at home 3 case-control 0.94 (95% CI 0.67–1.33) during adulthood at work Lin HH 2007 tuberculosis 4 case-control studies 4.01 (95% CI 2.54–6.34) Saulyte J 2014 allergic rhinitis, allergic dermatitis, and food allergy in adults and children 63 studies for allergic rhinitis 1.10 (95% CI 1.06–1.15) 9 cohort 1.07 (95% CI 1.03–1.12) for allergic dermatitis 3 case-control 1.09 (95% CI 1.04–1.14) for allergic rhinitis 51 cross-sectional 1.43 (95% CI 1.12–1.83) for food allergy 58 studies for allergic dermatitis 14 cohort 5 case-control 39 cross-sectional 6 studies for food allergies 5 cohort 1 cross-sectional Sun K 2014 diabetes 6 cohort studies 1.21 (95% CI 1.07–1.38) Oono IP 2011 stroke 20 studies 1.25 (95% CI 1.12–1.38) 10 cohort 1.22 (95% CI 1.08–1.38) for cohort studies 6 case-control 1.41 (95% CI 1.15–1.72) for case-control studies 4 cross-sectional 1.03 (95% CI 0.69–1.53) for cross-sectional studies Tinuoye O 2013 physician-diagnosed childhood asthma 20 studies 1.32 (95% CI 1.23–1.42) 4 cohort 1.26 (95% CI 0.91–1.73) for cohort studies 2 case-control 1.41 (95% CI 1.31–2.32) for case-control studies 14 cross-sectional 1.31 (95% CI 1.22–1.43) for cross-sectional studies Yang Y 2013 breast cancer 10 cohort studies. 1.01 (95% CI 0.96–1.06) 0.96 (95% CI 0.81–1.14) for passive smoking at home 1.01 (95% CI 0.93–1.10) for passive smoking in the workplace He J 1999 coronary heart disease 18 studies 1.25 (95% CI 1.17–1.32) 10 cohort 1.17 (95% CI 1.11–1.24) for passive smoking at home 8 case-control 1.11 (95% CI 1.00–1.23) for passive smoking in the workplace Taylor R 2007 lung cancer 55 studies 1.27 (95% CI 1.17–1.37) 7 cohort 1.15 (95% CI 1.03–1.28) for North America 25 population-based case-control 1.31 (95% CI 1.16–1.48) for Asia 23 non-population-based case-control 1.31 (95% CI 1.24–1.52) for Europe Open in a separate window Table 2 Appraisal of the included meta-analyses on the impact of passive smoking on various diseases. Author ‘A priori’ design provided Duplicate study selection/data extraction Comprehensive literature search Status of publication as inclusion criteria List of studies included/excluded provided Characteristics of included studies documented Scientific quality assessed and documented Appropriate formulation of conclusions Appropriate methods of combining studies; Assessment of publication bias; and Conflict of interest statement. Total yes Lee CC yes yes yes no yes yes no yes yes yes yes 9 Van H MJ, no no no yes yes yes no no yes yes yes 6 Jones DT yes yes yes no yes yes yes no yes yes yes 9 Jones LL yes yes yes no yes no yes yes yes yes yes 9 Zeng XT no yes no yes yes yes yes no yes yes no 7 Strachan DP no no yes no no yes no no yes no no 3 Murray RL yes yes yes no yes yes no no yes yes yes 8 Zhou J no no yes no no yes no no yes yes yes 5 Lin HH no yes no no yes yes yes yes yes yes yes 8 Saulyte J no yes yes no yes yes yes no yes yes yes 8 Sun K no no yes no yes yes yes no yes no yes 6 Oono IP no yes no no yes yes no yes yes yes no 6 Tinuoye O no no yes no no yes no no yes yes yes 5 Yang Y yes yes yes no yes yes yes yes yes yes yes 10 He J no yes yes no no yes no no no yes no 4 Taylor R yes yes yes yes yes yes no yes yes yes yes 10 Open in a separate window The Main Health Consequences of Passive Smoking Fig 2 shows the integrated results on the impact of passive smoking on specific diseases. The included 16 meta-analyses covered 25 diseases or health problems. There was statistically significant positive relationship between exposure environmental tobacco smoke and the risk of eleven diseases, especially invasive meningococcal disease in children (OR 2.18; 95% CI 1.63–2.92) and other three diseases or health problems with a 1.5 to 2.0-fold increase in the risk: cervical cancer (OR 1.73; 95% CI 1.35–2.21), Neisseria meningitidis carriage (OR 1.68; 95% CI 1.19–2.36), and Streptococcus pneumoniae carriage (OR 1.66; 95% CI 1.33–2.07). The increase in the risk of other seven diseases associated with exposure to passive smoking was statistically significant but small in impact size (OR was less than 1.5): lower respiratory infections in infancy (OR 1.42; 95% CI 1.33–1.51), food allergy (OR 1.43; 95% CI 1.12–1.83), childhood asthma (OR 1.32; 95% CI 1.23–1.42), lung cancer (OR 1.27; 95% CI 1.17–1.37), stroke (OR 1.25; 95% CI 1.12–1.38), allergic rhinitis (OR 1.09; 95% CI 1.04–1.14), and allergic dermatitis (OR 1.07; 95% CI 1.03–1.12). Of these 25 diseases or health problems, eight diseases were not found to be significantly associated with passive smoking. They were invasive Haemophilus influenzae type B (Hib) disease, invasive pneumococcal disease, Crohn's disease, pancreatic cancer, ulcerative colitis, breast cancer, bladder cancer, and pharyngeal carriage for Hib. In addition, the effects of passive smoking on increased risk of coronary heart disease, tuberculosis, diabetes, and middle ear disease in children (recurrent otitis media, middle ear effusion, and glue ear) were not conclusive, because the number of included studies was small or the quality of the corresponding meta-analysis was low. Open in a separate window Fig 2 Summary of estimates of associations between passive smoking and the risk of specific diseases or health problems. Passive smoking and cancer risk We investigated the association of passive smoking with the risk of lung cancer, cervical cancer, pancreatic cancer, breast cancer, and bladder cancer. Based on 55 observational studies (7 cohort studies, 25 population-based case-control studies and 23 non-population-based case-control studies), passive smoking were found to be associated with the increased risk of lung cancer (OR 1.27; 95% CI 1.17 to 1.37). The ORs for lung cancer in North America, Asia, and Europe were similar [ 19 ]. 11 case-control studies, involving 3,230 cases and 2,982 controls, suggested a positive relationship between passive smoking and cervical cancer (OR 1.73; 95% CI 1.35–2.21) [ 15 ]. Pancreatic cancer [ 21 ], breast cancer [ 13 ], and bladder cancer were not found to be associated with passive smoking. Passive smoking and allergic diseases A meta-analysis of observational studies published in PLOS Medicine systematically reviewed the effects of exposure to environmental smoke on allergic diseases [ 3 ]. The pooled ORs of 63 studies for allergic rhinitis, 58 studies for allergic dermatitis, and 6 studies for food allergies were 1.07 (95% CI 1.03–1.12), 1.09 (95% CI 1.04–1.14), and 1.43 (95% CI 1.12–1.83) respectively. Another meta-analysis investigated the association between passive smoking and the risk of physician-diagnosed childhood asthma [ 9 ], and suggested that there was consistent evidence of a modest positive association between them (OR 1.32; 95% CI: 1.23–1.42). Passive smoking and pediatric invasive bacterial disease and bacterial carriage Passive smoking was also thought to be associated with pediatric invasive bacterial disease and bacterial carriage. A meta-analysis involving 30 case-control studies for invasive bacterial disease and 12 cross-sectional studies for bacterial carriage indicated that the risk of invasive meningococcal disease, pharyngeal carriage for Neisseria, meningitidies and Streptococcus pneumoniae were significantly associated with passive smoking, and the ORs were 2.18, 95% CI 1.63 to 2.92), 1.68 (95% CI, 1.19–2.36), and 1.66 (95% CI 1.33–2.07), respectively. The risk of invasive pneumococcal disease, invasive Hib disease, and pharyngeal carriage for Hib were not found to be related to exposure to environmental smoke. Discussion The health effects of environmental tobacco smoke are attracting more and more attention worldwide. Increasing numbers of original studies and meta-analyses are being published focusing on this important issue. In the present overview of systematic reviews based on sixteen systematic reviews involving 450 original observational studies, we found that passive smoking could significantly increase the risk of eleven diseases, especially invasive meningococcal disease in children, cervical cancer, Neisseria meningitidis carriage, and Streptococcus. pneumoniae carriage, but not associated with other eight diseases. Cancers were one of the most common investigated health outcomes associated with passive smoking. We found that exposure to environmental tobacco smoke could increase the risk of lung cancer and cervical cancer, but was not the risk of pancreatic cancer, breast cancer, or bladder cancer. It appears that passive smoking could increase the risk of some diseases among children, especially bacterial infections (e.g., lower respiratory infections in infancy, middle ear disease in children, invasive meningococcal disease in children, allergic diseases in children, and childhood asthma). Previously, there were some reviews focusing on the health effects of exposure to environmental tobacco smoke. But they were qualitative or only involved children or limited to several diseases [ 24 – 26 ]. We used a systematic overview to summarize the quantitative estimates of the associations between passive smoking and various diseases based on all latest available meta-analyses. It should be noted that, in the present overview, we excluded meta-analyses evaluating the effects of smoking during pregnancy on fetus or offspring health, because the effects was obviously different from the health effects of active smoking or conventional passive smoking in the general population. The quality of included original studies influences the reliability of the results and conclusions of the corresponding meta-analysis; similarly, the validity of the results of an overview of systematic reviews depends on the quality of the included systematic reviews. We used AMSTAR protocol, an internationally recognized assessment tool, to appraise the methodological quality of all included meta-analyses, and found that there were two meta-analyses with low quality. Accordingly, the conclusions drawn based on these two meta-analyses involving middle ear disease in children and coronary heart disease need to be interpreted with caution. The evidence level of meta-analyses partly depends on the number and the design type of included original studies. Although there was no consensus about the minimum number of original studies included in meta-analysis, but more caution is needed when an association is assessed based on a small number of original studies. In our overview, we found a significant positive association between passive smoking and tuberculosis (OR 4.01; 95% CI 2.54–6.34), but it was only based on 4 case-control studies. More studies should be conducted to further assess the relationship between them. Similarly, the effect of passive smoking on diabetes was based on 6 cohort studies (OR 1.21; 95% CI 1.07–1.38), and more original studies are also needed. There were several strengths in our research. Firstly, we followed the primary rationale and method of Cochrane overviews of reviews [ 6 ] to summarize the health consequences of certain exposure. Overview of systematic reviews is primarily intended to summarize multiple reviews addressing the effects of two or more potential interventions for a single condition or health problem. Up to now, most of overviews have been conducted to evaluate the effects of several interventions [ 27 , 28 ], and very few overviews have addressed the effects of a single exposure factor on multiple diseases or health problems based on observational studies. Our present overview expands the application of overviews of systematic reviews. Additionally, our study provides robust and comprehensive scientific information for smoking ban in public places and for educational pamphlets about passive smoking. Some limitations in our overview should be noted. Firstly, we only included systematic reviews but not original studies. The associations of passive smoking with some diseases might have been investigated by original studies but not synthesized by meta-analyses and, therefore, were not summarized in this overview. Secondly, the mechanism on the health effects of passive smoking was not be examined since our study only intended to summarize relevant observational epidemiological evidence. In summary, our overview of systematic reviews of up-to-date epidemiological evidence suggests that passive smoking is significantly associated with an increasing risk of many diseases and health problems, especially diseases in children and cancers. This study provides comprehensive population-based evidence about toxic effect of exposure to environmental tobacco smoke and should benefit developing health promotion strategies of smoking control. Stricter regulations against cigarette smoking should be formulated and implemented, because smoking harms not only own health but also the health of neighboring people. 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Epub 2014 Dec 23. Elevation of serum alkaline phosphatase (ALP) level in postmenopausal women is caused by high bone turnover Keijiro Mukaiyama 1 , Mikio Kamimura , Shigeharu Uchiyama , Shota Ikegami , Yukio Nakamura , Hiroyuki Kato Affiliations Expand Affiliation 1 Departments of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto City, Nagano, 390-8621, Japan, kmuka312@yahoo.co.jp. PMID: 25534961 DOI: 10.1007/s40520-014-0296-x Item in Clipboard Elevation of serum alkaline phosphatase (ALP) level in postmenopausal women is caused by high bone turnover Keijiro Mukaiyama et al. Aging Clin Exp Res . 2015 Aug . Show details Display options Display options Format Abstract PubMed PMID Aging Clin Exp Res Actions Search in PubMed Search in NLM Catalog Add to Search . 2015 Aug;27(4):413-8. doi: 10.1007/s40520-014-0296-x. Epub 2014 Dec 23. Authors Keijiro Mukaiyama 1 , Mikio Kamimura , Shigeharu Uchiyama , Shota Ikegami , Yukio Nakamura , Hiroyuki Kato Affiliation 1 Departments of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto City, Nagano, 390-8621, Japan, kmuka312@yahoo.co.jp. PMID: 25534961 DOI: 10.1007/s40520-014-0296-x Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Background: Most of the alkaline phosphatase (ALP) isoenzymes are derived from the bones and liver. High levels of ALP are often encountered during routine blood investigation in elderly patients. However, because ALP includes various isoenzymes from other tissues, an accurate diagnosis is usually not possible on the basis of elevated ALP alone. Aims: To identify the cause of increased ALP in postmenopausal women. Methods: We measured serum ALP in a group of 626 postmenopausal osteoporotic women before and after treatment with a bisphosphonate (either alendronate or risedronate). We analyzed the correlations between ALP levels and bone metabolic markers or hepatic function markers. Results: The ALP and BAP levels of people in their 80s were significantly higher than those of people in their 60s. With bisphosphonate therapy, the BAP decreased, and the elevated ALP decreased to normal range levels. ALP was highly and significantly correlated with BAP both before and after treatment. The changes in levels of ALP correlated well with the changes in BAP levels before and after bisphosphonate therapy. Markers of liver function correlated with total ALP (p < 0.01), but the correlation was much smaller than that between ALP and BAP. Discussion: Bisphosphonate treatment lowered ALP levels, and this decrease was strongly correlated with a decrease in BAP. Among blood test data, the decrease in BAP had the strongest correlation with the ALP decrease. Conclusion: For treatment of osteoporosis, ALP is an acceptable alternative to BAP. Elevated ALP in postmenopausal women is mainly caused by high bone turnover. PubMed Disclaimer Similar articles Comparison of the effects of alendronate and risedronate on bone mineral density and bone turnover markers in postmenopausal osteoporosis. Sarioglu M, Tuzun C, Unlu Z, Tikiz C, Taneli F, Uyanik BS. Sarioglu M, et al. Rheumatol Int. 2006 Jan;26(3):195-200. doi: 10.1007/s00296-004-0544-z. Epub 2004 Dec 2. Rheumatol Int. 2006. PMID: 15580349 Clinical Trial. Comparison of bone and total alkaline phosphatase and bone mineral density in postmenopausal osteoporotic women treated with alendronate. Watts NB, Jenkins DK, Visor JM, Casal DC, Geusens P. Watts NB, et al. Osteoporos Int. 2001;12(4):279-88. doi: 10.1007/s001980170117. Osteoporos Int. 2001. PMID: 11420777 Clinical Trial. Use of bone alkaline phosphatase to monitor alendronate therapy in individual postmenopausal osteoporotic women. Kress BC, Mizrahi IA, Armour KW, Marcus R, Emkey RD, Santora AC 2nd. Kress BC, et al. Clin Chem. 1999 Jul;45(7):1009-17. Clin Chem. 1999. PMID: 10388477 Clinical Trial. [Biochemical markers of bone turnover. New aspect. Biochemical markers of bone turnover in long term treatment with bisphosphonate]. Asano S, Suzuki A, Itoh M. Asano S, et al. Clin Calcium. 2009 Aug;19(8):1179-85. Clin Calcium. 2009. PMID: 19638702 Review. Japanese. Risedronate: a review of its pharmacological properties and clinical use in resorptive bone disease. Dunn CJ, Goa KL. Dunn CJ, et al. Drugs. 2001;61(5):685-712. doi: 10.2165/00003495-200161050-00013. Drugs. 2001. PMID: 11368289 Review. See all similar articles Cited by Recombinant Human Peptide Growth Factors, Bone Morphogenetic Protein-7 (rhBMP7), and Platelet-Derived Growth Factor-BB (rhPDGF-BB) for Osteoporosis Treatment in an Oophorectomized Rat Model. Reis TG, Del Colletto AMS, Silva LAS, Koga BAA, Sogayar MC, Carreira ACO. Reis TG, et al. Biomolecules. 2024 Mar 7;14(3):317. doi: 10.3390/biom14030317. Biomolecules. 2024. PMID: 38540737 Free PMC article. Cross-sectional studies of the causal link between asthma and osteoporosis: insights from Mendelian randomization and bioinformatics analysis. Chen L, Li C, Chen H, Xie Y, Su N, Luo F, Huang J, Zhang R, Chen L, Chen B, Yang J. Chen L, et al. Osteoporos Int. 2024 Mar 2. doi: 10.1007/s00198-024-07037-0. Online ahead of print. Osteoporos Int. 2024. PMID: 38430243 Predictors of bone mineral density in patients receiving glucocorticoid replacement for Addison's disease. Furman K, Gut P, Sowińska A, Ruchała M, Fichna M. Furman K, et al. Endocrine. 2024 Feb 9. doi: 10.1007/s12020-024-03709-3. Online ahead of print. Endocrine. 2024. PMID: 38334892 Alpha-lipoic Acid Prevents Bone Loss in Type 2 Diabetes and Postmenopausal Osteoporosis Coexisting Conditions by Modulating the YAP/Glut4 Pathway. Xu L, Zhang C, Bao J, Han G, Wang C, Cai Y, Xu G, Sun H, Liu M. Xu L, et al. Cell Biochem Biophys. 2024 Jan 23. doi: 10.1007/s12013-024-01216-w. Online ahead of print. Cell Biochem Biophys. 2024. PMID: 38261247 The Therapeutic Potential of Two Egyptian Plant Extracts for Mitigating Dexamethasone-Induced Osteoporosis in Rats: Nrf2/HO-1 and RANK/RANKL/OPG Signals. Saleh SR, Saleh OM, El-Bessoumy AA, Sheta E, Ghareeb DA, Eweda SM. Saleh SR, et al. Antioxidants (Basel). 2024 Jan 1;13(1):66. doi: 10.3390/antiox13010066. Antioxidants (Basel). 2024. PMID: 38247490 Free PMC article. See all "Cited by" articles MeSH terms Aged Actions Search in PubMed Search in MeSH Add to Search Aged, 80 and over Actions Search in PubMed Search in MeSH Add to Search Alendronate / administration & dosage* Actions Search in PubMed Search in MeSH Add to Search Alkaline Phosphatase / blood* Actions Search in PubMed Search in MeSH Add to Search Biomarkers / blood Actions Search in PubMed Search in MeSH Add to Search Bone Density Conservation Agents / administration & dosage Actions Search in PubMed Search in MeSH Add to Search Bone Remodeling / physiology* Actions Search in PubMed Search in MeSH Add to Search Bone and Bones / metabolism* Actions Search in PubMed Search in MeSH Add to Search Female Actions Search in PubMed Search in MeSH Add to Search Humans Actions Search in PubMed Search in MeSH Add to Search Isoenzymes / blood Actions Search in PubMed Search in MeSH Add to Search Japan Actions Search in PubMed Search in MeSH Add to Search Middle Aged Actions Search in PubMed Search in MeSH Add to Search Osteoporosis, Postmenopausal* / drug therapy Actions Search in PubMed Search in MeSH Add to Search Osteoporosis, Postmenopausal* / metabolism Actions Search in PubMed Search in MeSH Add to Search Postmenopause / metabolism* Actions Search in PubMed Search in MeSH Add to Search Retrospective Studies Actions Search in PubMed Search in MeSH Add to Search Risedronic Acid / administration & dosage* Actions Search in PubMed Search in MeSH Add to Search Treatment Outcome Actions Search in PubMed Search in MeSH Add to Search Substances Biomarkers Actions Search in PubMed Search in MeSH Add to Search Bone Density Conservation Agents Actions Search in PubMed Search in MeSH Add to Search Isoenzymes Actions Search in PubMed Search in MeSH Add to Search Alkaline Phosphatase Actions Search in PubMed Search in MeSH Add to Search Risedronic Acid Actions Search in PubMed Search in MeSH Add to Search Alendronate Actions Search in PubMed Search in MeSH Add to Search Related information Cited in Books MedGen PubChem Compound (MeSH Keyword) LinkOut - more resources Full Text Sources Springer Other Literature Sources scite Smart Citations Full text links [x] Springer [x] Cite Copy Download .nbib .nbib Format: AMA APA MLA NLM Send To Clipboard Email Save My Bibliography Collections Citation Manager [x] NCBI Literature Resources MeSH PMC Bookshelf Disclaimer The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). 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+Effects of alcohol consumption on indices of iron stores and of iron stores on alcohol intake markers - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Effects of alcohol consumption on indices of iron stores and of iron stores on alcohol intake markers J B Whitfield 1 , G Zhu , A C Heath , L W Powell , N G Martin Affiliations Expand Affiliation 1 Department of Clinical Biochemistry, Royal Prince Alfred Hospital, and University of Sydney, Sydney, Australia. johnwit@bioc.rpa.cs.nsw.gov.au PMID: 11505030 Item in Clipboard Clinical Trial Effects of alcohol consumption on indices of iron stores and of iron stores on alcohol intake markers J B Whitfield et al. Alcohol Clin Exp Res . 2001 Jul . Show details Display options Display options Format Abstract PubMed PMID Alcohol Clin Exp Res Actions Search in PubMed Search in NLM Catalog Add to Search . 2001 Jul;25(7):1037-45. Authors J B Whitfield 1 , G Zhu , A C Heath , L W Powell , N G Martin Affiliation 1 Department of Clinical Biochemistry, Royal Prince Alfred Hospital, and University of Sydney, Sydney, Australia. johnwit@bioc.rpa.cs.nsw.gov.au PMID: 11505030 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Background: Alcohol increases body iron stores. Alcohol and iron may increase oxidative stress and the risk of alcohol-related liver disease. The relationship between low or "safe" levels of alcohol use and indices of body iron stores, and the factors that affect the alcohol-iron relationship, have not been fully characterized. Other aspects of the biological response to alcohol use have been reported to depend on iron status. Methods: We have measured serum iron, transferrin, and ferritin as indices of iron stores in 3375 adult twin subjects recruited through the Australian Twin Registry. Information on alcohol use and dependence and smoking was obtained from questionnaires and interviews. Results: Serum iron and ferritin increased progressively across classes of alcohol intake. The effects of beer consumption were greater than those of wine or spirits. Ferritin concentration was significantly higher in subjects who had ever been alcohol dependent. There was no evidence of interactions between HFE genotype or body mass index and alcohol. Alcohol intake-adjusted carbohydrate-deficient transferrin was increased in women in the lowest quartile of ferritin results, whereas adjusted gamma-glutamyltransferase, aspartate aminotransferase, and alanine aminotransferase values were increased in subjects with high ferritin. Conclusions: Alcohol intake at low level increases ferritin and, by inference, body iron stores. This may be either beneficial or harmful, depending on circumstances. The response of biological markers of alcohol intake can be affected by body iron stores; this has implications for test sensitivity and specificity and for variation in biological responses to alcohol use. PubMed Disclaimer Similar articles Effect of type of alcoholic beverages on carbohydrate-deficient transferrin, sialic acid, and liver enzymes. Sillanaukee P, van der Gaag MS, Sierksma A, Hendriks HF, Strid N, Pönniö M, Nikkari ST. Sillanaukee P, et al. Alcohol Clin Exp Res. 2003 Jan;27(1):57-60. doi: 10.1097/01.ALC.0000047302.67780.FA. Alcohol Clin Exp Res. 2003. PMID: 12544006 [Effect of body iron stores in the indicators of alcohol abuse and alcoholic liver injury]. Cylwik B, Daniluk M, Chrostek L, Szmitkowski M. Cylwik B, et al. Pol Merkur Lekarski. 2010 Jun;28(168):450-3. Pol Merkur Lekarski. 2010. PMID: 20642102 Polish. CDT, GGT, and AST as markers of alcohol use: the WHO/ISBRA collaborative project. Conigrave KM, Degenhardt LJ, Whitfield JB, Saunders JB, Helander A, Tabakoff B; WHO/ISBRA Study Group. Conigrave KM, et al. Alcohol Clin Exp Res. 2002 Mar;26(3):332-9. Alcohol Clin Exp Res. 2002. PMID: 11923585 [Diagnostic tests of alcohol consumption]. Chrostek L, Szmitkowski M. Chrostek L, et al. Pol Merkur Lekarski. 2002 Aug;13(74):154-7. Pol Merkur Lekarski. 2002. PMID: 12420351 Review. Polish. [The effect of alcohol on iron metabolism]. Cylwik B, Chrostek L, Szmitkowski M. Cylwik B, et al. Pol Merkur Lekarski. 2008 Jun;24(144):561-4. Pol Merkur Lekarski. 2008. PMID: 18702344 Review. Polish. See all similar articles Cited by The influence of iron on bone metabolism disorders. Zhang H, Yang F, Cao Z, Xu Y, Wang M. Zhang H, et al. Osteoporos Int. 2024 Feb;35(2):243-253. doi: 10.1007/s00198-023-06937-x. Epub 2023 Oct 19. Osteoporos Int. 2024. PMID: 37857915 Review. Sex difference in the association between blood alcohol concentration and serum ferritin. Yehia A, Sousa RAL, Abulseoud OA. Yehia A, et al. Front Psychiatry. 2023 Jul 21;14:1230406. doi: 10.3389/fpsyt.2023.1230406. eCollection 2023. Front Psychiatry. 2023. PMID: 37547205 Free PMC article. Association between iron accumulation in the dorsal striatum and compulsive drinking in alcohol use disorder. Tan H, Hubertus S, Thomas S, Lee AM, Gerhardt S, Gerchen MF, Sommer WH, Kiefer F, Schad L, Vollstädt-Klein S. Tan H, et al. Psychopharmacology (Berl). 2023 Feb;240(2):249-257. doi: 10.1007/s00213-022-06301-7. Epub 2022 Dec 29. Psychopharmacology (Berl). 2023. PMID: 36577866 Free PMC article. Dietary Iron Intake and Biomarkers of Iron Status in Slovenian Population: Results of SI.Menu/Nutrihealth Study. Lavriša Ž, Hristov H, Hribar M, Koroušić Seljak B, Gregorič M, Blaznik U, Zaletel K, Oblak A, Osredkar J, Kušar A, Žmitek K, Lainščak M, Pravst I. Lavriša Ž, et al. Nutrients. 2022 Dec 3;14(23):5144. doi: 10.3390/nu14235144. Nutrients. 2022. PMID: 36501175 Free PMC article. Lifestyle and dietary factors, iron status and one-carbon metabolism polymorphisms in a sample of Italian women and men attending a Transfusion Medicine Unit: a cross-sectional study. Bortolus R, Filippini F, Chiaffarino F, Udali S, Rinaldi M, Gandini G, Montagnana M, Lippi G, Olivieri O, Parazzini F, Friso S. Bortolus R, et al. Br J Nutr. 2023 Jul 14;130(1):65-70. doi: 10.1017/S0007114522003245. Epub 2022 Oct 28. Br J Nutr. 2023. PMID: 36305043 Free PMC article. See all "Cited by" articles Publication types Clinical Trial Actions Search in PubMed Search in MeSH Add to Search Research Support, Non-U.S. Gov't Actions Search in PubMed Search in MeSH Add to Search Research Support, U.S. Gov't, P.H.S. 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+Decrease in hepatic very-low-density lipoprotein–triglyceride secretion after weight loss is inversely associated with changes in circulating leptin - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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+    the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Diabetes Obes Metab. Author manuscript; available in PMC 2012 Nov 2. Published in final edited form as: Diabetes Obes Metab. 2010 Jul; 12(7): 584–590. doi: 10.1111/j.1463-1326.2009.01191.x PMCID: PMC3487704 NIHMSID: NIHMS414324 PMID: 20590733 Decrease in hepatic very-low-density lipoprotein–triglyceride secretion after weight loss is inversely associated with changes in circulating leptin Faidon Magkos , 1, 2 Elisa Fabbrini , 1, 3 Jennifer McCrea , 1 Bruce W. Patterson , 1 J. Christopher Eagon , 1 and Samuel Klein 1 Faidon Magkos 1 Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA 2 Department of Nutrition and Dietetics, Harokopio University, Athens, Greece Find articles by Faidon Magkos Elisa Fabbrini 1 Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA 3 Center for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele, Rome, Italy Find articles by Elisa Fabbrini Jennifer McCrea 1 Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA Find articles by Jennifer McCrea Bruce W. Patterson 1 Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA Find articles by Bruce W. Patterson J. Christopher Eagon 1 Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA Find articles by J. Christopher Eagon Samuel Klein 1 Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA Find articles by Samuel Klein Author information Copyright and License information PMC Disclaimer 1 Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA 2 Department of Nutrition and Dietetics, Harokopio University, Athens, Greece 3 Center for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele, Rome, Italy Corresponding author / To whom reprint requests should be addressed: Samuel Klein, M.D., Center for Human Nutrition, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8031, St Louis, MO 63110., Phone: (314) 362-8708, Fax: (314) 362-8230, ude.ltsuw.MOD@nielKS PMC Copyright notice The publisher's final edited version of this article is available  at Diabetes Obes Metab Abstract Aim Although weight loss usually decreases very-low-density lipoprotein–triglyceride (VLDL-TG) secretion rate, the change in VLDL-TG kinetics is not directly related to the change in body weight. Circulating leptin also declines with weight loss and can affect hepatic lipid metabolism. The aim of this study was to determine whether circulating leptin is associated with weight loss-induced changes in VLDL-TG secretion. Methods Ten extremely obese subjects were studied. VLDL-TG secretion rate and the contribution of systemic (derived from lipolysis of subcutaneous adipose tissue TG) and nonsystemic fatty acids (derived primarily from lipolysis of intrahepatic and intraperitoneal TG, and de novo lipogenesis) to VLDL-TG production were determined by using stable isotopically-labeled tracer methods before and 1 y after gastric bypass surgery. Results Subjects lost 33±12% of body weight, and VLDL-TG secretion rate decreased by 46±23% (p=0.001), primarily due to a decrease in the secretion of VLDL-TG from nonsystemic fatty acids (p=0.002). Changes in VLDL-TG secretion rates were not significantly related to reductions in body weight, body mass index, plasma palmitate flux, free fatty acid or insulin concentrations. The change in VLDL-TG secretion was inversely correlated with the change in plasma leptin concentration (r=−0.72, p=0.013), due to a negative association between changes in leptin and VLDL-TG secretion from nonsystemic fatty acids (r=−0.95, p<0.001). Conclusions Weight loss-induced changes in plasma leptin concentration are inversely associated with changes in VLDL-TG secretion rate. Additional studies are needed to determine whether the correlation between circulating leptin and VLDL-TG secretion represents a cause-and-effect relationship. Keywords: tracers, VLDL, lipoprotein, liver, adipokines INTRODUCTION An increase in plasma triglyceride (TG) concentration is associated with obesity and is an important risk factor for cardiovascular disease [ 1 ]. Very-low-density lipoprotein (VLDL) is the major carrier of TG in plasma during postabsorptive conditions, and hypertriglyceridemia associated with obesity is primarily due to an increase in hepatic VLDL-TG secretion rate [ 2 – 4 ]. In general, weight loss decreases VLDL-TG secretion and plasma TG concentrations [ 5 – 9 ]. However, a direct relationship between the amount of weight lost and the decline in VLDL-TG secretion rate has not been detected. A moderate 10–15% diet-induced decrease in body weight is associated with considerable variability in the change in VLDL-TG kinetics, from a slight increase to a decline of up to 80% in VLDL-TG secretion rate [ 5 , 6 , 9 , 10 ]. In addition, a similar 40–50% reduction in VLDL-TG secretion rate has been reported after both moderate (~10%) [ 7 ] and marked (~25%) [ 8 ] weight loss. These observations suggest that weight loss-induced alterations in hepatic VLDL-TG secretion rate are regulated by other factors than simply weight loss alone. Leptin, the protein product of the ob/ob gene, has pleotropic neuroendocrine effects and is likely involved in the regulation of hepatic TG metabolism [ 11 ]. Data from studies conducted in animal models demonstrate that leptin administration lowers plasma TG and VLDL-TG concentrations [ 12 – 15 ], reduces intrahepatic TG content [ 13 – 17 ] and suppresses VLDL-TG synthesis and secretion [ 13 , 15 , 16 ], independently of its effects on food intake and body weight. Moreover, leptin replacement in leptin-deficient, lipodystrophic animals [ 18 ] and human subjects [ 19 , 20 ] markedly reduces hepatic TG content and plasma TG concentrations. In contrast, many obese persons have increased intrahepatic TG content, plasma TG concentrations and VLDL-TG secretion rates [ 2 ], despite increased plasma leptin concentrations [ 21 , 22 ]. The dissociation between leptin concentration and its purported action in obese persons has been attributed to “leptin resistance” and attenuated hepatic leptin signaling [ 23 – 25 ]. For instance, leptin reduces intrahepatic TG content in lean but not in diet-induced obese animals [ 25 ]. Weight loss reduces plasma leptin concentrations [ 21 , 22 ] and presumably restores hepatic leptin sensitivity [ 11 , 13 , 14 , 17 , 23 ]. The purpose of the present study was to evaluate the relationship between weight loss-induced changes in hepatic VLDL-TG secretion rate and changes in circulating leptin. We hypothesized that the decline in VLDL-TG secretion rate would correlate directly with the decline in circulating leptin. VLDL-TG secretion was determined in vivo in morbidly obese subjects before and 1 y after Roux-en-Y gastric bypass (RYGBP) surgery, because these subjects usually experience a large range in treatment-induced body weight loss and VLDL kinetics [ 8 ]. METHODS Subjects Ten extremely obese subjects (body mass index [BMI] > 40 kg/m 2 ; 9 women and 1 man, aged 42 ± 11 y) who were scheduled to undergo RYGBP surgery at Barnes-Jewish Hospital, St. Louis, MO, participated in the study. All subjects completed a comprehensive medical evaluation, including a 2-hour oral glucose tolerance test (OGTT). Two subjects were newly diagnosed as having type 2 diabetes mellitus based on the results of the OGTT, but neither was being treated with diabetes medications. Subjects were excluded if they had any history or evidence of liver disease, consumed ≥ 20 g alcohol per day, had severe fasting hypertriglyceridemia (≥ 400 mg/dL), or were taking medications known to affect hepatic metabolic function or plasma lipid metabolism. All subjects gave their written informed consent before participating in this study, which was approved by the Human Studies Committee and the Center for Applied Research Sciences Advisory Committee of Washington University School of Medicine in St. Louis, MO. Experimental protocol Subjects were instructed to consume their normal diet for at least three days before being admitted to the Clinical Research Unit (CRU) in the afternoon before the isotope tracer infusion study, which was performed two days before RYBGP surgery. At 1900 h, they consumed a standard meal containing 12 kcal/kg adjusted body weight, which contained 55% of total energy as carbohydrate, 30% as fat, and 15% as protein. Adjusted body weight was calculated as ideal body weight (the midpoint of the medium frame of the Metropolitan Life Insurance Company Table) + 0.25 × (actual body weight – ideal body weight). Thereafter, subjects fasted until completion of the isotope infusion study the next day. At 0500 h the following morning, after subjects fasted overnight, one catheter was inserted into a forearm vein to administer stable isotopically-labeled tracers, and a second catheter was inserted into a vein in the contralateral hand, which was heated to 55°C by using a thermostatically-controlled box, to obtain arterialized blood samples. At 0600 h, a bolus of [1,1,2,3,3- 2 H 5 ]glycerol (75 μmol/kg; Cambridge Isotope Laboratories, Andover, MA), dissolved in 0.9% NaCl solution, was administered, and a constant infusion of [2,2- 2 H 2 ]palmitate (0.024 μmol/kg·min; Cambridge Isotope Laboratories, Andover, MA) bound to human albumin, was started and maintained for 12 h. Blood samples were obtained immediately before starting the tracer infusion to determine plasma substrate and hormone concentrations and background substrate tracer-to-tracee ratios (TTR), and at 5, 15, 30, 60, 90, and 120 min and then every hour for 10 h to determine glycerol and palmitate TTR in plasma and in VLDL-TG. Blood was immediately placed in chilled tubes containing sodium EDTA to determine substrate concentrations and TTRs, and in chilled tubes containing EDTA and aprotinin (Trasylol) to determine plasma concentrations of leptin and insulin. All samples were immediately put in an ice bath, and plasma was separated by centrifugation within 30 min of collection. Aliquots of plasma were kept in the refrigerator to isolate VLDL, and the remaining plasma samples were stored at −80°C until additional analyses were performed. We have found that, under these conditions, ex vivo lipolysis of plasma TG is not detectable [ 26 , 27 ]. Two days after the tracer infusion study was performed, subjects underwent RYGBP surgery. Six subjects had open and four had laparoscopic procedures. Both procedures involved constructing a small proximal gastric pouch by stapling across the stomach. The Roux limb was formed by transecting the jejunum 30 cm distal to the ligament of Treitz and creating a jejunostomy distal to the transection; a 75-cm limb was constructed for subjects with a BMI < 50 kg/m 2 and a 150-cm limb was constructed for those with a BMI ≥ 50 kg/m 2 . All procedures were performed by the same surgeon (JCE). One year after RYGBP surgery, subjects were readmitted to the CRU. The same studies performed before surgery were repeated. Sample analyses Plasma insulin and leptin concentrations were measured by using ELISA (Diagnostic Systems Laboratories, Fremont, CA). The intra-assay and inter-assay coefficients of variation for leptin measurements were 3.8% and 4.4%, respectively. Plasma free fatty acid (FFA) concentrations were quantified by using gas chromatography (HP 5890 Series II GC, Hewlett-Packard, Palo Alto, CA) after adding heptadecanoic acid to plasma as an internal standard [ 28 ]. VLDL-TG concentrations were determined by using a colorimetric enzymatic kit (SIGMA Chemicals, St. Louis, MO) [ 29 ]. Samples obtained before and after surgery were analyzed simultaneously. The VLDL fraction was isolated by centrifugation and tube slicing as previously described [ 7 ], and samples were stored at −80°C until final analyses were performed. Glycerol and palmitate TTRs in plasma and VLDL-TG were determined by using gas chromatography – mass spectrometry (Agilent Technologies/HP 6890 Series GC System – 5973 Mass Selective Detector, Hewlett-Packard, Palo Alto, CA), as previously described [ 8 , 29 , 30 ]. The total analytical variability of measuring plasma FFA and VLDL-TG concentrations by these methods is 3.6% and 4.9%, respectively, whereas the analytical variability of measuring the TTR of free palmitate and glycerol in plasma, and of palmitate and glycerol bound to VLDL-TG is 1.3%, 7.8%, 4.0%, and 4.0%, respectively [ 29 ]. Calculations The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated as the product of fasting plasma insulin (in mIU/L) and glucose (in mmol/L) concentrations divided by 22.5 [ 31 ]. Palmitate rate of appearance (Ra) in plasma, which provides a reliable index of total FFA Ra [ 32 ], was calculated by dividing the palmitate tracer infusion rate by the average plasma palmitate TTR value between 60 and 240 min. The fractional turnover rate (FTR) of VLDL-TG was determined by fitting the TTR time-courses of free glycerol in plasma and glycerol in VLDL-TG to a multicompartmental model [ 29 , 30 , 33 ]. The rate of hepatic VLDL-TG secretion (in μmol per liter plasma per min), which represents the amount of VLDL-TG secreted by the liver per unit of plasma, was calculated by multiplying the FTR of VLDL-TG (in % per min) by the steady-state concentration of VLDL-TG (in μmol/L) in plasma [ 8 , 30 ]. The proportion of fatty acids within VLDL-TG derived from systemic plasma FFA (generated by lipolysis of subcutaneous adipose tissue TG) and nonsystemic fatty acids (generated by lipolysis of intrahepatic and intraperitoneal TG, hepatic lipolysis of circulating TG, and de novo hepatic fatty acid synthesis) were calculated by accounting for isotopic dilution between plasma and VLDL-TG palmitate by using a multicompartmental model [ 7 , 8 , 30 , 33 ]. The absolute secretion rates of VLDL-TG from systemic and nonsystemic fatty acids were then calculated by multiplying total VLDL-TG secretion rate by the relative contribution from each source of fatty acids [ 7 , 8 , 30 ]. Statistical analyses All data sets were tested for normality according to the Anderson-Darling procedure; not normally distributed variables were log-transformed for analysis. Data are presented as means ± standard deviation (s.d.) for normally distributed variables and means with 95% confidence interval (c.i.) for not normally distributed variables. Results before and after surgery were compared with Student’s two-tailed t test for paired samples. Pearson’s correlation analysis was used to examine associations between variables of interest. A p-value < 0.05 was considered statistically significant. RESULTS At 1 y after RYGBP surgery, subjects lost an average of 33 ± 12% (52 ± 22 kg) of their initial body weight; range 16–50% (25–91 kg) ( Table 1 ). Surgery-induced weight loss resulted in a decrease in fasting plasma glucose, insulin, leptin, FFA, and VLDL-TG concentrations ( Table 1 ). Mean HOMA-IR value decreased from 10.8 (6.5, 17.9) at baseline to 2.0 (0.8, 5.4) after surgery (p = 0.004). Table 1 Body mass and metabolic profile of the study participants at baseline and 1 year after gastric bypass surgery Before surgery After surgery p - value Body weight (kg) 158 ± 27 106 ± 28 < 0.001 Body mass index (kg/m 2 ) 58 ± 11 39 ± 11 < 0.001 Glucose (mmol/L) 6.3 ± 1.5 4.6 ± 0.4 0.013 Free fatty acids (μmol/L) 562 ± 110 454 ± 87 0.027 VLDL-triglyceride (mmol/L) 0.64 (0.38, 1.08) 0.39 (0.21, 0.71) 0.021 Insulin (mIU/L) 39 (24, 62) 10 (4, 26) 0.007 Leptin (ng/mL) 126 ± 47 56 ± 39 0.001 Open in a separate window Data are means ± s.d. or means with 95% c.i. Total palmitate Ra decreased by 44 ± 14% at 1 y after surgery (102 ± 24 vs. 190 ± 56 μmol/min; p < 0.001). Palmitate Ra was still lower after surgery-induced weight loss after adjusting for the change in weight, by expressing the data per kg of body weight (0.97 ± 0.15 vs. 1.21 ± 0.34 μmol/kg·min, respectively; p = 0.035). The rate of VLDL-TG secretion was ~50% lower 1 y after surgery than at baseline (p = 0.001) ( Figure 1 ). Approximately two-thirds of the decline in VLDL-TG secretion rate was accounted for by a decrease in the contribution of nonsystemic fatty acids to VLDL-TG (3.4 [2.2–5.2] vs. 1.0 [0.5–1.7] μmol/L·min before and after weight loss, respectively; p = 0.002), whereas about one-third of the decline in VLDL-TG secretion rate was accounted for by a decrease in the contribution of systemic plasma FFA to VLDL-TG (3.8 [2.5–5.7] vs. 2.7 [1.9–3.9] μmol/L·min before and after weight loss, respectively; p = 0.043) ( Figure 1 ). Therefore, the relative contribution of fatty acids derived from systemic and nonsystemic sources to total VLDL-TG production was different after than before surgery; nonsystemic fatty acids accounted for 48 ± 16% and 28 ± 9% of newly secreted VLDL-TG before and 1 y after surgery, respectively (p = 0.004) ( Figure 1 ). Open in a separate window Figure 1 Total very-low-density lipoprotein–triglyceride (VLDL-TG) secretion rate ( top panel ), relative contribution from systemic and nonsystemic fatty acids to total VLDL-TG production ( middle panel ), and absolute VLDL-TG secretion rates from systemic and nonsystemic fatty acids ( bottom panel ) before and 1 year after Roux-en-Y gastric bypass surgery. Data are means ± s.d. for the relative contribution of different fatty acid sources to total VLDL-TG production and means with 95% c.i. for absolute VLDL-TG secretion rates. * Significantly different from value before weight loss, p < 0.05. Changes in VLDL-TG secretion rates that occurred 1 y after RYGBP surgery were not significantly associated with changes in body weight, BMI, plasma FFA, glucose and insulin concentrations, HOMA-IR values, or palmitate Ra (all p-values > 0.05). However, the weight loss-induced change in total VLDL-TG secretion rate was inversely related to the change in plasma leptin concentration (r = −0.72, p = 0.013, R 2 = 52%) ( Figure 2 ), which was entirely due to a strong, inverse association between plasma leptin concentration and secreted VLDL-TG derived from nonsystemic fatty acids (r = −0.95, p < 0.001, R 2 = 90%) ( Figure 2 ). No significant relationship was detected between the change in VLDL-TG derived from systemic plasma FFA and the change in plasma leptin concentrations (r = 0.148, p = 0.701). Open in a separate window Figure 2 Relationship between weight loss-induced changes in plasma leptin concentration and corresponding changes in total very-low-density lipoprotein–triglyceride (VLDL-TG) secretion rate ( top panel ), VLDL-TG secretion from systemic plasma fatty acids ( middle panel ), and VLDL-TG secretion from nonsystemic fatty acids ( bottom panel ). The scale for VLDL-TG secretion rates is log-transformed. DISCUSSION Weight loss is associated with a decline in hepatic VLDL-TG secretion rate which contributes to the decrease in plasma TG concentration. However, the decline in VLDL-TG secretion rate does not directly correlate with the decrease in body weight. In this study, we evaluated whether changes in plasma leptin concentration after RYGBP surgery-induced weight loss was associated with changes in hepatic VLDL-TG secretion rate. Our data demonstrate that the change in circulating leptin that occurs after RYGBP surgery-induced weight loss is inversely correlated with the change in VLDL-TG production; the smaller the reduction in plasma leptin, the greater the reduction in hepatic VLDL-TG secretion rate. Moreover, this relationship was entirely due to a strong inverse correlation between changes in plasma leptin and the contribution of nonsystemic fatty acids, presumably derived from lipolysis of visceral and intrahepatic TG stores and de novo hepatic lipogenesis, to VLDL-TG production. These data suggest that leptin is involved in regulating the decline in hepatic VLDL-TG secretion that occurs with weight loss, but additional mechanistic studies are needed to confirm this hypothesis. In general, weight loss in obese subjects causes a decline in hepatic VLDL-TG secretion rate [ 5 – 8 ], which is almost entirely due to a decrease in the contribution of nonsystemic fatty acids to VLDL-TG production [ 7 , 8 ]. However, considerable variability has been reported in the response of VLDL-TG kinetics to similar reductions in body weight, and the change in VLDL-TG secretion has not been associated with corresponding changes in body weight [ 5 , 6 , 9 , 10 ]. We were also unable to demonstrate a relationship between changes in body weight and changes in VLDL-TG secretion rate in our group of extremely obese subjects. Although plasma insulin and FFA are important regulators of VLDL-TG metabolism in vivo [ 34 – 37 ], we did not detect a relationship between changes in fatty acid flux, plasma FFA concentrations, plasma insulin concentrations, or insulin sensitivity (assessed by HOMA-IR) and changes in VLDL-TG secretion rate. All our subjects exhibited an increase in insulin sensitivity, as determined by HOMA-IR, which could have contributed to the decline in VLDL-TG secretion after weight loss, even though there was not a direct correlation between the two. The effect of leptin on VLDL-TG metabolism is likely independent of insulin action. Data from studies conducted in rodents demonstrate that the reduction in intrahepatic fat content and VLDL-TG secretion rate induced by leptin are independent of hepatic insulin sensitivity [ 17 ] and the effects of insulin on the same metabolic pathways [ 15 ]. These observations and our data suggest that substrate availability and insulin sensitivity are not important regulators of VLDL-TG kinetics after weight loss. In contrast, we found a remarkably close correlation between changes in plasma leptin concentration and the hepatic secretion rate of VLDL-TG comprised of nonsystemic fatty acids. In fact, the subject who had the greatest decrease in plasma leptin concentration had a very minimal change in the rate of VLDL-TG secretion from nonsystemic fatty acids, despite losing 65 kg of weight, whereas VLDL-TG secretion from nonsystemic fatty acids was almost completely suppressed in the subject who had a small increase in plasma leptin concentration. Our findings underscore the need for additional studies to elucidate the role of leptin in VLDL metabolism in human subjects. The results from our study cannot determine whether the correlation we observed between changes in plasma leptin concentration and the secretion of VLDL-TG represents a cause-and-effect relationship or is simply an association. Data from studies conducted in both animal models and human subjects support the notion that circulating leptin is actively involved in regulating VLDL-TG production from nonsystemic fatty acids. First, leptin deficiency in both animals [ 38 ] and humans [ 39 ] is associated with an increase in intrahepatic TG content, which is likely an important source of nonsystemic fatty acids for VLDL-TG production [ 40 ]. Second, leptin administration in rodents with steatosis [ 13 – 18 ] and patients with lipodystrophy [ 19 , 20 ] decreases intrahepatic TG content, possibly by stimulating hepatic fatty acid oxidation [ 13 , 15 ] and decreasing de novo lipogenesis [ 41 ]. Third, leptin administration decreases VLDL-TG secretion rate and plasma TG concentration in animals [ 13 , 15 , 16 ], and leptin administration during weight loss therapy in obese men and women causes a more pronounced reduction in plasma TG concentrations than weight loss alone [ 42 , 43 ]. In contrast, obesity is associated with high plasma leptin concentrations, increased intrahepatic TG content and increased VLDL-TG secretion rates [ 2 , 21 , 22 ], suggestive of hepatic leptin resistance. The summation of these data and the findings from our study imply that weight loss increases hepatic leptin sensitivity, [ 11 , 13 , 14 , 17 , 23 – 25 , 44 ], which in turn increases the influence of leptin in regulating VLDL-TG metabolism in obese subjects. Therefore, the higher the plasma leptin concentration after weight loss the greater the decrease in VLDL-TG secretion rate. However, the metabolic effects of circulating leptin represent the combination of leptin concentration and sensitivity, so that accounting for differences in leptin sensitivity among our subjects could have influenced the relationship we detected between leptin concentration and VLDL-TG kinetics. In summary, weight loss induced by RYGBP surgery causes a variable decline in hepatic VLDL-TG secretion rate that is not correlated with the amount of weight loss itself. The data from the present study demonstrate that the decrease in VLDL-TG secretion is almost entirely due to a decrease in the contribution of nonsystemic fatty acids to VLDL-TG production, which is strongly and inversely associated with changes in plasma leptin concentration. These results underscore the potential importance of circulating leptin in the regulation of weight-loss induced changes in hepatic lipoprotein metabolism; however, additional studies are needed to determine the mechanisms responsible for the link between leptin and VLDL-TG secretion after weight loss. Acknowledgments This study was supported by National Institutes of Health grants DK-37948, DK-56341 (Clinical Nutrition Research Unit), UL1 RR024992 (Clinical and Translational Science Award), and RR-00954 (Biomedical Mass Spectrometry Resource), and a grant from the American Heart Association (0510015Z). The authors thank Donna Marin, Freida Custodio, and Junyoung Kwon for technical assistance, the nursing staff of the Clinical Research Unit and Barnes-Jewish Hospital Surgery Unit for their help in performing the studies, and the study subjects for their participation. Footnotes Author contributions: FM and SK designed research; EF, JMC, and JCE performed research; FM, EF, JMC, and BWP processed samples and analyzed data; FM and SK interpreted data and wrote the paper. The authors have no conflicts of interest associated with the content of this manuscript. References 1. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996; 3 :213–219. [ PubMed ] [ Google Scholar ] 2. Grundy SM. Metabolic complications of obesity. Endocrine. 2000; 13 :155–165. [ PubMed ] [ Google Scholar ] 3. 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+False Estimates of Elevated Creatinine - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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+    the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Perm J. 2012 Spring; 16(2): 51–52. doi: 10.7812/tpp/11-121 PMCID: PMC3383162 PMID: 22745616 False Estimates of Elevated Creatinine Manpreet Samra , MD and Antoine C Abcar , MD Author information Copyright and License information PMC Disclaimer Manpreet Samra, MD, is a Nephrologist at the Los Angeles Medical Center in CA. E-mail: gro.pk@armas.x.teerpnam . Antoine C Abcar, MD, is a Nephrologist at the Los Angeles Medical Center in CA. E-mail: gro.pk@racba.c.eniotna . Copyright © 2012 The Permanente Journal Abstract One of the most common reasons for a nephrology consult is an elevated creatinine. An elevation in the serum creatinine concentration usually reflects a reduction in the glomerular filtration rate (GFR). Given the association of elevated creatinine and risk of cardiovascular mortality, it is important to keep in mind that at times the elevation of the creatinine is not representative of a true reduction in GFR. There are various causes of factitious elevation of creatinine. They can be broadly grouped into increased production of creatinine, interference with the assay and decreased tubular secretion of creatinine. Introduction A colleague asks about a patient: a woman, age 48 years, diagnosed with hypertension for 2 years and with hyperlipidemia for 10 months who has had a steadily increasing creatinine level, from 0.7 to 1.8 over the last 8 months. Her medications include hydrochlorothiazide per os 12.5 mg/day and fenofibrate per os 200 mg/day. One of the most common reasons for nephrology consult is elevated creatinine, which usually reflects a reduction in glomerular filtration rate (GFR). Given the association of elevated creatinine with cardiovascular mortality, it is important to keep in mind that elevated creatinine is not always representative of a reduction in GFR. Here, we will discuss the various causes of false estimates of elevated creatinine. Patients have few signs and symptoms during early renal disease. Early detection of abnormal kidney function is important, because early treatment usually slows disease progression. Because it is not possible to directly measure kidney function or the GFR, a surrogate is needed. The endogenous marker most commonly used to measure kidney function is creatinine. 1 Creatinine is generated in muscle and is proportionate to muscle mass and remains relatively constant. Eighty-five percent to 90% of creatinine is excreted by the kidney; the rest undergoes tubular secretion. It is most commonly measured by a colorimetric assay called the Jaffe reaction. In the Jaffe reaction, creatinine combines with picric acid to form a colored complex that is measured to quantify the creatinine. With this in mind, we can discern multiple factors that may artificially increase the estimated creatinine level. These can be grouped into three categories: increased production of creatinine, interference with the assay, and decreased tubular secretion of creatinine. Increased Creatinine Production Creatinine is produced in muscle by the nonenzymatic conversion of creatine and phosphocreatinine. The creatinine generated is proportional to muscle mass and is relatively constant. The liver has an important role in the formation of creatinine through methylation of guanidine aminoacetic acid. The serum creatinine can vary by 0.5 to 1.0 mg/dL according to diurnal and menstrual variations, race, and diet (and method of meat preparation). An increase in serum creatinine can result from increased ingestion of cooked meat (which contains creatinine converted from creatine by the heat from cooking) or increased intake of protein and creatine supplements, in excess of the recommended dosage. Creatine is present in the organs, muscles, and body fluids of animals. Creatine supplements promote protein synthesis and are a quickly available source of energy for muscle contraction, hence they are used to enhance athletic performance. Furthermore, intense exercise can increase creatinine by increasing muscle breakdown. 2 , 3 Interference With the Assay As stated earlier, the Jaffe reaction is a colorimetric assay. It can be influenced by other endogenous chromogens such as acetone and acetoacetate (such as in diabetic ketoacidosis), fasting, lipemia, and hemolysis, resulting in an overestimate of the serum creatinine. Drugs that can interfere with the assay include antibiotics such as cephalosporins, specifically cefoxitin and cefazolin; barbiturates; N-acetylcyteine; and chemotherapeutic agents such as flucytosine (although by a different assay: the Kodak Ektachem method). 4 , 5 Another material known to interfere with the Jaffe reaction is nitromethane, a common component of radio-controlled-vehicle fuels. The Kodak Ektachem method uses an ammonia reaction to quantify creatinine. Creatinine is converted to N-methylhydantoin and ammonia. Flucytosine is the only agent known to cause a false elevated creatinine result when this method is used. 6 This artificial result is attributed to the 4-amino group of flucytosine, which is converted to free ammonia by creatine iminohydrolase. More specific creatinine assays not subject to such interference are being investigated. One such assay, the VITROS CREA, employs an oxidation reaction to measure endogenous creatinine levels and will soon be available at laboratories within Kaiser Permanente. The VITROS CREA assay will quantify creatinine with greater precision. Decreased Secretion Approximately 15% of creatinine is secreted in the tubules. It is secreted by the organic cation secretory pump that can be inhibited by other organic cations. Trimethoprim, cimetidine, and other H2-blockers medications can inhibit this process and cause an increase in the measured serum creatinine 7 , 8 ( Table 1 ). Table 1 Common causes of false estimates of elevated creatinine Open in a separate window Case in Question In the above-mentioned patient we stopped the fenofibrate, and we saw her creatinine trend toward normal in a few months. It is postulated that fibrates (particularly fenofibrate) impair the generation of vasodilatory prostaglandins and could alter intrarenal hemodynamics, possibly altering GFR, but the definitive mechanism by which this occurs is still to be elucidated. 9 Case studies of renal transplant patients have shown evidence of tubular toxicity caused by fenofibrates and increased creatinine production. 10 The magnitude of changes in creatininemia ranged from 8% to 18% for fenofibrate. The change in creatinine, though, has been shown to be reversible after fibrate withdrawal. In conclusion, when elevated serum creatinine is detected, it is important to evaluate the patient as a whole to rule out possible causes. Disclosure Statement The author(s) have no conflicts of interest to disclose. Acknowledgments Leslie E Parker, ELS, provided editorial assistance. References 1. Shemesh O, Golbetz H, Kriss JP, Myers BD. Limitations of creatinine as a filtration marker in glomerulopathic patients. Kidney Int. 1985 Nov; 28 (5):830–8. [ PubMed ] [ Google Scholar ] 2. Hamilton RW, Gardner LB, Penn AS, Goldberg M. Acute tubular necrosis caused by exercise-induced myoglobinuria. Ann Intern Med. 1972 Jul; 77 (1):77–82. [ PubMed ] [ Google Scholar ] 3. Oh MS. Does serum creatinine rise faster in rhabdomyolysis? Nephron. 1993; 63 (3):255–7. [ PubMed ] [ Google Scholar ] 4. Molitch ME, Rodman E, Hirsch CA, Dubinsky E. Spurious serum creatinine elevations in ketoacidosis. Ann Intern Med. 1980 Aug; 93 (2):280–1. [ PubMed ] [ Google Scholar ] 5. Saah AJ, Koch TR, Drusano GL. Cefoxitin falsely elevates creatinine levels. JAMA. 1982 Jan 8; 247 (2):205–6. [ PubMed ] [ Google Scholar ] 6. Mitchell EK. Flucytosine and false elevation of serum creatinine level. Ann Intern Med. 1984 Aug; 101 (2):278. [ PubMed ] [ Google Scholar ] 7. Berg KJ, Gjellestad A, Nordby G, et al. Renal effects of trimethoprim in ciclosporin- and azathioprine-treated kidney allografted patients. Nephron. 1989; 53 (3):218–22. [ PubMed ] [ Google Scholar ] 8. Kemperman FA, Silberbusch J, Slaats EH, Prins AM, Krediet RT, Arisz L. Follow-up of GFR estimated from plasma creatinine after cimetidine administration in patients with diabetes mellitus type 2. Clin Nephrol. 2000 Oct; 54 (4):255–60. [ PubMed ] [ Google Scholar ] 9. Broeders N, Knoop C, Antoine M, Tielemans C, Abramowicz D. Fibrate-induced increase in blood urea and creatinine: is gemfibrozil the only innocuous agent? Nephrol Dial Transplant. 2000 Dec; 15 (12):1993–9. [ PubMed ] [ Google Scholar ] 10. Angeles C, Lane BP, Miller F, Nord EP. Fenofi brate-associated reversible acute allograft dysfunction in 3 renal transplant recipients: biopsy evidence of tubular toxicity. Am J Kidney Dis. 2004 Sep; 44 (3):543–50. 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+Dysregulation of phosphate metabolism and conditions associated with phosphate toxicity - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Published online 2015 Jun 3. doi: 10.1038/bonekey.2015.74 PMCID: PMC4455690 PMID: 26131357 Dysregulation of phosphate metabolism and conditions associated with phosphate toxicity Ronald B Brown 1 and Mohammed S Razzaque a, 2, 3 Ronald B Brown 1 Department of Hospitality Management and Dietetics, College of Human Ecology, Kansas State University, Manhattan, KS, USA Find articles by Ronald B Brown Mohammed S Razzaque 2 Department of Applied Oral Sciences, Forsyth Institute, Cambridge, MA, USA 3 Division of Research & Development, VPS Healthcare, Abu Dhabi, UAE Find articles by Mohammed S Razzaque Author information Article notes Copyright and License information PMC Disclaimer 1 Department of Hospitality Management and Dietetics, College of Human Ecology, Kansas State University, Manhattan, KS, USA 2 Department of Applied Oral Sciences, Forsyth Institute, Cambridge, MA, USA 3 Division of Research & Development, VPS Healthcare, Abu Dhabi, UAE a Department of Applied Oral Sciences, The Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA. E-mails: gro.htysrof@euqazzarm ; or moc.htlaehspv@euqazzarsm Received 2014 Oct 9; Accepted 2015 Mar 25. Copyright © 2015, International Bone & Mineral Society Abstract Phosphate homeostasis is coordinated and regulated by complex cross-organ talk through delicate hormonal networks. Parathyroid hormone (PTH), secreted in response to low serum calcium, has an important role in maintaining phosphate homeostasis by influencing renal synthesis of 1,25-dihydroxyvitamin D, thereby increasing intestinal phosphate absorption. Moreover, PTH can increase phosphate efflux from bone and contribute to renal phosphate homeostasis through phosphaturic effects. In addition, PTH can induce skeletal synthesis of another potent phosphaturic hormone, fibroblast growth factor 23 (FGF23), which is able to inhibit renal tubular phosphate reabsorption, thereby increasing urinary phosphate excretion. FGF23 can also fine-tune vitamin D homeostasis by suppressing renal expression of 1-alpha hydroxylase (1α(OH)ase). This review briefly discusses how FGF23, by forming a bone–kidney axis, regulates phosphate homeostasis, and how its dysregulation can lead to phosphate toxicity that induces widespread tissue injury. We also provide evidence to explain how phosphate toxicity related to dietary phosphorus overload may facilitate incidence of noncommunicable diseases including kidney disease, cardiovascular disease, cancers and skeletal disorders. Introduction All living organisms are dependent on exogenous sources of phosphorus. In humans and animals, dietary phosphorus must be acquired in sufficient amounts to avoid nutrition-related deficiencies such as rickets. In the body, exogenous phosphorus is metabolized to phosphate. Dietary phosphorus overload may contribute to dysregulation of phosphate metabolism leading to phosphate toxicity. 1 In this review, we discuss the regulation of phosphate metabolism, and how its dysregulation can lead to phosphate toxicity. We define phosphate toxicity as excessive levels of extracellular and intracellular phosphate that are harmful to cellular function. In addition, several conditions associated with phosphate toxicity such as ectopic calcification, chronic kidney disease (CKD) and tumorigenesis are discussed. The active roles of calciotropic hormones vitamin D and parathyroid hormone (PTH) to regulate phosphate homeostasis are well known. 2 , 3 However, physiologic phosphate regulation cannot be fully explained by the actions of these hormones alone, 4 , 5 , 6 , 7 , 8 and the identification of fibroblast growth factor 23 (FGF23), which can influence both vitamin D and PTH functions, helped us gain further insights into the physiologic regulation of phosphate homeostasis. Skeletal-derived FGF23 exerts phosphate-lowering effects in the kidney via a complex endocrine network; studies have identified osteoblasts and osteocytes as the main FGF23-producing cells. 9 , 10 In addition to renal phosphate-lowering effects, FGF23 can lower 1,25-dihydroxyvitamin D production by suppressing the renal expression of 1-alpha hydroxylase (1α(OH)ase) and by increasing catabolism in the kidney. Studies have claimed that FGF23 may also suppress PTH synthesis. FGF23 mediates its functions by interacting with an FGF receptor (FGFR) in a dependent manner using alpha-klotho as a cofactor. Although almost all tissues and organs express one or more isoforms of FGFRs, the restricted presence of alpha-klotho provides organ specificity to FGF23 functions. 11 , 12 , 13 , 14 FGF23 was initially identified in the ventrolateral thalamic nucleus of the mouse brain, 15 and its clinical importance was subsequently shown in patients with autosomal dominant hypophosphatemic rickets. 16 The FGF23 gene has three exons separated by two introns, and the gene encodes a 32-kDa glycoprotein containing 251 amino acid residues: 24 amino acids constitute a hydrophobic signal sequence, an N terminus of 155 amino acids constitute the FGF core homology region and 72 amino acids form the C-terminal domain. 17 , 18 , 19 , 20 After cleavage of the 24-amino-acid signal sequence, the mature protein (25–251)-FGF23 is secreted into the circulation where three distinct forms of the FGF23 protein can be detected: a full-length mature form (25–251)-FGF23, a shorter form (25–179)-FGF23 lacking the unique C-terminal tail of 72 amino acids and a C-terminal tail. The shorter form without a C-terminal tail arises from proteolytic cleavage at the 176RXXR179 site, 17 , 18 , 19 , 20 and it can also be detected in the serum. Recent studies have shown that the C terminus is not only the potential alpha-klotho-interacting site, but it also determines the functionality of the FGF23 protein. The chimeric protein containing the N terminus of FGF2 and C terminus of FGF23 could act as a phosphatonin and could reduce the renal expression of 1α(OH)ase. 19 , 20 It is worth mentioning that the presence of the C terminus of FGF23 in the chimeric protein paved the way for the alpha-klotho interaction. Recently, a family with sequence similarity 20, member C (Fam20C), was shown to phosphorylate FGF23. Such phosphorylation blocks O-glycosylation by polypeptide N-acetylgalactosaminyltransferase 3. This observation suggests that the interplay between phosphorylation and O-glycosylation of FGF23 may be a critical posttranslational modification by which the activity of secreted FGF23 protein is determined. 21 Once secreted, FGF23 protein binds its receptors to exert diverse functions. In vitro studies have shown that bioactive FGF23 protein can bind to FGFR1c, FGFR3c and FGFR4, but not to FGFR2c. 22 In vivo studies have suggested that FGFR1c is the main target for FGF23 in the kidney 23 , 24 as loss of FGFR3 or FGFR4 activity did not affect FGF23-mediated hypophosphatemia in Hyp mice. 24 It is of relevance that Hyp mouse is the model for human X-linked hypophosphatemia related to mutations that inactivate the endopeptidases of the X chromosome (PHEX); the inactivation of PHEX leads to increased serum levels of FGF23, a phosphaturic hormone that induces excessive renal phosphate excretion and severe hypophosphatemia. Moreover, conditional deletion of FGFR1 in the kidney abolished phosphaturic effects of recombinant FGF23 administration. 25 It is of relevance that no such abolition following administration of recombinant FGF23 was noted in FGFR3 or FGFR4 knockout mice. 25 The in vivo functions of FGF23 are also elegantly demonstrated in genetically modified mouse models. For instance, FGF23 knockout mice develop severe hyperphosphatemia owing to increased renal reabsoption of phosphate, 26 , 27 whereas FGF23-overproducing transgenic mice or Hyp mice are hypophosphatemic owing to excessive urinary phosphate excretion. 28 , 29 Such FGF23-mediated hypophosphatemia is an alpha-klotho-dependent phenomenon, and miscommunication of FGF23 and alpha-klotho can lead to dysregulation of renal phosphate homeostasis. 1 , 14 , 30 , 31 Renal Phosphate Regulation Under normal physiologic conditions, the kidneys maintain serum phosphate balance by fine-tuning urinary phosphate excretion. Filtrated phosphate is reabsorbed in the renal proximal tubular epithelial cells using sodium-dependent phosphate (Na/Pi) cotransporters 32 , 33 , 34 ( Figure 1 ). Although these cells contain three types of Na/Pi cotransporters, the type 2 cotransporter family that includes Na/Pi2a (encoded by the SLC34a1 gene) and NaPi2c (encoded by the SLC34a3 gene) is believed to be most active in renal phosphate uptake. In contrast to the type 2 cotransporter system, the type 1 cotransporter (NPT1) is mostly an anion carrier, whereas the type 3 cotransporter system comprises two transporters, PiT1 (encoded by the SLC20a1 gene) and PiT2 (encoded by the SLC20a2 gene), and their role in phosphate transport is an active area of research. Studies have shown that FGF23 could suppress the expression of Na/Pi2a and Na/Pi2c, leading to less renal phosphate uptake with increased urinary phosphate excretion. 25 In fact, transgenic mice overexpressing FGF23 showed severe urinary phosphate wasting owing to suppressed expression and reduced activity of renal Na/Pi2a, 28 , 29 whereas Fgf23 knockout mice develop severe hyperphosphatemia owing to increased renal expression and activity of Na/Pi2a. 26 , 27 It is of particular interest that genetically restoring FGF23 systemic actions in Fgf23 knockout mice reduced Na/Pi2a activity, resulting in reversal of hyperphosphatemia to hypophosphatemia. 29 It is important to note that the segment of the nephron on which FGF23 exerts its most potent effects is not yet clear, as alpha-klotho, the cofactor for FGF23 bioactivities, is mostly present in the distal convoluted tubule, whereas Na/Pi cotransporter activity and vitamin D metabolizing enzymes are mainly present in the proximal tubular epithelial cells. 35 Although further studies are needed to determine the exact molecular mechanisms of FGF23-mediated renal phosphate transport, miscommunication between FGF23 and alpha-klotho leads to altered phosphate balance. Open in a separate window Figure 1 Simplified diagram showing multiorgan interactions in the regulation of phosphate homeostasis. Fibroblast growth factor (FGF) 23 produced in the bone cells can suppress renal Na/Pi2a and Na/Pi2c cotransporter activities to increase the urinary excretion of phosphate. Similarly, FGF23 can also suppress renal expression of 1-alpha hydroxylase (1α(OH)ase) to reduce the production of 1,25-dihydroxyvitamin D (1,25(OH) 2 D), which can suppress intestinal NaPi2b activities to reduce phosphate absorption, resulting in decreased serum phosphate levels. Of relevance, parathyroid hormone (PTH) can induce the expression of the 1α(OH)ase, and thereby it can increase the production of 1,25(OH) 2 D, which in turn can inhibit PTH and 1α(OH)ase expression. Such transcriptional repression feedback maintains vitamin D homeostasis. The figure is adopted with modification from our earlier publication. 1 , 45 (Dashed lines indicate that the interactions either might not be direct or not scientifically validated by multiple groups). Pathological conditions in CKD are mostly owing to miscommunication between bone-derived FGF23 and kidney-derived alpha-klotho, which leads to the development of phosphate toxicity. In CKD patients, reduced levels of alpha-klotho leaves FGF23 nonfunctional, thereby limiting the kidneys' ability to excrete urinary phosphate. In vivo studies conducted on Fgf23 knockout mice have shown that bioactive FGF23 protein could significantly reduce serum phosphate level in these mutant mice. It is of particular significance that bioactive FGF23 protein failed to exert phosphate-lowering effects in Fgf23/alpha-klotho double knockout mice, 36 , 37 suggesting that FGF23 loses its phosphate regulating abilities without alpha-klotho. Moreover, FGF23-induced hypophosphatemia in Hyp mice is reversed to hyperphosphatemia in the Hyp mice without alpha-klotho activity (Hyp/alpha-klotho double mutant mice), despite high serum FGF23 levels in double mutant mice. 3 , 36 In accordance with these animal studies, an inactivating mutation in the human alpha-klotho gene resulted in severe hyperphosphatemia, despite high serum FGF23 levels in a patient with tumoral calcinosis. 38 From the above-cited human and experimental studies, it is clear that alpha-klotho has an indispensable role in FGF23-mediated phosphate metabolism. 14 , 17 , 18 , 36 , 39 , 40 As mentioned, features of phosphate toxicity appear in various organs when there is a dysregulation of the FGF23-alpha-klotho system. Phosphate Toxicity Phosphate toxicity arising from a disproportionate accumulation of phosphate in the body has been shown to accelerate mammalian aging, produce bone deformities and reduce overall survival. 41 Genetically altered alpha-klotho-knockout mice develop phosphate toxicity as early as at 3 weeks of age, which affects weight gain and the bone maturation process, produces a generalized soft tissue atrophy and results in reduced life span. 1 , 14 , 40 , 41 , 42 , 43 , 44 , 45 , 46 In vivo studies found that phosphate toxicity in alpha-klotho ablated mice is associated with increased renal activity of NaPi2a. However, phosphate burden was lowered in hyperphosphatemic alpha-klotho-knockout mice by generating NaPi2a/alpha-klotho double-knockout mice, which resulted in prolonged survival. 41 More importantly, compared with a normal-phosphate diet (0.6%), phosphate toxicity reappeared when a high-phosphate diet (1.2%) was fed to NaPi2a/alpha-klotho mutant mice, with the appearance of premature aging-like features leading to early death. 41 These in vivo experimental observations clearly suggest that phosphate toxicity related to diet can contribute to the progression of the mammalian aging process, affecting both bone health and overall survival. Phosphorous has a very strong electronegative attraction with calcium—having electronegative values on the Pauling scale of 2.1 for phosphorus and 1.0 for calcium. 47 The strength of this attraction may help explain why phosphate toxicity owing to dietary phosphorus overload can so easily impair calcium metabolism. The chemical bonding of phosphorus with calcium is most evident in the body's hydroxyapatite mineral matrix of bone. These two minerals normally unite to form bone tissue in a calcium:phosphorus ratio of approximately 2:1 by weight, averaging 2.07:1 in spongy trabecular bone tissue 48 and 2.17:1 in harder cortical bone tissue. 49 Of relevance, the mean calcium:phosphorus ratio in studies of human milk is approximately in the range of 2:1 by weight. 50 Referring to the calcium:phosphorus ratio, the Food and Nutrition Board that set the recommended dietary allowances (RDAs) as part of the Dietary Reference Intakes 51 noted that ‘there is little or no evidence for relating the two nutrients, one to the other, during most of human life (p.154).' Nevertheless, the RDA that the Board set for calcium relative to that of phosphorus is equivalent to an ample calcium:phosphorus ratio of 1.4:1 for adults and 1.7:1 for adults aged 50 years and over. However, data from NHANES III reported by Chang et al . 52 showed average intakes of 758 mg of calcium and 1242, mg of phosphorus for adults, which is equivalent to an average calcium:phosphorus ratio of only 0.61:1. As noted by Uribarri and Calvo,, 53 the data reported by Chang et al . 52 show a consistent association between increasing mortality in adult subjects and a decreasing calcium:phosphorus ratio as dietary phosphorus intake increases more than calcium intake. In an earlier study, calcium retention increased when college women consumed 1500, mg of calcium and 800 mg of phosphorus with a calcium:phosphorus ratio of 1.88:1; however, increasing subjects' phosphorus intake to 1400, mg with a calcium:phosphorus ratio of 1.07:1 significantly reduced calcium utilization. 54 More recent research showed that decreasing the calcium:phosphorus ratio in a diet fed to young women by increasing phosphorus intake disrupted calcium metabolism, resulting in increased bone resorption as indicated by higher levels of serum PTH and urinary calcium. 55 Researchers used a calcium-adequate diet in an experimental animal model to demonstrate how lowering the calcium:phosphorus ratio by increasing the diet's phosphorus content produced defects in tooth enamel and dentin. 56 The findings of these studies imply that lowering excessive phosphorus intake rather than increasing calcium intake beyond adequate levels is required to properly balance the dietary calcium:phosphorus ratio. Unfortunately, the US adult population's average calcium intake of 758 mg reported by Chang et al . 52 is below RDA levels of 1000, mg and 1200, mg calcium for adults 50 years and older. Generally, the USDA Dietary Guidelines for Americans is incongruous with the latest findings on dietary phosphorus overload, with little indication for change in the 2015 Dietary Guidelines. 57 For example, a 2000-calorie eating pattern recommended by the MyPlate program of the USDA Center for Nutrition Policy & Promotion 58 averages 1884, mg of phosphorus a day—a daily overload far above the intake level where mortality effects are seen. Of particular concern, unrestricted consumption of phosphate can induce systemic complications related to phosphate toxicity ( Table 1 ). Table 1 Partial list of pathological events or diseases that can induce altered phosphate balance 14 , 40 , 43 , 102 Hypophosphatemia X-linked hypophosphatemic rickets Vitamin D resistance/deficiency Severe dietary deficiency Sepsis Respiratory alkalosis Renal tubular defects (Fanconi syndrome) Renal transplantation Metabolic acidosis Hyperparathyroidism Hormones (insulin, glucagon and cortisol) Diuretics Diabetic ketoacidosis Hyperphosphatemia Vitamin D intoxication Tumor lysis syndrome Tumor calcinosis Rhabdomyolysis Respiratory acidosis Phosphate enema Metabolic acidosis Magnesium deficiency Intravenous/oral phosphate therapy Hypoparathyroidism Hemolysis Chronic kidney disease Bowel infarction Bisphosphonate therapy Acromegaly Open in a separate window Please note that metabolic acidosis can induce either hypophosphatemia or hyperphosphatemia depending on clinical situations. It is believed that nonlactic metabolic acidosis associated with hypophosphatemia can be connected to impaired tubular reabsorption of bicarbonate and that phosphorus administration can improve such acidosis. 103 On the other hand, respiratory or metabolic acidosis may hydrolyze intracellular organic phosphate-containing compounds and release them into the extracellular compartment. Cell lysis disorders, such as tumor lysis syndrome, hemolytic anemia and rhabdomyolysis, may all give rise to hyperphosphatemia. 104 Phosphate Toxicity Associated with Ectopic Calcification Calcium–phosphorus (CaxPi) product in serum, calculated by multiplying serum calcium and phosphorus levels, should be less than 55 mg 2 dl −2 in adults. 59 CaxPi product and other anions containing calcium normally account for 5% of serum calcium, whereas free ionized calcium accounts for 45% of serum calcium and the remaining serum calcium is bonded to albumin. 60 Elevated levels of serum phosphorus in hyperphosphatemia—associated with impaired kidney function, dietary phosphorus overload or both—unite with free calcium to form an additional CaxPi product. Accumlated excess CaxPi product is likely to be deposited into soft tissue causing ectopic calcification. 61 In addition, elevated serum levels of osteocalcin, a noncollagenous bone matrix protein and a marker for osteoblast function, are associated with FGF23 levels. 62 Osteocalcin is also found in calcified atherosclerotic plaque. 63 These associations provide evidence that rising serum calcium–phosphate product associated with hyperphosphatemia upregulates osteocalcin, which stimulates mineral deposition in soft tissue as ectopic calcification. An opposite action is seen in the protein osteopontin, which inhibits mineral deposition and regresses calcification. 64 Vascular calcification in rats reversed when they were switched to a low-phosphate diet, which the researchers suggested was associated with calcification inhibition by osteopontin. 65 One type of soft tissue that is susceptible to ectopic calcification from the deposition of CaxPi product is the endothelium of the arterial system. Arterial calcification increases mortality risk by threefold to fourfold. 66 Calcification causes a hard or stable plaque to form in arterial vessels, which is related to arteriolosclerosis, hypertension, left ventricular hypertrophy and aortic valve disease. In vitro and in vivo experiments showed that a high phosphorus load acutely increases endothelial dysfunction by impairing vasodilation, raising the risk for cardiovascular disease. 67 High levels of serum phosphorus in healthy young adults have been associated with coronary atherosclerosis 68 and with left ventricular hypertrophy, 69 and high levels of serum phosphorus in a cohort study were associated with a 40% greater risk of heart failure. 70 A meta-analysis showed that serum phosphorus, but not serum calcium or PTH, was independently associated with mortality and risk for cardiovascular disease in CKD patients. 71 Dietary phosphorus overload was found to raise systolic blood pressure, except from dairy products, which researchers attributed to nutrients in dairy other than phosphorus. 72 The exact molecular mechanisms of how extracellular phosphate might exert its cytotoxicity is not yet clearly defined. Studies, however, have shown that extracellular phosphate can form insoluble nanoparticles with calcium and fetuin-A, commonly referred to as calciprotein particles (CPPs); these CPPs are highly bioactive ligands that can induce cytotoxicity, ranging from cell death to including osteogenic transformation of vascular smooth muscle cells (VSMCs). Furthermore, CPPs are detected in the circulation, both in human and animal models, particularly in patients with CKD, implicating a role in phosphate-mediated tissue injuries. 73 Calcium phosphate and other crystals may be deposited in joints causing acute inflammation and damaged cartilage. 74 Mice fed high-phosphate diets developed ectopic tumoral calcifications around joints. 75 Other types of ectopic calcifications from calcium phosphate occur in the formation of kidney stones, often in combination with calcium oxalate, 76 in bone tissue irregularities such as bone spurs or osteophytes 77 and within visceral organs and the epidermis. 61 Vascular calcification is a complex, ectopic biomineralization process, and phosphate toxicity can not only facilitate essential hydroxyapatite deposition in the calcifying vessels but also initiate the early events of apoptotic cell death, which is inflicted on both endothelial cells and VSMCs. Studies have shown higher risk for cardiovascular mortality in CKD patients undergoing hemodialysis treatment. Phosphate Toxicity Associated with CKD The estimated prevalence of CKD within the global population is 8–16%. 78 The role of phosphate toxicity in the pathology of CKD and beyond is published elsewhere. 1 , 45 , 73 , 79 A high concentration of extracellular phosphate is toxic to cells, and it leads to premature cellular aging. The kidneys regulate urinary excretion of phosphate to maintain the serum phosphate level that is circulated throughout the body. Dietary phosphate overload can lead to an increased phosphate burden, and it damages the kidneys through tubular injury and interstitial fibrosis; studies have found that subjects with high serum phosphorus had a higher risk for developing kidney diseases. 80 Glomerular filtration rate decreases as serum phosphorus increases in kidney disease, and mortality from associated cardiovascular disease in dialysis patients is 20% annually. Of relevance, renal aging can accelerate systemic aging. 81 As mentioned, increased serum calcium and phosphate levels are usually considered main contributors to vascular calcification, and the estimation of CaxPi product has long been used to predict vascular pathology in CKD patients. 82 However, recent studies have found that serum phosphate levels in patients undergoing hemodialysis treatment correlates with vascular calcification more strongly than does the CaxPi product. 83 In fact, the clinical utility of the CaxPi product has been questioned in recent studies, noting that the cause of calcification is more complicated than just the precipitation of the CaxPi product. 84 It is of clinical relevance that, in contrast to hyperphosphatemia, associations between serum calcium levels and cardiovascular events or disease outcomes of CKD patients are not yet clearly established. However, a few studies have shown that hypercalcemia may have predictive value in determining the negative outcome of CKD patients. 85 Although phosphate toxicity is known to promote disease progression in patients with CKD, its association with tumorigenesis is not studied in similar depth and detail. We next present evidence of this association and suggest some innovative theories of tumorigenesis. We believe that these suggestions are not based on deductive speculation, but rather on inductive theory generation grounded in reliable evidence. Phosphate Toxicity Associated with Tumorigenesis Hippocrates first observed that vessels attached to tumors appeared like legs on a crab. Thus, the name cancer, derived from the Latin word for crab, came into use to describe tumors. 86 Today, the elaborate vessel system of tumors is considered to be complicit with the aggressive tendency for neoplasms to grow uncontrollably and metastasize throughout the body. However, a novel theory of tumor vessel function may be induced from biological findings related to phosphate toxicity. In biology, the mycorrhiza fungal root system of plants absorbs and sequesters phosphorus from soil. 87 Evidence suggests that tumor vessels may function similarly in humans to absorb and sequester excess phosphorus from extracellular fluid. Cancer patients have been observed to retain and store phosphorus in tumors, 88 and cancer cells accumulate up to twice as much phosphorus as normal cells. 89 Just as tumorigenesis in tomato plants has been positively associated with phosphorus, 90 a cellular environment high in phosphorus in humans has been found to induce tumor neovascularization and angiogenesis, or new blood vessel formation in neoplasms. 91 Dietary phosphorus overload has been found to stimulate tumor growth in lung tissue. 92 Increasing phosphorus levels in cultured breast cancer cells were observed to change cellular behavior and metabolism, thus supporting the role of inorganic phosphate in modulating tumor metabolism and metastasis. 93 An average daily phosphorus intake of 1395, mg in men followed up for 22 years in the Health Professionals Follow-Up Study was associated with an increased overall risk of prostate cancer and with lethal and high-grade prostate cancer. 94 Farmers of Liuchong Village in the Hubei province of China claimed that cancer cases increased in their village from drinking water contaminated by a nearby phosphate mine. 95 Many studies have examined the association of meat and dairy intake with cancer, but a review of meta-analyses showed inconsistent findings. 96 Few studies have examined the phosphate intake from meat and dairy in association with cancer. In addition, it is difficult to isolate the effect of phosphorus in one or two foods without considering the total phosphate content of the diet. For example, subjects with high intake of dietary phosphate from meat and dairy but with overall normal phosphate intake may show less increase in cancer incidence than subjects with low intake of phosphate from meat and dairy but with a high overall phosphate intake. Comparisons of diets containing similar amounts of total phosphate at baseline should be investigated for cancer risk as the phosphate content rises from meat and dairy intake. From the above-mentioned evidence, it is likely that dietary phosphate consumption might influence tumorigenesis, possibly as a storage mechanism to help maintain phosphate homeostasis, and further research using meaningful experimental designs is warranted to validate such speculation. Conclusion The endocrine communication between bone-derived FGF23 and kidney-derived alpha-klotho is essential for physiologic regulation of phosphate balance. As we have briefly discussed, dysregulation of FGF23/alpha-klotho system provokes phosphate imbalance and induces a wide range of organs/tissue damage in blood vessels, bone and kidney. Of clinical importance, phosphate toxicity induced by excessive exogenous phosphate administration in humans can be fatal. 97 , 98 , 99 In fact, it is becoming more evident from experimental and human observations that features of phosphate toxicity can appear after consumption of a high-phosphate diet, even when serum phosphate levels are within the normal range. 3 , 43 , 45 , 79 Recent survey results highlight that even future medical professionals and CKD patients undergoing hemodialysis are not adequately aware of the hidden source of phosphate in their diet, and emphasize the need for educational initiatives to raise awareness of the risk posed by dietary items with hidden phosphate ingredients. 100 , 101 Taking into account human and animal observations, maintaining phosphate balance through adequate dietary intake appears to be important for a healthy life and for longevity. In addition, phosphate imbalance owing to bone–kidney miscommunication can induce serious debilitating complications. Acknowledgments Part of the original research that formed the basis of this review article was performed by Razzaque's lab members (Drs Teruyo Nakatani, Junko Akiyoshi, Satoko Osuka, Shigeko Kato, Kazuyoshi Uchihashi and Mutsuko Ohnishi) at the Harvard School of Dental Medicine, Boston, MA, USA. Footnotes The authors declare no conflict of interest. References Razzaque MS. Phosphate toxicity: new insights into an old problem . Clin Sci (Lond) 2011; 120 : 91–97. [ PMC free article ] [ PubMed ] [ Google Scholar ] Rodriguez M, Felsenfeld AJ. PTH, FGF-23 and early CKD . Nephrol Dial Transplant 2008; 23 : 3391–3393. [ PubMed ] [ Google Scholar ] Razzaque MS. Osteo-renal regulation of systemic phosphate metabolism . IUBMB Life 2011; 63 : 240–247. [ PMC free article ] [ PubMed ] [ Google Scholar ] Patel S, Barron JL, Mirzazedeh M, Gallagher H, Hyer S, Cantor T
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Epub 2012 May 31. Hypoparathyroidism Hafsah Al-Azem 1 , Aliya A Khan Affiliations Expand Affiliation 1 McMaster University, 1101-75 Bold St, Hamilton, Ontario L8P 1T7, Canada. PMID: 22863393 DOI: 10.1016/j.beem.2012.01.004 Item in Clipboard Review Hypoparathyroidism Hafsah Al-Azem et al. Best Pract Res Clin Endocrinol Metab . 2012 Aug . Show details Display options Display options Format Abstract PubMed PMID Best Pract Res Clin Endocrinol Metab Actions Search in PubMed Search in NLM Catalog Add to Search . 2012 Aug;26(4):517-22. doi: 10.1016/j.beem.2012.01.004. Epub 2012 May 31. Authors Hafsah Al-Azem 1 , Aliya A Khan Affiliation 1 McMaster University, 1101-75 Bold St, Hamilton, Ontario L8P 1T7, Canada. PMID: 22863393 DOI: 10.1016/j.beem.2012.01.004 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia and low or inappropriately normal levels of parathyroid hormone (PTH). Pseudohypoparathyroidism is characterized by similar findings however PTH is elevated due to PTH resistance. PTH is a key calcium regulating hormone essential for calcium homeostasis, vitamin D-dependant calcium absorption, renal calcium reabsorption and renal phosphate clearance. The most common cause of hypoparathyroidism is iatrogenic in the setting of anterior neck surgery. Hypoparathyroidism may be due to congenital or acquired disorders. Causes include autoimmune diseases, genetic abnormalities, destruction or infiltrative disorders of the parathyroids. Impaired secretion of PTH may be seen with hypomagnesemia or hypermagnesemia Work-up includes a comprehensive history, physical examination, and a relevant biochemical investigation. Treatment of symptomatic or profound asymptomatic hypocalcemia (Corrected Calcium (Ca) < 1.9 mmol/L) is aimed at rapid intravenous administration of calcium and oral supplementation of vitamin D metabolites. Oral calcium and vitamin D analogs are critical in the treatment of hypocalcemia. In the long-term management of hypoparathyroidism thiazide diuretics are of value as they enhance renal calcium reabsorption and increase serum calcium and are of particular benefit in those with activating mutations of the calcium-sensing receptor. Parathyroid hormone replacement is of great value in improving serum calcium and lowering serum phosphate as well as the doses of calcium and calcitriol supplementation required. It has been shown to lower urinary calcium losses. Careful monitoring of vitamin D, phosphorous, and calcium is necessary during acute and long-term therapy. Although hypocalcemic patients commonly present with symptoms of neuromuscular irritability with perioral numbers paresthesias, tingling, seizures and, bronchospasm; hypocalcemia may be identified on the biochemical profile of an asymptomatic patient. Copyright © 2012 Elsevier Ltd. All rights reserved. PubMed Disclaimer Similar articles 1alpha(OH)D3 One-alpha-hydroxy-cholecalciferol--an active vitamin D analog. Clinical studies on prophylaxis and treatment of secondary hyperparathyroidism in uremic patients on chronic dialysis. Brandi L. Brandi L. Dan Med Bull. 2008 Nov;55(4):186-210. Dan Med Bull. 2008. PMID: 19232159 Review. Treatment of hypocalcemia caused by hypoparathyroidism or pseudohypoparathyroidism with domestic-made calcitriol: a prospective and self-controlled clinical trial. Wang O, Xing XP, Meng XW, Xia WB, Li M, Jiang Y, Hu YY, Liu HC. Wang O, et al. Chin Med J (Engl). 2009 Feb 5;122(3):279-83. Chin Med J (Engl). 2009. PMID: 19236804 Clinical Trial. Management of Hypoparathyroidism: Present and Future. Bilezikian JP, Brandi ML, Cusano NE, Mannstadt M, Rejnmark L, Rizzoli R, Rubin MR, Winer KK, Liberman UA, Potts JT Jr. Bilezikian JP, et al. J Clin Endocrinol Metab. 2016 Jun;101(6):2313-24. doi: 10.1210/jc.2015-3910. Epub 2016 Mar 3. J Clin Endocrinol Metab. 2016. PMID: 26938200 Free PMC article. Review. [Hypoparathyroidism: the present state of art]. Krysiak R, Handzlik-Orlik G, Kedzia A, Machnik G, Okopień B. Krysiak R, et al. Wiad Lek. 2013;66(1):18-29. Wiad Lek. 2013. PMID: 23905424 Review. Polish. Hypocalcemic disorders. Bove-Fenderson E, Mannstadt M. Bove-Fenderson E, et al. Best Pract Res Clin Endocrinol Metab. 2018 Oct;32(5):639-656. doi: 10.1016/j.beem.2018.05.006. Epub 2018 May 28. Best Pract Res Clin Endocrinol Metab. 2018. PMID: 30449546 Review. See all similar articles Cited by Concurrent Denosumab and Parenteral Iron Therapy Precipitating Severe Hypocalcemia and Hypophosphatemia. Ye S, Grill V, Luo J, Nguyen HH. Ye S, et al. JCEM Case Rep. 2024 Feb 1;2(2):luae005. doi: 10.1210/jcemcr/luae005. eCollection 2024 Feb. JCEM Case Rep. 2024. PMID: 38304007 Free PMC article. New Approach to Addison Disease: Oral Manifestations Due to Endocrine Dysfunction and Comorbidity Burden. Bugălă NM, Carsote M, Stoica LE, Albulescu DM, Ţuculină MJ, Preda SA, Boicea AR, Alexandru DO. Bugălă NM, et al. Diagnostics (Basel). 2022 Aug 28;12(9):2080. doi: 10.3390/diagnostics12092080. Diagnostics (Basel). 2022. PMID: 36140482 Free PMC article. Review. Metabolic Bone Diseases and New Drug Developments. Natesan V, Kim SJ. Natesan V, et al. Biomol Ther (Seoul). 2022 Jul 1;30(4):309-319. doi: 10.4062/biomolther.2022.007. Epub 2022 Mar 28. Biomol Ther (Seoul). 2022. PMID: 35342038 Free PMC article. Review. Prevalence and Risk Factors for Osteopathy in Chronic Pancreatitis. Tang XY, Ru N, Li Q, Qian YY, Sun H, Zhu JH, He L, Wang YC, Hu LH, Li ZS, Zou WB, Liao Z. Tang XY, et al. Dig Dis Sci. 2021 Nov;66(11):4008-4016. doi: 10.1007/s10620-020-06732-2. Epub 2021 Jan 12. Dig Dis Sci. 2021. PMID: 33433813 Use of Recombinant Human Parathyroid Hormone to Treat Hungry Bone Syndrome in Hemodialysis Patient. Ahmed C, Kendi F, Gebran N, Barcebal C, Dahmani K, El Houni A, Budruddin M. Ahmed C, et al. Oman Med J. 2020 Jul 31;35(4):e164. doi: 10.5001/omj.2020.106. eCollection 2020 Jul. Oman Med J. 2020. PMID: 32904907 Free PMC article. 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+Gout and the risk of Parkinson's disease: a cohort study - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Gout and the risk of Parkinson's disease: a cohort study Mary De Vera 1 , M Mushfiqur Rahman , James Rankin , Jacek Kopec , Xiang Gao , Hyon Choi Affiliations Expand Affiliation 1 Arthritis Research Centre of Canada and University of British Columbia, Vancouver, British Columbia, Canada. PMID: 18975349 DOI: 10.1002/art.24193 Free article Item in Clipboard Gout and the risk of Parkinson's disease: a cohort study Mary De Vera et al. Arthritis Rheum . 2008 . Free article Show details Display options Display options Format Abstract PubMed PMID Arthritis Rheum Actions Search in PubMed Search in NLM Catalog Add to Search . 2008 Nov 15;59(11):1549-54. doi: 10.1002/art.24193. Authors Mary De Vera 1 , M Mushfiqur Rahman , James Rankin , Jacek Kopec , Xiang Gao , Hyon Choi Affiliation 1 Arthritis Research Centre of Canada and University of British Columbia, Vancouver, British Columbia, Canada. PMID: 18975349 DOI: 10.1002/art.24193 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Objective: Several studies have suggested that higher serum uric acid levels lead to a lower risk of Parkinson's disease (PD) because uric acid exerts antioxidant effects on neurons. Our objective was to examine the relationship between gout and the risk of PD in persons age > or = 65 years. Methods: We conducted a population-based cohort study using the British Columbia Linked Health Database and PharmaCare data (i.e., prescription drug data for those age > or = 65 years). We compared incidence rates of PD between 11,258 gout patients and 56,199 controls matched on age, sex, date of gout diagnosis, and length of medical record. Cox proportional hazards models were used to estimate the relative risk (RR) of PD, adjusting for age, sex, prior comorbid conditions, and use of diuretics and nonsteroidal antiinflammatory drugs. Results: Over an 8-year median followup, we identified 1,182 new cases of PD. Compared with individuals without gout, the multivariate RR of PD among those with gout was 0.70 (95% confidence interval [95% CI] 0.59-0.83). In subgroup analyses, the inverse association was similarly present in both sexes and was evident among those who did not use diuretics (RR 0.66, 95% CI 0.54-0.81), but not among diuretic users (RR 0.80, 95% CI 0.58-1.10, P for interaction 0.35). Conclusion: Our population-based data provide evidence for a protective effect of gout on the risk of PD and support the purported protective role of uric acid. PubMed Disclaimer Similar articles Association between gout and the development of Parkinson's disease: a systematic review and meta-analysis. Fazlollahi A, Zahmatyar M, Alizadeh H, Noori M, Jafari N, Nejadghaderi SA, Sullman MJM, Gharagozli K, Kolahi AA, Safiri S. Fazlollahi A, et al. BMC Neurol. 2022 Oct 11;22(1):383. doi: 10.1186/s12883-022-02874-0. BMC Neurol. 2022. PMID: 36221048 Free PMC article. Clinical associations between gout and multiple sclerosis, Parkinson's disease and motor neuron disease: record-linkage studies. Pakpoor J, Seminog OO, Ramagopalan SV, Goldacre MJ. Pakpoor J, et al. BMC Neurol. 2015 Feb 28;15:16. doi: 10.1186/s12883-015-0273-9. BMC Neurol. 2015. PMID: 25884318 Free PMC article. Risk of Parkinson's disease in a gout Mediterranean population: A case-control study. Pou MA, Orfila F, Pagonabarraga J, Ferrer-Moret S, Corominas H, Diaz-Torne C. Pou MA, et al. Joint Bone Spine. 2022 Nov;89(6):105402. doi: 10.1016/j.jbspin.2022.105402. Epub 2022 Apr 30. Joint Bone Spine. 2022. PMID: 35504516 Gout, hyperuricemia, and Parkinson's disease: a protective effect? Alonso A, Sovell KA. Alonso A, et al. Curr Rheumatol Rep. 2010 Apr;12(2):149-55. doi: 10.1007/s11926-010-0083-4. Curr Rheumatol Rep. 2010. PMID: 20425025 Review. Gout is not associated with a lower risk of Parkinson's disease: A systematic review and meta-analysis. Ungprasert P, Srivali N, Thongprayoon C. Ungprasert P, et al. Parkinsonism Relat Disord. 2015 Oct;21(10):1238-42. doi: 10.1016/j.parkreldis.2015.08.030. Epub 2015 Aug 28. Parkinsonism Relat Disord. 2015. PMID: 26330027 Review. See all similar articles Cited by Biologic targets of prescription medications and risk of neurodegenerative disease in United States Medicare beneficiaries. Song Y, Racette BA, Camacho-Soto A, Searles Nielsen S. Song Y, et al. PLoS One. 2023 May 17;18(5):e0285011. doi: 10.1371/journal.pone.0285011. eCollection 2023. PLoS One. 2023. PMID: 37195983 Free PMC article. Low serum uric acid levels and levodopa-induced dyskinesia in Parkinson's disease. Soares NM, Pereira GM, Dutra ACL, Artigas NR, Krimberg JS, Monticelli BE, Schumacher-Schuh AF, Almeida RMM, Rieder CRM. Soares NM, et al. Arq Neuropsiquiatr. 2023 Jan;81(1):40-46. doi: 10.1055/s-0043-1761294. Epub 2023 Mar 14. Arq Neuropsiquiatr. 2023. PMID: 36918006 Free PMC article. Influence of Guanine-Based Purines on the Oxidoreductive Reactions Involved in Normal or Altered Brain Functions. Zuccarini M, Pruccoli L, Balducci M, Giuliani P, Caciagli F, Ciccarelli R, Di Iorio P. Zuccarini M, et al. J Clin Med. 2023 Feb 1;12(3):1172. doi: 10.3390/jcm12031172. J Clin Med. 2023. PMID: 36769818 Free PMC article. Review. Inflammatory rheumatic diseases and the risk of Parkinson's disease: A systematic review and meta-analysis. He L, Zhao H, Wang F, Guo X. He L, et al. Front Neurol. 2022 Nov 10;13:999820. doi: 10.3389/fneur.2022.999820. eCollection 2022. Front Neurol. 2022. PMID: 36438950 Free PMC article. Dose-response meta-analysis on urate, gout, and the risk for Parkinson's disease. Chang H, Wang B, Shi Y, Zhu R. Chang H, et al. NPJ Parkinsons Dis. 2022 Nov 22;8(1):160. doi: 10.1038/s41531-022-00433-5. NPJ Parkinsons Dis. 2022. PMID: 36418349 Free PMC article. Review. 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+Myogenic hyperuricemia in hypoparathyroidism - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Myogenic hyperuricemia in hypoparathyroidism T Nishimura 1 , I Mineo , T Shimizu , M Kawachi , A Ono , H Nakajima , M Kuwajima , N Kono , S Tarui Affiliations Expand Affiliation 1 Second Department of Internal Medicine, Osaka University Medical School, Japan. PMID: 1665007 DOI: 10.1007/978-1-4899-2638-8_48 Item in Clipboard Myogenic hyperuricemia in hypoparathyroidism T Nishimura et al. Adv Exp Med Biol . 1991 . Show details Display options Display options Format Abstract PubMed PMID Adv Exp Med Biol Actions Search in PubMed Search in NLM Catalog Add to Search . 1991:309A:213-6. doi: 10.1007/978-1-4899-2638-8_48. Authors T Nishimura 1 , I Mineo , T Shimizu , M Kawachi , A Ono , H Nakajima , M Kuwajima , N Kono , S Tarui Affiliation 1 Second Department of Internal Medicine, Osaka University Medical School, Japan. PMID: 1665007 DOI: 10.1007/978-1-4899-2638-8_48 Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID No abstract available PubMed Disclaimer Similar articles Increased plasma uric acid after exercise in muscle phosphofructokinase deficiency. Kono N, Mineo I, Shimizu T, Hara N, Yamada Y, Nonaka K, Tarui S. Kono N, et al. Neurology. 1986 Jan;36(1):106-8. doi: 10.1212/wnl.36.1.106. Neurology. 1986. PMID: 2934643 Renal function in treated hypoparathyroidism. A possible direct nephrotoxic effect of vitamin D. Parfitt AM. Parfitt AM. Adv Exp Med Biol. 1977;81:455-64. doi: 10.1007/978-1-4613-4217-5_46. Adv Exp Med Biol. 1977. PMID: 899936 No abstract available. Serum myoglobin, ionized calcium, and parathyroid function during rhabdomyolysis. Liu ET, Bristow MR, Stone MJ, Willerson JT. Liu ET, et al. Arch Intern Med. 1983 Jan;143(1):154-7. Arch Intern Med. 1983. PMID: 6849596 Elevated creatine kinase and lactate dehydrogenase levels in a child with hypoparathyroidism. Klar A, Korn-Lubetzki I, Gross-Tsur V, Amir N. Klar A, et al. Isr J Med Sci. 1990 Jan;26(1):53-5. Isr J Med Sci. 1990. PMID: 2179162 Review. No abstract available. [McArdle's syndrome]. Pernow B. Pernow B. Lakartidningen. 1972 Aug 30;69(36):4005-10. Lakartidningen. 1972. PMID: 4560859 Review. Swedish. No abstract available. 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+Effect of Oral Vitamin C Supplementation on Serum Uric Acid: A Meta-analysis of Randomized Controlled Trials - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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+            and transmitted securely. Log in Show account info Close Account Logged in as: username Dashboard Publications Account settings Log out Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now . Search PMC Full-Text Archive Search in PMC Advanced Search User Guide Journal List HHS Author Manuscripts PMC3169708 Other Formats PDF (738K) Actions Cite Collections Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than  characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Share Permalink Copy RESOURCES Similar articles Cited by other articles Links to NCBI Databases Journal List HHS Author Manuscripts PMC3169708 As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with,
+    the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Arthritis Care Res (Hoboken). Author manuscript; available in PMC 2012 Sep 1. Published in final edited form as: Arthritis Care Res (Hoboken). 2011 Sep; 63(9): 1295–1306. doi: 10.1002/acr.20519 PMCID: PMC3169708 NIHMSID: NIHMS300040 PMID: 21671418 Effect of Oral Vitamin C Supplementation on Serum Uric Acid: A Meta-analysis of Randomized Controlled Trials Stephen P. Juraschek , BA, Edgar R. Miller, III , MD, PhD, and Allan C. Gelber , MD, MPH, PhD Author information Copyright and License information PMC Disclaimer Department of Medicine, Johns Hopkins University School of Medicine, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and Welch Center for Prevention, Epidemiology and Clinical Research, Baltimore MD Address correspondence and reprint requests to: Allan C. Gelber, MD, MPH, PhD Johns Hopkins University School of Medicine 5200 Eastern Avenue Mason F Lord Building, Center Tower, Suite 4100 Baltimore, MD 21224 Phone: (410) 550-2018 Fax: (410) 550-2072 ude.imhj@reblega PMC Copyright notice The publisher's final edited version of this article is available free at Arthritis Care Res (Hoboken) Abstract Objective To assess the effect of vitamin C supplementation on serum uric acid (SUA) by pooling the findings from published randomized, controlled trials (RCTs). Methods A total of 2,082 publications identified through systematic search were subjected to the following inclusion criteria: (1) RCTs conducted on human subjects; (2) reported end-trial SUA means and variance; (3) study design with oral vitamin C supplementation and concurrent control groups; and (4) trial duration of at least one week. Trials that enrolled children or patients on dialysis were excluded. Two investigators independently abstracted trial and participant characteristics. SUA effects were pooled by random-effects models and weighted by inverse variance. Results Thirteen RCTs were identified in MEDLINE, EMBASE, and CENTRAL databases. The total number of participants was 556, median dose of vitamin C was 500 mg/d, trial size ranged from 8 to 184 participants, and median study duration was 30 days. Pretreatment SUA values ranged from 2.9 to 7.0 mg/dL (SI: 172.5 – 416.4 μmol/L). The combined effect of these trials was a significant reduction in SUA of -0.35 mg/dL (95% CI: -0.66, -0.03; P = 0.032; SI: -20.8 μmol/L). Trial heterogeneity was significant ( I 2 = 77%; P < 0.01). Subgroup analyses based on trial characteristics indicated larger reductions in uric acid in trials that were placebo-controlled. Conclusions In aggregate, vitamin C supplementation significantly lowered SUA. Future trials are needed to determine whether vitamin C supplementation can reduce hyperuricemia or prevent incident and recurrent gout. Hyperuricemia is a well-established risk factor for gout ( 1 ). In population-based studies, the risk of gout steadily increases at successively higher levels of serum uric acid (SUA) ( 2 ) with a ten-fold increase in risk reported among those with serum urate levels > 9 mg/dL ( 3 ). Medications to prevent gout recurrence either act by reducing uric acid synthesis (e.g. xanthine oxidase inhibition) or via enhanced uric acid excretion (e.g. probenecid) ( 1 ). Although medical therapy is effective at preventing gout flares ( 4 ), both classes of drugs carry significant side effect profiles ( 5 - 7 ). Dietary approaches to lower uric acid thus provide an alternative and attractive approach to gout management ( 8 ). Recommendations to reduce consumption of high protein foods such as meat or seafood (to reduce purine intake), consume vegetable-based proteins, and lower alcohol consumption continue to play a critical role in disease management ( 9 ). Supplementation with vitamin C has also been examined as an alternative dietary approach ( 10 ). In vitro and animal models have demonstrated that vitamin C has uricosuric properties, inhibits uric acid synthesis ( 11 ), and lowers SUA ( 12 , 13 ). Furthermore, in small lab-based, clinical studies in humans, ascorbic acid has been shown to lower SUA ( 14 - 20 ). Human observational studies have also reported an inverse association between plasma ascorbic acid ( 21 ) or vitamin C intake ( 22 ) and SUA concentrations. A prospective cohort study reported that vitamin C intake from diet sources was associated with a lower risk for developing gout ( 23 ). Moreover, a recent randomized trial of daily intravenous infusion of 500 mg of vitamin C for 10 days in patients with acute ischemic stroke resulted in a significant reduction in serum uric acid compared to placebo infusion ( 24 ). Over the past 30 years at least 13 randomized, controlled clinical trials have examined the effect of oral vitamin C supplementation on SUA measurements ( 10 , 25 - 36 ). However, these trials have yielded inconclusive results. To date, there have been no published systematic reviews which have pooled the results of these individual studies together. To provide more stable estimates of the efficacy of vitamin C supplementation on SUA and to examine trial characteristics that predict stronger effects, we performed a meta-analysis of these published trials. Materials and Methods We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from January 1966 through September 2010 using the following terms: kidney, kidney disease(s), nephropathy, glomerulonephritis, renal insufficiency, gout, uricosuria, hyperuricosuria, hypouricosuria, hyperuricemia, hypouricemia, nephrolithiasis, uric acid, ascorbic acid, antioxidant(s), vitamin(s), randomized controlled trials, and clinical trials. The search was limited to human studies without language restrictions. See Appendix for search details. Search results were complemented with trials found in bibliographies of original research papers and previous reviews. For inclusion in the primary analysis, studies were required to meet the following pre-specified criteria: (1) randomized controlled trials on human subjects; (2) intervention and control groups reported end-trial SUA means and variance; (3) the intervention included oral vitamin C supplementation and a concurrent control group; (4) constituent differences between treatment and control groups did not include agents with known antihyperuricemic activity; and (5) trial was of at least seven days duration. Trials that included children or patients with end-stage renal disease were excluded. Each included trial was required to explicitly state the word “random” in the description of treatment assignment. Further details regarding randomization methods used (blocking, random number generation, etc.) were not required. Two investigators (SPJ, ERM) independently abstracted the articles. Discrepancies were resolved by adjudication. The following information was retrieved from each article: (1) study population, mean age, and percent male; (2) mean pretreatment SUA and ascorbic acid concentrations; (3) mean trial-end SUA and ascorbic acid concentrations: and (4) characteristics affecting trial quality: design (parallel, crossover, factorial), blinding (open, single, double, triple), intervention dose, type of control, trial duration, mechanism of SUA measurement, mention of concealment, description of randomization, intention-to-treat analysis, evaluation of losses to follow-up, and subject compliance. We recorded blinding as reported by trial authors; however, when it was not explicitly mentioned, we examined trials’ Methods sections for blinding of participants, providers, and outcome assessors. An attempt was made to contact authors of publications where SUA was measured but not fully reported ( 37 - 41 ). For each trial following a parallel design, effect was calculated as the difference in baseline and end-trial SUA between the intervention and placebo groups ( 25 - 27 , 30 , 32 - 35 ). This is demonstrated by the equation: (E T -B T ) – (E C -B C ), where E is an end-trial SUA value and B is a baseline SUA value for treatment (T) and control (C) groups ( 42 , 43 ). The variance in SUA baseline change, i.e. E-B, was calculated with the equation: Variance (E-B) = Variance (E) + Variance (B) – 2*Covariance. The correlation coefficient was assumed to be 0.7, and a sensitivity analysis was conducted using a correlation coefficient of 0.5. The standard error of the difference in baseline change, i.e. (E T -B T ) – (E C -B C ), was calculated using the equation, Standard Error = SQRT(SD T 2 /n T + SD C 2 /n C ) ( 44 ). For the three crossover trials in this meta-analysis ( 28 , 33 , 36 ), we utilized the following equation: E T - E C , where E is an end-trial SUA value for treatment (T) and control (C) groups ( 44 ). Standard error was calculated as above using Standard Error = SQRT(SD T 2 T /n T + SD C 2 C /n C )( 44 ). A sensitivity analysis for crossover trials using the equation, Variance (E-B) = Variance (E) + Variance (B) – 2*Covariance, with the correlation coefficient assumed to be 0.7, yielded virtually the same results (not shown). Three of the thirteen trials did not conform to the algorithms described above. Huang et al directly provided the difference in baseline change and its variance ( 10 ), which was utilized in place of the abovementioned calculation. Furthermore, one parallel trial did not report baseline SUA values, instead providing only end-trial SUA measurements( 31 ). This trial was treated as a crossover trial in our meta-analysis. In another trial, Vrca et al reported only median SUA values in the form of a figure ( 29 ). These values were estimated from the figure and assumed to be equal to mean SUA values. Variance was estimated from p-values given in the text using the most conservative estimate when a range was reported (e.g. P < 0.01 was estimated to be P = 0.01). Other abstraction nuances are as follows. One trial examined two distinct vitamin C interventions and was treated as two separate trials in our analysis ( 36 ). Another trial seemed to mislabel standard deviation as “SEM” ( 34 ). Close review of its Methods section supported interpretation of these data as mean +/- SD rather than SEM. Moreover, several trials examined the effect of vitamin C supplementation on SUA in the context of exercise ( 26 , 30 , 31 , 34 , 35 ). In general, we attempted to minimize this variable by examining SUA values measured prior to physical exertion, with the exception of Yanai et al who only reported post-training values ( 30 ). In similar fashion, whenever possible we attempted to avoid inclusion of other supplements and pharmaceuticals in our results by comparing vitamin C supplementation to placebo rather than to other treatment arms. In one trial, however, baseline SUA was provided for a vitamin E intervention, rather than placebo ( 35 ). In this case, we compared vitamin C to vitamin E since its baseline SUA values made it possible to calculate baseline change. Other circumstances in which vitamin C was administered with other supplements and pharmaceuticals are described in Table 1 and the Results section. Table 1 Clinical trials examining the effect of vitamin C supplementation upon serum uric acid, ordered by year of study. Source (year) Country Population Size Mean Age, y (SD) % Male Study Design †† Study Duration, d * Intervention (per day) Control Baseline Uric Acid (mg/dL) ** Pretreatment Plasma Ascorbic Acid (μmol/L) *** Uric Acid Measurement Completing Trial (%) Naziroglu et al ( 25 ) , 2009 † Turkey Postmenopausal & Diabetic Women 40 51 (45 - 65) 0 PO 42 Vit C 1000mg, Vit E 600mg, Estradiol 0.625mg, Medroxyprogesterone 5mg Estradiol 0.625mg, Medroxyprog esterone 5mg 3.6 (1.1) - Routine kits, autoanalyzer 100 Teixeira et al ( 26 ) , 2009 Portugal Athletes 20 19.7 (3.6) 70 PD 28 Vit C 400mg, Vit E 272mg, β-carotene 30mg, Lutein 2mg, Selenium 400μg, Zinc 30mg, Magnesium 600mg Placebo 4.9 (1.0) 56.2 (24.0) Enzymatic method at 550 nm using commercial kit (Horiba ABX A11A01670) 100 Huang et al ( 10 ) , 2005 † USA Adult Nonsmokers 184 58.2 (13.7) 45 FPT 60 Vit C 500mg Placebo 5.2 (1.5) 62.2 (15.5) Hitachi 917 autoanalyzer Roche Diagnostics; uricase-peroxidase method with ascorbate oxidase incubation 92 Polidori et al ( 27 ) , 2005 Italy Acute Ischemic Stroke 59 77.0 (7.2) 53 PO 90 Vit C 200mg, Aspirin 300mg Aspirin 300mg 2.9 (0.9) 27.0 (4.5) High performance liquid chromatography with Supelco columns 100 Van Hoydonck et al ( 28 ) , 2004 Belgium Healthy Male Smokers 42 52 (12) 100 XD 28 Vit C 500mg Placebo - 45 (20) Enzyme-linked calorimetric assay (Roche, Basel, Switzerland) 81 Vrca et al ( 29 ) , 2004 † Croatia Patients with Graves’ Disease 57 - 9 PO 28 Vit C 200mg, β-carotene 6mg, Vit E 36mg, Selenium 60μg, Methimazole at varying doses Methimazole at varying doses 3.5 + - Olympus AU500 Analyser 100 Yanai et al ( 30 ) , 2004 Japan Healthy, Nonsmoking male athletes 8 20.4 (1.6) 100 PS 21 Vit C 1000mg Placebo 5.2 (0.8) - Uricase calorimetric method 100 Nieman et al ( 31 ) , 2002 † USA Ultramarath on Runners 29 47.7 (12.1) - PD 7 Vit C 1500mg Placebo - - Hematology Laboratory 97 Martinez-Abundis et al ( 32 ) , 2001 Mexico Obese male volunteers 16 26.5 (6.3) 100 PD 28 Vit C 1000mg Placebo 7.0 (1.2) - Enzymatic methods 100 Hamilton et al ( 33 ) , 2000 † UK Healthy Adults 32 35 (9) 50 XD 42 Vit C 500mg Vit E 73.5mg as placebo 4.4 (0.9) 63.6 (12.5) Commercial kits on a Cobas Fara (Roche Dianostic Systems) 94 Rokitzki et al ( 34 ) , 1994 Germany Male Athletes 24 38.5 (8.5) 100 PD 31.5 Vit C 200mg, Vit E 400 IU Placebo 5.9 (1.0) 46.3 (12.8) Enzymatic test 92 Maxwell et al ( 35 ) , 1993 UK Healthy Students 16 19.6 (1.5) 67 PO 21 Vit C 400mg Vit E 400mg 4.8 (1.0) 77.7 (19.3) Automated uricase-peroxidase system 100 Kyllastinen et al ( 36 ) (a), 1990 Finland Long-stay Hospital Patients 29 81 + (68 - 93) 0 XD 42 Vit C 200mg Placebo - - Routine laboratory methods 93 Kyllastinen et al ( 36 ) (b), 1990 † Finland Long-stay Hospital Patients 29 81 + (68 - 93) 0 XD 42 Vit C 2000mg Placebo - - Routine laboratory methods 93 Open in a separate window † Trials reporting significant baseline reductions in Uric Acid †† F is factorial; P is parallel; X is crossover; T is triple blind; D is double blind; S is single blind; O is open * 1 Month = 30 days ** Uric acid converted from μmol/L to mg/dL by dividing by 59.48 *** Vitamin C converted from mg/dL to μmol/L by multiplying by 56.776 + Median value. The pooled estimate and 95% confidence interval were calculated with a random effects model; trial effects were weighted by inverse variance. Heterogeneity between studies was assessed by the Q statistic and by the I 2 statistic ( 45 ). Individual trial influence was determined by removing each trial from the overall analysis. Publication bias was examined by funnel plot of standard error versus SUA effect, Begg's rank correlation test, and Egger's linear regression test. Statistical analyses were performed using STATA 8.2 (Stata Corp, College Station, TX). All SUA units were reported as mg/dL with International System of Units (SI) reported in parentheses, converting to μmol/L by multiplying by 59.48. Subgroup analyses were performed on select trial characteristics. Trial characteristics included: vitamin C dose (median value, < 500; ≥ 500 mg/day), trial duration (median value, < 30 days, ≥ 30 days), administration of vitamin C alone or with other vitamins, minerals, or pharmacologic agents (yes or no), trial design (parallel or crossover), double-blind design (yes or no), trial mention of participant compliance (yes or no), allocation concealment (yes or not reported), trial target population (healthy, yes or no), placebo use (yes or no), and trial size (median, < 29, ≥ 29 participants). Subject characteristics examined in subgroup analyses, according to the median value for the characteristic, were baseline serum ascorbic acid (median value, < 56.2 μmol/L, ≥ 56.2 μmol/L), mean age (median value, < 47.7, ≥ 47.7), percentage of male subjects (median value, < 53%, ≥ 53%), and baseline SUA (median value, < 4.85 mg/dL, ≥ 4.85 mg/dL; SI: 288.5 μmol/L). Results Search results are displayed in Figure 1 . Among the trials abstracted, the principal exclusion factors were: (1) lack of randomization ( 46 ), (2) missing SUA variance ( 37 , 38 ), and (3) incomplete SUA effects ( 39 - 41 ). Characteristics of the 13 clinical trials, satisfying our inclusion criteria are summarized in Table 1 . These 13 trials were conducted between 1990 and 2009, comprising 556 participants. Trial size ranged from 8 to 184 participants; mean age ranged from 20 to 81. With regard to trial design, 3 of the 13 trials were crossover, 10 were parallel; 9 were double-blind trials, 1 was single blind, and 3 reported no blinding. Trials were conducted over the course of 7 to 90 days with a median duration of 30 days. Among crossover trials, washout periods ranged from 1 week to 2 months. Pretreatment SUA values ranged from 2.9 to 7.0 mg/dL (SI: 172.5 – 416.4 μmol/L); pretreatment plasma ascorbic acid ranged from 27.0 to 77.7 μmol/L. Eight trials administered vitamin C as the only intervention, while 5 trials administered vitamin C in combination with other vitamins, minerals, or pharmacologic agents. The median dose of vitamin C was 500 mg/d, ranging from 200 mg/d to 2000 mg/d. Trial subjects were quite heterogeneous, ranging from healthy adults, the most common subject description, to several inpatient populations diagnosed with stroke, Graves’ Disease, or in long-term care. Open in a separate window Figure 1 Search Results Flow diagram of the trial selection process. Vitamin C supplementation was associated with reductions in SUA in 8 of the 13 trials included in this meta-analysis ( 10 , 26 , 28 , 30 , 31 , 33 , 34 , 36 ). Six of the 13 trials reported significant baseline reductions in SUA ( 10 , 25 , 29 , 31 , 33 , 36 ). The overall pooled effect of vitamin C supplementation on SUA was -0.35 mg/dL (95% CI: -0.66, -0.03; P = 0.032; SI: -20.8 μmol/L) ( Figure 2 ). Notably, the pooled effect was significant for heterogeneity with Q = 57 ( I 2 = 77%; P < 0.01). Using a covariance correlation value of 0.5 rather than 0.7 (see Methods), yielded a similar magnitude SUA effect at -0.34 ( P = 0.027). Open in a separate window Figure 2 Forest Plot of the Pooled Effect of Vitamin C Supplementation on Serum Uric Acid Net change in each individual study for serum uric acid in randomized controlled trials of vitamin C supplementation and overall pooled result. The area of each square is proportional to the study weight in the analysis. Horizontal lines represent 95% confidence intervals (CIs). The red diamond represents the pooled estimate and the 95% CI obtained from inverse-variance weighted random-effects models. Subgroup analyses are summarized in Table 2 . SUA reduction was -0.78 mg/dL (95% CI: -1.46, -0.09; SI: -46.4 μmol/L) in trials with subjects possessing baseline SUA values ≥ 4.85 mg/dL (SI: 288.5 μmol/L). There was a significant difference between trials with participants possessing baseline SUA values below 4.85 mg/dL (SI: 288.5 μmol/L) versus those above 4.85 mg/dL ( P = 0.030). Furthermore, stratifying trials by reported use of placebo showed significant SUA reductions in trials utilizing placebo at -0.59 mg/dL (95% CI: -0.95, -0.24; SI: -35.1 μmol/L), while trials that did not use a placebo had no effect (0.19 mg/dL; 95% CI: -0.07, 0.45; SI: 11.3 μmol/L). The pooled effects of these groups were significantly different ( P = 0.01). Also, trials utilizing at least a 500 mg daily dose of vitamin C, and trials where vitamin C was the only intervention, reduced vitamin C at -0.59 mg/dL (95% CI: -1.05, -0.13; SI: -35.1 μmol/L) and -0.54 mg/dL (95% CI: -0.96, -0.11; SI: -32.1 μmol/L), respectively. These effect sizes were not significantly different, however, when compared to trials utilizing smaller doses ( P = 0.10) and trials administered vitamin C in combination with other vitamins, minerals, or pharmacologic agents ( P = 0.16). Table 2 Subgroup analyses consisting of the pooled effect sizes of vitamin C supplementation on serum uric acid level, stratified by trial and subject characteristics. Change in serum uric acid (mg/dL) Sub-group N § Effect 95% CI I 2 P * LL UL Dose <500 mg/d 6 0.02 -0.21 0.26 0.0% 0.10 ≥500 mg/d 8 -0.59 -1.05 -0.13 79.9% Duration <30 days 7 -0.49 -1.20 0.22 85.2% 0.52 ≥30 days 7 -0.25 -0.56 0.06 63.0% Baseline Serum Ascorbic Acid <56.2 μmol/L 3 -0.02 -0.30 0.27 0.0% 0.20 ≥56.2 μmol/L 4 -0.33 -0.75 0.09 53.7% Mean Age <47.7 6 -0.53 -1.32 0.27 85.3% 0.55 ≥47.7 7 -0.29 -0.61 0.04 66.1% %Male <53 6 -0.26 -0.59 0.07 58.5% 0.66 ≥53 7 -0.41 -1.06 0.24 85.6% Baseline Serum Uric Acid <4.85 mg/dL 5 0.13 -0.12 0.37 0.0% 0.03 ≥4.85 mg/dL 5 -0.78 -1.46 -0.09 85.0% Trial Design Parallel 10 -0.37 -0.80 0.07 83.8% 0.91 Crossover 4 -0.31 -0.63 0.02 0.0% Vit C Only Intervention Yes 9 -0.54 -0.96 -0.11 78.1% 0.16 No 5 0.04 -0.20 0.29 0.0% Placebo Use Yes 10 -0.59 -0.95 -0.24 71.2% 0.01 No 4 0.19 -0.07 0.45 0.0% Allocation Concealment Yes 4 -0.31 -0.75 0.13 76.5% 0.89 Not Reported 10 -0.37 -0.86 0.11 79.1% Double-blind Design Yes 9 -0.50 -0.66 -0.35 0.0% 0.75 No 5 -0.30 -1.17 0.58 90.8% Trial Reported Compliance Yes 5 -0.35 -0.75 0.05 71.1% 0.92 No 9 -0.34 -0.87 0.18 0.0% Healthy Trial Population Yes 7 -0.60 -1.26 0.06 82.5% 0.20 No 7 -0.15 -0.49 0.20 71.1% Trial Size <29 5 -0.58 -1.58 0.41 87.9% 0.37 ≥29 9 -0.23 -0.51 0.05 63.4% Open in a separate window * P-values represent comparison of effects between subgroups. Category bounds were determined by the median of abstracted values. § N represents the number of trials. The number of trials may not always add to 13 due to the treatment of one trial as two groups (Kyllastinen et al, 1990) and due to the varying availability of subgroup data in each trial. Trial quality features are contained in Table 3 . The majority of trials did not report details regarding allocation concealment (3 of 13) or randomization method (0 of 13). Only 1 trial clearly reported intention-to-treat ( 10 ), and only 1 trial reported blinding of the assessor in addition to subjects and care provider ( 10 ). Five of 13 trials mentioned trial subjects’ compliance with treatment protocol, and only 1 trial ( 10 ) discussed losses to follow-up. Table 3 Trial Quality Design Features Allocation Concealment Randomization Method Intention-to-Treat Analysis Blinding of Participants Blinding of Providers Blinding of Outcome Assessor Description of Subject Compliance Evaluation of Treatment-Specific Losses to Follow-up Naziroglu et al ( 25 ) , 2009 Not Reported Not Reported Not Reported No No No No - Teixeira et al ( 26 ) , 2009 Not Reported Not Reported Not Reported Yes Yes No Yes - Huang et al ( 10 ) , 2005 Yes Not Reported Yes Yes Yes Yes Yes Yes Polidori et al ( 27 ) , 2005 Yes Not Reported Not Reported No No No Yes - Van Hoydonck et al ( 28 ) , 2004 Not Reported Not Reported No Yes Yes No Yes No Vrca et al ( 29 ) , 2004 Not Reported Not Reported Not Reported No No No No - Yanai et al ( 30 ) , 2004 Not Reported Not Reported No Yes No No No - Nieman et al ( 31 ) , 2002 Not Reported Not Reported Not Reported Yes Yes No Yes No Martinez-Abundis et al ( 32 ) , 2001 Not Reported Not Reported No Yes Yes No No - Hamilton et al ( 33 ) , 2000 Not Reported Not Reported No Yes Yes No No No Rokitzki et al ( 34 ) , 1994 Not Reported Not Reported Not Reported Yes Yes No No No Maxwell et al ( 35 ) , 1993 Not Reported Not Reported No No No No No - Kyllastinen et al ( 36 ) , 1990 Yes Not Reported No Yes Yes No No No Open in a separate window Summary of design characteristics reported by trials included in our meta-analysis. Trials that reported no loss to follow up did not receive a “yes” or “no” designation. In a plot of SUA effect versus standard error, trials appeared to follow the shape of a funnel ( Figure 3 ). Publication bias was also examined by performing Begg's rank correlation test, which yielded a non-significant Kendall score of -22 ( P = 0.23). Egger's linear regression test confirmed these findings with a non-significant SUA bias coefficient at P = 0.67 ( 44 ), suggesting that publication bias was not a significant factor in this meta-analysis. Furthermore, a random-effects analysis was conducted after the omission of each trial to examine the influence of the omitted study on the pooled effect. As such, the overall effects ranged from -0.20 mg/dL ( P = 0.09; SI: -11.9 μmol/L) to -0.40 mg/dL ( P = 0.019; SI: -23.8 μmol/L), following omission of trials with greatest weight for ( 30 ) and against ( 27 ) an overall reduction in SUA. Open in a separate window Figure 3 Begg's Funnel Plot with Pseudo 95% Confidence Limits Begg's funnel plot with pseudo 95% confidence limits (sloped lines). Serum uric acid effect (mg/dL) is plotted on the y-axis, and the standard error is plotted on the x-axis. The vertical line represents the overall pooled effect (-0.35 mg/dL). Circles represent the SUA effect and standard error of each trial. Discussion This study is the first quantitative review of published randomized, clinical trials examining the effect of oral vitamin C supplementation on SUA. Overall, vitamin C supplementation reduced SUA with a mean aggregate effect of -0.35 mg/dL ( P = 0.032; SI: -20.8 μmol/L). Although only 6 of the 13 trials reported significant reductions in SUA, pooling these small trials made it possible to estimate an overall effect, a key advantage of the meta-analysis method. These findings support the observed inverse associations between intake of dietary and supplemental vitamin C and SUA levels. Vitamin C is an essential micronutrient in a number of physiologic processes. When plasma ascorbate levels fall below 11 μmol/L, clinical features of scurvy may develop ( 47 ). The median dose of vitamin C used in trials was 500 mg/d, which is well above the recommended dietary allowance for vitamin C, 90 mg/d in men and 75 mg/d in women. Surpassing the tolerable upper intake level of 2 g/d ( 48 ) may cause osmotic diarrhea, gastrointestinal disturbance ( 49 ), and calcium oxalate nephrolithiasis ( 50 ). Most studies report few side effects, however, when doses are below the tolerable upper intake level ( 49 ). None of the trials included in this meta-analysis reported adverse effects from vitamin C supplementation. Several studies have described biological mechanisms by which vitamin C reduces SUA. In vivo studies suggest that vitamin C has uricosuric properties, increasing renal fractional clearance of uric acid, thereby reducing SUA ( 14 ). This is likely due to competitive inhibition of an anion exchange transport system at the proximal tubule in the nephron ( 16 ). Vitamin C may act specifically at uric acid reabsorption sites in the apical brush border of the proximal tubule, such as urate transporter 1 (URAT1), and a sodium-dependent anion cotransporter, SLC5A8/A12 ( 22 , 51 - 53 ). It is also possible that vitamin C increases the glomerular filtration rate by reducing glomerular microvascular ischemia and increasing dilatation of afferent arterioles ( 10 , 54 - 56 ). Furthermore, as an effective antioxidant vitamin C decreases free radical-induced damage to body cells ( 57 ), thereby reducing production and ultimately serum concentration of uric acid ( 22 ). There are a number of limitations to this meta-analysis that warrant consideration. Heterogeneity between trials was found to be significant ( I 2 = 77%; P < 0.01). An attempt to address heterogeneity by performing subgroup analyses based on trial characteristics did not fully explain differences in effect as demonstrated by elevated I 2 values within strata. Significance observed among some subgroup strata may indicate that baseline SUA, dose of vitamin C, use of vitamin C alone without any other supplement(s), and placebo use play a greater role in heterogeneity than other subject and trial characteristics. However, strata based on the comparison of patient characteristics across trials, specifically mean age, percent male gender, baseline serum ascorbate, and baseline serum uric acid, are prone to ecological bias and should be interpreted with additional caution ( 58 ). Another important consideration is publication bias. Although our funnel plot ( Figure 3 ) and other analyses did not support the presence of publication bias (Egger's test: P = 0.70), during the search we identified one trial whose authors decided not to report SUA findings because of non-significant results ( 41 ). It is possible that other trials lacking significant results were never published, skewing the overall results toward an effect. Another interpretation of the asymmetrical funnel plot is “small study effects.” Smaller studies often lack methodological rigor in design and analysis, contributing to inflated treatment effects ( 44 ). This is particularly evidenced by trials’ rare mention of design quality features in this meta-analysis ( Table 3 ). Further, even when optimally designed, small trials suffer from the inherent limitation of low statistical power. Indeed, small trial size and the paucity of reported assurances regarding trial quality constitute an important limitation of this meta-analysis. Another important consideration affecting interpretation of our results is the method by which SUA is measured. Of the thirteen trials included in this study, there are considerable differences in the manner by which SUA was determined and in the detail provided to describe this critical aspect of trial methodology ( Table 1 ). Prior research describes the ability of vitamin C to interfere with SUA measurements ( 19 , 59 - 64 ). Moreover, depending on the biochemical assay, vitamin C has been demonstrated to artificially increase ( 15 , 65 , 66 ) or decrease measured SUA ( 67 ). Artificial reduction in SUA is particularly related to the use of a biochemical assay employing the oxidase-peroxidase system, i.e. the Trinder method ( 68 ). In one study, Martinello et al (2006) administered vitamin C to eighteen volunteers and measured SUA via the Trinder method and ultraviolent light (UV) ( 67 ). The Trinder method found a significant baseline decrease in SUA, while UV showed no change in SUA ( 67 ). Although the exact mechanism of interference is not understood, it is believed that vitamin C as an antioxidant depletes the hydrogen peroxide utilized by the Trinder method to produce chromophore and detect SUA ( 69 ). Contrary to expectations in this meta-analysis, however, the one trial that explicitly describes use of the oxidase-peroxidase system without addressing vitamin C interference ( 35 ) did not observe a reduction in SUA after vitamin C supplementation. A number of researchers note that the addition of ascorbate oxidase, which oxidizes ascorbic acid to dehydroascorbic acid, does not interfere with the chromogen system responsible for SUA detection ( 69 - 71 ). Of all the trials included in this meta-analysis, this method was only explicitly mentioned by Huang and colleagues ( 10 ). Despite potential interference in serum measurements, prior small clinical studies have documented concurrent increase in uric acid excretion after introduction of vitamin C ( 14 , 16 ). Mitch et al (1980) notes, however, that urine uric acid measures are also susceptible to interference, depending on the measurement assay used ( 62 ). As SUA measurement integrally affects conclusions, future trials should employ methods that minimize vitamin C interference in serum measurements and also quantify urinary excretion of uric acid. One trial in this meta-analysis that reported null effects of vitamin C on SUA included 300mg/d of aspirin in its combination therapy ( 27 ). Aspirin has a mixed effect on the uric acid excretion with doses >3 grams/day causing uricosuria, while doses between 1-2 grams promote UA retention ( 72 ). Recent studies suggest that even small doses of aspirin, i.e. doses between 75 - 325 mg/day, also decrease uric acid clearance, causing uric acid retention ( 73 - 75 ). It is hypothesized that aspirin competes with uric acid at tubular secretion and reabsorption receptors and more globally suppresses glomerular filtration rate ( 72 , 75 - 77 ). Consistent with this hypothesis, the trial utilizing aspirin in this meta-analysis ( 27 ) contributed the largest weight against vitamin C reduction of SUA. It is possible that aspirin inhibits the uricosuric action of vitamin C, nullifying its effect. Exclusion of this trial increased the magnitude and significance of our pooled effect to -0.40 mg/dL ( P = 0.019; SI: -23.8 μmol/L). Five of the 13 trials in this study ( 26 , 30 , 31 , 34 , 35 ) evaluated SUA in the context of exercise. As acute exercise is known to increase oxidative stress and levels of serum and salivary uric acid ( 39 , 40 , 78 - 82 ), we attempted to avoid inclusion of this variable in our pooled analysis. This was not possible in one of the trials, because the authors did not measure pre-exercise SUA values ( 30 ). Conducting the meta-analysis using the SUA values measured closest to the conclusion of exercise rather than pre-exercise SUA values, revealed an overall SUA reduction of -0.42 ( P = 0.012), which is greater and more significant than the pooled effect reported in our analysis. This may suggest that the role of vitamin C is more pronounced in contexts of oxidative stressors and that greater protection against acute hyperuricemia could be achieved. Additional trials are necessary to evaluate this hypothesis. Hyperuricemia has been associated with a wide range of diseases, including hypertension, obesity, renal disease, metabolic syndrome, obstructive sleep apnea, stroke, vascular dementia, and preeclampsia ( 83 ). However, large trials of vitamin C on cardiovascular events ( 84 , 85 ) as well as a recent meta-analysis on mortality have failed to demonstrate significant protective effects ( 86 ). These studies did not examine gout among their outcomes. Among all of the aforementioned clinical outcomes, the strongest support for a casual relationship exists between elevated SUA and gout ( 1 ). Importantly, none of the trials included in this meta-analysis examined vitamin C in a population of patients with gout, though an exploratory subgroup analysis suggests that greater SUA reduction could be achieved in individuals with SUA above 4.85 mg/dL ( Table 2 ). If vitamin C with its low cost and relatively innocuous side effect profile were administered to patients with gout as an adjunctive therapy, it is possible that a greater number would achieve target SUA levels, reducing the likelihood of flares. It has yet to be determined, however, whether vitamin C would enhance or add to the SUA reduction of standard anti-hyperuricemic agents. In summary, this meta-analysis suggests that oral vitamin C supplementation results in modest SUA reduction. Future trials of adequate size and duration should address issues of vitamin C assay interference and should measure both SUA and renal excretion of uric acid. Furthermore, future trials should be adequately powered to evaluate whether or not the urate-lowering effects of vitamin C are enhanced in patients with elevated SUA as found in our exploratory subgroup analysis and described in a previous trial ( 10 ). Ultimately, whether vitamin C supplementation lowers the risk of gout or hyperuricemia needs to be determined. ​ Significance and Innovation Combining the results of thirteen randomized, controlled trials resulted in a significant reduction in SUA of -0.35 mg/dL (95% CI: -0.66, -0.03; P = 0.032; SI: -20.8 μmol/L). The thirteen trials were very heterogeneous ( I 2 = 77%). Reductions in SUA were larger among trials administering 500 mg/d or greater of vitamin C, trials administering vitamin C without other interventions, and trials that used a placebo group. Acknowledgments Supported in part by a NIH/NHLBI T32HL007024 Cardiovascular Epidemiology Training Grant, the Donald B. and Dorothy Stabler Foundation and the Ira Fine Discovery Fund. Appendix: Search Terms utilized on September 4th, 2010 MEDLINE: 1041 Publications (“1966/01/01”[PDAT] : “3000”[PDAT]) AND (kidney[TW] OR “kidney diseases”[MH] OR “kidney diseases”[TW] OR (kidney[TIAB] AND disease[TIAB]) OR (kidney[TIAB] AND diseases[TIAB]) OR nephropath*[TW] OR glomerulonephritis[MH] OR glomerulonephritis[TIAB] OR (renal[TIAB] AND insufficiency[TIAB]) OR “renal insufficiency”[TIAB] OR gout[TW] OR uricosuria[TW] OR hyperuricosuria[TW] OR hypouricosuria[TW] OR hyperuricemia[TW] OR hypouricemia[TW] OR nephrolithiasis[TW] OR nephrolithiasis[MH] OR “uric acid”[TW] OR (uric[TIAB] AND acid[TIAB])) AND (“ascorbic acid”[TW] OR “ascorbic acid”[MH] OR (ascorbic[TIAB] AND acid[TIAB]) OR antioxidant*[TW] OR antioxidant*[MH] OR vitamin*[TW] OR vitamin*[MH]) AND ((“randomized controlled trial”[PT] OR “random allocation”[MH] OR “randomized controlled trials as topic”[MH] OR “randomized controlled trial”[TIAB] OR “randomised controlled trial”[TIAB]) OR (“controlled clinical trial”[PT] OR “clinical trial”[PT] OR “clinical trials as topic”[MH] OR “clinical trials”[TIAB]) OR (“double-blind method”[MH] OR “single-blind method”[MH]) NOT (animal[MH] NOT human[MH]) NOT (review[PT] OR meta-analysis[PT])) EMBASE: 1198 Publications ‘kidney’/exp OR ‘kidney’:ab,ti OR ‘kidney diseases’/exp OR ‘kidney diseases’:ab,ti OR ‘kidney disease’/exp OR ‘kidney disease’:ab,ti OR (‘kidney’:ab,ti AND disease*:ab,ti) OR ‘nephropathy’/exp OR nephropath*:ab,ti OR ‘glomerulonephritis’/exp OR ‘glomerulonephritis’:ab,ti OR ‘renal insufficiency’/exp OR ‘renal insufficiency’:ab,ti OR (‘renal’:ab,ti AND ‘insufficiency’:ab,ti) OR ‘gout’/exp OR ‘gout’:ab,ti OR ‘uricosuria’/exp OR ‘uricosuria’:ab,ti OR ‘hyperuricosuria’/exp OR ‘hyperuricosuria’:ab,ti OR ‘hypouricosuria’:ab,ti OR ‘hyperuricemia’/exp OR ‘hyperuricemia’:ab,ti OR ‘hypouricemia’/exp OR ‘hypouricemia’:ab,ti OR ‘nephrolithiasis’/exp OR ‘nephrolithiasis’:ab,ti OR ‘uric acid’/exp OR ‘uric acid’:ab,ti OR (‘uric’:ab,ti AND ‘acid’:ab,ti) AND (‘ascorbic acid’/exp OR ‘ascorbic acid’:ab,ti OR (‘ascorbic’:ab,ti AND ‘acid’:ab,ti) OR ‘antioxidant’/exp OR antioxidant*:ab,ti OR ‘vitamin’/exp OR vitamin*:ab,ti) AND ([randomized controlled trial]/lim OR ‘randomized controlled trial’/exp OR ‘random allocation’/exp OR ‘randomized controlled trial’:ab,ti OR ‘randomised controlled trial’:ab,ti OR [controlled clinical trial]/lim OR [clinical trial]/lim OR ‘clinical trials’:ab,ti OR ‘double-blind method’/exp OR ‘single-blind method’/exp) AND ([adult]/lim OR [aged]/lim) NOT ([animals]/lim NOT [humans]/lim) NOT ([review]/lim OR [meta analysis]/lim) AND [embase]/lim AND [1966-2010]/py CENTRAL: 723 Publications ((kidney) OR (kidney diseases) OR ((kidney):ti,ab AND (disease*):ti,ab) OR (nephropathy) OR (nephropath*):ti,ab OR (glomerulonephritis) OR (glomerulonephritis):ti,ab OR (renal insufficiency) OR (renal insufficiency):ti,ab OR ((renal):ti,ab AND (insufficiency):ti,ab) OR (gout) OR (gout):ti,ab OR (uricosuria) OR (uricosuria):ti,ab OR (hyperuricosuria) OR (hyperuricosuria):ti,ab OR (hypouricosuria) OR (hypouricosuria):ti,ab OR (hyperuricemia) OR (hyperuricemia):ti,ab OR (hypouricemia) OR (hypouricemia):ti,ab OR (nephrolithiasis) OR (nephrolithiasis):ti,ab OR (uric acid) OR (uric acid):ti,ab OR ((uric):ti,ab AND (acid):ti,ab)) AND ((ascorbic acid) OR ((ascorbic):ti,ab AND (acid):ti,ab) OR (antioxidant) OR (antioxidant*):ti,ab OR (vitamins) OR (vitamin*):ti,ab) NOT (review):pt NOT (meta analysis):pt, from 1966 to 2010 in Clinical Trials References 1. 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+Top 14 Health Benefits of Exercise + Safety Tips - SelfHacked Skip to content drugs labs resources supplements health Home Posts Substances Testing Science Conditions Healthy Living About Get SelfDecode Evidence Based This post has 104 references 4.3 /5 16 Top 14 Health Benefits of Exercise + Safety Tips Written by Aleksa Ristic, MS (Pharmacy) | Last updated: March 3, 2023 Medically reviewed by Puya Yazdi, MD |     Written by Aleksa Ristic, MS (Pharmacy) | Last updated: March 3, 2023 SelfHacked has the strictest sourcing guidelines in the health industry and we almost exclusively link to medically peer-reviewed studies, usually on PubMed. We believe that the most accurate information is found directly in the scientific source. We are dedicated to providing the most scientifically valid, unbiased, and comprehensive information on any given topic. Our team comprises of trained MDs, PhDs, pharmacists, qualified scientists, and certified health and wellness specialists. 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A plus sign next to the number “[1+, 2+, etc...]” means that the information is found within the full scientific study rather than the abstract. For much of history, high levels of intense daily exercise was probably a necessary requirement for human survival. However, in most industrialized countries the necessity for physical activity to sustain life is declining. As a result, we are seeing a decline in physical fitness in many of these populations. The purpose of this article is to explore the scientific literature and uncover the role that physical activity plays in the maintenance of good health and the avoidance of chronic disease. We will also discuss different types of exercise and why, for some people, exercise may not be a great option. What is Exercise? Physical exercise refers to any bodily activity that enhances or maintains physical fitness, health, and wellbeing [ 1 ]. The idea that physical activity is important for health and disease prevention is not a new concept but has been appreciated for millennia. Indeed, Hippocrates (∼450 BC) stated that the body falls sick when exercise is deficient. The Global Burden of Disease Study carried out by the World Health Organization included physical inactivity as one of the most important risk factors threatening global health [ 2 ]. In fact, research from the U.S. Centers for Disease Control and Prevention has attributed 23.3% of US deaths to the lack of regular exercise. Health Benefits of Exercise 1) Enhances Cognition Exercise boosts BDNF , which increases neuronal survival, enhances learning, and protects against cognitive decline [ 3 ]. One study found that three 60 minute sessions of moderate physical activity per week increased memory. This was possibly due to increased blood flow to certain parts of the brain (hippocampus) [ 4 ]. Even in old people, aerobic exercise can increase cognition, brain size, and power [ 5 ]. Studies have shown that without a regular exercise regime the brain deteriorates and loses cognitive power much faster [ 6 ]. In fact, one study found that elderly people who engage in aerobic exercise had bigger brains. Non-aerobic yoga or toning exercises did not produce the same effect [ 7 ]. In obese children, physical activity improved executive function and mathematics test scores [ 8 ]. By supporting nerve growth, metabolism, and vascular function, exercise promotes brain plasticity [ 9 ]. Moderate physical activity increases neurotrophins, proteins that support brain plasticity (ability to change). As such, exercise is probably even more important for the young (<25), developing brain [ 10 ]. Recent studies have shown that the beneficial effects of exercise on the brain can be increased by the consumption of natural products like omega-3 fatty acids or plant polyphenols [ 11 ]. 2) Supports Heart Health Many studies have shown that regular physical activity is associated with a reduced risk of cardiovascular disease [ 12 ]. One long-term study looked at the effects of regular exercise on men and women over the age of 73. It found that total exercise, exercise intensity, and leisure time intensity were all associated with a l ower risk of heart attack [ 13 ]. For women, the beneficial effects of exercise on the heart requires just 1 hour of walking per week [ 14 ]. Energy expenditure of 1600-2200 calories per week via exercise is needed for mild heart disease [ 15 , 16 ]. Low-intensity exercise (<45% of max intensity) improves the health of people with heart disease [ 17 ]. A recent study confirmed that regular walking is the best form of physical activity for heart health [ 18 ]. Exercise improves heart health by reducing “bad” cholesterol ( LDL ) and increasing “good” cholesterol ( HDL ) [ 19 , 20 ]. 3) Helps With Diabetes and Metabolic Syndrome Aerobic and anaerobic training decrease the risk of developing type 2 diabetes [ 21 , 22 , 23 ]. In one study, every extra 500kcal burned per week through exercise decreased the risk of diabetes by 6% [ 24 ]. Exercise increases insulin sensitivity [ 25 ]. 40 minutes of intense exercise per week reduced the risk of diabetes in middle-aged men [ 26 ]. Weight loss via exercise can reduce the risk of diabetes by 40-60% among overweight individuals [ 27 ]. Moderate physical activity for >150 minutes per week was found to be more effective than the drug metformin [ 27 ]. One study showed that diabetics who walked at least two hours per week had 39-54% lower mortality [ 28 ]. Inactive men with diabetes were found to be 1.7 times more likely to die than physically active diabetics. This relationship also applies to those with metabolic syndrome [ 29 , 30 ]. Resistance training (e.g. weightlifting) might help regulate blood sugar more than aerobic exercise [ 31 ]. 4) Improves Mental Health People who engage in regular physical activity experience fewer depressive and anxious symptoms [ 32 ]. Both aerobic (e.g swimming) and anaerobic (e.g. weight training) exercise effectively lower depression and enhance mood [ 33 ]. Individuals who maintain a reasonable level of aerobic fitness are less likely to relapse into depression [ 34 ]. People with chronic anxiety often have a dysregulated HPA axis . Studies have shown that exercise improves the way the HPA axis modulates stress reactivity and anxiety [ 35 , 36 ]. High levels of physical activity are associated with improved heart rate variability scores (stress resilience marker) [ 37 ]. One study found that college students who exercised regularly experienced less stress and hassle than those who didn’t [ 38 ]. Another study found that regular physical activity buffered the stressful effects of widowhood in elderly subjects [ 39 ]. Exercise increases norepinephrine , which helps the brain deal with stress more effectively [ 40 ]. In one study, both African dance (rigorous exercise) and yoga caused significant improvements in stress levels [ 41 ]. As well as reducing mental stress, some forms of exercise are very effective at reducing cellular stress. For example, yoga has been shown to improve antioxidant status and limit oxidative damage [ 42 ]. 5) Boosts Sleep Quality The idea that exercise helps sleep has existed for thousands of years [ 43 ]. Disturbed sleep is a common symptom of anxiety. Thus, exercise’s positive effect on sleep may be due to its ability to buffer anxiety [ 44 , 45 ]. Sleep deprivation can cause, and be caused by, depression. Thus, exercise may improve sleep quality through its ability to decrease anxiety and depression [ 46 , 47 ]. People who exercise regularly may have improved thermoregulation. This means they can cool down more efficiently before sleep (important for deep sleep cycles) [ 48 ]. Exercise may improve sleep quality by improving your circadian rhythm . Many studies have shown that routine exercise can shift the circadian system towards a healthy light-dark cycle [ 49 , 50 , 51 , 52 ]. Individuals undergoing cancer treatment often suffer from impaired sleep quality. A suitable exercise regime can help these people sleep better, possibly by affecting sleep-influencing cytokines, such as IL-6 [ 53 ]. The most positive effects on sleep quality occur when exercise is completed 4-8 hours before bedtime [ 47 ]. Evidence suggests that exercise does not need to be intense to elicit a positive effect on sleep; walking intensity will do the job [ 54 ]. Exercise is a great option for insomniacs and might help them avoid the negative side effects of long-term use of sleeping pills [ 55 ]. For sleep, the best time to exercise is in the morning or at about 4-5 PM [ 56 ]. 6) Supports Longevity A large number of population studies over the last 50 years have shown that low physical activity is associated with increased total mortality [ 2 ]. In one experiment, people who went from unfit to fit in 5 years had 44% less chance of dying than those that stayed unfit [ 57 ]. Another study found that the physical fitness of healthy middle-aged men is a strong predictor of mortality. Just small increases in physical fitness are associated with a significantly lower risk of death [ 58 ]. One study found that people who engage in physical activity and fitness had a 20 – 35% lower risk of dying from all causes [ 59 , 60 ]. The older you are, the greater the impact physical activity will have on your life expectancy [ 61 ]. The great news is that longevity benefits can be achieved by relatively small amounts of activity [ 62 ]. 7) Helps Prevent Brain Degeneration Individuals who exercise regularly have lower rates of age-related memory and cognitive decline than sedentary people [ 63 ]. In fact, one study showed that women who exercise the most have a 20% lower risk of developing cognitive impairment [ 64 ]. Resistance training exercises can improve the memory of elderly individuals with prior memory problems and protect against the development of Alzheimer’s disease [ 65 ]. One study found that individuals older than 65 had much less chance of dementia if they exercised at least 3 times per week [ 66 ]. 8) Helps Prevent Cancer Regular physical activity is associated with reduced risk of cancers, especially colon and breast cancer [ 67 , 68 , 69 ]. In fact, a recent study found that exercise can reduce the chances of getting 13 different types of cancers [ 70 ]. Physically active individuals have a 30-40% lower risk of colon cancer than those that are inactive. Active women have 26-40% less chance of cancer-related death than their inactive counterparts [ 71 , 72 ]. Regular exercise also increases the reported quality of life among cancer patients [ 73 , 74 ]. Intense exercise and walking both reduce the risk of breast cancer [ 75 ]. Exercise is associated with improved breast cancer survival rate, possibly due to its ability to reduce IL-6 [ 76 ]. 9) Strengthens the Bones Bone density can be increased with regular physical activity , especially resistance training. This is why the National Institute for Health recommends weight-bearing exercises, which force you to work against gravity, for good bone health [ 77 ]. Examples include weight training, hiking and stair climbing. Resistance training may be more effective than traditional pharmacological and nutritional approaches for improving bone health. This is because it influences other risk factors for osteoporosis, such as strength, balance, and muscle mass [ 78 ]. One study looked at schoolgirls who engaged in three sessions of high-impact exercise per week. After two years the girls had experienced a “ substantial bone mineral accrual advantage ” [ 79 ]. Similarly, both Tai Chi and resistance training prevent bone density loss in elderly women ( 80 , 81 ). Improved bone health from resistance training is achievable with light weights. For example, one study found that low weight, high repetition resistance training increased bone density by 8% in adults [ 82 ]. 10) Boosts Metabolism and Fat Loss Along with a healthy, calorie-controlled diet, increased physical activity is the only proven strategy for weight control. Dietary supplements and other complementary approaches may only bring minor additional benefits [ 83 ]. One study found that 45 minutes of hard exercise increased post-exercise energy expenditure. This revved up metabolism lasted for 14 hours [ 84 ]. Aerobic exercise can help you burn fat, especially belly fat, which correlates with the risk of type 2 diabetes and heart disease [ 85 , 86 , 87 ]. Exercise can increase muscle mass, which helps boost metabolism, even at rest [ 88 , 89 , 90 ]. Regular physical activity can mitigate the risks associated with being overweight or obese [ 34 ]. 11) Increases Muscle Strength Exercise increases functional strength and, thus, can make everyday activities easier, especially for the elderly [ 91 ]. Healthy muscles let you move freely and keep your body strong. They also allow improve joint health and support heart health [ 92 , 93 ]. One study instructed 40 individuals with a bone disease to complete a 3-month supervised resistance exercise program. The participants had an increase in lean body mass (muscle) and reported improved quality of life [ 94 ]. In elderly individuals, resistance training can limit muscle loss associated with old age [ 95 ]. 12) Reduces Back Pain Studies indicate that moderate, controlled exercise is effective in preventing lower back pain and does not increase the risk of back injury [ 96 , 97 ]. The science suggests that most forms of exercise are equally effective at treating back pain [ 98 ]. In one study, 2.5 years of aerobic exercise was enough for sufferers of lower back pain to significantly lower their intake of pain medication [ 99 ]. 13) Increases Libido and Sexual Function Exercise frequency and physical fitness enhance self-confidence and energy levels, which can lead to greater sexual desires and performance [ 100 ]. Men who engage in regular physical activity are less likely to experience erectile dysfunction [ 101 ]. 14) Supports the Joints One study found that arthritic subjects who engaged in a water exercise program experienced improvements in physical function and less pain [ 102 ]. For arthritis sufferers, regular exercise can increase functional ability (e.g ability to climb stairs) and range of motion [ 102 ]. Exercise Recommendations The type of exercise you decide to engage in will depend on your specific health goals. Regardless of the type of exercise you decide to engage in, there are four basic principles of an effective exercise program [ 103 ]: Overload – you should engage in an activity that is harder than your normal or habitual baseline. Essentially, this means that you must push past your comfort zone at each training session. Progression – Over time, you should steadily and safely increase the amount of effort. Adaptation – Using the principles of overload and progression effectively, your body will adapt to function at the new performance level with comfort. Specificity – Benefits from physical activity and exercise are specific to the tissues and organs subjected to progressive overload. Thus, you should train in a way that strengthens your weakest areas to create a healthy, balanced body. What’s most important is that you avoid being inactive. In a way, it’s more important to a sedentary lifestyle than to engage in intense exercise [ 104 ]. Safety If you have a diagnosed condition, work with your doctor to determine the best exercise options and intensity level, according to your condition, health goals, and other factors. Start slowly . Cardiac events, such as a heart attack, are rare during physical activity. But the risk certainly does increase when someone suddenly becomes much more active than usual. Pregnant women should avoid overly intense physical activity. People with “adrenal fatigue” may fair better with exercise that doesn’t overstimulate the HPA axis , such as yoga or walking. About the Author Aleksa Ristic MS (Pharmacy) Aleksa received his MS in Pharmacy from the University of Belgrade, his master thesis focusing on protein sources in plant-based diets. Aleksa is passionate about herbal pharmacy, nutrition, and functional medicine. He found a way to merge his two biggest passions—writing and health—and use them for noble purposes. His mission is to bridge the gap between science and everyday life, helping readers improve their health and feel better. RATE THIS ARTICLE ( 7 votes, average: 4.29 out of 5) Loading... FDA Compliance The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition. Leave a Reply Cancel reply Your email address will not be published. Required fields are marked * Comment * Name * Email * Website Save my name, email, and website in this browser for the next time I comment. Contents What is Exercise? Health Benefits of Exercise 1) Enhances Cognition 2) Supports Heart Health 3) Helps With Diabetes and Metabolic Syndrome 4) Improves Mental Health 5) Boosts Sleep Quality 6) Supports Longevity 7) Helps Prevent Brain Degeneration 8) Helps Prevent Cancer 9) Strengthens the Bones 10) Boosts Metabolism and Fat Loss 11) Increases Muscle Strength 12) Reduces Back Pain 13) Increases Libido and Sexual Function 14) Supports the Joints Exercise Recommendations Safety Joe Cohen, CEO About Joe Joe Cohen flipped the script on conventional and alternative medicine… and it worked. Frustrated by the lack of good information and tools, Joe decided to embark on a learning journey to decode his DNA and track his biomarkers in search of better health. 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+Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000 - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000 Christine M Pfeiffer 1 , Samuel P Caudill , Elaine W Gunter , John Osterloh , Eric J Sampson Affiliations Expand Affiliation 1 National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA. cpfeiffer@cdc.gov PMID: 16087991 DOI: 10.1093/ajcn.82.2.442 Free article Item in Clipboard Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000 Christine M Pfeiffer et al. Am J Clin Nutr . 2005 Aug . Free article Show details Display options Display options Format Abstract PubMed PMID Am J Clin Nutr Actions Search in PubMed Search in NLM Catalog Add to Search . 2005 Aug;82(2):442-50. doi: 10.1093/ajcn.82.2.442. Authors Christine M Pfeiffer 1 , Samuel P Caudill , Elaine W Gunter , John Osterloh , Eric J Sampson Affiliation 1 National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA. cpfeiffer@cdc.gov PMID: 16087991 DOI: 10.1093/ajcn.82.2.442 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Background: Mandatory folic acid fortification of cereal-grain products was introduced in the United States in 1998 to decrease the risk that women will have children with neural tube defects. Objective: The objective was to determine the effect of folic acid fortification on concentrations of serum and red blood cell (RBC) folate, serum vitamin B-12, and plasma total homocysteine (tHcy) and methylmalonic acid (MMA) in the US population. Design: Blood was collected from a nationally representative sample of approximately 7300 participants aged > or = 3 y in the National Health and Nutrition Examination Survey (NHANES) during 1999-2000 and was analyzed for these B vitamin-status indicators. The results were compared with findings from the prefortification survey NHANES III (1988-1994). Results: The reference ranges (5th-95th percentiles) were 13.1-74.3 nmol/L for serum folate, 347-1167 nmol/L for RBC folate, and 179-738 pmol/L for serum vitamin B-12. For plasma tHcy and MMA, the reference ranges for serum vitamin B-12-replete participants with normal serum creatinine concentrations were 3.2-10.7 mumol/L and 60-210 nmol/L, respectively. The prevalence of low serum folate concentrations (<6.8 nmol/L) decreased from 16% before to 0.5% after fortification. In elderly persons, the prevalence of high serum folate concentrations (>45.3 nmol/L) increased from 7% before to 38% after fortification; 3% had marginally low serum vitamin B-12 concentrations (<148 pmol/L) and 7% had elevated plasma MMA concentrations (>370 nmol/L). Seventy-eight percent of the US population had plasma tHcy concentrations <9 micromol/L. Conclusions: Every segment of the US population appears to benefit from folic acid fortification. Continued monitoring of B vitamin concentrations in the US population is warranted. PubMed Disclaimer Comment in Science-based micronutrient fortification: which nutrients, how much, and how to know? Rosenberg IH. Rosenberg IH. Am J Clin Nutr. 2005 Aug;82(2):279-80. doi: 10.1093/ajcn.82.2.279. Am J Clin Nutr. 2005. PMID: 16087969 No abstract available. Similar articles Population Reference Values for Serum Methylmalonic Acid Concentrations and Its Relationship with Age, Sex, Race-Ethnicity, Supplement Use, Kidney Function and Serum Vitamin B12 in the Post-Folic Acid Fortification Period. Ganji V, Kafai MR. Ganji V, et al. Nutrients. 2018 Jan 12;10(1):74. doi: 10.3390/nu10010074. Nutrients. 2018. PMID: 29329201 Free PMC article. Vitamin B-12 and homocysteine status in a folate-replete population: results from the Canadian Health Measures Survey. MacFarlane AJ, Greene-Finestone LS, Shi Y. MacFarlane AJ, et al. Am J Clin Nutr. 2011 Oct;94(4):1079-87. doi: 10.3945/ajcn.111.020230. Epub 2011 Sep 7. Am J Clin Nutr. 2011. PMID: 21900461 Trends in blood folate and vitamin B-12 concentrations in the United States, 1988 2004. Pfeiffer CM, Johnson CL, Jain RB, Yetley EA, Picciano MF, Rader JI, Fisher KD, Mulinare J, Osterloh JD. Pfeiffer CM, et al. Am J Clin Nutr. 2007 Sep;86(3):718-27. doi: 10.1093/ajcn/86.3.718. Am J Clin Nutr. 2007. PMID: 17823438 Folic acid fortification: why not vitamin B12 also? Selhub J, Paul L. Selhub J, et al. Biofactors. 2011 Jul-Aug;37(4):269-71. doi: 10.1002/biof.173. Epub 2011 Jun 14. Biofactors. 2011. PMID: 21674649 Review. The use of blood concentrations of vitamins and their respective functional indicators to define folate and vitamin B12 status. Selhub J, Jacques PF, Dallal G, Choumenkovitch S, Rogers G. Selhub J, et al. Food Nutr Bull. 2008 Jun;29(2 Suppl):S67-73. doi: 10.1177/15648265080292S110. Food Nutr Bull. 2008. PMID: 18709882 Review. See all similar articles Cited by Folate induces stemness and increases oxygen consumption under glucose deprivation by notch-1 pathway activation in colorectal cancer cell. Rodríguez Silva J, Monsalves-Álvarez M, Sepúlveda C, Donoso-Barraza C, Troncoso R, Hirsch S. Rodríguez Silva J, et al. Mol Cell Biochem. 2024 Mar 27. doi: 10.1007/s11010-024-04987-1. Online ahead of print. Mol Cell Biochem. 2024. PMID: 38536555 Folate, vitamin B12, and homocysteine status in the Korean population: data from the 2013-2015 Korea National Health and Nutrition Examination Survey. Song S, Song BM, Park HY. Song S, et al. Epidemiol Health. 2024;46:e2024007. doi: 10.4178/epih.e2024007. Epub 2023 Dec 11. Epidemiol Health. 2024. PMID: 38186250 Free PMC article. Dietary intake, nutritional adequacy and food sources of vitamins involved in the methionine-methylation cycle from Spanish children aged one to <10 years: results from the EsNuPI study. Partearroyo T, Samaniego-Vaesken ML, Rodríguez-Alonso P, Soto-Méndez MJ, Hernández-Ruiz Á, Gil Á, Varela-Moreiras G. Partearroyo T, et al. Front Nutr. 2023 Dec 14;10:1248908. doi: 10.3389/fnut.2023.1248908. eCollection 2023. Front Nutr. 2023. PMID: 38156277 Free PMC article. Prenatal folic acid and vitamin B 12 imbalance alter neuronal morphology and synaptic density in the mouse neocortex. Tat L, Cannizzaro N, Schaaf Z, Racherla S, Bottiglieri T, Green R, Zarbalis KS. Tat L, et al. Commun Biol. 2023 Nov 8;6(1):1133. doi: 10.1038/s42003-023-05492-9. Commun Biol. 2023. PMID: 37938221 Free PMC article. Prevalence and predictors of low folate levels among stroke survivors in a country without mandatory folate food fortification: Analysis of a Ghanaian sample. Sarfo FS, Boateng R, Opare-Addo PA, Gyamfi RA, Nguah SB, Ovbiagele B. Sarfo FS, et al. J Stroke Cerebrovasc Dis. 2023 Sep;32(9):107239. doi: 10.1016/j.jstrokecerebrovasdis.2023.107239. Epub 2023 Jul 20. J Stroke Cerebrovasc Dis. 2023. PMID: 37480805 See all "Cited by" articles Publication types Research Support, U.S. Gov't, Non-P.H.S. Actions Search in PubMed Search in MeSH Add to Search MeSH terms Adult Actions Search in PubMed Search in MeSH Add to Search Aged Actions Search in PubMed Search in MeSH Add to Search Dietary Supplements Actions Search in PubMed Search in MeSH Add to Search Erythrocytes / chemistry Actions Search in PubMed Search in MeSH Add to Search Female Actions Search in PubMed Search in MeSH Add to Search Folic Acid / administration & dosage* Actions Search in PubMed Search in MeSH Add to Search Food, Fortified* Actions Search in PubMed Search in MeSH Add to Search Homocysteine / blood Actions Search in PubMed Search in MeSH Add to Search Humans Actions Search in PubMed Search in MeSH Add to Search Male Actions Search in PubMed Search in MeSH Add to Search Methylmalonic Acid / blood Actions Search in PubMed Search in MeSH Add to Search Middle Aged Actions Search in PubMed Search in MeSH Add to Search Nutrition Surveys Actions Search in PubMed Search in MeSH Add to Search Reference Values Actions Search in PubMed Search in MeSH Add to Search Time Factors Actions Search in PubMed Search in MeSH Add to Search United States Actions Search in PubMed Search in MeSH Add to Search Vitamin B 12 / blood* Actions Search in PubMed Search in MeSH Add to Search Substances Homocysteine Actions Search in PubMed Search in MeSH Add to Search Methylmalonic Acid Actions Search in PubMed Search in MeSH Add to Search Folic Acid Actions Search in PubMed Search in MeSH Add to Search Vitamin B 12 Actions Search in PubMed Search in MeSH Add to Search Related information MedGen PubChem Compound (MeSH Keyword) LinkOut - more resources Full Text Sources Elsevier Science Silverchair Information Systems Medical MedlinePlus Health Information Full text links [x] Elsevier Science [x] Cite Copy Download .nbib .nbib Format: AMA APA MLA NLM Send To Clipboard Email Save My Bibliography Collections Citation Manager [x] NCBI Literature Resources MeSH PMC Bookshelf Disclaimer The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). 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+Short term effects of reduced exposure to cigarette smoke on white blood cells, platelets and red blood cells in adult cigarette smokers - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Sunday Monday Tuesday Wednesday Thursday Friday Saturday Report format: Summary Summary (text) Abstract Abstract (text) PubMed Send at most: 1 item 5 items 10 items 20 items 50 items 100 items 200 items Send even when there aren't any new results Optional text in email: Save Cancel Create a file for external citation management software Create file Cancel Your RSS Feed Name of RSS Feed: Number of items displayed: 5 10 15 20 50 100 Create RSS Cancel RSS Link Copy Full text links Elsevier Science Full text links Actions Cite Collections Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Display options Display options Format Abstract PubMed PMID Share Permalink Copy Page navigation Title & authors Abstract Similar articles Cited by Publication types MeSH terms Substances Related information LinkOut - more resources Title & authors Abstract Similar articles Cited by Publication types MeSH terms Substances Related information LinkOut - more resources Randomized Controlled Trial Regul Toxicol Pharmacol Actions Search in PubMed Search in NLM Catalog Add to Search . 2010 Jul-Aug;57(2-3):333-7. doi: 10.1016/j.yrtph.2010.04.005. Epub 2010 Apr 13. Short term effects of reduced exposure to cigarette smoke on white blood cells, platelets and red blood cells in adult cigarette smokers Hans J Roethig 1 , Tamara Koval , Raheema Muhammad-Kah , Yan Jin , Paul Mendes , Martin Unverdorben Affiliations Expand Affiliation 1 Altria Client Services, Richmond, VA 23219, USA. PMID: 20394790 DOI: 10.1016/j.yrtph.2010.04.005 Item in Clipboard Randomized Controlled Trial Short term effects of reduced exposure to cigarette smoke on white blood cells, platelets and red blood cells in adult cigarette smokers Hans J Roethig et al. Regul Toxicol Pharmacol . 2010 Jul-Aug . Show details Display options Display options Format Abstract PubMed PMID Regul Toxicol Pharmacol Actions Search in PubMed Search in NLM Catalog Add to Search . 2010 Jul-Aug;57(2-3):333-7. doi: 10.1016/j.yrtph.2010.04.005. Epub 2010 Apr 13. Authors Hans J Roethig 1 , Tamara Koval , Raheema Muhammad-Kah , Yan Jin , Paul Mendes , Martin Unverdorben Affiliation 1 Altria Client Services, Richmond, VA 23219, USA. PMID: 20394790 DOI: 10.1016/j.yrtph.2010.04.005 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Previous studies indicate that cigarette smokers have a 5-30% higher white blood cell counts (WBC) compared to non-smokers and higher red blood cell counts. Methods: This study was to pool hematology data from three similar studies and analyze the data for effects on WBC, its subpopulations, platelets, red blood cell count (RBC) and hematocrit in adult cigarette smokers three days after using an electrically heated cigarette smoking system (EHCSS) as a potential reduced exposure product (PREP) or no-smoking compared to smoking a conventional cigarette. Results: Lower exposure to cigarette smoke in adult, long term smokers, by using an EHCSS or stopping smoking, leads to statistically significant decreases of up to 9% in WBC, neutrophils, lymphocytes, platelets, RBC and hematocrit within three days. Switching from CC-smoking to EHCSS-smoking or no-smoking resulted in lower WBC and vice versa within 3 days. Conclusion: This clinical model may be used as a screening tool to find new technologies that could provide insights on changes in inflammation resulting from the change in cigarette smoke. Copyright 2010 Elsevier Inc. All rights reserved. PubMed Disclaimer Similar articles Acute effects of cigarette smoking on pulmonary function. Unverdorben M, Mostert A, Munjal S, van der Bijl A, Potgieter L, Venter C, Liang Q, Meyer B, Roethig HJ. Unverdorben M, et al. Regul Toxicol Pharmacol. 2010 Jul-Aug;57(2-3):241-6. doi: 10.1016/j.yrtph.2009.12.013. Epub 2010 Mar 15. Regul Toxicol Pharmacol. 2010. PMID: 20233598 Clinical Trial. Effects of different levels of cigarette smoke exposure on prognostic heart rate and rate--pressure-product parameters. Unverdorben M, van der Bijl A, Potgieter L, Venter C, Munjal S, Qiwei Liang, Meyer B, Röthig HJ. Unverdorben M, et al. J Cardiovasc Pharmacol Ther. 2008 Sep;13(3):175-82. doi: 10.1177/1074248408321571. Epub 2008 Jul 15. J Cardiovasc Pharmacol Ther. 2008. PMID: 18628485 Clinical Trial. Short-term exposure evaluation of adult smokers switching from conventional to first-generation electrically heated cigarettes during controlled smoking. Roethig HJ, Kinser RD, Lau RW, Walk RA, Wang N. Roethig HJ, et al. J Clin Pharmacol. 2005 Feb;45(2):133-45. doi: 10.1177/0091270004271253. J Clin Pharmacol. 2005. PMID: 15647405 Clinical Trial. [Smoking reduction and temporary abstinence: new approaches for smoking cessation]. Le Houezec J, Säwe U. Le Houezec J, et al. J Mal Vasc. 2003 Dec;28(5):293-300. J Mal Vasc. 2003. PMID: 14978435 Review. French. Effects of cigarette smoke and nicotine on platelets and experimental coronary artery thrombosis. Folts JD, Gering SA, Laibly SW, Bertha BG, Bonebrake FC, Keller JW. Folts JD, et al. Adv Exp Med Biol. 1990;273:339-58. doi: 10.1007/978-1-4684-5829-9_33. Adv Exp Med Biol. 1990. PMID: 2288288 Review. See all similar articles Cited by Impacts of cigarette smoking on blood circulation: do we need a new approach to blood donor selection? Wang J, Wang Y, Zhou W, Huang Y, Yang J. Wang J, et al. J Health Popul Nutr. 2023 Jul 5;42(1):62. doi: 10.1186/s41043-023-00405-2. J Health Popul Nutr. 2023. PMID: 37408051 Free PMC article. Review. Biomarkers of Exposure and Potential Harm in Two Weeks of Smoking Abstinence: Changes in Biomarkers of Platelet Function, Oxidative Stress, and Inflammation. Makena P, Scott E, Chen P, Liu HP, Jones BA, Prasad GL. Makena P, et al. Int J Mol Sci. 2023 Mar 27;24(7):6286. doi: 10.3390/ijms24076286. Int J Mol Sci. 2023. PMID: 37047257 Free PMC article. Clearing the Haze: How Does Nicotine Affect Hematopoiesis before and after Birth? Cool T, Baena ARY, Forsberg EC. Cool T, et al. Cancers (Basel). 2021 Dec 30;14(1):184. doi: 10.3390/cancers14010184. Cancers (Basel). 2021. PMID: 35008347 Free PMC article. Review. Fourteen days of smoking cessation improves muscle fatigue resistance and reverses markers of systemic inflammation. Darabseh MZ, Maden-Wilkinson TM, Welbourne G, Wüst RCI, Ahmed N, Aushah H, Selfe J, Morse CI, Degens H. Darabseh MZ, et al. Sci Rep. 2021 Jun 10;11(1):12286. doi: 10.1038/s41598-021-91510-x. Sci Rep. 2021. PMID: 34112815 Free PMC article. Elevated Neutrophil to Lymphocyte Ratio in Older Adults with Cocaine Use Disorder as a Marker of Chronic Inflammation. Soder HE, Berumen AM, Gomez KE, Green CE, Suchting R, Wardle MC, Vincent J, Teixeira AL, Schmitz JM, Lane SD. Soder HE, et al. Clin Psychopharmacol Neurosci. 2020 Feb 29;18(1):32-40. doi: 10.9758/cpn.2020.18.1.32. Clin Psychopharmacol Neurosci. 2020. 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+Potential Mechanisms Underlying the Role of Coffee in Liver Health - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Epub 2018 Jul 24. Potential Mechanisms Underlying the Role of Coffee in Liver Health Louise J M Alferink 1 , Jessica C Kiefte-de Jong 2 3 , Sarwa Darwish Murad 1 Affiliations Expand Affiliations 1 Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. 2 Department of Epidemiology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. 3 Global Public Health, Leiden University College, The Hague, The Netherlands. PMID: 30041273 DOI: 10.1055/s-0038-1666869 Item in Clipboard Review Potential Mechanisms Underlying the Role of Coffee in Liver Health Louise J M Alferink et al. Semin Liver Dis . 2018 Aug . Show details Display options Display options Format Abstract PubMed PMID Semin Liver Dis Actions Search in PubMed Search in NLM Catalog Add to Search . 2018 Aug;38(3):193-214. doi: 10.1055/s-0038-1666869. Epub 2018 Jul 24. Authors Louise J M Alferink 1 , Jessica C Kiefte-de Jong 2 3 , Sarwa Darwish Murad 1 Affiliations 1 Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. 2 Department of Epidemiology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. 3 Global Public Health, Leiden University College, The Hague, The Netherlands. PMID: 30041273 DOI: 10.1055/s-0038-1666869 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Coffee, the most consumed hot beverage worldwide, is composed of many substances, of which polyphenols, caffeine, and diterpenoids are well studied. Evidence on potential effects of coffee on human health has been accumulating over the past decades. Specifically, coffee has been postulated to be hepatoprotective in several epidemiological and clinical studies. Several underlying molecular mechanisms as to why coffee influences liver health have been proposed. In this review, the authors summarized the evidence on potential mechanisms by which coffee affects liver steatosis, fibrosis, and hepatic carcinogenesis. The experimental models reviewed almost unanimously supported the theorem that coffee indeed may benefit the liver. Either whole coffee or its specific compounds appeared to decrease fatty acid synthesis (involved in steatogenesis), hepatic stellate activation (involved in fibrogenesis), and hepatic inflammation. Moreover, coffee was found to induce apoptosis and increased hepatic antioxidant capacity, which are involved in carcinogenesis. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. PubMed Disclaimer Conflict of interest statement The authors declare no competing financial, professional, or personal interests. Similar articles Molecular Bases Underlying the Hepatoprotective Effects of Coffee. Salomone F, Galvano F, Li Volti G. Salomone F, et al. Nutrients. 2017 Jan 23;9(1):85. doi: 10.3390/nu9010085. Nutrients. 2017. PMID: 28124992 Free PMC article. Review. Retinoic acids and hepatic stellate cells in liver disease. Lee YS, Jeong WI. Lee YS, et al. J Gastroenterol Hepatol. 2012 Mar;27 Suppl 2:75-9. doi: 10.1111/j.1440-1746.2011.07007.x. J Gastroenterol Hepatol. 2012. PMID: 22320921 Review. Curcumin and liver disease. Vera-Ramirez L, Pérez-Lopez P, Varela-Lopez A, Ramirez-Tortosa M, Battino M, Quiles JL. Vera-Ramirez L, et al. Biofactors. 2013 Jan-Feb;39(1):88-100. doi: 10.1002/biof.1057. Epub 2013 Jan 10. Biofactors. 2013. PMID: 23303639 Review. Coffee and non-alcoholic fatty liver disease: brewing evidence for hepatoprotection? Chen S, Teoh NC, Chitturi S, Farrell GC. Chen S, et al. J Gastroenterol Hepatol. 2014 Mar;29(3):435-41. doi: 10.1111/jgh.12422. J Gastroenterol Hepatol. 2014. PMID: 24199670 Review. [Coffee as hepatoprotective factor]. Szántová M, Ďurkovičová Z. Szántová M, et al. Vnitr Lek. 2016 Winter;62(12):990-997. Vnitr Lek. 2016. PMID: 28139128 Review. Czech. See all similar articles Cited by Dietary Patterns, Foods, and Nutrients to Ameliorate Non-Alcoholic Fatty Liver Disease: A Scoping Review. Montemayor S, García S, Monserrat-Mesquida M, Tur JA, Bouzas C. Montemayor S, et al. Nutrients. 2023 Sep 14;15(18):3987. doi: 10.3390/nu15183987. Nutrients. 2023. PMID: 37764771 Free PMC article. Review. Population-attributable risk of modifiable lifestyle factors to hepatocellular carcinoma: The multi-ethnic cohort. Zhou K, Lim T, Dodge JL, Terrault NA, Wilkens LR, Setiawan VW. Zhou K, et al. Aliment Pharmacol Ther. 2023 Jul;58(1):89-98. doi: 10.1111/apt.17523. Epub 2023 Apr 13. Aliment Pharmacol Ther. 2023. PMID: 37051717 Free PMC article. Severe liver fibrosis in the HCV cure era: Major effects of social vulnerability, diabetes, and unhealthy behaviors. Carrieri P, Carrat F, Di Beo V, Bourlière M, Barré T, De Ledinghen V, Pageaux GP, Bureau M, Cagnot C, Dorival C, Delarocque-Astagneau E, Marcellin F, Pol S, Fontaine H, Protopopescu C; ANRS CO22 HEPATHER study group. Carrieri P, et al. JHEP Rep. 2022 Mar 30;4(6):100481. doi: 10.1016/j.jhepr.2022.100481. eCollection 2022 Jun. JHEP Rep. 2022. PMID: 35514789 Free PMC article. Effect of Coffee Consumption on Non-Alcoholic Fatty Liver Disease Incidence, Prevalence and Risk of Significant Liver Fibrosis: Systematic Review with Meta-Analysis of Observational Studies. Ebadi M, Ip S, Bhanji RA, Montano-Loza AJ. Ebadi M, et al. Nutrients. 2021 Aug 30;13(9):3042. doi: 10.3390/nu13093042. Nutrients. 2021. PMID: 34578919 Free PMC article. Diet and exercise in NAFLD/NASH: Beyond the obvious. Semmler G, Datz C, Reiberger T, Trauner M. Semmler G, et al. Liver Int. 2021 Oct;41(10):2249-2268. doi: 10.1111/liv.15024. Epub 2021 Aug 21. Liver Int. 2021. PMID: 34328248 Free PMC article. Review. 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+HbA1c Levels Are Associated with Chronic Kidney Disease in a Non-Diabetic Adult Population: A Nationwide Survey (KNHANES 2011–2013) - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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+            and transmitted securely. Log in Show account info Close Account Logged in as: username Dashboard Publications Account settings Log out Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now . Search PMC Full-Text Archive Search in PMC Advanced Search User Guide Journal List PLoS One PMC4696727 Other Formats PDF (417K) Actions Cite Collections Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than  characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Share Permalink Copy RESOURCES Similar articles Cited by other articles Links to NCBI Databases Journal List PLoS One PMC4696727 As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with,
+    the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice PLoS One. 2015; 10(12): e0145827. Published online 2015 Dec 30. doi: 10.1371/journal.pone.0145827 PMCID: PMC4696727 PMID: 26716684 HbA1c Levels Are Associated with Chronic Kidney Disease in a Non-Diabetic Adult Population: A Nationwide Survey (KNHANES 2011–2013) Seok Hui Kang , 1 Da Jung Jung , 2 Eun Woo Choi , 1 Kyu Hyang Cho , 1 Jong Won Park , 1 and Jun Young Do 1
+, * Seok Hui Kang 1 Division of Nephrology, Department of Internal Medicine, Yeungnam University Hospital, Daegu, Republic of Korea Find articles by Seok Hui Kang Da Jung Jung 2 Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea Find articles by Da Jung Jung Eun Woo Choi 1 Division of Nephrology, Department of Internal Medicine, Yeungnam University Hospital, Daegu, Republic of Korea Find articles by Eun Woo Choi Kyu Hyang Cho 1 Division of Nephrology, Department of Internal Medicine, Yeungnam University Hospital, Daegu, Republic of Korea Find articles by Kyu Hyang Cho Jong Won Park 1 Division of Nephrology, Department of Internal Medicine, Yeungnam University Hospital, Daegu, Republic of Korea Find articles by Jong Won Park Jun Young Do 1 Division of Nephrology, Department of Internal Medicine, Yeungnam University Hospital, Daegu, Republic of Korea Find articles by Jun Young Do Sheng-Nan Lu, Editor Author information Article notes Copyright and License information PMC Disclaimer 1 Division of Nephrology, Department of Internal Medicine, Yeungnam University Hospital, Daegu, Republic of Korea 2 Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea Kaohsiung Chang Gung Memorial Hospital, TAIWAN Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: SHK. Performed the experiments: SHK. Analyzed the data: SHK JYD. Contributed reagents/materials/analysis tools: DJJ EWC. Wrote the paper: KHC. Drafting the work: JWP JYD. Final approval of the version to be published: JYD. * E-mail: rk.ca.uy.dem@odyj Received 2015 Aug 25; Accepted 2015 Dec 9. Copyright © 2015 Kang et al This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. Associated Data Supplementary Materials S1 Fig: Adjusted restricted cubic spline curve showing odds ratio and 95% confidence interval (dashed line) for chronic kidney disease associated with HbA1c level (median value = 5.6% or 38 mmol/mol). Spline curve was adjusted for age and sex. (TIF) pone.0145827.s001.tif (503K) GUID: F0E68B19-04B7-44A5-BE3D-BC6362B901A3 S1 Table: Linear regression analyses for the number of metabolic syndrome components or estimated glomerular filtration rate according to HbA1c level. (DOCX) pone.0145827.s002.docx (22K) GUID: 124AFFCF-D9FD-4366-B909-F927B753D937 S2 Table: Logistic regression analyses for metabolic syndrome or chronic kidney disease according to HbA1c level. (DOCX) pone.0145827.s003.docx (24K) GUID: 621496B7-D661-4F95-B6C1-9263AD765667 S3 Table: AUCs, IDI, and NRI for multivariable models with or without HbA1c level. (DOCX) pone.0145827.s004.docx (19K) GUID: 121869CD-538F-48F9-A062-46FD096BEB92 Data Availability Statement All relevant data are within the paper and its Supporting Information files. Abstract Background Many studies have reported an association between glycated hemoglobin A1c (HbA1c) and metabolic syndrome (MetS) in non-diabetes patients. Each component of MetS is in fact related to chronic kidney disease (CKD) incidence and progression. Therefore, HbA1c in non-diabetic mellitus (DM) may be intrinsically associated with the prevalence of CKD. The hypothesis of the present study was that high HbA1c in non-DM patients is associated with CKD. Patients and Methods The total number of participants in this study was 24,594. The participants were divided into three groups according to their HbA1c levels: a Low group (<5.7% or <39 mmol/mol), a Middle group (5.7–6.0% or 39–42 mmol/mol), and a High group (>6.0% or >42 mmol/mol). The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Results The number of participants allocated to the Low, Middle, and High groups was 8,651, 4,634, and 1,387, respectively. Linear regression analyses were performed to evaluate the association between variables. Standardized β ± standard error was 0.25 ± 0.22 for waist circumference, 0.44 ± 0.20 for fasting glucose, –0.14 ± 0.30 for high-density lipoprotein cholesterol levels, 0.15 ± 2.31 for triglyceride levels, 0.21 ± 0.00 for systolic blood pressure, 0.10 ± 0.00 for diastolic blood pressure, and –0.22 ± 0.42 for eGFR ( P < 0.001 for all variables). eGFR in non-diabetes participants was inversely associated with the HbA1c level, where eGFR decreased as HbA1c levels increased. Standardized βs were –0.04 ± 0.42 in multivariable analysis ( P < 0.001). The proportion of participants with only MetS, only CKD, or both MetS and CKD was higher in the High group than in the Low and Middle groups. Conclusion High HbA1c in non-DM patients may be associated with CKD. Renal function in patients with high HbA1c levels may need to be monitored. Background Chronic kidney disease (CKD) is a widely recognized public health issue and associated with high morbidity and mortality when compared to the non-CKD population [ 1 , 2 ]. The United States Real Data System 2014 Annual Data Report showed that CKD occurs in approximately 13.6% of the general population [ 3 ]. Indeed, the prevalence of CKD appears to be rising rapidly with increased life expectancy. Overall Medicare expenditures for CKD were $44,581 million in 2012 [ 3 ]. Screening for and effective monitoring of CKD are essential for increasing patient quality of life and decreasing the public health burden. Glycated hemoglobin (HbA1c) is an important indicator for long-term glucose control and has recently been recommended for use in the diagnosis of diabetes mellitus (DM) by the American Diabetes Association (ADA) [ 4 ]. However, the use of HbA1c for identifying pre-diabetes is a controversial topic [ 5 ]. In 2015, the ADA suggested that an HbA1c of 5.7–6.4% (39–46 mmol/mol) is reasonable for the diagnosis of pre-diabetes and that patients with HbA1c > 6.0% (>42 mmol/mol) should be considered to be at very high risk for DM [ 4 ]. Although the clinical significance of HbA1c as a surrogate marker of metabolic syndrome (MetS) has not yet been fully examined, many studies have reported an association between HbA1c and MetS in non-DM patients [ 6 – 8 ]. Each component of MetS is in fact related to CKD incidence and progression [ 9 ]. Therefore, HbA1c in non-DM may be intrinsically associated with the prevalence of CKD. The aim of the present study was to evaluate the clinical association between HbA1c and CKD in non-DM patients. The hypothesis of the present study was that high HbA1c in non-DM patients is associated with CKD. Patients and Methods Study population Data from the Korean National Health and Nutrition Examination Survey (KNHANES 2011–2013) were used for this analysis. The KNHANES is a nationwide, multi-stage, stratified survey of a representative sample of the South Korean population and is conducted by the Korea Centers for Disease Control and Prevention. The total number of participants from KNHANES analyzed in this study was 24,594. Participants were excluded from the present study based on the following criteria: data could not be provided for HbA1c (n = 2,350) or renal function (n = 2) or participants were younger than 18 years of age (n = 5,385) or had DM (defined as a self-reported history of a DM diagnosis, a fasting glucose level of ≥126 mg/dL, or HbA1c ≥ 6.5% (≥48 mmol/mol; n = 2,185). As a result, 14,672 participants were ultimately included in this study. Ethical approval for this study was obtained from the institutional review board of Yeungnam University Hospital (2015-04-004). The board waived the need for informed consent, as the subjects’ records and information were anonymized and de-identified prior to analysis. Study variables Clinical and laboratory data collected during clinical examination included the following: age, sex, serum creatinine (mg/dL), body mass index (BMI, kg/m 2 ), waist circumference (WC, cm), HbA1c (%, mmol/mol), fasting blood glucose (mg/dL), total cholesterol (mg/dL), high-density lipoprotein (HDL) cholesterol levels (mg/dL), triglyceride levels (mg/dL), systolic blood pressure (mmHg), diastolic blood pressure (mmHg), smoking status, alcohol intake, and levels of physical activity. HbA1c levels were measured using a high performance liquid chromatography system (HLC-723G7; Tosoh Co., Tokyo, Japan). In the present study, the participants were divided into three groups according to their HbA1c levels: a Low group (<5.7% or <39 mmol/mol), a Middle group (5.7–6.0% or 39–42 mmol/mol), and a High group (>6.0% or >42 mmol/mol). Serum creatinine levels were measured using a Hitachi Automatic Analyzer (alkaline picrate, Jaffé kinetic). The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [ 10 ]. CKD was defined as an eGFR <60 mL/min/1.73 m 2 . Urine albumin level was measured from random samples using a turbidimetric immunoassay (Hitachi Automatic Analyzer 7600, Hitachi). Urine creatinine level was measured using a colorimetric method (Hitachi Automatic Analyzer 7600, Hitachi). Urine albumin and creatinine concentrations were measured in the same laboratory for all surveys. The inter-assay coefficient of variation for all laboratory work was consistenly low (<3.1%). The urine albumin-creatinine ratio (UACR) was calculated in mg per g of creatinine (mg/g). Albuminuria was defined as UACR ≥30 mg/g. Patients were classified according to smoking status as current smokers, ex-smokers, or non-smokers. Alcohol intake was defined using the Korean version of ‘standard drinking’ based on the WHO classification [ 11 , 12 ]. Alcohol intake was classified into 3 categories: abstinence (no consumption of alcohol within the last year); moderate drinking (women: 0.1–19.99 g pure alcohol/day; men: 0.1–39.99 g pure alcohol/day), and heavy drinking (women: ≥20 g pure alcohol/day; men: ≥40 g pure alcohol/day). Physical activity was assessed by the presence of exercise. The presence of exercise was defined as moderate activity for more than 30 min/day, for 5 days/week or intense activity for more than 20 min/day, for 3 days/week, or walking more than 30 min/day, for 5 days/week. Coronary artery disease (CAD) was defined as a self-reported history of angina or myocardial infarction. Cerebrovascular accident (CVA) was defined as a self-reported history of stroke. MetS was defined according to the Adult Treatment Panel III criteria using the modified cutoff values for Asian populations as suggested by the Asia-Pacific guidelines [ 13 , 14 ]. Briefly, elevated blood glucose was defined as a fasting blood glucose level ≥100 mg/dL or a self-reported history of DM. Elevated blood pressure was defined as a systolic or diastolic blood pressure ≥130/85 mmHg and a self-reported history of hypertension. A low HDL cholesterol level was defined as <40 mg/dL in men and <50 mg/dL in women. Elevated triglyceride levels were defined as a serum triglyceride level of ≥150 mg/dL. Abdominal obesity was defined as a WC >90 cm in men and >80 cm in women. MetS was defined as the presence of ≥3 components of MetS. Statistical analyses The data were analyzed using the Statistical package for the Social Sciences software package (SPSS v.21, Chicago, IL., USA). Categorical variables were expressed as both counts and percentages. Continuous variables were expressed as the mean ± standard deviation (SD). UACR was a non-parametric variable expressed as a median (95% CI), and was compared using the Kruskal-Wallis test. The Pearson’s χ 2 or Fisher’s exact test was used to analyze categorical variables. For continuous variables, means were compared using a one-way analysis of variance. Correlations were analyzed in order to assess the strength of the relationship between continuous variables. Linear regression analysis was performed to assess independent predictors of eGFR or number of MetS components. Variance inflation factor was used to identify multicollinearity for the multivariable linear regression model. Variance inflation factor greater than 10 was not accepted. Logistic regression analyses were used for estimating the odds ratios (OR) and 95% confidence intervals (CI), which were then applied towards determining the relationship between HbA1c and CKD or MetS. Confounders were defined by their likelihood of preceding or contributing to the development of MetS or CKD. The selection of confounder was based on previous literatures [ 15 , 16 ]. For MetS, the covariates were HbA1c, age, sex, BMI, alcohol intake, smoking status, and physical activity. For CKD, the covariates were HbA1c, age, sex, BMI, alcohol intake, smoking status, physical activity, CAD, CVA, WC, HDL cholesterol levels, triglyceride levels, systolic blood pressure, and diastolic blood pressure. Discrimination–which is the ability of the model to differentiate between participants who have CKD or MetS and those who do not–was examined using the area under the receiver operating characteristic (AUROC) curve. AUROC analysis was also performed in order to calculate cutoff values, sensitivity, and specificity. Optimal cutoff risk point was defined as the maximum Youden index in the AUROC. The AUROC was calculated using the MedCalc software package (v.11.6.1.0, MedCalc, Mariakerke, Belgium). We also calculated the integrated discrimination improvement (IDI) and the net reclassification improvement (NRI) with a category-free option among models, following the methodology of Penica et al. [ 17 , 18 ]. A restricted cubic spline curve was used to evaluate non-linear relationships between the HbA1c level and CKD, which was adjusted for age and sex. The restricted cubic spline curve was plotted using statistical software SAS version 9.4 (SAS Campus Drive, Cary, NC, USA). A P -value less than 0.05 was considered statistically significant. Results Clinical characteristics of participants The number of participants allocated to the Low, Middle, and High groups was 8,651, 4,634, and 1,387, respectively ( Table 1 ). Age, BMI, WC, eGFR, total cholesterol, fasting blood glucose, triglyceride levels, and systolic and diastolic blood pressure were higher in the High group than either the Low or Middle group. Table 1 Clinical characteristics of participants by HbA1c level. Low (n = 8,651) Middle (n = 3,865) High (n = 2,156) P -value * Age (years) 43.2 ± 15.6 53.2 ± 15.4 59.7 ± 12.6 <0.001 Sex (male, %) 3,608 (41.7%) 2,037 (44.0%) 563 (40.6%) 0.017 HbA1c (%, mmol/mol) 5.35 ± 0.22, 35 ± 2 5.82 ± 0.11, 40 ± 1 6.20 ± 0.11, 44 ± 1 <0.001 Body mass index (kg/m 2 ) 23.0 ± 3.2 24.0 ± 3.3 24.9 ± 3.3 <0.001 Creatinine (mg/dL) 0.82 ± 0.19 0.84 ± 0.18 0.86 ± 0.37 <0.001 Waist circumference (cm) 78.3 ± 9.5 81.9 ± 9.3 84.6 ± 9.2 <0.001 Total cholesterol (mg/dL) 184.0 ± 33.7 196.8 ± 36.0 199.4 ± 39.8 <0.001 Fasting blood glucose (mg/dL) 90.1 ± 7.9 95.3 ± 8.9 102.1 ± 10.2 <0.001 Triglyceride (mg/dL) 115.3 ± 91.3 138.6 ± 105.1 152.4 ± 104.5 <0.001 High density lipoprotein (mg/dL) 54.6 ± 12.9 51.9 ± 11.9 49.6 ± 11.7 <0.001 Systolic blood pressure (mmHg) 114.9 ± 15.8 120.0 ± 16.8 124.6 ± 17.0 <0.001 Diastolic blood pressure (mmHg) 74.8 ± 10.4 76.3 ± 10.3 77.0 ± 10.4 <0.001 Physical activity (%) 3897 (45.0%) 1,993 (45.2%) 543 (40.9%) <0.001 Coronary artery disease (%) 72 (0.8%) 113 (2.4%) 70 (5.0%) <0.001 Cerebrovascular accident (%) 65 (0.8%) 87 (1.9%) 45 (3.2%) <0.001 Alcohol intake <0.001 Abstinence 1866 (21.6%) 1,334 (28.8%) 505 (36.4%) Moderate drinking 6071 (70.2%) 2,929 (63.2%) 784 (56.5%) Heavy drinking 382 (4.4%) 147 (3.2%) 39 (2.8%) Unknown 332 (3.8%) 224 (4.8%) 59 (4.3%) Smoking 0.004 Non-smoker 5190 (60.0%) 2,616 (56.5%) 806 (58.1%) Ex-smoker 1490 (17.2%) 897 (19.4%) 265 (19.1%) Current smoker 1653 (19.1%) 902 (19.5%) 257 (18.5%) Unknown 318 (3.7%) 219 (4.7%) 59 (4.3%) eGFR (mL/min/1.73 m 2 ) 96.6 ± 18.0 91.0 ± 17.0 87.0 ± 17.2 <0.001 Open in a separate window Data are expressed as numbers (percentages) for categorical variables and mean ± standard deviations for continuous variables. * P values were tested by one-way analysis of variance for continuous variables and Pearson χ 2 test or Fisher exact test for the categorical variables. The proportion of participants with only MetS in the Low, Middle, and High groups was 9.1%, 20.4%, and 33.9%, respectively ( P < 0.001), whereas the proportion of participants with only CKD in the Low, Middle, and High groups was 0.9%, 2.0%, and 3.5%, respectively ( P < 0.001). The proportion of participants with both MetS and CKD in the Low, Middle, and High groups was 0.2%, 0.7%, and 2.0%, respectively ( P < 0.001). The proportion of participants with only MetS, only CKD, or both MetS and CKD was higher in the High group than in the Low and Middle groups. Association between HbA1c level and MetS or CKD We performed univariate linear regression analyses to evaluate the association between HbA1c and each MetS components. Standardized β ± standard error was 0.25 ± 0.22 for WC, 0.44 ± 0.20 for fasting glucose,–0.14 ± 0.30 for HDL cholesterol levels, 0.15 ± 2.31 for triglyceride levels, 0.21 ± 0.00 for systolic blood pressure, and 0.10 ± 0.00 for diastolic blood pressure ( P < 0.001 for all variables). There were positive associations between HbA1c levels and WC, fasting glucose, triglyceride levels, systolic blood pressure, and diastolic blood pressure, and negative association between HbA1c levels and HDL cholesterol levels. In addition, HbA1c in non-diabetes participants was associated with the number of MetS components observed ( S1 Table ). Numbers of MetS components increased in accordance with increased HbA1c levels. Univariate and multivariable linear regression analyses were also performed to evaluate the association between HbA1c level and eGFR ( S1 Table ). eGFR in non-diabetes participants was inversely associated with the HbA1c level, where eGFR decreased as HbA1c levels increased. Logistic regression showed that the OR for only MetS with a 1% (11 mmol/mol) increase in HbA1c was 7.53 (95% CI, 6.51–8.70) in univariate analysis and 3.38 (95% CI, 2.85–4.00) in multivariable analysis ( S2 Table ). The OR for only CKD with a 1% (11 mmol/mol) increase in HbA1c was 9.32 (95% CI, 6.16–14.11) in univariate analysis and 2.13 (95% CI, 1.33–3.40) in multivariable analysis. The OR for both MetS and CKD with a 1% (11 mmol/mol) increase in the level of HbA1c was 21.49 (95% CI, 10.86–42.52) on univariate analysis and 4.12 (95% CI, 1.80–9.39) on multivariable analysis. A restricted cubic spline curve was plotted, with 5.6% (38 mmol/mol) as the median HbA1c level, and it was adjusted for age and sex ( S1 Fig ). A high HbA1c level was associated with increased OR for CKD. To estimate the incremental value of HbA1c level to predict only MetS, only CKD or both MetS and CKD, we compared the probabilities of events and nonevents of models using relative IDI and category-free NRI ( S3 Table ). The IDI of adding HbA1c level to the multivariable model improved significantly. The addition of HbA1c to multivariable models resulted in a significant improvement of the category-free NRI. The AUROC value of HbA1c was 0.700 (95% CI, 0.692–0.708) for only MetS, 0.685 (95% CI, 0.678–0.693) for only CKD, and 0.760 (95% CI, 0.752–0.768) for both MetS and CKD ( P < 0.001). The cutoff value was >5.7% (> 39 mmol/mol) for only MetS, >5.6% (>38 mmol/mol) for only CKD, and >5.7% (>39 mmol/mol) for both MetS and CKD ( Fig 1 ). Sensitivity and specificity for predicting only MetS were 56.7% and 74.2%, respectively. Those for predicting only CKD were 64.2% and 63.8%, respectively, while those for predicting both MetS and CKD were 65.1% and 74.2%, respectively. Open in a separate window Fig 1 Receiver operating characteristic curves of HbA1c for the prediction of metabolic syndrome or chronic kidney disease. A. Only metabolic syndrome. B. Only chronic kidney disease. C. Both metabolic syndrome and chronic kidney disease. Association between HbA1c level and UACR In participants with eGFR ≥60 mL/min/1.73 m 2 , the correlation coefficient between UACR and HbA1c was 0.043 ( P < 0.001). UACR in the Low, Middle, and High groups was 9.2 (95% CI, 8.1–10.2), 11.5 (95% CI, 9.9–13.1), and 15.9 (95% CI, 12.6–19.1), respectively ( P < 0.001). The portion of participants with albuminuria in the Low, Middle, and High groups was 329 (4.3%), 239 (5.6%), and 104 (8.2%), respectively ( P < 0.001). Discussion In the present study, a clear association was observed between HbA1c and MetS in non-DM Asian patients, which is in line with numerous other studies that have shown an association between these two variables [ 6 – 9 , 19 – 23 ]. Studies aiming to investigate this association should exclude patients with DM as this condition is a critical confounding factor for the prevalence of MetS and certain studies have reported no exclusion of patients with HbA1c ≥ 6.5% (≥48 mmol/mol) [ 21 , 23 ]. While a few previous studies did exclude DM patients with HbA1c ≥ 6.5% (≥48 mmol/mol), the majority of these were single-center studies with a possibility of selection bias [ 8 , 21 , 23 ]. The present study analyzed a nationwide, multi-stage, stratified survey of a representative sample of the South Korean population and excluded patients with HbA1c ≥ 6.5% (≥48 mmol/mol). Results were adjusted for variable confounders and revealed that HbA1c in non-DM patients is associated with the number of MetS components. The linear regression analyses did show an association between HbA1c and each component of MetS as continuous variables. The present study showed an association between the HbA1c level and CKD with or without MetS. The associations between insulin resistance and CKD are very complex and not clear. Previous studies have shown that each component of MetS is associated with development and progression of CKD. Among the components of MetS, insulin resistance may be the most important related etiological factor for CKD [ 24 ]. HbA1c is an indicator predicting insulin resistance. High HbA1c level in pre-diabetes is associated with insulin resistance or metabolic syndrome, which can lead to development and progression of CKD. Our results suggest that high HbA1c is mainly associated with insulin resistance, which may result in development of CKD. However, CKD results in interference with the intracellular signaling pathway initiated by insulin, which results in insulin resistance [ 25 ]. The literature has shown conflict results concerning an association between HbA1c and CKD. Certain studies have shown that HbA1c is associated with development of CKD in non-DM patients [ 26 – 29 ]. Gerstein et al. conducted a prospective study with an average 4.5-year follow-up and successfully showed that HbA1c is associated with development of overt nephropathy defined by albuminuria or proteinuria [ 26 ]. Zhang et al. evaluated a cross-sectional study using a German cohort and showed an association between HbA1c and eGFR or CKD defined as eGFR < 60 mL/min/1.73 m 2 [ 27 ]. Although DM was adjusted for in multivariable analysis, this study did include DM patients. A study by Plantinga et al. enrolled non-DM patients using data from the USA; however, this group evaluated the association between CKD and pre-diabetic status classified by fasting glucose level [ 28 ]. In contrast to the afore-mentioned studies, there have been reports that no association exists between the two variables if variable cardiovascular risk factors are adjusted for [ 30 – 33 ]. Selvin et al. observed no significant difference in the development of CKD in patients with HbA1c 5.7–6.5% (39–48 mmol/mol) when compared to patients with HbA1c <5.7% (<39 mmol/mol) [ 31 ]. However, that study did not include HbA1c as a diagnostic criterion for DM and could possibly include DM patients. To the best of our knowledge, this is the first study to evaluate the association between HbA1c and CKD in an Asian population. The results of the present study do show an association between HbA1c and eGFR as a continuous variable for renal function or CKD as a categorical variable. In addition, we calculated IDI and NRI as more advanced prediction analyses; these analyses showed that in comparison with multivariable models using only traditional risk factors, the addition of HbA1c to multivariable models improved both IDI and NRI. Unfortunately, cross-sectional study such as this cannot evaluate the causal relationship among these variables. Further prospective studies are needed to identify the causality between two variables. The present study showed the association between HbA1c and albuminuria as a surrogate marker for early CKD. In participants with eGFR ≥60 mL/min/1.73 m 2 , UACR and the proportion of participants with albuminuria increased as HbA1c increased. Previous studies demonstrated that HbA1c level is associated with albuminuria in participants with DM [ 34 – 39 ]. Poor glycemic control in DM plays a key role in rapid progression to diabetic nephropathy, which is caused by variable hemodynamic, metabolic, or endothelial dysfunction [ 40 ]. Many previous studies have demonstrated pathophysiology or factors associated with progression to albuminuria in DM, but there have been few studies regarding the association between HbA1c and albuminuria in non-DM participants. The present study reveals that high-normal HbA1c levels previously considered to be in the normal range may be associated with albuminuria and may function as a marker for early CKD in non-DM participants. The pathophysiology of the association between CKD and HbA1c in non-DM participants may be the same as that in high-glucose DM participants. This may ultimately result in subclinical or clinical atherosclerosis in various vessels. Glycemic control is a well-known risk factor for the development of atherosclerosis in DM participants. Previous studies also showed a positive association between prediabetes and atherosclerosis as measured by carotid intimal thickness, subclinical myocardial damage, or coronary artery calcium [ 41 – 43 ]. These pathologic changes can develop in the renal vasculature, which results in CKD with albuminuria. Very low HbA1c level may be associated with malnutrition, inflammation, and atherosclerosis. However, in our study, a spline curve showed that low HbA1c level is not associated with CKD compared to median HbA1c level. Two factors may be associated with this discordance. First, malnutrition combined with low HbA1c level is common in participants with severe comorbidities, such as advanced cancer or end-stage renal disease, compared with the general population. Participants enrolled in our study may have been healthier than other selected populations who visited hospitals, which could have resulted in selection bias. Second, HbA1c may be used as a nutritional marker, but it mainly reflects glucose intake. The numbers of participants with total cholesterol < 100 mg/dL as another marker of malnutrition were 6, 7, and 0 in the Low, Middle, and High groups, respectively. There were few participants with malnutrition defined by total cholesterol level in our study. This study has a number of limitations. First, it is a retrospective cross-sectional design and therefore cannot establish causality between two variables. Second, the available data did not include post-prandial blood glucose levels as a criterion for DM and a small number of DM patients could therefore have included. However, all participants have HbA1c < 6.5% (<48 mmol/mol) and a fasting blood glucose <126 mg/dL. Third, KDIGO guidelines define CKD as eGFR < 60 mL/min/1.73 m 2 for >3 months [ 44 ]. In our study, CKD was defined using a single serum creatinine or single spot urine sample. However, the effect of these limitations will be reduced by the strength of a nation-wide representative sample. In conclusion, high HbA1c in non-DM patients may be associated with CKD. Renal function in patients with high HbA1c levels may need to be monitored. Supporting Information S1 Fig Adjusted restricted cubic spline curve showing odds ratio and 95% confidence interval (dashed line) for chronic kidney disease associated with HbA1c level (median value = 5.6% or 38 mmol/mol). Spline curve was adjusted for age and sex. (TIF) Click here for additional data file. (503K, tif) S1 Table Linear regression analyses for the number of metabolic syndrome components or estimated glomerular filtration rate according to HbA1c level. (DOCX) Click here for additional data file. (22K, docx) S2 Table Logistic regression analyses for metabolic syndrome or chronic kidney disease according to HbA1c level. (DOCX) Click here for additional data file. (24K, docx) S3 Table AUCs, IDI, and NRI for multivariable models with or without HbA1c level. (DOCX) Click here for additional data file. (19K, docx) Funding Statement This work was supported by the 2014 Yeungnam University Research Grant. 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+PERCEIVED WEIGHT DISCRIMINATION AMPLIFIES THE LINK BETWEEN CENTRAL ADIPOSITY AND NONDIABETIC GLYCEMIC CONTROL (HBA1C) - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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+    the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Ann Behav Med. Author manuscript; available in PMC 2012 Apr 1. Published in final edited form as: Ann Behav Med. 2011 Apr; 41(2): 243–251. doi: 10.1007/s12160-010-9238-9 PMCID: PMC3082470 NIHMSID: NIHMS255179 PMID: 21136227 PERCEIVED WEIGHT DISCRIMINATION AMPLIFIES THE LINK BETWEEN CENTRAL ADIPOSITY AND NONDIABETIC GLYCEMIC CONTROL (HBA1C) Vera K. Tsenkova , Ph.D., Deborah Carr , Ph.D., Dale A. Schoeller , Ph.D., and Carol D. Ryff , Ph.D. Vera K. Tsenkova School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA Find articles by Vera K. Tsenkova Deborah Carr Department of Sociology and Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, NJ, USA Find articles by Deborah Carr Dale A. Schoeller Department of Nutritional Sciences, University of Wisconsin— Madison, Madison, WI, USA Find articles by Dale A. Schoeller Carol D. Ryff Department of Psychology, Institute on Aging, University of Wisconsin— Madison, Madison, WI, USA Find articles by Carol D. Ryff Author information Copyright and License information PMC Disclaimer Vera K. Tsenkova, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA; Contributor Information . PMC Copyright notice The publisher's final edited version of this article is available  at Ann Behav Med Abstract Background While the preclinical development of type 2 diabetes is partly explained by obesity and central adiposity, psychosocial research has shown that chronic stressors such as discrimination have health consequences as well. Purpose We investigated the extent to which the well-established effects of obesity and central adiposity on nondiabetic glycemic control (indexed by HbA 1c ) were moderated by a targeted psychosocial stressor linked to weight: perceived weight discrimination. Methods Data came from the nondiabetic subsample (n=938) of the Midlife in the United States (MIDUS II) survey. Results Body mass index (BMI), waist-to-hip ratio, and waist circumference were linked to significantly higher HbA 1c ( p < .001). Multivariate-adjusted models showed that weight discrimination exacerbated the effects of waist-to-hip ratio on HbA 1c ( p < .05), such that people who had higher WHR and reported weight discrimination had the highest HbA 1c levels. Conclusions Understanding how biological and psychosocial factors interact at nondiabetic levels to increase vulnerability could have important implications for public health and education strategies. Effective strategies may include targeting sources of discrimination, rather than solely targeting health behaviors and practices of overweight and obese persons. Keywords: diabetes, weight discrimination, obesity, individual differences Introduction The prevalence of type 2 diabetes has risen steadily over the last three decades ( 1 ) and this trend is expected to persist. In the United States, more than 23 million adults have diabetes, 57 million have pre-diabetes, and an estimated one-third of children born in the year 2000 will suffer from diabetes at some point in their lifetime ( 2 , 3 ). The preclinical progression to type 2 diabetes is only partly explained by obesity and fat distribution, sedentary lifestyle, genetics, and aging. Even obesity and central adiposity, perhaps the most frequently documented and most well understood risk factors for type 2 diabetes, do not translate to an inevitable risk for diabetes: while more than 80% of people with type 2 diabetes are obese, most obese people never develop diabetes ( 4 ). Therefore, researchers have looked for additional factors at multiple levels that influence glycemic control ( 5 ). Emerging studies have documented that psychosocial vulnerabilities, such as various types of stress and depression, may dysregulate glycemic control even before type 2 diabetes is diagnosed ( 6 – 9 ). The interplay of these and other risk factors, however, is not well understood: biomedical research tends to overlook psychosocial influences, whereas psychosocial models frequently treat traditional biological risk factors as noise factors to be controlled for statistically. The overarching goal of this study was to integrate these separate strands of previous biomedical and psychosocial research by investigating whether the impact of the established health risk factors on glycemic control was moderated by perceived discrimination. Stigma is described as a social construction influenced by cultural, historical, and situational factors ( 10 ), and the visibility and perceived controllability of the stigmatized condition are important determinants of who will be stigmatized. Characteristics perceived to be the responsibility of the person bearing the stigma are more likely to be denigrated ( 11 ). Biopsychosocial models of discrimination have a broader interest in the role of stress as a determinant of social disparities in health ( 12 ) and describe perceived race discrimination as a class of stressors with consequences for health outcomes ( 13 ). Previous research has documented the direct harmful physical health consequences of perceived discrimination for a range of outcomes including mortality, hypertension, poor self-rated health, and blood pressure reactivity ( 13 – 18 ), as well as mental health ( 19 – 21 ). Weight discrimination is an important social stressor which has only recently garnered scholarly attention. Theoretical work on the origins of weight stigma has identified perceived controllability of the cause of obesity as particularly important ( 22 , 23 ). The prevalence of weight discrimination is comparable to rates of race discrimination, particularly among women ( 24 ), and translates into unfair treatment for overweight and obese persons in domains of employment, healthcare, and education ( 25 , 26 ). Obesity is considered one of the most enduring stigmas, due in part to the perception that extra weight is due to characterological flaws such as laziness, gluttony, or lack of self-discipline ( 25 , 26 ). Building on this prior work that has documented links between discrimination and health, the focus of our study was to investigate individual differences in the relationship between obesity, central adiposity, and glycemic control. Specifically, measures of obesity (body mass index=BMI) and central adiposity (waist-to-hip ratio and waist circumference) were the key biological risk factors, given their well-documented causal relationships with dysregulated glycemic control and type 2 diabetes ( 27 , 28 ). Specific to obesity, perceived discrimination due to one’s body weight was the key psychosocial factor and was expected to amplify the effects of obesity and central adiposity on nondiabetic glycemic control. Treating weight discrimination as an individual difference variable draws explicit attention to the fact that some individuals, but not others, perceive themselves to experience such discrimination. Our focus on perceived discrimination as an individual difference variable is not about accuracy versus distortion in perceptions of how one is treated based on personal weight/body size— rather, it is about the fact that some obese people see themselves as treated unfairly by others, while other obese people do not. Thus, the central question was whether obese people who also perceived daily weight discrimination (whether warranted or not) were more likely to have dysregulated glycemic control than obese people who did not report discrimination due to weight. We know of no studies that investigate whether perceived discrimination attributed specifically to one’s body weight exacerbates the harmful physical health effects of body weight. However, animal research provides initial evidence that stress and obesity have interactive effects on glycemic control. In a series of experiments, blood samples were drawn from obese and lean mice after exposure to stress. Both lean and obese animals evidenced increases in plasma glucose levels attributable to the stress: however, the effect was significantly larger in the obese mice ( 29 ). In our study, glycemic control was indexed by glycosylated hemoglobin (HbA 1c ) and provided a time-integrated measure of blood glucose levels over the previous two to three months. Glycemic control is essential for the management of type 1 and type 2 diabetes, as high HbA 1c is linked to diabetes-related complications and cardiovascular events ( 30 ). Recent research highlights the importance of nondiabetic HbA 1c as a cardiovascular risk factor ( 31 ) and predictor of other diseases ( 32 , 33 ), suggesting that some health correlates of glycemic control might emerge earlier (i.e., at nondiabetic levels) than normally recognized. Current guidelines by the American Diabetes Association recommend the use of HbA 1c to diagnose diabetes, with a threshold of ≥6.5 ( 34 ). Specific Hypotheses Consistent with prior studies, BMI, waist-to-hip ratio, and waist circumference were expected to be linked to higher nondiabetic HbA 1c , after control variables were adjusted. We predicted that perceived weight discrimination would exacerbate the effects of BMI, waist-to-hip ratio, and waist circumference, resulting in higher HbA 1c. This inquiry builds upon studies documenting the direct effects of perceived discrimination on health outcomes; however, prior work on the moderating effects of discrimination are notably absent from existing research. Methods and Procedures Study Population and Design This study used data from the Midlife in the US (MIDUS) II, a longitudinal follow-up of the original MIDUS I study (N = 7,108) conducted in 1995/96 to investigate the role of behavioral, psychological, and social factors in understanding differences in physical and mental health. All eligible participants were non-institutionalized, English-speaking adults in the coterminous United States, aged 25 to 74. Approximately 9–10 years after the baseline interview respondents were re-contacted (longitudinal retention rate was 75%, adjusted for mortality). MIDUS II added comprehensive biomarker assessments on a subsample of participants who had completed a phone interview and self-administered questionnaires. Forty-three percent of the MIDUS II participants who were eligible to participate in the biological data collection agreed to be in the study. This rate is somewhat lower than other epidemiological studies involving a visit to a health clinic (e.g., 57% response rate in the Cardiovascular Health Study) ( 35 ). However, the MIDUS biological protocol is more intensive than other studies, requiring significant travel for most respondents, and also an overnight stay at the clinic. There were no significant differences between the biological subsample and the main MIDUS sample in the proportion who are obese or who reported experiences of weight-related discrimination. Additionally, the biological subsample was not significantly different from the main MIDUS sample on age, sex, race, marital status, or income, although respondents in the biological protocol were significantly more likely to have a college degree and significantly less likely to have only high school or some college compared with the main sample ( 36 ). All analyses in this study used data from the biological subsample of MIDUS II and included 1255 participants ages 35 to 86 ( M =57.32, SD =11.55), more than half of whom (57%) were female. We excluded 317 participants from analyses because of a self-reported diabetes diagnosis, taking anti-diabetic medications, fasting glucose above 126 mg/dl, HbA 1c level above 6.5%, or missing data on any variables used in the analyses, yielding a final sample of 938 nondiabetic participants with complete data. The nondiabetic subsample of the biomarker sample included 96 twin pairs, thus raising potential concerns about non-independence. We employed a resampling strategy: one family member from each family in the MIDUS data was selected and then analyses were re-estimated with data that had been purged of dependencies among sample respondents. These findings were then compared with the results obtained when MIDUS samples were combined (and thus included dependencies in the data). We found no evidence for bias: the patterns of all main effects and interactions remained the same and coefficient sizes varied only slightly. More details on MIDUS participants and subsamples is available in another publication ( 36 ). Table 1 includes the descriptive information for all variables. Table 1 Means (and SDs) or Proportions for All Measures (N = 938) Mean (SD) or proportion Dependent Variable HbA 1c (range: 3.6–6.5) 5.76 (.38) Independent Variables Body mass index (range: 14.99–64.06) 29.02 (6.05) Waist to hip ratio (range: .62–1.15 ) 0.88 (0.09) Waist circumference (range: 24.02–56.10) 37.75 (6.4) Perceived weight discrimination (1=Yes) 0.09 Control Variables Race (1=White) 0.83 Gender (1=Male) 0.43 Age (range: 35–86) 56.87 (11.55) Income (range: 0–300,000) 73,801 (59,275) Education (8–21) 14 (3.1) Taking cholesterol medications (1=Yes) 0.24 Number of Cholesterol Medications (range: 0–2) 0.26 (.5) Exercise 3 Times a Week (1=yes) 0.79 Fast Food Consumption Weekly (range: 0– 5) 2.34 (.91) Current Smoker (1=yes) 0.13 Global Sleep Score (range: 0–19) 6.05 (3.6) Time Lag (months between survey and bio assessments) (range: 0–62) 26.39 (14.33) Open in a separate window Measures Dependent variable: HbA 1c The HbA 1c assay was a colorimetric total-hemoglobin determination combined with an immunoturbidometric HbA 1c assay, carried out using a Cobas Integra Systems instrument (Roche Diagnostics) ( 37 , 38 ). The Roche Diagnostics protocol stated that an intra-assay coefficient of variation (CV) for this method ranged between 2.2%–2.3%, and the inter-assay CV was 2.4%. Duplicate samples submitted for quality control (QC) monitoring of our samples documented a 0.43% CV. Obesity and central adiposity Obesity and central adiposity were the biological independent variables expected to predict nondiabetic HbA 1c . Obesity, indexed by BMI, was calculated using measurements obtained by MIDUS staff and was derived by dividing a respondent’s weight (in kilograms) by their height (in meters squared). Consistent with guidelines established by the National Heart, Lung, and Blood Institute (NHLBI), values below 18.5 indicated an individual was underweight, values from 18.5 to 24.9 were considered normal, values from 25 to 29.9 indicated an individual was overweight, and values of 30 or greater identified an individual as obese ( 39 ). Central adiposity was indexed by waist-to-hip ratio and waist circumference. Waist-to-hip ratio was calculated by dividing an individual’s waist in inches (measured around the abdomen just above the hip bone) by their hip (maximum hip extension measurement); a waist-to-hip ratio of 0.90 or higher (for men) and 0.80 or higher (for women) was considered high-risk ( 39 ). Current high-risk cut points for waist circumference were 40 inches for men and 35 inches for women ( 39 ). Perceived weight discrimination Perceived weight discrimination was the psychosocial independent variable in this study ( 19 ). Nine questions assessed the frequency of exposure to daily occurrences of perceived discrimination ( 40 ). We focus here on indicators of interpersonal or daily discrimination, rather than institutional discrimination because the latter represents only a small proportion of the actual instances of unfair treatment based on personal characteristics ( 41 ). Respondents were asked, “How often on a day-to-day basis do you experience each of the following types of discrimination?” (1) “you are treated with less courtesy than other people”; (2) “you are treated with less respect than other people”; (3) “you receive poorer service than other people at restaurants or stores”; (4) “people act as if they think you are not smart”; (5) “people act as if they are afraid of you”; (6) “people act as if they think you are dishonest”; (7) “people act as if they think you are not as good as they are”; (8) “you are called names or insulted”; and (9) “you are threatened or harassed.” The four response categories ranged from 1 (“never”) to 4 (“often”). Respondents who indicated that they had ever experienced any such mistreatment were then asked: “What was the main reason for the discrimination you experienced?” A dichotomous indicator was created based on responses to both sets of questions and revealed whether one had ever (at least once) experienced mistreatment and this mistreatment was due to weight or height. Approximately 9% of the sample reported experiencing such discrimination. While it was not possible to ascertain how many of the participants reported mistreatment due specifically to weight, further analyses showed that all the individuals reporting such discrimination had high-risk BMI, waist-to-hip ratio, or waist circumference as defined by established cut-points described in the previous paragraph ( 39 ). Control variables Selected sociodemographic, health and psychosocial variables that have been linked to higher HbA 1c levels and risk for type 2 diabetes were included in the regression models as covariates. Since higher HbA 1c levels have been documented among older adults and ethnic minorities ( 42 , 43 ), sociodemographic covariates included age , race, and gender . BMI is a powerful predictor of type 2 diabetes that is independent of central adiposity ( 44 ) and was also included as a control variable. Statins influence glycemic control ( 45 ), thus we controlled for taking cholesterol medications and number of cholesterol medications . Health behaviors linked to risk for type 2 diabetes were controlled for and included exercise frequency ( 46 ) , frequent consumption of fast food ( 47 ), and current smoking ( 48 ). Sleep patterns have been consistently linked to risk for type 2 diabetes ( 49 ) so we included a measure of global sleep , based on The Pittsburgh Sleep Quality Index (PSQI) questionnaire that summed sleep disturbances over a 1-month time interval (continuous, range 0–19). The final control variable pertained to the time lag (in months) between the time when psychosocial and biological data were collected. Overview of Data Analytic Plan Hierarchical multiple regression was used and all models were multivariate-adjusted. All continuous independent variables and control variables were mean-centered and all categorical variables were dichotomous. All interaction terms were computed such that they were the product of the main effects variables centered at their mean. Statistically significant interaction terms were interpreted by graphing predicted scores for respondents in theoretically meaningful groups (i.e., people who report weight discrimination vs. those who do not). Building main effect models involved two steps. At step 1 of the multivariate model all covariates were entered (age, race, gender, income, education, taking cholesterol medications, number of cholesterol medications, exercise, fast food consumption, smoking status, and global sleep score). At step 2, one of each of the three measures of obesity and central adiposity (BMI, waist-to-hip ratio, or waist circumference) was added to the covariates. Building interaction models included three steps: at step 1 all covariates were entered, at step 2 one measure of either obesity or central adiposity was included together with perceived weight discrimination (i.e., BMI and Perceived Weight Discrimination), and at step 3 the interactive effect of the two measures from step 2 was included (i.e., BMI × Perceived Weight Discrimination). Results Bivariate Analyses Bivariate correlations showed that HbA 1c levels were positively linked to BMI ( r = .16, p < .001), waist-to-hip ratio ( r = .10, p < .01), and waist circumference ( r = .17, p < .001). Sleep problem scores were correlated with BMI ( r = .10, p < .01) but not waist-to-hip ratio and waist circumference. T-tests showed that people who reported discrimination due to weight were significantly younger ( t (936) = 5.44, p < .001) and had higher BMI ( t (936) = −9.54, p < .001) and waist circumference ( t (936) = −5.95, p < .001) but not waist-to-hip ratio. People who reported discrimination did not differ significantly from those who did not in their health behaviors (smoking, exercise, and fast food consumption). Main Effects Models: Obesity, Central Adiposity, and HbA 1c We estimated main effect models to investigate the independent effects of obesity and central adiposity on nondiabetic HbA 1c . We hypothesized that individuals with high BMI, waist-to-hip ratio, and waist circumference would have higher HbA 1c , net of control variables. Results of the three rounds of step additions confirmed that after adjusting for control variables, BMI ( R 2 =0.156, b=0.008, p <.001), waist-to-hip ratio ( R 2 =0.157, b=0.749, p <.001), and waist circumference ( R 2 =0.164, b=0.011, p <.001) were linked to higher HbA 1c levels. Interaction Models We estimated two-way interaction models to evaluate the combined effects of obesity and central adiposity and perceived weight discrimination on HbA 1c . We hypothesized that perceived weight discrimination would exacerbate the effects of BMI, waist-to-hip ratio, and waist circumference, resulting in higher HbA 1c . Results showed that, net of all control variables, there was a significant two-way interaction effect only between waist-to-hip ratio and weight discrimination on HbA 1c ( R 2 =0.171, b=0.851, p <.05). A graph of the analysis showed that weight discrimination exacerbated the effects of waist-to-hip ratio on HbA 1c (see Table 2 and Figure 1 ). Specifically, weight discrimination did not affect HbA 1c levels among people with lower waist-to-hip ratio: however, for people with high waist-to-hip ratio, weight discrimination emerged as a vulnerability factor. Perceived weight discrimination did not moderate the effects of BMI or waist circumference on HbA 1c . Open in a separate window Figure 1 Weight Discrimination Exacerbates the Effects of Waist-to-Hip Ratio on HbA 1c ( p <0.05) Note: Waist-to-hip ratios in this figure include all waist-to-hip values used in the analyses. Unstandardized regression coefficients were used to plot the interaction. Table 2 Multivariate Linear Regression Results (unstandardized coefficients) for Waist-to-hip Ratio, Weight Discrimination, and HbA 1c (N=938) Variables Step 1 Step 2 Step 3 b (SE) R 2 b (SE) R 2 b (SE) R 2 Age .009 *** (.001) .009 *** (.001) .009 *** (.001) Race (1=White) − .083 * (.033) − .088 ** (.033) − .086 ** (.033) Gender (1=Male) − .088 *** (.024) − .156 *** (.033) − .152 *** (.033) Global Sleep Score .001 (.003) .001 (.003) .001 (.003) Income .001 (.001) .001 (.001) .001 (.001) Education − .004 (.005) − .003 (.005) − .004 (.005) Taking Cholesterol Meds (1=Yes) − .159 (.101) − .189 † (.101) − .197 * (.101) # Cholesterol Meds .217 * (.091) .232 ** (.090) .238 ** (.090) Regular Exercise (1=yes) − .055 † (.029) − .048 * (.029) − .047 (.029) Fast Food Consumption (1=yes) .012 (.013) .012 (.013) .012 (.013) Current Smoker (1=yes) .077 * (.036) .067 † (.036) .068 † (.036) Body Mass Index .008 *** (.002) .005 * (.002) .005 * (.002) Time Lag Variable − .002 * (.001) − .002 ** (.001) − .002 ** (.001) Waist-to-hip Ratio __________ .580 ** (.180) .488 ** (.186) Weight Discrimination (1=Yes) .156 *** .077 † (.042) .075 † (.041) Waist-to-hip Ratio × Weight Discrimination __________ .168 ** .851 * (.430) .17 1 * Open in a separate window * p < .05. ** p < .01. *** p < .001. † p <.10. Note: R 2 values at each step include the R 2 value of the current and all previous steps (i.e. R 2 for Step 3 is the cumulative R 2 value for Steps 1, 2, and 3). Discussion Our study capitalized on the strengths of a large national sample survey of Americans to investigate risk factors and psychosocial influences as complementary in their relationship to nondiabetic glycemic control. Results supported the predicted hypotheses: the negative influence of all indices of obesity and central adiposity on HbA 1c was confirmed at nondiabetic levels, and importantly, the exacerbating power of perceived weight discrimination was documented. Including weight discrimination as a targeted measure of stress linked with the key biological risk factors helped document that the physical burden of carrying excessive weight was significantly exacerbated by perceptions of discriminatory treatment due to the high body weight. Specifically, the highest HbA 1c levels were observed among people who had high waist-to-hip ratio and who reported weight discrimination. The prevalence of perceived weight discrimination has increased by 66% over the last decade ( 50 ) and obese individuals face multiple forms of prejudice and weight stigma, including both interpersonal slights, insults, and work-related discrimination ( 25 ). This study contributed to the growing literature on discrimination and health by documenting that the negative influence of self-reported weight discrimination was not limited to psychosocial aspects of daily life or self-reported health outcomes, but also extended to a powerful biomarker of physical health. This finding has potentially important implications for public health policy and education. Recent studies on race and health reveal that the well-documented health disadvantage of blacks relative to whites may be exacerbated even further due to blacks’ elevated risk of discriminatory treatment – which may discourage them from engaging in healthy behaviors or from seeking timely medical care ( 13 ). We suspect that a similar pattern may occur among overweight and obese Americans. While our study documented that the negative effects of weight discrimination were independent of certain health behaviors, such as smoking, exercise, and fast food consumption, previous studies ( 25 , 51 ) have documented that obese individuals might not seek timely health care or comply with proper health care regimens due to fear of mistreatment, teasing, and the demoralization that results from this mistreatment. Thus, perceptions of persistent mistreatment may exacerbate the already harmful consequences of central adiposity for a range of physical outcomes, including glycemic control. Possible Mechanisms While the specific pathways that link obesity, central adiposity, discrimination, and glycemic control are unclear, the psychosocial moderation of waist-to-hip ratio but not other body weight measures provides initial clues into possible mechanisms. BMI, for example, is a surrogate measure of body fat that may provide misleading information about body fat content, especially among older adults for whom it may not detect the “conversion” of lean to fat tissue that accompanies normal aging, or among non-Caucasian people, for whom the relationship between BMI and body fat varies widely for different race/ethnic groups ( 52 ). Waist circumference and waist-to-hip ratio, in contrast, reflect central adiposity, which has been described as a superior measure in predicting risk in the Diabetes Prevention Program ( 53 ). Hip circumference is potentially important because it indexes muscle and/or fat mass at thehips ( 54 , 55 ), and larger sizes of leg muscle and leg fat have been linked to metabolic protection against higher glucose levels and risk for diabetes ( 55 ). One mechanism that links lower leg fat to metabolic problems is its relative insensitivity to lipolytic stimuli and high sensitivity to antilipolytic stimuli: in effect, leg fat might act as a “sink” for circulating free fatty acids generated by central adiposity ( 52 , 56 ). This uptake of free fatty acids prevents fat storage in liver, sketetal muscle, and pancreas, where high levels would cause insulin resistance and beta-cell dysfunction. Since free fatty acids are a major mediator of the stress response ( 57 ) and widely accepted as important contributors to the development of diabetes ( 58 ), they represent a potential mechanism that might explain our results. Relevant to the present findings, chronic psychosocial stress such as perceived discrimination might introduce the major stress hormones (norepinephrine, epinephrine, and cortisol), as well as more free fatty acids that modify the relationship between the free fatty acids (produced by visceral fat and taken up by leg fat depots) and glycemic control, and this effect is more pronounced in people with an existing vulnerability (such as high waist-to-hip ratio). Future studies on psychosocial moderation of obesity and central adiposity are essential for documenting intervening mechanisms: for example, the testable hypothesis that free fatty acids are the main pathway that links stress to obesity, central adiposity, and glycemic control is an important next investigation. Limitations Finally, despite this study’s conceptual and methodological strengths, the main limitations pertained to its cross-sectional design which does not allow claims of causality. Furthermore, an important next step is identifying factors that differentiate between obese people who report discrimination and those who do not. Including competing measures of different stressors should be the first part of this inquiry: does perceived general stress make people more susceptible to perceive discrimination, and importantly, are coping skills a potential buffer in this relationship? Implications for Prevention and Intervention Public policies and educational interventions designed to lessen risk for type 2 diabetes and regulate glycemic levels typically target the behaviors of overweight and obese persons, including their diets, caloric intake levels, and physical fitness levels. The value of such work is undeniable. However, our study suggests that perceived weight discrimination among people at risk for developing type 2 diabetes is another potentially useful target for interventions. Fostering effective strategies for managing health behaviors as well as for coping with weight-related discrimination may be useful combined objectives for clinicians. For instance, research on coping with weight stigma has documented that a range of coping responses used to deal with stigma and effective strategies (e.g., positive self-talk, obtaining social support) are linked with higher psychological well-being among women who report weight stigma ( 59 ). Promoting both effective coping skills for dealing with weight stigma while also diminishing negative responses such as overeating or using food for comfort could have important consequences for glycemic control. Our study did not adjudicate whether perceptions of weight discrimination were objective or perceived only, although previous research has documented both perceived and objective weight-based stigmatization and unfair treatment for overweight and obese persons in domains of employment, healthcare, and education ( 25 , 26 ). In fact, even health professionals specializing in obesity show strong weight bias, indicating pervasive and powerful stigma ( 60 , 61 ). Therefore, interventions also need to address “those who do the discriminating” against overweight and obese persons ( 62 ). Public education about the challenges facing obese persons and about the pervasiveness of prejudicial attitudes towards them may help to reduce discriminatory treatment. Legislative changes also may be effective. To date, Michigan is the only state that prohibits employment discrimination on the basis of weight: the Elliot Larsen Civil Rights Act bans discrimination in employment on the basis of height and weight. In the remaining 49 states, obesity is not a protected category. The Civil Rights Act of 1964 does not identify weight as a protected characteristic, and only in rare instances can severely obese people seek legal protection under Americans with Disabilities Act (ADA) legislation. Expanding protected categories to include obese persons may be effective for reducing the extent to which prejudicial beliefs against stigmatized individuals are translated into discriminatory treatment. This study provides initial evidence that viewing biological and psychosocial factors as complementary influences is important for understanding variations in glycemic control. Ultimately, the goal is to design targeted interventions for individuals who are considered at risk for developing diabetes due to the combined presence of various psychosocial (i.e., perceived weight discrimination) and biological risk factors (e.g. obesity). Strategies that tackle both the discriminatory social environment faced by obese persons and their adaptations to these environments may be consequential for minimizing diabetes risk at the population level. Footnotes Conflict of Interest Statement The authors have no financial disclosures related to products or corporate holdings mentioned in this manuscript. Contributor Information Vera K. Tsenkova, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA. Deborah Carr, Department of Sociology and Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, NJ, USA. Dale A. 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