diff --git a/Adrenal Nodule information/Diagnosis of Cushing's Syndrome Clinical Practice Guideline.pdf_semantic.json b/Adrenal Nodule information/Diagnosis of Cushing's Syndrome Clinical Practice Guideline.pdf_semantic.json new file mode 100644 index 0000000000000000000000000000000000000000..05897b39f40851f647f0c66caba7813a65dfde4f --- /dev/null +++ b/Adrenal Nodule information/Diagnosis of Cushing's Syndrome Clinical Practice Guideline.pdf_semantic.json @@ -0,0 +1,1969 @@ +[ + { + "text": "about the balance between risks and benefits; strong recommen- dations based on low-quality evidence usually indicate the pan- el’s strong preference against the alternative course of action but are subject to change with new research. Given a weak recom- mendation, careful consideration of the patient’s circumstances, values, and preferences is appropriate to determine the best course of action. Linked to each recommendation is a description of the evi- dence , values that panelists considered in making the recommen- dation(whenmakingtheseexplicitwasnecessary),and remarks , asectioninwhichpanelistsoffertechnicalsuggestionsfortesting conditions, dosing, and monitoring. These technical comments reflect the best available evidence applied to a typical patient. Oftenthisevidencecomesfromtheunsystematicobservationsof the panelists and should therefore be considered suggestions. 1.0 Definition, pathophysiology, and etiology of hypercortisolism Cushing’s syndrome comprises a large group of signs and symp- tomsthatreflectprolongedandinappropriatelyhighexposureof tissue to glucocorticoids (Table 1). Whereas the most common cause is iatrogenic from medically prescribed corticosteroids, endogenous Cushing’s syndrome is an uncommon disorder. Eu- ropean population-based studies reported an incidence of two to three cases per 1 million inhabitants per year (4, 5", + "tokenCount": 298, + "pageStart": 3, + "pageEnd": 3, + "hash": "c63b75de1b3e8a6fdbdcd080759dbf866fa5600f48a611f82d04f3058b8f3ee3" + }, + { + "text": "Excess cor- tisol production, the biochemical hallmark of endogenous Cush- ing’s syndrome, may be caused by either excess ACTH secretion (from a pituitary or other ectopic tumor) or independent adrenal overproduction of cortisol. Although Cushing’s syndrome is clinically unmistakable when full blown, the spectrum of clinical presentation is broad, and the diagnosis can be challenging in mild cases. Few, if any, features of Cushing’s syndrome are unique, but some are more discriminatory than others, including reddish purple striae, plethora, proximal muscle weakness, bruising with no obvious trauma, and unexplained osteoporosis (6–8). More often pa- tientshaveanumberoffeaturesthatarecausedbycortisolexcess but that are also common in the general population, such as obesity, depression, diabetes, hypertension, or menstrual irreg- ularity. As a result, there is an overlap in the clinical presentation of individuals with and without the disorder (Table 1", + "tokenCount": 214, + "pageStart": 3, + "pageEnd": 3, + "hash": "8c4074fc293d42357ddef46ed3915f272540088e3387ff7a4f231696becfe622" + }, + { + "text": "We en- courage caregivers to consider Cushing’s syndrome as a second- ary cause of these conditions, particularly if additional features of the disorder are present. (see Who should be tested below.) If Cushing’s syndrome is not considered, the diagnosis is all too often delayed. In addition, overactivity of the hypothalamic-pituitary-adre- nal (HPA) axis occurs without true Cushing’s syndrome, so that there is an overlap between physiological and pathophysiolog- ical causes of hypercortisolism (Table 2). Thus, certain psychi- atric disorders (depression, anxiety disorder, obsessive-compul- sive disorder), poorly controlled diabetes mellitus, and alcoholism can be associated with mild hypercortisolism and may produce test results suggestive of Cushing’s syndrome, in- cluding abnormal dexamethasone suppressibility and mildly el- evated UFC (9", + "tokenCount": 200, + "pageStart": 3, + "pageEnd": 3, + "hash": "db697c176d1cfeee1f0cb36c33f620ab11b9507de4cbfa8c04a2402f54b96a08" + }, + { + "text": "Circulating cortisol concentrations are usually normal (or slightly reduced) in obesity, but severe obesity can raise UFC. It is thought that higher brain centers stimulate CRH release in these conditions, with subsequent activation of the entireHPAaxis(10).Thenegativefeedbackinhibitionofcortisol on CRH and pituitary ACTH release partially restrains the re- TABLE 1. Overlapping conditions and clinical features of Cushing’s syndrome a Symptoms Signs Overlapping conditions Features that best discriminate Cushing’s syndrome; most do not have a high sensitivity Easy bruising Facial plethora Proximal myopathy (or proximal muscle weakness) Striae (especially if reddish purple and \u0001 1 cm wide) In children, weight gain with decreasing growth velocity Cushing’s syndrome features in the general population that are common and/or less discriminatory Depression Dorsocervical fat pad ( \u0002 buffalo hump \u0002 ) Hypertension b Fatigue Facial fullness Incidental adrenal mass Weight gain Obesity Vertebral osteoporosis b Back pain Supraclavicular fullness Polycystic ovary syndrome Changes in appetite Thin skin b Type 2 diabetes b Decreased concentration Peripheral edema Hypokalemia Decreased libido Acne Kidney stones Impaired memory (especially short term) Hirsutism or female balding Unusual infections Insomnia Poor skin healing Irritability Menstrual abnormalities In children, slow growth In children, abnormal genital virilization In children, short stature In children, pseudoprecocious puberty or delayed puberty a Features are listed in random order. b Cushing’s syndrome is more likely if onset of the feature is at a younger age. 1528 Nieman et al. Guidelines for the Diagnosis of Cushing’s Syndrome J Clin Endocrinol Metab, May 2008, 93(5):1526–1540 Downloaded from https://academic.oup.com/jcem/article/93/5/1526/2598096 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 433, + "pageStart": 3, + "pageEnd": 3, + "hash": "f70a1ed0a1dee46477ac2c4a0dc975f7a585e8b947c79693ff07afa68fb6574a" + }, + { + "text": "sulting hypercortisolemia. As a result, the overlap in UFC ex- cretion is limited to values up to about 4-fold normal. 2.0 Morbidity and mortality of Cushing’s syndrome:", + "tokenCount": 50, + "pageStart": 4, + "pageEnd": 4, + "hash": "5a31899330222051d02d15cd19815d507298a1868d2aa533cb461b6db9624f5a" + }, + { + "text": "rationale for diagnosis and treatment The earliest reports of mortality in Cushing’s syndrome likely described individuals with severe hypercortisolism, representing one end of the clinical spectrum. These reports documented a mediansurvivalof4.6yr,andin1952a5-yrsurvivalofjust50%, with most deaths caused by vascular (myocardial infarction, ce- rebrovascular accident) or infectious complications (11, 12).", + "tokenCount": 95, + "pageStart": 4, + "pageEnd": 4, + "hash": "5f358a8ab3d6501224e9285790e4e5f1f0006dd69aa84e889529adcae1aec406" + }, + { + "text": "However, with modern-day treatments the standard mortality ratio (SMR) after successful normalization of cortisol was sim- ilar to that of an age-matched population during 1–20 yr of follow-up evaluation in one study (13).", + "tokenCount": 50, + "pageStart": 4, + "pageEnd": 4, + "hash": "ca3b8fd40e532a3e9553f6c325970fbbac8027e3a20f0aff415890c321de8f1a" + }, + { + "text": "Because markers of car- diovascular risk remain abnormal for up to 5 yr after surgery, further studies are needed to assess long-term SMR (14). In pa- tients who have persistent moderate hypercortisolism despite treatment, SMR is increased 3.8- to 5.0-fold, compared with the general population (4, 5).", + "tokenCount": 75, + "pageStart": 4, + "pageEnd": 4, + "hash": "dfaa357ee4f449b37e8c2920d9aac975417db86ed60e53927e0a4c5db640bb39" + }, + { + "text": "These data are consistent with the increased cardiovascular mortality and morbidity reported in patients with iatrogenic Cushing’s syndrome secondary to the chronic use of synthetic corticosteroids (15).", + "tokenCount": 40, + "pageStart": 4, + "pageEnd": 4, + "hash": "cb481f2466da0b3820cdce92d725c18bd4fd9b7c6075df2ee79200436404f92f" + }, + { + "text": "Successful treatment of hypercortisolism reverses, but may not normalize, features of Cushing’s syndrome. Bone mineral density and cognitive dysfunction improve after successful sur- gical treatment of Cushing’s syndrome but do not normalize in all patients (16, 17).", + "tokenCount": 61, + "pageStart": 4, + "pageEnd": 4, + "hash": "80a09b0e2b626b91e85624f1803520dac1ea776378b180c75e3fa0bde203bfff" + }, + { + "text": "Additionally, quality of life improves after surgical treatment but remains below that of age- and gender- matched subjects for up to 15 yr (18). Indirect evidence support- ing the need for intervention includes the finding that the risk of infection is lower in patients with mild to moderate, compared with severe, hypercortisolism (19).", + "tokenCount": 68, + "pageStart": 4, + "pageEnd": 4, + "hash": "51b20e4af68e098c89fe147b26f54742c895b93e9d78e42d6609515b368ca89a" + }, + { + "text": "There are limited and conflicting data regarding whether sur- gical treatment of patients with mild hypercortisolism in the set- tingofanadrenalincidentalomaissuperiortomedicaltreatment of comorbidities alone (20–23).", + "tokenCount": 53, + "pageStart": 4, + "pageEnd": 4, + "hash": "dc25a2da0ac4e1e930b14b71ec527bed06beaf53d2a4749bd287952f6d6b89aa" + }, + { + "text": "Although there are no formal controlled studies of conse- quences of cure in pediatric Cushing’s syndrome, improvements in growth and body composition after treatment are reported in both patients with adrenal and those with pituitary causes (24, 25).", + "tokenCount": 52, + "pageStart": 4, + "pageEnd": 4, + "hash": "523524dff8c086d4b25f02ef65826688687f8f1951d1f7e985f85c37e0568f24" + }, + { + "text": "Final stature in patients with endogenous Cushing’s syn- drome was reported to be disappointing (26), but more recent data showed that most patients reach a final height within their predicted parental target range (24).", + "tokenCount": 44, + "pageStart": 4, + "pageEnd": 4, + "hash": "cd2fe6a4b5ab8c0df6d2dca449a649393ed07eddcc602d4c64383812fb996cba" + }, + { + "text": "Treatment of patients with moderate to severe Cushing’s syn- drome clearly reduces mortality and morbidity. Because Cush- ing’s syndrome tends to progress and severe hypercortisolism is probably associated with a worse outcome, it is likely that early recognition and treatment of mild disease would reduce the risk ofresidualmorbidity.However,nodataaddressingthisassump- tion have been reported.", + "tokenCount": 90, + "pageStart": 4, + "pageEnd": 4, + "hash": "734238c364758a94ee36a40ffff46a70adf2491fbf61312d5b725f08728103e6" + }, + { + "text": "OurrecommendationsfortestingforCushing’ssyndromeare based on direct evidence from observational studies indicating a large treatment effect (which we have rated as low to moderate quality evidence) on morbidity and mortality in patients diag- nosed with the condition.", + "tokenCount": 56, + "pageStart": 4, + "pageEnd": 4, + "hash": "919c6772fcb57ac5ed8d59a3b3a127350be5e9ac330abd10a31bdfa7bb971ffb" + }, + { + "text": "The next section of this document focuses on evidence that bears indirectly on these recommenda- tions. The research in this area yields data on the likelihood of Cushing’s syndrome in certain populations and on the accuracy of currently available tests in these populations.", + "tokenCount": 52, + "pageStart": 4, + "pageEnd": 4, + "hash": "5bd6c859a2b95030089f380ee7d12b5b7243343eb7525c81ca339aeb84a2721b" + }, + { + "text": "As a result, the majority of our recommendations are based on very low- to low-quality evidence. Higher-quality evidence to support testing should come from studies directly comparing the effect of testing strategies on patient-important outcomes.", + "tokenCount": 45, + "pageStart": 4, + "pageEnd": 4, + "hash": "4a0f6995e9bd8603d9b93186cbc4c01a2136e6a590fa18984aa36e643bf995b9" + }, + { + "text": "To date such evidence is not available in this field. These guidelines focus on the more common clinical scenar- ios, with brief mention of conditions and situations that are rare or more complicated than space limitations allow; we hope that the reader will investigate these further.", + "tokenCount": 53, + "pageStart": 4, + "pageEnd": 4, + "hash": "16f151a079033501ce6cd98d1e58bc94e65a4e6d144ba57cc456e43bc1ad5ba7" + }, + { + "text": "3.0 Diagnosis of Cushing’s syndrome Who should be tested 3.1Werecommendobtainingathoroughdrughistorytoexclude exogenous glucocorticoid exposure leading to iatrogenic Cush- ing’s syndrome before conducting biochemical testing (1 QQQQ ).", + "tokenCount": 67, + "pageStart": 4, + "pageEnd": 4, + "hash": "e2026bea096b86114ece2b6374c884de736148b044dcfdf41a844207b7a8818b" + }, + { + "text": "3.2 We recommend testing for Cushing’s syndrome in the fol- lowing groups: • Patients with unusual features for age ( e.g. osteoporosis, hypertension) (Table 1) (1 QQEE ) • Patientswithmultipleandprogressivefeatures,particularly those that are more predictive of Cushing’s syndrome (Ta- ble 1) (1 QQEE ) • Children with decreasing height percentile and increasing weight (1 QEEE ) • Patients with adrenal incidentaloma compatible with ade- noma (1 QEEE ).", + "tokenCount": 117, + "pageStart": 4, + "pageEnd": 4, + "hash": "3308ccfdd4504de20abf7f34b3a6e3ca44b9afdd79a675d06deb33201a8f6087" + }, + { + "text": "3.3 We recommend against widespread testing for Cushing’s syndrome in any other patient group (1 QEEE ). 3.1 Evidence Features of Cushing’s syndrome may occur as a result of exog- enousglucocorticoiduse.TheseverityoftheCushingoidfeatures TABLE 2.", + "tokenCount": 68, + "pageStart": 4, + "pageEnd": 4, + "hash": "481d64c3d5700eb63bfa96855ce63badabed7450ad6a8cd8c9bbc793801a93a2" + }, + { + "text": "Conditions associated with hypercortisolism in the absence of Cushing’s syndrome a Conditions Some clinical features of Cushing’s syndrome may be present Pregnancy Depression and other psychiatric conditions Alcohol dependence Glucocorticoid resistance Morbid obesity Poorly controlled diabetes mellitus Unlikely to have any clinical features of Cushing’s syndrome Physical stress (hospitalization, surgery, pain) Malnutrition, anorexia nervosa Intense chronic exercise Hypothalamic amenorrhea CBG excess (increased serum but not urine cortisol) a Whereas Cushing’s syndrome is unlikely in these conditions, it may rarely be present.", + "tokenCount": 133, + "pageStart": 4, + "pageEnd": 4, + "hash": "88fb6fbecba8a8bbe18496fd26cce1ad60d657c5da00249ec93a4a2d9c2e01ce" + }, + { + "text": "If there is a high clinical index of suspicion, the patient should undergo testing, particularly those within the first group. J Clin Endocrinol Metab, May 2008, 93(5):1526–1540 jcem.endojournals.org 1529 Downloaded from https://academic.oup.com/jcem/article/93/5/1526/2598096 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 93, + "pageStart": 4, + "pageEnd": 4, + "hash": "35baa0b845171cf48ffa67d54ffcc7aaaef05cab83fbb5b4face30c7e136ea41" + }, + { + "text": "depends on the potency of the preparation used, its dose, the route and duration of its administration, and whether concom- itant medications prolong its half-life (27). A thorough drug his- tory noting current or recent use of these medications, oral, rec- tal, inhaled, topical, or injected, should be obtained before embarking on any biochemical testing (28).", + "tokenCount": 80, + "pageStart": 5, + "pageEnd": 5, + "hash": "3c62b165c23cd435710d8042662869ec5e09c3e3b3834254a485c2ba621730c9" + }, + { + "text": "In particular, glu- cocorticoid components of skin creams (including bleaching agents), herbal medications, “tonics,” and joint or nerve injec- tions may be overlooked.", + "tokenCount": 44, + "pageStart": 5, + "pageEnd": 5, + "hash": "b3ce548f258243889af0a4a18d3d58f056b948fdfc6b012038aadcffdd61bd17" + }, + { + "text": "Megestrol acetate (medroxyprogester- one acetate) is a synthetic progesterone derivative that has glu- cocorticoid activity and in high doses may cause Cushing’s syndrome (29).", + "tokenCount": 48, + "pageStart": 5, + "pageEnd": 5, + "hash": "78d39fb93fe5b720050ddbb90e2e193a2d090ff6a64d0b46a435c7c5b9062f9b" + }, + { + "text": "Our recommendation is based on high-quality evidence because it derives from the common observation that pursuing the alternative, testing to establish the diagnosis of Cushing’s syndrome without first excluding exogenous glu- cocorticoiduse,isassociatedwithaverylargeriskofundesirable effects (including unnecessary testing and the associated conse- quences) without expectation of benefit.", + "tokenCount": 77, + "pageStart": 5, + "pageEnd": 5, + "hash": "9f3b423223899c0d551dac869739104a80f370024127f078b3159d01cbcbcb41" + }, + { + "text": "3.2 Evidence Cushing’s syndrome is more likely to be present when a large number of signs and symptoms, especially those with high dis- criminatory index ( e.g. myopathy, plethora, red striae, easy bruising, and thin skin in the young) are present (6, 8).", + "tokenCount": 65, + "pageStart": 5, + "pageEnd": 5, + "hash": "186f4fb9f663fad090e42b0c1da97fd4629f14c2328ec34a0e68f271f6cc1d52" + }, + { + "text": "However, there is a wide spectrum of clinical manifestations at any given level of hypercortisolism. Because Cushing’s syndrome tends to progress, accumulation of new features increases the probability that the syndrome is present.", + "tokenCount": 45, + "pageStart": 5, + "pageEnd": 5, + "hash": "d38af38c5407354ffbedeaaab17123bedb99595cdbc502b37c9c5fa3524a5bc8" + }, + { + "text": "A review of old photographs of the patient may help the clinician better appreciate whether physical changes have occurred over time. In children, the sensitivity of combined reduced linear growth and increased weight is quite high.", + "tokenCount": 40, + "pageStart": 5, + "pageEnd": 5, + "hash": "4d6e311a2459b05fbe584859a17ef6c7ce703c9883eee6597a96ffad034af281" + }, + { + "text": "Although the probability of Cushing’s syndrome has not been evaluated in a large number of children, clinical experience suggests that the specificity of these clinical features for the diagnosis is also very high (30).", + "tokenCount": 41, + "pageStart": 5, + "pageEnd": 5, + "hash": "a2c87f3ead1200975f031e49c2e34b546a0778cc2e010bafdb0627b2e83b6db8" + }, + { + "text": "As a result, tests for Cushing’s syndrome are not indicated in obese children unless their statural growth rate has slowed. Clinicians often evaluate patients with an incidentally found adrenal nodule for autonomous adrenal cortisol excess.", + "tokenCount": 47, + "pageStart": 5, + "pageEnd": 5, + "hash": "3f6357ee8d9e7218ae61977563a8b7ed4f635f2f1b503f62c217c2144cd3ed54" + }, + { + "text": "Such patients usually do not present with overt clinical features of Cushing’s syndrome, but biochemical hypercortisolism is presentinalargefraction(upto10%).Bulow etal.", + "tokenCount": 41, + "pageStart": 5, + "pageEnd": 5, + "hash": "bf66073aa30c19b8214eb3f5d6c8c7645aa588925e0951f917b1a7ef74f97ef8" + }, + { + "text": "(31)reported 2% prevalence of Cushing’s syndrome; Libe et al. (32) reported 18%; Terzolo et al. (21) quoted 5–20%, depending on referral bias and diagnostic tests and criteria.", + "tokenCount": 50, + "pageStart": 5, + "pageEnd": 5, + "hash": "b78b46268e7c967ea47c0b31944cc22cf7c5653bbb0178ece5f3fd3609b06027" + }, + { + "text": "3.3 Evidence Testing for Cushing’s syndrome in certain high-risk populations has shown an unexpectedly high incidence of unrecognized Cushing’s syndrome as compared with the general population.", + "tokenCount": 40, + "pageStart": 5, + "pageEnd": 5, + "hash": "53b3d37f4b333c06ba676ace33ea8a2194cd73f55c1cf0f1514c7c2ef55d4661" + }, + { + "text": "Although there are limited data on the prevalence of the syn- drome in these disorders, the diagnosis should be considered. In one study, 2–3.3% of patients with poorly controlled di- abetes mellitus had surgically confirmed Cushing’s syndrome or mild hypercortisolism.", + "tokenCount": 64, + "pageStart": 5, + "pageEnd": 5, + "hash": "a224eb4d0f2b79eb7051589e631cbb15504853dc9f5583d20bfe2b5e6a720abe" + }, + { + "text": "Most of these patients had unilateral ad- renal adenomas (33). In another recent report, one of 99 patients with newly diagnosed diabetes mellitus had surgically proven Cushing’s disease (34).", + "tokenCount": 43, + "pageStart": 5, + "pageEnd": 5, + "hash": "af920b22bc4498414fb5597d5ec524719eda69a88408a8e25c11ae962245cf59" + }, + { + "text": "Another study of 86 consecutive obese subjects referred to an endocrine clinic with diabetes mellitus, hypertension, and/or the polycystic ovary syndrome found a 5.8% incidence of Cushing’s syndrome (35).", + "tokenCount": 47, + "pageStart": 5, + "pageEnd": 5, + "hash": "800e905f192fd156837e823c9f98823b6ead15a729b840ae610ebec13e73c1ca" + }, + { + "text": "Screening studies of patients with hypertension reported a 0.5–1% prevalence of Cushing’s syndrome (36, 37). Unsus- pected Cushing’s syndrome also was found in as many as 10.8% of older patients with osteoporosis and vertebral fracture in whom comprehensive testing was done for secondary causes (38).", + "tokenCount": 75, + "pageStart": 5, + "pageEnd": 5, + "hash": "707027750c5e056ba124f39c2f701e7fdd5ebd06e39a79a01d4a06e421c19d0e" + }, + { + "text": "Unfortunately, there is little information on additional co- morbidities and risk factors in these studies. The few data on the outcome, after surgical remission of hy- percortisolism, in patients with unsuspected Cushing’s syn- drome are mixed; hypertension and diabetes did not improve in all individuals (20–23).", + "tokenCount": 69, + "pageStart": 5, + "pageEnd": 5, + "hash": "593a46c39a3c252c98032aa8982355a3fb9c4ad0a75df2c3b30f34bf55cfd0e5" + }, + { + "text": "Patients with familial disease that puts them at risk of Cush- ing’s syndrome ( e.g. Carney complex, multiple endocrine neo- plasia-1) should be evaluated by an endocrinologist as part of a surveillance screening program.", + "tokenCount": 53, + "pageStart": 5, + "pageEnd": 5, + "hash": "81af0342f5dea76979b60af9e1dfca793b990da123ecb43873ef64a7701876e2" + }, + { + "text": "3.3 Values Because of the rarity of Cushing’s syndrome, the high prevalence of conditions such as diabetes mellitus, obesity, and depression, andthelimitationsofthescreeningtests,theriskoffalse-positive test results is high.", + "tokenCount": 53, + "pageStart": 5, + "pageEnd": 5, + "hash": "6cf202d51f0f041082ebf8461aa15333ad0a3536fbabb713139a0b6ebee5057e" + }, + { + "text": "False-positive results, with their attendant costs, are reduced if case detection is limited to individuals with an increased pretest probability of having the disorder. The sub- sequent testing, labeling, and treatment may harm individuals with false-positive results and distract attention from the treat- ment of the conditions that prompted testing.", + "tokenCount": 64, + "pageStart": 5, + "pageEnd": 5, + "hash": "e1d5a0073ce6807fce241ae4dee1541580bd5799e246c119f906d07bf65a5d0d" + }, + { + "text": "The proposed testing strategy places higher value on reducing the number of false-positive test results, particularly in patients with very mild disease in whom the benefits of intervention are unproven. Conversely, once the clinical scenario suggests a high pretest probability of the disorder, sensitivity needs to be high so that cases are not missed.", + "tokenCount": 63, + "pageStart": 5, + "pageEnd": 5, + "hash": "c5f4c3bf1a042c1541aa1f2e893118a484468bbc5af410cc4d720034e66b9c76" + }, + { + "text": "This approach also seeks to use more convenient and less expensive tests. Initial testing 3.4 For the initial testing for Cushing’s syndrome, we recom- mendoneofthefollowingtestsbasedonitssuitabilityforagiven patient (Fig.", + "tokenCount": 54, + "pageStart": 5, + "pageEnd": 5, + "hash": "f027f41a87e8df8bf51e4781c347a45d4a598cc66fd15cd9997b34d0c06c7625" + }, + { + "text": "1) (1 QEEE ): 3.4.1 UFC (at least two measurements) 3.4.2 Late-night salivary cortisol (two measurements) 3.4.3 1-mg overnight DST 3.4.4 Longer low-dose DST (2 mg/d for 48 h) 3.5 We recommend against the use of the following to test for Cushing’s syndrome (1 QEEE ):", + "tokenCount": 92, + "pageStart": 5, + "pageEnd": 5, + "hash": "856b8e249178cd3af80b2bd507a8cbe0997c1b04db87c81b96e1b5a135db14dd" + }, + { + "text": "• Random serum cortisol or plasma ACTH levels • Urinary 17-ketosteroids • Insulin tolerance test • Loperamide test • Tests designed to determine the cause of Cushing’s syn- drome ( e.g.", + "tokenCount": 49, + "pageStart": 5, + "pageEnd": 5, + "hash": "9d7147562abaa28ae9ff580301b9bda686fddaa22feffe8e270dcd063a52941a" + }, + { + "text": "pituitary and adrenal imaging, 8 mg DST). 3.6 In individuals with normal test results in whom the pretest probability is high (patients with clinical features suggestive of 1530 Nieman et al.", + "tokenCount": 45, + "pageStart": 5, + "pageEnd": 5, + "hash": "b42f90b86387d1142995feb9fd36292f6bd69010482d93676a2195a571d12182" + }, + { + "text": "Guidelines for the Diagnosis of Cushing’s Syndrome J Clin Endocrinol Metab, May 2008, 93(5):1526–1540 Downloaded from https://academic.oup.com/jcem/article/93/5/1526/2598096 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 72, + "pageStart": 5, + "pageEnd": 5, + "hash": "ff1fcbc856e62ff8dac438999f1d14b8790e11a636ff529706340a4bfea48f83" + }, + { + "text": "Cushing’s syndrome and adrenal incidentaloma or suspected cy- clic hypercortisolism), we recommend further evaluation by an endocrinologist to confirm or exclude the diagnosis (1 QEEE ).", + "tokenCount": 43, + "pageStart": 6, + "pageEnd": 6, + "hash": "01c776a8be4d2c631f34ddba25cda60af7ec5f200fcf48ad09b5d0f46b965e5b" + }, + { + "text": "3.7 In other individuals with normal test results (in whom Cush- ing’s syndrome is very unlikely), we suggest reevaluation in 6 months if signs or symptoms progress (2 QEEE ).", + "tokenCount": 43, + "pageStart": 6, + "pageEnd": 6, + "hash": "ece5bd5a3ac0db1628f4e6cbfc46280a200c133a96187d18fb646d514c492322" + }, + { + "text": "3.8 In individuals with at least one abnormal test result (for whom the results could be falsely positive or indicate Cushing’s syndrome), we recommend further evaluation by an endocrinol- ogist to confirm or exclude the diagnosis (1 QEEE ).", + "tokenCount": 54, + "pageStart": 6, + "pageEnd": 6, + "hash": "ffacfe937602f035dd98711f31be335935641dd22a2b5a7566a9a8bb648c9ed2" + }, + { + "text": "3.4 Evidence In this section, we first discuss the testing strategies and then provide evidence for and remarks about each of the recom- mended tests that can be used to identify patients with Cushing’s syndrome.", + "tokenCount": 46, + "pageStart": 6, + "pageEnd": 6, + "hash": "39bcf5cb2dc87db674d82e7a17211f9cfee7b5c9cfba78ded88ee324ca525cd9" + }, + { + "text": "Nonendocrinologist clinicians may perform the initial eval- uation for Cushing’s syndrome (or refer to an endocrinologist). In this setting, the goal is to choose a test with a high sensitivity for the disorder; unfortunately, no test has optimally high spec- ificity, so that false-positive results may occur.", + "tokenCount": 70, + "pageStart": 6, + "pageEnd": 6, + "hash": "1d513890bd7d6c1a7e357d2319cad810f57be7c5705f155ee9350744cd05d03a" + }, + { + "text": "The four recom- mended tests have acceptable diagnostic accuracy when the sug- gested cutoff points are used (2, 30). If the initial testing results arenormal,assumingthatthereisnoreasontomistrusttheresult (see remarks below), then the patient is very unlikely to have Cushing’s syndrome.", + "tokenCount": 70, + "pageStart": 6, + "pageEnd": 6, + "hash": "060a18d864c8003a323e90896ba56967750d13195398b7a0b3a167d7159fef62" + }, + { + "text": "Thus, the patient can be reassured and no further testing need be done; a recommen- dation to return in 6 months if symptoms progress ensures that evolving symptoms or new features will not be ignored.", + "tokenCount": 41, + "pageStart": 6, + "pageEnd": 6, + "hash": "7b6a1732a951340f4e343de4cfde20a9bb1d8966f24a65ae3cb6ef649d7d0868" + }, + { + "text": "Inpatientswithahighpretestprobability of Cushing’s syndrome, to expedite diagno- sis, the physician may elect to perform two tests simultaneously. 3.4 Remarks for all tests Measurement of cortisol (urine, serum, or salivary) is the end point for each of the rec- ommended tests.", + "tokenCount": 77, + "pageStart": 6, + "pageEnd": 6, + "hash": "ce0473c20cfe8c1312a8631b960f1b606434ddc4aa024706a31df9cc188f9ae7" + }, + { + "text": "As with all hormone as- says, the physician must be aware that sev- eral collection and assay methods are available for the measurement of cortisol, and results for a single sample measured in various assays may be quite different (39).", + "tokenCount": 49, + "pageStart": 6, + "pageEnd": 6, + "hash": "aab9a29d90c29d16afe7c17d396adc4df0f084267692ee745dc543854c143866" + }, + { + "text": "Assays differ widely in their accuracy; re- sults near the cutoff value on a single mea- surement often can be explained by assay variability. In particular, the expected sali- vary and serum concentrations in these tests are close to the functional limit of detection of the assays.", + "tokenCount": 60, + "pageStart": 6, + "pageEnd": 6, + "hash": "a713fac5f44bc3f3ab6a453908fbcf36265459cce251e897757b7faa58140d69" + }, + { + "text": "Because precision deteriorates at these levels, assays should be chosen on the basis of their performance at this low range. Normal ranges vary substantially, de- pendingonthemethodused,soitisessential to interpret test results in the context of the appropriate normal range.", + "tokenCount": 53, + "pageStart": 6, + "pageEnd": 6, + "hash": "a3edf23cf47d25aa78b20cc13677e6f2b41cb7b94915744a07f3eda11c081a82" + }, + { + "text": "Antibody-based immunoassays such asunextractedRIAandELISAcanbeaffectedbycross-reactivity with cortisol metabolites and synthetic glucocorticoids. In con- trast, structurally based assays such as HPLC and tandem mass spectrometry (LC-MS/MS) do not pose this problem and are being used with increasing frequency.", + "tokenCount": 79, + "pageStart": 6, + "pageEnd": 6, + "hash": "a16088cc36eb62a32589756259325e99c909875da3bde9e512741e982eb7942a" + }, + { + "text": "However, there are also drugs (carbamazepine and fenofibrate) that may interfere with someofthesechromatographicmethods(Table3),therebycaus- ing falsely elevated values (40, 41).", + "tokenCount": 49, + "pageStart": 6, + "pageEnd": 6, + "hash": "20ddfb20ccdba73ac4f362dd41714fcc19ba8a3772cf7e9116fd05c9206a2eb9" + }, + { + "text": "Upper limits of normal are much lower with HPLC or LC-MS/MS than in antibody-based assays. For example, urine cortisol values obtained using HPLC may be as low as 40% of the value measured by RIA (42, 43).", + "tokenCount": 54, + "pageStart": 6, + "pageEnd": 6, + "hash": "f8a166277688dcedd747d349c4070b3114d118d13ccd2b0790434b0a2e304414" + }, + { + "text": "Estrogens increase the cortisol-binding globulin (CBG) con- centration in the circulation. Because serum assays measure total cortisol, false-positive rates for the overnight DST are seen in 50% of women taking the oral contraceptive pill (44).", + "tokenCount": 53, + "pageStart": 6, + "pageEnd": 6, + "hash": "b120871a05b498f6eadf5e5b58f2f59eed01df8d47cb930eb9137b8c5879f44f" + }, + { + "text": "Wherever possible, estrogen-containing drugs should be withdrawn for 6 wkbeforetestingorretesting(45).Conversely,decreasesinCBG or albumin, which occur in the critically ill or nephrotic patient, are associated with decreased serum cortisol values (39, 46).", + "tokenCount": 61, + "pageStart": 6, + "pageEnd": 6, + "hash": "99abfb8f3de4b99082ed47a3afeab95e168c6e18c341c9191dcb182efec132b3" + }, + { + "text": "Because the hypercortisolism of Cushing’s syndrome can be variable, we recommend that at least two measurements of urine or salivary cortisol be obtained. This strategy increases confi- denceinthetestresultsifconsistentlynormalorabnormalresults are obtained.", + "tokenCount": 59, + "pageStart": 6, + "pageEnd": 6, + "hash": "8f75149c9c1dcbc93de130294d1b2ba6e2abc4ae1f96ef0411138b151308f728" + }, + { + "text": "Cushing’s syndrome suspected Perform one of the following tests ANY ABNORMAL RESULT Normal (CS unlikely) Consult endocrinologist Discrepant (Suggest additional evaluation) Normal (CS unlikely) ABNORMAL Cushing’s syndrome Exclude exogenous glucocorticoid exposure (consider endocrinologist consultation) 24-h UFC (> 2 tests) Overnight Late night salivary 1-mg DST cortisol (> 2 tests) Consider caveats for each test (see text) Use 48-h, 2-mg DST in certain populations (see text) Perform 1 or 2 other studies shown above Suggest consider or repeating the abnormal study Suggest Dex-CRH or midnight serum cortisol in certain populations (see text) Exclude physiologic causes of hypercortisolism (Table 2) FIG.", + "tokenCount": 166, + "pageStart": 6, + "pageEnd": 6, + "hash": "4dd61817a3e51aba08dc1313b4c02f5a41a016ed75a2e8787b2fe8983178b219" + }, + { + "text": "Algorithm for testing patients suspected of having Cushing’s syndrome (CS). All statements are recommendations except for those prefaced by suggest. Diagnostic criteria that suggest Cushing’s syndrome are UFC greater than the normal range for the assay, serum cortisol greater than 1.8 \u0002 g/dl (50 nmol/liter) after 1 mg dexamethasone (1-mg DST), and late-night salivary cortisol greater than 145 ng/dl (4 nmol/liter).", + "tokenCount": 106, + "pageStart": 6, + "pageEnd": 6, + "hash": "72473c186c8b76207b1097b4b296a306d50281bb9b3d5f8bacbf7f1f48fdecc2" + }, + { + "text": "J Clin Endocrinol Metab, May 2008, 93(5):1526–1540 jcem.endojournals.org 1531 Downloaded from https://academic.oup.com/jcem/article/93/5/1526/2598096 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 70, + "pageStart": 6, + "pageEnd": 6, + "hash": "bfff484a1b7e37b4915c41b57740b40a60fe87d93e65ef471a34ef831bce0f89" + }, + { + "text": "Remarks for dexamethasone tests Variable absorption and metabolism of dexamethasone may in- fluence the result of both the overnight 1-mg DST and the 48-h, 2 mg/d test.", + "tokenCount": 47, + "pageStart": 7, + "pageEnd": 7, + "hash": "c1340552f8ad7ba4f99bfe40c45e88f494c64a304da560145222283b7215a54c" + }, + { + "text": "Drugs such as phenytoin, phenobarbitone, carbam- azepine, rifampicin, and alcohol induce hepatic enzymatic clear- ance of dexamethasone, mediated through CYP 3A4, thereby reducing the plasma dexamethasone concentrations (Table 3) (47).", + "tokenCount": 71, + "pageStart": 7, + "pageEnd": 7, + "hash": "76291247c665752126ee13f68155ce21e76acae36ef533b905c92b65ee8ffcc6" + }, + { + "text": "Conversely, dexamethasone clearance may be reduced in patients with liver and/or renal failure. Dexamethasone levels show interindividual variation, however, even in healthy indi- viduals on no medication.", + "tokenCount": 49, + "pageStart": 7, + "pageEnd": 7, + "hash": "974cc15d1da922a3ee52aa3acb85055d691862843ae32bf8d2d60aa62d941134" + }, + { + "text": "To evaluate for false-positive and negative responses, some experts have advocated simultaneous measurement of both cor- tisol and dexamethasone for these tests to ensure adequate plasma dexamethasone concentrations [ \u0001 5.6 nmol/liter (0.22 \u0002 g/dl)] (48).", + "tokenCount": 64, + "pageStart": 7, + "pageEnd": 7, + "hash": "2720a3f14e4971158b53426574850af3332df18bddd61ec2a403699092ec0869" + }, + { + "text": "However, given the limited availability outside the United States and cost of the dexamethasone assay, this other- wise desirable approach may not be feasible. As noted above, false-positive rates for the overnight DST are seen in 50% of women taking the oral contraceptive pill because of increased CBG levels (44).", + "tokenCount": 66, + "pageStart": 7, + "pageEnd": 7, + "hash": "e67de3dc799097f140beb7b81c9129eec8587fd61029df0ded00b2a2f524dd68" + }, + { + "text": "3.4.1 Evidence for use of UFC The introduction of UFC represented a major advance over mea- surement of 17-hydroxycorticosteroids (17OHCS), which re- flects both urine metabolites and cortisol.", + "tokenCount": 51, + "pageStart": 7, + "pageEnd": 7, + "hash": "0e6548648cfdb423f3d660ac43aa8af621b8a72e1bd77decf27edf46182bf894" + }, + { + "text": "Because 17OHCS has high rates of false-positive and negative results, it is now rarely used. Since the 1970s, experts have advocated the use of UFC for making the diagnosis of Cushing’s syndrome (49, 50).", + "tokenCount": 49, + "pageStart": 7, + "pageEnd": 7, + "hash": "a1972389ee1ec7c9055dee059c56041dd0d5f73a1469625cdf7cebd0ecc1eb54" + }, + { + "text": "UFC pro- vides an integrated assessment of cortisol secretion over a 24-h period. It measures the cortisol that is not bound to CBG, which is filtered by the kidney unchanged. Therefore, unlike serum cortisol, which measures both CBG-bound and free hormone, UFC is not affected by conditions and medications that alter CBG.", + "tokenCount": 68, + "pageStart": 7, + "pageEnd": 7, + "hash": "89e61a57418a8cf94f99979ccd48309a8fb12325c5c301b13be8aef7c3279a4b" + }, + { + "text": "For example, healthy women taking oral estrogen may have increased CBG, and therefore high serum cortisol concen- tration, but their UFC remains normal. Because cortisol produc- tion is increased in Cushing’s syndrome, the amount of unbound hormone is higher, resulting in elevated UFC values.", + "tokenCount": 62, + "pageStart": 7, + "pageEnd": 7, + "hash": "a323b2c805ca99728540ceac73012f9f27af192d2b2bd864d8f8a900eef3b51b" + }, + { + "text": "As with any other test, sensitivity and specificity of UFC are subject to the cutoffs selected. When the assay upper limit of normal is used as a criterion, the overall evidence supports the diagnostic accuracy of UFC in adults suspected of having Cush- ing’s syndrome (2, 51).", + "tokenCount": 59, + "pageStart": 7, + "pageEnd": 7, + "hash": "7747e212ccc0adc57bc91241abdd93e50cf1b7c2ae748f8f3b089c99c82f199f" + }, + { + "text": "Sensitivity for Cushing’s syndrome in pediatric patients is high ( \u0003 89%) (30). Thus, to achieve the goal of high sensitivity, we recommend using the upper limit of normal for the particular assay as the criterion for a positive test, provided the creatinine shows that the collection is complete and there is not excessive volume.", + "tokenCount": 70, + "pageStart": 7, + "pageEnd": 7, + "hash": "700751d55d8f7d3f88a81cde6057546ef449b2bd4a69be3e99ad6b8784eadeed" + }, + { + "text": "For pediatric patients, the adult normal ranges may be used because most pediatric patients are of adult weight ( i.e. \u0001 45 kg). At the recommended cutoff point, false-positive elevations of UFC may be seen in several conditions.", + "tokenCount": 49, + "pageStart": 7, + "pageEnd": 7, + "hash": "d789ad0a7a393d01fddba55018b17ceaca56bef657df23383102ee77b9a0fde2" + }, + { + "text": "High fluid intake ( \u0003 5 liters/d) significantly increases UFC (52). Any physiological or pathological condition that increases cortisol production raises UFC (Table 2). Therefore, in these conditions a normal result is more reliable than an abnormal one. At the recommended cutoff point, false-negative results of urine cortisol collections also may occur.", + "tokenCount": 67, + "pageStart": 7, + "pageEnd": 7, + "hash": "5d6f8bab5f79ee976359a3d53947f3305fcf30c4c1fde7cc69b2941549c4a098" + }, + { + "text": "Because UFC reflects renal filtration, values are significantly lower in patients with moderate to severe renal impairment. A falsely low UFC can occur when creatinine clearance falls less than 60 ml/min, and UFC levels fall linearly with more severe renal failure (53).", + "tokenCount": 54, + "pageStart": 7, + "pageEnd": 7, + "hash": "da68c36f39488f744e6a8941643bdcc74410a2525ee43bead9d2a75b2e87c485" + }, + { + "text": "UFC can be normal if a patient has cyclic disease and collects urine when the disease is inactive. Finally, it may be normal in some patients with mild Cushing’s syndrome, in whom salivary cor- tisol may be more useful (54).", + "tokenCount": 54, + "pageStart": 7, + "pageEnd": 7, + "hash": "8425a23e644ede87c2e279dc7c7e8797070035178db9b0cd346e1663c6363ca6" + }, + { + "text": "3.4.1 Remarks for UFC Sample collection and instructions It is important to ensure that patients provide a complete 24-h urine collection with appropriate total volume and urinary cre- atininelevels.Thismayrequirepatienteducationusingbothoral and written instructions.", + "tokenCount": 54, + "pageStart": 7, + "pageEnd": 7, + "hash": "ec3bf175b376c971e627e5043452d7056676d26d1efcc669070627d77ed82418" + }, + { + "text": "The first morning void is discarded so that the collection begins with an empty bladder. All subsequent voids throughout the day and night should be included in the collection, which is kept refrigerated (but not frozen), up to and including the first morning void on the second day.", + "tokenCount": 55, + "pageStart": 7, + "pageEnd": 7, + "hash": "671ded7d362cccd2f776891eabdab41c7536c5354243425015c28eda878cf05c" + }, + { + "text": "Once the bladderhasbeenemptiedintothecollectiononthesecondmorn- ing, the sample is complete. Patients should be instructed not to drink excessive amounts of fluid and to avoid the use of any glucocorticoid preparations, including steroid-containing skin or hemorrhoid creams, during TABLE 3.", + "tokenCount": 63, + "pageStart": 7, + "pageEnd": 7, + "hash": "2698d4c9000b1bf8edef731365fd90470c0b77ef64af8352b7a4c05513cd549f" + }, + { + "text": "Selected drugs that may interfere with the evaluation of tests for the diagnosis of Cushing’s syndrome a Drugs Drugs that accelerate dexamethasone metabolism by induction of CYP 3A4 Phenobarbital Phenytoin Carbamazepine Primidone Rifampin Rifapentine Ethosuximide Pioglitazone Drugs that impair dexamethasone metabolism by inhibition of CYP 3A4 Aprepitant/fosaprepitant Itraconazole Ritonavir Fluoxetine Diltiazem Cimetidine Drugs that increase CBG and may falsely elevate cortisol results Estrogens Mitotane Drugs that increase UFC results Carbamazepine (increase) Fenofibrate (increase if measured by HPLC) Some synthetic glucocorticoids (immunoassays) Drugs that inhibit 11 \u0001 -HSD2 (licorice, carbenoxolone) a This should not be considered a complete list of potential drug interactions.", + "tokenCount": 212, + "pageStart": 7, + "pageEnd": 7, + "hash": "6dab7a3a17e95475eb694766365a2b7f0c6f26114e4a30eff3f4f1915610a0fe" + }, + { + "text": "Data regarding CYP3A4 obtained from http://medicine.iupui.edu/flockhart/table.htm. 1532 Nieman et al. Guidelines for the Diagnosis of Cushing’s Syndrome J Clin Endocrinol Metab, May 2008, 93(5):1526–1540 Downloaded from https://academic.oup.com/jcem/article/93/5/1526/2598096 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 107, + "pageStart": 7, + "pageEnd": 7, + "hash": "9f7974e4a0f883fce4bac0acd414951374bf407f368b22f7f9c2a46ef53e1f4c" + }, + { + "text": "the collection. Because UFC levels in a patient with Cushing’s syndrome are variable, at least two collections should be per- formed, particularly in children in whom reproducibility can be low.", + "tokenCount": 41, + "pageStart": 8, + "pageEnd": 8, + "hash": "52292ce31ef8f83ca01917ac2f403cc950d7f0233eda8a34b643993de825770c" + }, + { + "text": "3.4.2 Evidence for late-night salivary cortisol In healthy individuals with stable conventional sleep-wake cy- cles, the level of serum cortisol begins to rise at 0300–0400 h, reaches a peak at 0700–0900 h, and then falls for the rest of the day to very low levels when the person is unstressed and asleep at midnight (55).", + "tokenCount": 81, + "pageStart": 8, + "pageEnd": 8, + "hash": "fa599e21d7905c20337feb7f22f961278b5254d3a01f8897830f2006d4c07ef9" + }, + { + "text": "The loss of circadian rhythm with absence of a late-night cortisol nadir is a consistent biochemical abnormality in patients with Cushing’s syndrome (56, 57). This difference in physiology forms the basis for measurement of a midnight serum or late-night salivary cortisol.", + "tokenCount": 58, + "pageStart": 8, + "pageEnd": 8, + "hash": "e4206156b5a81c1095f365852b1f777efe1bdaa898b1b3c0600c6ef2b81d5585" + }, + { + "text": "Biologically active free cortisol in the blood is in equilibrium with cortisol in the saliva, and the concentration of salivary cor- tisol does not appear to be affected by the rate of saliva produc- tion.", + "tokenCount": 44, + "pageStart": 8, + "pageEnd": 8, + "hash": "7bcad8288a179ba51c08b1a655c575fb7f73b1bb9bd47f2e4e3d9b5f892d2405" + }, + { + "text": "Furthermore, an increase in blood cortisol is reflected by a change in the salivary cortisol concentration within a few min- utes (58). Various methods have been used to measure cortisol in the saliva, resulting in different reference ranges and yielding differences in sensitivity and specificity (59–67).", + "tokenCount": 58, + "pageStart": 8, + "pageEnd": 8, + "hash": "c68349eae98651cb823e30aee83d7566d17aabcde820320a9360ec22ee7f8389" + }, + { + "text": "The best-vali- datedassaysusedintheUnitedStatestomeasuresalivarycortisol are an ELISA and an assay performed by LC-MS/MS (28).", + "tokenCount": 40, + "pageStart": 8, + "pageEnd": 8, + "hash": "db1fd842253354fdae4069106f24458c6ec7e29931a36fbfca59a891b279fe82" + }, + { + "text": "When these two assay techniques are used, normal subjects usually have salivary cortisol levels at bedtime, or between 2300 and 2400 h, of less than 145 ng/dl (4 nmol/liter).", + "tokenCount": 43, + "pageStart": 8, + "pageEnd": 8, + "hash": "89c89082655f0e2aabec96367fa0ae0f66315b050b60b9376d499ebaece68e22" + }, + { + "text": "Using a variety of assays and diagnostic criteria, investigators from different coun- tries have reported that late-night salivary cortisol levels yield a 92–100%sensitivityanda93–100%specificityforthediagnosis of Cushing’s syndrome (59–67).", + "tokenCount": 59, + "pageStart": 8, + "pageEnd": 8, + "hash": "a633dda3a457387037c937d4577cb8a61720a70b1801a11705e059c7742ab323" + }, + { + "text": "Overall, the evidence in adults suggeststhattheaccuracyofthistestissimilartothatofUFC(2). This easily performed, noninvasive test has been used in children to differentiate patients with Cushing’s syndrome from those with simple obesity.", + "tokenCount": 55, + "pageStart": 8, + "pageEnd": 8, + "hash": "137616628d01a7a991707697833fd5fc751cdf59f5fc1a297d9feebf48c10a21" + }, + { + "text": "Investigators have reported high sensitivity (100%) and specificity (95.2%) for Cushing’s syndrome in this setting (68). The influence of gender, age, and coexisting medical condi- tions on the late-night salivary cortisol concentrations has not beenfullycharacterized.Itisimportanttonotethatthecircadian rhythm is blunted in many patients with depressive illness and in shift workers (69, 70) and may be absent in the critically ill (71).", + "tokenCount": 102, + "pageStart": 8, + "pageEnd": 8, + "hash": "154803a802b5aad2a103553985820bec20d7fb6321b0f4270a6d81f6fb343745" + }, + { + "text": "Other populations may have a high percentage of false-positive results. For example, in a study of men aged 60 yr or older, Liu et al. (72) reported that 20% of all participants and 40% of diabetichypertensivesubjectshadatleastoneelevatedlate-night salivary cortisol measurement.", + "tokenCount": 72, + "pageStart": 8, + "pageEnd": 8, + "hash": "9bfaec46baa80a38b5f31b43aaa143ccc996e6bcebc72f72cb887604d4edca5a" + }, + { + "text": "Using the upper reference range of each assay as the cutoff point, Baid et al. (28) measured bed- time salivary cortisol levels in a large number of obese subjects and found a specificity of only 85% when they used a RIA tech- nique, but a better specificity of 92% when tandem mass spec- trometry was used.", + "tokenCount": 74, + "pageStart": 8, + "pageEnd": 8, + "hash": "1bc5ca56ff690422ad6a5b9ae6b7f00ec85e214ed6a9ad729605283677f974fc" + }, + { + "text": "3.4.2 Remarks for late-night salivary cortisol Most clinicians using the late-night salivary cortisol test ask pa- tientstocollectasalivasampleontwoseparateeveningsbetween 2300 and 2400 h.", + "tokenCount": 53, + "pageStart": 8, + "pageEnd": 8, + "hash": "9382ee79666f7e358d784977531b9110cee9450faf17fccc9563452e95a3d11a" + }, + { + "text": "Saliva is collected either by passive drooling into a plastic tube or by placing a cotton pledget (salivette) in the mouth and chewing for 1–2 min. The sample is stable at room or refrigerator temperature for several weeks and can be mailed to a reference laboratory.", + "tokenCount": 58, + "pageStart": 8, + "pageEnd": 8, + "hash": "9e3323f6c87832cef5611903d0ea955151885084e1b8ece88eec2259ee10d1f7" + }, + { + "text": "Reports show good correlation between salivary and simultaneous serum cortisol values in healthy vol- unteers(73,74).Whensampleswereobtainedatthesamesitting, those collected using the salivette device had lower cortisol con- centrations than those collected from passive drooling, but they correlated better with total and free serum cortisol levels (74).", + "tokenCount": 73, + "pageStart": 8, + "pageEnd": 8, + "hash": "1df8a1c77e9f4ff6b975a2372006de76614661d671078ffd814ce1b8fc71631f" + }, + { + "text": "Several factors that affect the salivary cortisol test should be considered when evaluating the results. The salivary glands ex- press 11 \u0001 -hydroxysteroid dehydrogenase type 2 (11 \u0001 -HSD2), which converts the biologically active cortisol to inactive corti- sone (75).", + "tokenCount": 64, + "pageStart": 8, + "pageEnd": 8, + "hash": "72d9b6820f7a1aae15e5fcd1753b4e90acaab829dead213f62fe036f96f7c61e" + }, + { + "text": "It is theoretically possible that individuals using lico- rice or chewing tobacco (both of which contain the 11 \u0001 -hydrox- ysteroid dehydrogenase type 2 inhibitor glycyrrhizic acid) may have a falsely elevated late-night salivary cortisol.", + "tokenCount": 57, + "pageStart": 8, + "pageEnd": 8, + "hash": "aa13f0504c18767b09fc013d92c2391b4b9a338276fcae439efcc3f5e0f2c130" + }, + { + "text": "Patients who smoke cigarettes also have been shown to have higher late-night salivary cortisol measurements than do nonsmokers (76). Al- though the duration of this effect is not known, it seems prudent to avoid cigarette smoking on the day of collection.", + "tokenCount": 53, + "pageStart": 8, + "pageEnd": 8, + "hash": "58af8e6cb6fcedb8e10af038240ebb5b7b322b93e31d77a10097641f612e9e0a" + }, + { + "text": "Direct con- tamination of the salivette by steroid-containing lotion or oral gels also may result in false-positive results. Because the test assumes a nadir of cortisol in the late evening, it may not be appropriate for shift workers or those with variable bedtimes, and the timing of the collection should be adjusted to the time of sleepingforthosewithbedtimesconsistentlylongaftermidnight.", + "tokenCount": 87, + "pageStart": 8, + "pageEnd": 8, + "hash": "c0d70350c58e9c158816cdec631e25c38d57beea40c9d248579077b9e57693d2" + }, + { + "text": "Similarly, nocturnal salivary cortisols may be transiently abnor- mal in individuals crossing widely different time zones. Finally, stress immediately before the collection also may increase sali- vary cortisol physiologically; therefore, ideally, samples should be collected on a quiet evening at home (64).", + "tokenCount": 62, + "pageStart": 8, + "pageEnd": 8, + "hash": "984695e12961f03d4256ed4b9c0f4148481382af50a70986a1a3b8819a9c9f9c" + }, + { + "text": "Theoretically, contamination with blood might increase sal- ivary cortisol levels. Although Kivlighan et al. (77) reported that minor to moderate blood leakage as a result of vigorous tooth brushing had no effect on salivary cortisol values, the possible effect of gingivitis or oral sores or injury is not known.", + "tokenCount": 70, + "pageStart": 8, + "pageEnd": 8, + "hash": "16de53d9cf3aa0bc4e9029a7b6bf467da0bba13ee31f5006fb407df2aa028bae" + }, + { + "text": "3.4.3 Evidence for the 1-mg DST In normal subjects, the administration of a supraphysiological dose of glucocorticoid results in suppression of ACTH and cor- tisol secretion.", + "tokenCount": 45, + "pageStart": 8, + "pageEnd": 8, + "hash": "bb2446a44c618172787d0d414eba9b07a40adf90082f511564b36da24d767f75" + }, + { + "text": "In endogenous Cushing’s syndrome of any cause, there is a failure of this suppression when low doses of the syn- thetic glucocorticoid dexamethasone are given (78).", + "tokenCount": 43, + "pageStart": 8, + "pageEnd": 8, + "hash": "ba372a11cd85940b24cce0dc91c68a56d1477a13acb1eba47c2d772a3147efee" + }, + { + "text": "Theovernighttestisasimpleoutpatienttest.Variousdosesof dexamethasone have been used, but 1 mg dexamethasone is usu- ally given between 2300 and 2400 h, and cortisol is measured between 0800 and 0900 h the following morning.", + "tokenCount": 61, + "pageStart": 8, + "pageEnd": 8, + "hash": "1a3661b82ef96a92952a04999ae10b572579c019c4f4ef3bfc0532acc6db6ee6" + }, + { + "text": "Higher doses (1.5or2mg)donotsignificantlyimprovetheaccuracyofthetest (49). Researchers have used cutoff values for the suppression of serum cortisol from 3.6 to 7.2 \u0002 g/dl (100–200 nmol/liter) when measured by modern RIA (79).", + "tokenCount": 66, + "pageStart": 8, + "pageEnd": 8, + "hash": "a4e03e25e3af9698cabb8bcdf03347204d18a8881f657d6a37acd73a126c59e6" + }, + { + "text": "A widely cited normal response is a serum cortisol less than 5 \u0002 g/dl ( \u0004 140 nmol/liter) (7, 80). Because some patients with Cushing’s disease demonstrate sup- pressibility to dexamethasone, use of this diagnostic criterion J Clin Endocrinol Metab, May 2008, 93(5):1526–1540 jcem.endojournals.org 1533 Downloaded from https://academic.oup.com/jcem/article/93/5/1526/2598096 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 128, + "pageStart": 8, + "pageEnd": 8, + "hash": "2dd8e769c005a5759b361f160ac1e83310a8be37cd1ae8cce39ef9be523d38d1" + }, + { + "text": "misclassified up to 15% of such patients as negative (81, 82). Therefore,toenhancesensitivity,expertshaveadvocatedrequir- ing a lower cutoff for suppression of the postdexamethasone serum cortisol to less than 1.8 \u0002 g/dl (50 nmol/liter) to achieve sensitivityratesofgreaterthan95%(83).Atthe1.8 \u0002 g/dlcutoff, the sensitivity is high with specificity rates of 80%; specificity increasestogreaterthan95%ifthediagnosticthresholdisraised to 5 \u0002 g/dl (140 nmol/liter) (7).", + "tokenCount": 138, + "pageStart": 9, + "pageEnd": 9, + "hash": "c9f5ec7160f4f4e27ba2cb454e1cfb58ac0b4f29df11ba5823a7f95493f2fc92" + }, + { + "text": "Given our objective of using tests with high sensitivity at this stage, we recommend use of the more stringent cutoff of 1.8 \u0002 g/dl. Overall, the evidence in adults indicates that in studies with low prevalence of Cushing’s syndrome this test has similar per- formance as the others recommended for initial testing (2).", + "tokenCount": 69, + "pageStart": 9, + "pageEnd": 9, + "hash": "917d0999cb2ee1ede75ba95cbdd2ba79c645699c9b95d900b1a59d641706e233" + }, + { + "text": "Al- though the 1-mg overnight test is used as a screening test for pediatric patients, there are no specific data regarding its inter- pretation or performance in this population. 3.4.3 Remarks for the 1-mg DST See the earlier comments under 3.4 Remarks for dexamethasone tests .", + "tokenCount": 68, + "pageStart": 9, + "pageEnd": 9, + "hash": "a54a52862baa96df9d13e9c35f1a6155b7ac768287839b76c2b01cc7b3392507" + }, + { + "text": "3.4.4 Evidence for the 48-h, 2 mg/d DST Some endocrinologists prefer to use the 48-h, 2 mg/d low-dose DST(LDDST)asaninitialtestbecauseofitsimprovedspecificity as compared with the 1-mg test.", + "tokenCount": 64, + "pageStart": 9, + "pageEnd": 9, + "hash": "7d07ff7c03fd2840fc9bbb21ddf6571943809b0435981d3cb735e79b029d171d" + }, + { + "text": "With adequate written instruc- tions for the patient, the LDDST is easily performed in the out- patient setting. As described above ( Section 1.0 ), certain psychiatric condi- tions (depression, anxiety, obsessive compulsive disorder), mor- bid obesity, alcoholism, and diabetes mellitus can be character- ized by overactivation of the HPA axis but without true Cushing’s syndrome, i.e.", + "tokenCount": 93, + "pageStart": 9, + "pageEnd": 9, + "hash": "770fae4ec9ef9e0020d7054d84de89a056e473d68c0096069a75d2eca8c349b8" + }, + { + "text": "hypercortisolism is not autonomous. In these conditions, UFC measurements are less useful as an initial test. The optimal test is the LDDST. Previous studies using var- ious doses of dexamethasone and differing criteria for suppres- sion suggest that at least 2 wk of abstinence from alcohol are needed to reduce the false-positive rate (84).", + "tokenCount": 78, + "pageStart": 9, + "pageEnd": 9, + "hash": "c6dd8032f3e1d0d26ff0df90da7d028ad6b7e84c1cefc693943fbdd2f5db702d" + }, + { + "text": "First described by Liddle (85) in 1960, the LDDST initially evaluated urinary 17OHCS as an indicator of cortisol suppres- sion. However, using 17OHCS or UFC, sensitivity and specific- ity rates are less than 70–80%.", + "tokenCount": 55, + "pageStart": 9, + "pageEnd": 9, + "hash": "3e1baef9de6a0ce35d0dab5a7f4b5375b9da2dc8cde3763693c919e8bfe21414" + }, + { + "text": "Use of a serum cortisol end point is simpler and has higher diagnostic accuracy (78). With a cutoff value for suppression of 50 nmol/liter (1.8 \u0002 g/ dl), the initially reported sensitivity was greater than 95% for adultpatients(86).Withthisapproach,thesensitivityforCushing’s syndrome in 36 pediatric patients was 94% (87). With a slightly different protocol and a lower cortisol criterion [38 nmol/liter (1.4 \u0002 g/dl)], the sensitivity was 90% in another study (9).", + "tokenCount": 119, + "pageStart": 9, + "pageEnd": 9, + "hash": "a14c12385b9faea93f4bbd58782ea113fc1253429075f30ba045808f7292b91f" + }, + { + "text": "Subsequent reports showed lower diagnostic accuracy of the LDDST (7, 88–90). Overall, in 92 patients without Cushing’s syndrome, the specificity of the LDDST was 70% (95% confi- dence interval 69–87%). In 59 patients with Cushing’s syn- drome, sensitivity was 96% for the LDDST (91).", + "tokenCount": 81, + "pageStart": 9, + "pageEnd": 9, + "hash": "89fa30df1515e2e399bc90ac48b4a6ce2ab7a726b1b2ee98dccf07587f67529d" + }, + { + "text": "The reasons for this apparent decrease in specificity are unknown. Serum dexa- methasone levels were not evaluated; in healthy volunteers, dexamethasone levels 2 h after the last dose were 13.0 \u0005 6.1 \u0002 mol/liter (469.5 \u0005 220.4 \u0002 g/dl) (92).", + "tokenCount": 72, + "pageStart": 9, + "pageEnd": 9, + "hash": "59fd700f60faca44f52e24b7eaccc335330e7f4701c1933f337d4b25a3003d1f" + }, + { + "text": "Consequently, the overall evidence in adults indicates that this test has similar or slightly less diagnostic accuracy than the other tests recommended here for initial testing (2). 3.4.4 Remarks for the 48-h, 2 mg/d DST In addition to the general remarks on dexamethasone tests pre- sented in the Initial testing section, there are further consider- ationsfortheLDDST.Dexamethasoneisgivenindosesof0.5mg for 48 h, beginning at 0900 h on d 1, at 6-h intervals, i.e.", + "tokenCount": 124, + "pageStart": 9, + "pageEnd": 9, + "hash": "4df26e4071c7d6407f89828e648230a1e8669b4d26d711fee6a2d60ef8178a09" + }, + { + "text": "at 0900, 1500, 2100, and 0300 h. Serum cortisol is measured at 0900 h, 6 h after the last dose of dexamethasone. Yanovski et al. (9) proposed a different protocol:", + "tokenCount": 50, + "pageStart": 9, + "pageEnd": 9, + "hash": "82684038d7dbef090f5569efb8220fcbc5ab437872d21596bc04c0fb8c246d80" + }, + { + "text": "administering 48 h of dexameth- asone at 6-h intervals but beginning at 1200 h and obtaining serum cortisol at 0800 h, exactl y 2 h (rather than 6 h as in the usual protocol) after the last dexamethasone dose.", + "tokenCount": 57, + "pageStart": 9, + "pageEnd": 9, + "hash": "72b58a777e5874eb38b419334e977d6cfaceb2feed4b87fd20a08e17358803ec" + }, + { + "text": "For pediatric patients weighing more than 40 kg, the initial adult protocol described above and the adult threshold for nor- mal suppression [ \u0004 50 nmol/liter (1.8 \u0002 g/dl)] are used.", + "tokenCount": 45, + "pageStart": 9, + "pageEnd": 9, + "hash": "93b60b7d05f3ff7ee6d9382a5e3009bcccecf70eccc405e3bfaf0ae73d57dc20" + }, + { + "text": "For pa- tients weighing less than 40 kg, the dose is adjusted to 30 \u0002 g/kg \u0001 d (in divided doses) (87). 3.5 Evidence The diagnostic accuracy of various other tests previously advo- cated for the diagnosis of Cushing’s syndrome (urinary 17-ke- tosteroids,1600horotherrandomcortisollevels,andtheinsulin tolerance test) is too low to recommend them for testing (49).", + "tokenCount": 98, + "pageStart": 9, + "pageEnd": 9, + "hash": "9ec45dbd7ca51e37251ac453c710a9d6e9aeab1e19ec99aa3a86f812185bc369" + }, + { + "text": "Other tests, such as the loperamide test, have insufficient evi- dence for their diagnostic accuracy. The response to those tests used specifically to establish the cause of Cushing’s syndrome ( e.g.", + "tokenCount": 46, + "pageStart": 9, + "pageEnd": 9, + "hash": "6bd62f51ace18f1baff2a502c7cec714b3f66eb431976004967651f3b201fd70" + }, + { + "text": "pituitary, adrenal or thoracic imaging, plasma ACTH con- centration, CRH stimulation test, 8 mg dexamethasone suppres- sion test) may be both abnormal in healthy people and normal in patients with Cushing’s syndrome and therefore are not helpful in establishing the diagnosis (78).", + "tokenCount": 69, + "pageStart": 9, + "pageEnd": 9, + "hash": "a8c2030647ce183f7b070d71e52b531d79115535ec99e43ce42b3e5b93af6d56" + }, + { + "text": "3.6–3.8 Evidence Our recommendations for retesting patients with initially nor- mal test results who develop new or progressive signs or symp- toms of Cushing’s syndrome comes from the panel’s clinical ob- servations and relate to the recognition that the patient’s pretest probability of Cushing’s syndrome would be higher on retesting and that hypercortisolism may have evolved concomitantly with the progression of the clinical syndrome, enhancing the likeli- hood that repeat tests would be positive.", + "tokenCount": 113, + "pageStart": 9, + "pageEnd": 9, + "hash": "dffb86febdc8549c5cb09e6d304bd8a8321df6e265615bb86aea5da7896e02ad" + }, + { + "text": "Similarly, the recommendation to retest patients with sus- pected cyclic Cushing’s syndrome comes from the recognition that these individuals may have normal test results when the disorder is quiescent (93).", + "tokenCount": 43, + "pageStart": 9, + "pageEnd": 9, + "hash": "8660637677ddcac471618f872fdf6d2bf29822f2377f9d821945c8f423ae116e" + }, + { + "text": "The performance and interpretation of subsequent testing for Cushing’s syndrome requires considerable expertise (both in the clinic and in the laboratory) and may be followed by either com- plex testing to establish its cause and surgical treatments or ex- pert reassurance of patients that they do not have this condition.", + "tokenCount": 61, + "pageStart": 9, + "pageEnd": 9, + "hash": "83a58d9eadc1c045aa3a8692c98a55ca30d9fad14d6e2f0dfa045bfa3fe97f2e" + }, + { + "text": "Because of this, it is the panel’s observation that referral to en- docrinology centers with expertise and interest in Cushing’s syn- drome in patients with abnormal initial testing is likely to be associated with better patient outcomes.", + "tokenCount": 51, + "pageStart": 9, + "pageEnd": 9, + "hash": "186b2ce49c40e8292391757457aac840e679f5aa602f240b0326590179e29520" + }, + { + "text": "1534 Nieman et al. Guidelines for the Diagnosis of Cushing’s Syndrome J Clin Endocrinol Metab, May 2008, 93(5):1526–1540 Downloaded from https://academic.oup.com/jcem/article/93/5/1526/2598096 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 78, + "pageStart": 9, + "pageEnd": 9, + "hash": "ad1fe37d58d077ef07bd921f5aea6f817f1c983719c1ebf15591ec9854d8ffdc" + }, + { + "text": "The recommendation to perform additional testing in pa- tients with discordant results derives from the knowledge that some patients with Cushing’s syndrome, usually those with mild or cyclic disease, may have discordant results.", + "tokenCount": 45, + "pageStart": 10, + "pageEnd": 10, + "hash": "c6d9d8c6012ea500338ea9a1216c3f8b215782846690cedda4ca5cf5008bfa9c" + }, + { + "text": "Also, some pa- tients without Cushing’s syndrome may have only a minimally abnormal but discordant result. The distinction between these groupsisdifficult,andthereisnoonecorrectdiagnosticstrategy.", + "tokenCount": 46, + "pageStart": 10, + "pageEnd": 10, + "hash": "295076d4a646ed54187a727166b41c81774e012e27a1dec85f1d2f4bb92f787f" + }, + { + "text": "The test results’ validity should be evaluated in light of the ca- veats mentioned for specific patient situations and for each test and assay. For example, an abnormal UFC may not be accepted if the specimen volume and creatinine suggest overcollection.", + "tokenCount": 51, + "pageStart": 10, + "pageEnd": 10, + "hash": "fd227db51fcddeee67f60cc57b26f0db9c54360a11e8ae3a91a40cd420f475a8" + }, + { + "text": "Underlying disorders that may cause mild hypercortisolism (Ta- ble 2) should be considered and testing repeated when these are treated or resolved. Postponing additional testing to allow pro- gression of clinical and biochemical features may be useful.", + "tokenCount": 51, + "pageStart": 10, + "pageEnd": 10, + "hash": "81d6b5fbd7dff201c629f5f8276cdc514c09920256a95a9196f8d3285ee5aa4e" + }, + { + "text": "The patient should be reassured that this poses minimal risk in the setting of mild hypercortisolism. Subsequent evaluation 3.8 For the subsequent evaluation of abnormal test results from one of the high-sensitivity tests, we recommend performing an- other recommended test (Fig.", + "tokenCount": 56, + "pageStart": 10, + "pageEnd": 10, + "hash": "7dffc95c4f4164269f0d39053de8e92cfd4267902b68032dbb96924b3852f9ca" + }, + { + "text": "1, 1 QEEE ). 3.8.1 We suggest the additional use of the dexamethasone- CRHtestorthemidnightserumcortisoltestinspecificsituations (Fig. 1, 1 QEEE ).", + "tokenCount": 53, + "pageStart": 10, + "pageEnd": 10, + "hash": "0d81f731d1a5af4f6b41aa81aea86a47711704983956319865f5ab7a2c6fa870" + }, + { + "text": "3.8.2 We suggest against the use of the desmopressin test, exceptinresearchstudies,untiladditionaldatavalidateitsutility (2 QEEE ). 3.8.3 We recommend against any further testing for Cush- ing’s syndrome in individuals with concordantly negative results on two different tests (except in patients suspected of having the very rare case of cyclical disease) (1 QEEE ).", + "tokenCount": 91, + "pageStart": 10, + "pageEnd": 10, + "hash": "e40e17c53deac1a0a8621862fc11a19b142df4b92a0a57e7ec5196575783d683" + }, + { + "text": "3.8.4 We recommend tests to establish the cause of Cushing’s syndrome in patients with concordantly positive results from two different tests, provided there is no concern regarding pos- sible non-Cushing’s hypercortisolism (Table 2) (1 QQEE ). 3.8.5Wesuggestfurtherevaluationandfollow-upforthefew patients with concordantly negative results who are suspected of having cyclical disease and also for patients with discordant re- sults, especially if the pretest probability of Cushing’s syndrome is high (2 QEEE ).", + "tokenCount": 130, + "pageStart": 10, + "pageEnd": 10, + "hash": "ffaf03fe66566b3515da28b9a2b832621a192abde9be3d637f7b537f6dc3797e" + }, + { + "text": "3.8 Remarks If the initial test result is abnormal, further evaluation by an endocrinologist will ensure that the disorder is confirmed or re- futed and that the possibility of a false-positive result will be considered.", + "tokenCount": 46, + "pageStart": 10, + "pageEnd": 10, + "hash": "f524b0b6e3861ed38423e08e9d5f287152ef4a8c9e1b08272812428174c5597a" + }, + { + "text": "Conversely, in cases in which there is a high pretest proba- bility of Cushing’s syndrome but a normal initial test, use of an additional alternative test has the potential benefit of disclosing those with milder disease.", + "tokenCount": 49, + "pageStart": 10, + "pageEnd": 10, + "hash": "14ce4dcea8b1a8be36681e0aa34238dc64c51c917da91a1ffe383dea8a34977c" + }, + { + "text": "3.8.1 Evidence for the 48-h, 2 mg/d LDDST with CRH In an effort to improve the sensitivity of the 48-h, 2 mg/d test, researchers developed a combined CRH stimulation test.", + "tokenCount": 50, + "pageStart": 10, + "pageEnd": 10, + "hash": "490b964bdd13bde62d4d04e659b788fc69986657d2671ff8d2aae857979ba1db" + }, + { + "text": "In the- ory, dexamethasone suppresses serum cortisol levels in individ- uals without Cushing’s syndrome as well as a small number of those with Cushing’s disease, but if given CRH, patients with Cushing’s disease should respond with an increase in ACTH and cortisol.", + "tokenCount": 70, + "pageStart": 10, + "pageEnd": 10, + "hash": "89906db0bfca11c802221ac612e0840793ccad8af57cec3c64c4e2004405b8e5" + }, + { + "text": "The test is done by administering the 48-h 2 mg/d DST, followedbyadministrationofCRH(1 \u0002 g/kg,iv )2hafterthelast dose of dexamethasone.", + "tokenCount": 47, + "pageStart": 10, + "pageEnd": 10, + "hash": "f8527450711a7f511b4c43d020d4fea5d4fb5fbf141a325e423494f34e36b342" + }, + { + "text": "Cortisol is measured 15 min later. The initial report of this strategy showed high diagnostic ac- curacy (92, 94). All eight of 59 patients with proven Cushing’s disease who suppressed pre-CRH cortisol to less than 1.4 \u0002 g/dl ( \u0004 38 nmol/liter; sensitivity 86%) were properly characterized after CRH administration.", + "tokenCount": 78, + "pageStart": 10, + "pageEnd": 10, + "hash": "5c67fae5c447f463f09d51471656e178a1e6ff676883a3566281c6176b8bf0eb" + }, + { + "text": "Subsequent reports showed lower diagnostic accuracy of both the DST and the combined test (7, 88–90). Overall, in 92 patients without Cushing’s syndrome, the specificity of the LDDST was 70% (95% confidence interval 69–87%), com- pared with a 60% specificity for the dexamethasone-CRH test (95% confidence interval 59–79%). In 59 patients with Cush- ing’ssyndrome,sensitivitywas96%fortheLDDSTand98%for the dexamethasone-CRH test.", + "tokenCount": 124, + "pageStart": 10, + "pageEnd": 10, + "hash": "1611781e810c7e8e95258b5802efa3b9df1bcfc744e15bd8e24a5840b3fd238a" + }, + { + "text": "The reasons for the differences in the responses to the LDDST and the combined test are not clear. As discussed above, any dexamethasone test may give either false-positive or false-neg- ativeresultsinconditionsthatalterthemetabolicclearanceofthe agent; additionally, differences in the performance of cortisol assays may contribute.", + "tokenCount": 74, + "pageStart": 10, + "pageEnd": 10, + "hash": "a3e27ea6ece6fa3c411dc4270f97363906f37f4e85e7ef8c61d5f607a44ed5d2" + }, + { + "text": "3.8.1 Remarks for the dexamethasone-CRH test The dexamethasone-CRH test can be useful in patients with equivocal results for UFC.", + "tokenCount": 41, + "pageStart": 10, + "pageEnd": 10, + "hash": "75a144ebae4d84e2122a4cfb6cdcb8e95733db1409d7e5d4f3595cd3ef76c13c" + }, + { + "text": "A dexamethasone level should be measured at the time of CRH administration to exclude a false- positive result, and the serum cortisol assay must be accurate at these low levels of detection.", + "tokenCount": 40, + "pageStart": 10, + "pageEnd": 10, + "hash": "45145479980c6dcb5211c8604c6fd802bee07f0e308d9d6f7a108689de3c6eaa" + }, + { + "text": "Additionally, it is possible that the 2-h time interval between dexamethasone and CRH administra- tion is critical so that compliance must be assured. In the United States, ovine-sequence CRH is available com- mercially (ACTHREL; Ferring Corp., Malmo, Sweden) with Food and Drug Administration-approved labeling for the dif- ferential diagnosis of Cushing’s syndrome.", + "tokenCount": 89, + "pageStart": 10, + "pageEnd": 10, + "hash": "0e285f2e79a4987252f4f842d5fe7b75a9f4d49cde709478d347a3ad72f5bdad" + }, + { + "text": "In Europe, the hu- man-sequence peptide is in widespread use (Ferring) but has lower stimulatory effect than the ovine-sequence CRH (95). 3.8.1 Evidence for the midnight serum cortisol test As noted above, the nocturnal nadir of serum cortisol values is lost in patients with Cushing’s syndrome, forming the basis of this test.", + "tokenCount": 83, + "pageStart": 10, + "pageEnd": 10, + "hash": "edf1de56f521679eee1214cd04cf67425388bf586cf64d6dc2fd7ee3f8e11ebd" + }, + { + "text": "Because the test is cumbersome to perform, we do not suggest its use in initial testing for Cushing’s syndrome. How- ever, the test may be useful in specific situations detailed below.", + "tokenCount": 40, + "pageStart": 10, + "pageEnd": 10, + "hash": "0f76a2201d3c7e706719eac8a9381db0dffcee64bfe30432087b064e8827d256" + }, + { + "text": "Midnightserumcortisolmaybeassessedinthesleepingorawake state, using different diagnostic criteria. As with all tests, use of a higher diagnostic criterion is associated with reduced sensitiv- ity but increased specificity.", + "tokenCount": 49, + "pageStart": 10, + "pageEnd": 10, + "hash": "109f5dab8750813b8a510ce62e3c52c28263ad8e2a6140c3192ea8db5bb11eff" + }, + { + "text": "Sleeping midnight serum cortisol In one study, a single sleeping serum cortisol greater than 1.8 \u0002 g/dl ( \u0001 50 nmol/liter) had high sensitivity (100%) for the di- agnosis of Cushing’s syndrome (96).", + "tokenCount": 56, + "pageStart": 10, + "pageEnd": 10, + "hash": "48794533941c2c1d5b91f6082448ddc771026117c1ce3bcb03fda698cddad3eb" + }, + { + "text": "More recent larger studies confirm the poor specificity for this criterion (20.2%), with a cutoff point of 7.5 \u0002 g/dl having higher specificity (87%) (7). J Clin Endocrinol Metab, May 2008, 93(5):1526–1540 jcem.endojournals.org 1535 Downloaded from https://academic.oup.com/jcem/article/93/5/1526/2598096 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 108, + "pageStart": 10, + "pageEnd": 10, + "hash": "50fa9b36b4bee1806ecd330025da4777511341c3fa787c46ca7a01359aca4449" + }, + { + "text": "In 105 children with Cushing’s syndrome, measurement of sleepingmidnightcortisolhadhighersensitivitythanUFC(99 vs. 88%) (30). When used in patients with a high clinical index of suspicion of Cushing’s syndrome and who had normal UFC and full sup- pression on dexamethasone testing, a sleeping midnight serum cortisol of greater than 1.8 \u0002 g/dl or an awake value of greater than 7.5 \u0002 g/dl increases the probability of Cushing’s syndrome (96). Conversely, where there is a low clinical index of suspicion, such as in simple obesity, but lack of suppression on dexameth- asone testing and mildly elevated UFC, a sleeping midnight se- rum cortisol less than 1.8 \u0002 g/dl effectively excludes Cushing’s syndrome at the time of assessment (7).", + "tokenCount": 183, + "pageStart": 11, + "pageEnd": 11, + "hash": "fb918342af3cd2a7ff14084422bedad1213d51f63267ac6dc2933eb8d0accb2e" + }, + { + "text": "The midnight serum cortisoltestalsohasutilityinthecontextoffailureofsuppression on dexamethasone testing due to anticonvulsant medication, in which a sleeping midnight serum cortisol less than 1.8 \u0002 g/dl has been used to exclude Cushing’s syndrome (97).", + "tokenCount": 67, + "pageStart": 11, + "pageEnd": 11, + "hash": "55c043a75ff715919afb1f1f593a0146d475e46be9668225026cc214ea57c9d7" + }, + { + "text": "It is likely that similar values for awake measurements would have similar util- ity, but this has not been tested directly. Overall, the evidence in adult patients for the midnight serum cortisol accuracy is limited and inconsistent across studies, with at least one study showing that this test can enhance the accuracy of the UFC and 1-mg dexamethasone tests (2).", + "tokenCount": 74, + "pageStart": 11, + "pageEnd": 11, + "hash": "9bcf5797295d75b26623da7553956eae0ec9e9dbe366454f0c57a2091ac8a2b0" + }, + { + "text": "Awake midnight serum cortisol Sampling for midnight serum cortisol when the patient is awake is far easier. Initial studies suggested that an awake midnight serum cortisol greater than 7.5 \u0002 g/dl ( \u0001 207 nmol/liter) had a sensitivity and specificity greater than 96% (98, 99).", + "tokenCount": 62, + "pageStart": 11, + "pageEnd": 11, + "hash": "e7ba014eb33472d364a8f0199d24468fd337413287826ce3d48acc3a0119cdb6" + }, + { + "text": "However, when applied to an obese cohort, the specificity was only 83% (100). In an effort to improve on specificity, higher cutoff points have been advocated, inevitably at the cost of sensitivity:", + "tokenCount": 40, + "pageStart": 11, + "pageEnd": 11, + "hash": "7095ef54b61492e7cc3d1372e6c4fed65fe26fb04e0e30e8214bec35e1f7fcca" + }, + { + "text": "values of serum midnight cortisol greater than 8.3–12 \u0002 g/dl had 90– 92% sensitivity with specificity of 96% (63, 101). 3.8.1 Remarks for the midnight serum cortisol test The sleeping midnight cortisol requires inpatient admission for a period of 48 h or longer to avoid false-positive responses due tothestressofhospitalization;thisapproachmaynotbepossible in some practice settings.", + "tokenCount": 90, + "pageStart": 11, + "pageEnd": 11, + "hash": "d1a42b37d1152e5234d78e965c84388648a06f85c722af42a625a6750abb3351" + }, + { + "text": "If a sleeping value is desired, the blood sample must be drawn within 5–10 min of waking the patient, or through an indwelling line, to avoid false-positive results (96).", + "tokenCount": 40, + "pageStart": 11, + "pageEnd": 11, + "hash": "9627b77618020f0bb2fd34045330d1f70c9339389e3d45f3f458640cd31d9bdc" + }, + { + "text": "Young children may have their cortisol nadir earlier than midnight. In children, precatheterization is essential so that a sleeping sample for serum cortisol can be obtained. 3.8.2 Remarks for the desmopressin stimulation test The desmopressin stimulation test involves measurement of plasma ACTH just before and 10, 20, and 30 min after iv ad- ministration of 10 \u0002 g 1-desamino-8- D -arginine vasopressin.", + "tokenCount": 101, + "pageStart": 11, + "pageEnd": 11, + "hash": "be21b290c424a2ee832a9ec92d4ab02f0067ceb6119793752a2fba2e0dcb2839" + }, + { + "text": "In general, patients with Cushing’s disease show an increase in ACTH, but those with other causes of Cushing’s syndrome or those without Cushing’s syndrome do not respond (7, 22, 102).", + "tokenCount": 49, + "pageStart": 11, + "pageEnd": 11, + "hash": "100100fdc08ff058cfe067c754dd4267386cf7acaf53fa716131bda1ef589273" + }, + { + "text": "The sensitivity for patients with Cushing’s disease was 82–87%; whenotherpatientswithCushing’ssyndromewereincluded,the sensitivity was 63–75%.", + "tokenCount": 41, + "pageStart": 11, + "pageEnd": 11, + "hash": "5e727a35b9568714e05185ddd92effea95247d2a5f7e03330bbda062abef243c" + }, + { + "text": "The specificity ranged from 85 to 91%. Until additional data validate the utility of the test in a larger population of patients with all causes of Cushing’s syndrome, it seems prudent to restrict this test to research studies.", + "tokenCount": 45, + "pageStart": 11, + "pageEnd": 11, + "hash": "bb7c9b7def21b15618962dd79c98d7235e179b5722814ac188f1322cf7aef800" + }, + { + "text": "4.0 Special populations/considerations 4.1 Pregnancy: We recommend the use of UFC and against the useofdexamethasonetestingintheinitialevaluationofpregnant women (1 QQQE ).", + "tokenCount": 49, + "pageStart": 11, + "pageEnd": 11, + "hash": "a9233d0f4d043f2ee445610f4533db97c6332cae8420f8685bba5cd895c970f2" + }, + { + "text": "4.2 Epilepsy: We recommend against the use of dexamethasone testing in patients receiving antiepileptic drugs known to en- hance dexamethasone clearance and recommend instead mea- surements of nonsuppressed cortisol in blood, saliva, or urine (1 QQQE ).", + "tokenCount": 67, + "pageStart": 11, + "pageEnd": 11, + "hash": "c5cf11573c90615d674aee9d33551c06fb9dd9794401ca0b59ca6b4a2e21f0d7" + }, + { + "text": "4.3 Renal failure: We suggest using the 1-mg overnight DST rather than UFC for initial testing for Cushing’s syndrome in patients with severe renal failure (2 QEEE ).", + "tokenCount": 41, + "pageStart": 11, + "pageEnd": 11, + "hash": "05942311edd893b76301da224497f46d45161c0c8acaf2aa8ab25665f4cc69f0" + }, + { + "text": "4.4 Cyclic Cushing’s syndrome: We suggest use of UFC or mid- night salivary cortisol tests rather than DSTs in patients sus- pected of having cyclic Cushing’s syndrome (2 QEEE ).", + "tokenCount": 52, + "pageStart": 11, + "pageEnd": 11, + "hash": "2bdbc5aabc8fbe0e58b6218963789ed97abfbb073ea16773a0bfbaa20b232c9f" + }, + { + "text": "4.5 Adrenal incidentaloma: We suggest use of the 1-mg DST or late-night cortisol test, rather than UFC in patients suspected of having mild Cushing’s syndrome (2 QQEE ).", + "tokenCount": 46, + "pageStart": 11, + "pageEnd": 11, + "hash": "1ea35ad666be27ba7928a1655561afcf19a2da4a9d61d9830d5e57c97d028660" + }, + { + "text": "4.1 Evidence for choice of tests in pregnant women Screening for hypercortisolism is more difficult in pregnancy, particularly in the second and third trimesters. UFC excretion is normal in the first trimester; however, it increases up to 3-fold by term to overlap values seen in women with Cushing’s syndrome (103).", + "tokenCount": 73, + "pageStart": 11, + "pageEnd": 11, + "hash": "605ae78b2382c1faed1c549a857099e4d0f29adabce693e41a49162f342335ae" + }, + { + "text": "Thus, only UFC values in the second or third trimester greater than 3 times the upper limit of normal can be taken to indicate Cushing’s syndrome. Serum cortisol circadian variation is preserved in normal pregnancy, albeit with a higher midnight nadir. Whereas loss of circadian variation is characteristic of Cushing’s syndrome, diagnostic thresholds for evening serum or salivary cortisol in pregnant patients are not known (103, 104).", + "tokenCount": 89, + "pageStart": 11, + "pageEnd": 11, + "hash": "8a446a8f9efe6e0c68150cf3db3ecb95835fd29f3296f264629ca97b2aceb930" + }, + { + "text": "Furthermore,suppressionofserumandurinarycortisolbydexa- methasone is blunted in pregnancy (105). Thus, dexamethasone testing has an increased potential for false-positive results in pregnancy.", + "tokenCount": 50, + "pageStart": 11, + "pageEnd": 11, + "hash": "18c5849ae798bf9ba542d4d623b2cf0ac5b79e6684a256e75d7d21523418f57f" + }, + { + "text": "4.2 Evidence for choice of tests in patients receiving anticonvulsants As discussed above (see 3.4 Remarks for dexamethasone tests ), commonly used anticonvulsant medications, including phenyt- oin, phenobarbitone, and carbamazepine, induce hepatic enzy- matic clearance of dexamethasone, mediated through CYP 3A4, and may cause false-positive responses on testing.", + "tokenCount": 95, + "pageStart": 11, + "pageEnd": 11, + "hash": "b0e4fa9c037a2cd515031a593af49b77fed3ca0029d75b780cfb26a453585dcb" + }, + { + "text": "There are, however, no data to guide the length of time needed after with- drawal of such medication to allow dexamethasone metabolism to return to normal, and such a medication change may not be clinically possible.", + "tokenCount": 46, + "pageStart": 11, + "pageEnd": 11, + "hash": "c90f179e9408967c1dbdcc6a7177aa7e8ceaba83ee1d394967b3c42a8259f43b" + }, + { + "text": "Switching to nonenzyme-inducing medica- tion may correct this situation, but an alternative and more prac- tical approach is to use another test, such as assessment of mid- night salivary or serum cortisol, to exclude Cushing’s syndrome in these patients (97).", + "tokenCount": 62, + "pageStart": 11, + "pageEnd": 11, + "hash": "732dc4d18b94c7b37ee938f04787ecb0c0dce22606f6b84cd371060bc0d75f9d" + }, + { + "text": "4.3 Evidence for choice of tests in chronic renal failure As noted above (see 3.4.1), excreted urine cortisol values de- creasebelowcreatinineclearanceof60ml/minandarequitelow, 1536 Nieman et al.", + "tokenCount": 57, + "pageStart": 11, + "pageEnd": 11, + "hash": "c3a042d296f90f040c3ae29a9965426e822f8ef981df38c571bce5efdf6568ec" + }, + { + "text": "Guidelines for the Diagnosis of Cushing’s Syndrome J Clin Endocrinol Metab, May 2008, 93(5):1526–1540 Downloaded from https://academic.oup.com/jcem/article/93/5/1526/2598096 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 72, + "pageStart": 11, + "pageEnd": 11, + "hash": "ff1fcbc856e62ff8dac438999f1d14b8790e11a636ff529706340a4bfea48f83" + }, + { + "text": "below 20 ml/min (53). Although the cortisol circadian rhythm was present in one study, neither serum nor salivary midnight cortisol concentrations have been reported in this population (106 However, serum free cortisol values measured over a 24-h period were reported to be elevated (106). As a result, a normal (low) midnight cortisol value probably excludes Cushing’s syn- drome, but the diagnostic threshold for either serum or salivary cortisol is not known. The absorption and metabolism of 1 mg dexamethasone, as well as the cortisol response, have been re- ported to be both normal and abnormal (107–109", + "tokenCount": 132, + "pageStart": 12, + "pageEnd": 12, + "hash": "0dde4803c18edcb0d433fee0a17afc09bf5e608252159ddb82343bdd3c7928b7" + }, + { + "text": "Responses to administration of 3 and 8 mg dexamethasone were normal in some but not all patients (106, 108). In the absence of additional data, a normal response to 1 mg dexamethasone is likely to ex- clude Cushing’s syndrome, but an abnormal response is not diagnostic. 4.4 Evidence for choice of tests in cyclic Cushing’s syndrome Rarely patients have been described with episodic secretion of cortisol excess in a cyclical pattern with peaks occurring at in- tervals of several days to many months (93", + "tokenCount": 120, + "pageStart": 12, + "pageEnd": 12, + "hash": "312a3136bc0de124bb1e135bcee3a9ca60379380b80d0bd6d263890ead777270" + }, + { + "text": "Because the DST results may be normal in patients who are cycling out of hyper- cortisolism, these tests are not recommended for patients sus- pected of having cyclic disease. Instead, measurement of UFC or salivary cortisol may best demonstrate cyclicity. In patients for whom clinical suspicion is high but initial tests are normal, fol- low-up is recommended with repeat testing, if possible to coin- cide with clinical symptoms. 4.5 Evidence for choice of tests in adrenal incidentaloma UFC appears to be less sensitive than the 1-mg DST or late-night cortisol for the identification of Cushing’s syndrome in this pop- ulation (20–23). There is no consensus on the best algorithm or the best diagnostic criterion for the 1-mg DST. A suppressed ACTH or dehydroepiandrosterone sulfate concentration sup- ports the diagnosis of Cushing’s syndrome in patients with ad- renal masses (20–23", + "tokenCount": 200, + "pageStart": 12, + "pageEnd": 12, + "hash": "6317b5f50e9e681cc846c72460e7ac988cabb00cfc1040010c3b7a033ceb08c9" + }, + { + "text": "Measurement of ACTH or dehydroepi- androsteronesulfateisnotpartofinitialdiagnosticevaluationof a patient presenting with clinical features of Cushing’s syn- drome, but it may indicate subtle adrenal hyperfunction in this specific population. 5. Future directions and recommended research The evidence on which many of these recommendations have been made is of low to very low quality because there are limited data linking diagnostic strategies to patient outcomes as much of theworkhasfocusedondeveloping,validating,andascertaining diagnostic test performance. This focus may be due to the rarity of the disease and the availability of diverse diagnostic methods. In addition, published data, which are often from larger tertiary referral centers, might be biased toward more diagnostically challenging cases, higher pretest probability, and greater disease severity. Such bias may result in an overly sanguine view of the diagnostic performance of these tests, particularly compared with their expected performance in unselected populations in usual clinical practice. These issues highlight the need for further research and for improvements in the research methods used to determine whether testing will lead to improved patient outcomes. Investigation in the following areas would significantly im- prove the future care of patients with hypercortisolism: 1. Pooled information . A commitment from endocrinologists supported by national and international endocrine organiza- tions and funding agencies to establish databases of consecutive patients tested for Cushing’s syndrome allowing for prospective pooling of the diagnostic test information. This pooled infor- mation would help to define discriminatory symptoms and signs and provide data on the most accurate testing strategies. 2. Standardization of assays . The diagnosis of Cushing’s syn- drome is critically dependent on the quality and performance of cortisolassays,betheyfromserum,saliva,orurineandmeasured by RIA, ELISA, or LC-MS/MS. Clinicians need a greater appre- ciation of the robustness (or otherwise) of their particular assay and its variance from published cutoff data. National laborato- ries of excellence might be used as referral centers in difficult cases; approval by the health", + "tokenCount": 447, + "pageStart": 12, + "pageEnd": 12, + "hash": "30592414355bcbfcd7f2743f551fd5a8624f52aeec54852676e0ffaeeffabc38" + }, + { + "text": "authorities/insurance companies for such use would be important. 3. Improved clinical outcome data and targeted clinical trials . Initial testing for hypercortisolism may be desirable to the extent that its results will favorably affect outcomes that matter to pa- tients.Thereisapressingneedtoinvestigateoutcomesinpatients cured of Cushing’s syndrome with modern-day practice. In par- ticular, there are conflicting data on the need to treat mild or so-called subclinical Cushing’s syndrome, notably in patients with adrenal incidentalomas. Appropriately powered and rigor- ously designed randomized clinical trials to compare diagnostic- treatment strategies should be established to inform clinicians and patients on optimal management. Acknowledgments The members of the Task Force thank Dr. Robert Vigersky, the members of the Clinical Guidelines Subcommittee, the Clinical Affairs Core Com- mittee, and The Endocrine Society Council for their careful review of earlier versions of this manuscript and their helpful suggestions. We thank Patricia A. Stephens, Ph.D., medical writer on this guideline, who meticulously checked the references and formatted the guideline into its currentform.Inaddition,wethankthemanymembersofTheEndocrine Society who reviewed the draft version of this guideline when it was posted on the The Endocrine Society Web site and who sent a great number of comments, most of which were incorporated into the final version of the manuscript. We thank the European Society of Endocri- nology for their co-sponsorship of this guideline. Finally, we thank the staff at The Endocrine Society office for their helpful support during the development of this guideline. Address all correspondence to: The Endocrine Society, 8401 Con- necticut Avenue, Suite 900, Chevy Chase, Maryland 20815. E-mail: govt-prof@endo.society.org. Address all reprint requests for orders of 101 and more to: Heather Edwards, Reprint Sales Specialist, Cadmus Professional Communications, 8621 Robert Fulton Drive, Columbia, Maryland 21046. E-mail: endoreprints@cadmus.com. Address all re- print requests for orders of 100 or less to Society", + "tokenCount": 450, + "pageStart": 12, + "pageEnd": 12, + "hash": "33ca849b11d763aea6089973e8a2b09b91ad6e1d3ce4dfd2a417210898ad38af" + }, + { + "text": "Services. E-mail: societyservices@endo-society.org. J Clin Endocrinol Metab, May 2008, 93(5):1526–1540 jcem.endojournals.org 1537 Downloaded from https://academic.oup.com/jcem/article/93/5/1526/2598096 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 89, + "pageStart": 12, + "pageEnd": 12, + "hash": "e90714d441c5c70c00bacba626397cb8185f76a1d8c08e36e4c15cb3aa1299e3" + }, + { + "text": "Disclaimer Statement Clinical practice guidelines are developed to be of assistance to physi- cians by providing guidance and recommendations for particular areas of practice. The guidelines should not be considered inclusive of all proper approaches or methods, or exclusive of others. The guidelines cannot guarantee any specific outcome, nor do they establish a standard of care. The guidelines are not intended to dictate the treatment of a particular patient. Treatment decisions must be made based on the in- dependent judgment of health care providers and each patient’s individ- ual circumstances. The Endocrine Society makes no warranty, express or implied, re- garding the guidelines and specifically excludes any warranties of mer- chantability and fitness for a particular use or purpose. The Endocrine Society shall not be liable for direct, indirect, special, incidental, or con- sequential damages related to the use of the information contained herein. Disclosure of Task Force Lynnette K. Nieman , M.D. (chair)—Financial or Business/Organiza- tional Interests: UpToDate, HRA Pharma, Significant Financial Interest or Leadership Position: none declared; Beverly M. K. Biller , M.D.— Financial or Business/Organizational Interests: Novartis, consultant, Significant Financial or Leadership Position: none declared; James W. Findling , M.D.— Financial or Business/Organizational Interests: No- vartis, Corcept, Significant Financial or Leadership Position: none de- clared; John D. C. Newell-Price , M.D., F.R.C.P., Ph.D.—Financial or Business/Organizational Interests: Society for Endocrinology, United Kingdom, Clinical Endocrinology , Trustee to Pituitary Foundation , United Kingdom, Significant Financial Interest or Leadership Position: none declared; Martin Savage , M.D.—Financial or Business/Organiza- tional Interests: Society of Endocrinology, RDE, Significant Financial Interest or Leadership Position: Hormone Reproduction, Ipsen; Paul MichaelStewart ,M.D.,F.R.C.P.—FinancialorBusiness/Organizational Interests: International Society for Endocrinology, Significant Financial or Leadership", + "tokenCount": 450, + "pageStart": 13, + "pageEnd": 13, + "hash": "3440ebbcbd810fca2572e3400800bd323f33d536c7bffea49c592b2a3644a130" + }, + { + "text": "Position: none declared; * Victor M. Montori , M.D.— Financial or Business/Organizational Interests: none declared, Signifi- cant Financial or Leadership Position: none declared. *Evidence-based reviews for this guideline were prepared under contract with The Endo- crine Society. References 1. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, Guyatt GH, Harbour RT, Haugh MC, Henry D, Hill S, Jaeschke R, Leng G, Liberati A, Magrini N, Mason J, Middleton P, Mrukowicz J, O’Connell D, Oxman AD, Phillips B, Schunemann HJ, Edejer TT, Varonen H, Vist GE, Williams Jr JW, Zaza S 2004 Grading quality of evidence and strength of recommendations. BMJ 328:1490 2. Elamin MB, Murad MH, Mullan R, Erickson D, Harris K, Nadeem S, Ennis R, Erwin PJ, Montori VM 2008 Accuracy of diagnostic tests for Cushing syndrome: a systematic review and meta-analyses. J Clin Endocrinol Metab 93:1553–1562 3. 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Ramirez G, Gomez-Sanchez C, Meikle WA, Jubiz W 1982 Evaluation of the hypothalamic hypophyseal adrenal axis in patients receiving long-term he- modialysis.", + "tokenCount": 54, + "pageStart": 15, + "pageEnd": 15, + "hash": "ac97450dda29e29eb867fc4bbce64ab8a1c22b0c251e85fd0d43d22c9547ec97" + }, + { + "text": "Arch Intern Med 142:1448–1452 109. Workman RJ, Vaughn WK, Stone WJ 1986 Dexamethasone suppression testing in chronic renal failure: pharmacokinetics of dexamethasone and demonstration of a normal hypothalamic-pituitary-adrenal axis.", + "tokenCount": 62, + "pageStart": 15, + "pageEnd": 15, + "hash": "e9649d2a9ac1c347541c8c3b34428ad5ea36eaa690c920077c67e9b7f67a7150" + }, + { + "text": "J Clin En- docrinol Metab 63:741–746 1540 Nieman et al. Guidelines for the Diagnosis of Cushing’s Syndrome J Clin Endocrinol Metab, May 2008, 93(5):1526–1540 Downloaded from https://academic.oup.com/jcem/article/93/5/1526/2598096 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 94, + "pageStart": 15, + "pageEnd": 15, + "hash": "f390107d266322c58149d63d7d6ade23cc6d77414cf48332132863fad569e4c5" + } +] \ No newline at end of file diff --git a/Adrenal Nodule information/FINAL Adrenal Nodual Workflow Flyer copy.pdf_semantic.json b/Adrenal Nodule information/FINAL Adrenal Nodual Workflow Flyer copy.pdf_semantic.json new file mode 100644 index 0000000000000000000000000000000000000000..68f3d0553b3c0ffdc06a6d8cc02a76adab1645cf --- /dev/null +++ b/Adrenal Nodule information/FINAL Adrenal Nodual Workflow Flyer copy.pdf_semantic.json @@ -0,0 +1,72 @@ +[ + { + "text": "Evaluating adrenal nodules *See next page for hormonal workup reference Incidental adrenal nodule > 1 cm Found on non-contrast (non-con) CT? DO NOT BIOPSY adrenal mass without hormone workup and consulation Assess imaging characteristics Obtain adrenal protocol CT Suspicious appearance Hormonal workup* Abnormal DST or metanephrines or aldosterone : renin Normal hormonal workup Refer to Endocrine Surgery Adrenal Nodules Clinic Benign appearance Hormonal workup* • Size ≥4 cm in diameter • >10 Hounsfield units (HU) on non-con CT • CT contrast washout <40–60% • On MRI, hyperintense on T2 imaging or no signal loss on chemical-shift analysis • On 18F-FDG PET-CT, SUVmax ≥5 or adrenal-to- spleen or adrenal-to liver signal-intensity ratio ≥1 • Catecholamine Excess – Plasma fractionated metanephrines – Abnormal:", + "tokenCount": 220, + "pageStart": 1, + "pageEnd": 1, + "hash": "4419fbaa97a9f1c0b1b24bd865ba9cb6364e9bf24737b2c3d6f78a821897f791" + }, + { + "text": ">2x Upper Limit of Normal (ULN) • Adrenal hypercortisolism – 1mg Dexamethasone suppression test (DST) – Abnormal: >1.8 mcg/dl • Adrenal hyperaldosteronism – If patient has a history of HTN – Plasma aldosterone and renin – Abnormal:", + "tokenCount": 74, + "pageStart": 1, + "pageEnd": 1, + "hash": "2c29833c1fe3d5ee1831adc19a73181caee26e67fbaf79c01621e8728e31db9a" + }, + { + "text": "aldosterone >10 and renin <1.0 • Size 1-4 cm in diameter • ≤10 Hounsfield units (HU) on non-con CT • CT contrast washout ≥40–60% • Signal loss on MRI chemical-shift analysis • On 18F-FDG PET-CT, SUVmax <5 or adrenal-to- spleen or adrenal-to liver signal-intensity ratio <1 • Adrenal hypercortisolism – 1mg Dexamethasone suppression test (DST) – Abnormal:", + "tokenCount": 116, + "pageStart": 1, + "pageEnd": 1, + "hash": "621d65ce68ae4ef079456dca5e7aec1d3b59280e9befd94526f134f7ffcce4a6" + }, + { + "text": ">1.8 mcg/dl • Adrenal hyperaldosteronism – If patient has a history of HTN – Plasma aldosterone and renin – Abnormal: aldosterone >10 and renin <1.0 Size > 4cm AND ≤10 HU on non-con CT • Repeat adrenal protocol CT in 1 year to confirm stability • Consider follow-up imaging at 6 months in patients younger than 40 years of age • Autonomous cortisol secretion = most common hormonal excess to develop during surveillance and may be reevaluated at a 2- to 5-year interval Size 1–4cm AND >10 HU on non-con CT Size 1–4 cm AND ≤10 HU on non-con CT • Follow up with primary care provider • No further follow-up imaging needed unless symptoms or signs indicating hormone excess develop Ye s No", + "tokenCount": 177, + "pageStart": 1, + "pageEnd": 1, + "hash": "e6b6af236be13560be76f178128bb80c7e3f55b996d103bf8a48afff8f26f72e" + }, + { + "text": "GS-2727550-26 Hormonal workup reference 1. Cortisol evaluation Dexamethasone Suppression Test (DST) • Prescribe 1 mg of oral dexamethasone to be taken at 11 pm • The next morning at 8 am, a cortisol and dexamethasone level are drawn • If the 8 am cortisol is < 1.8 mcg/dL, cortisol excess is ruled out • If the am cortisol after dexamethasone is >1.8mcg/dL, then screening is POSITIVE or ABNORMAL • Cortisol between 1.8–5.0 mcg/dL may represent mild cortisol excess, therefore you need to proceed with confirmatory testing:", + "tokenCount": 150, + "pageStart": 2, + "pageEnd": 2, + "hash": "5f8e23e321bca92b2885a9999c904c74544a4de70384170cca08e64c73120462" + }, + { + "text": "– Morning serum corticotropin and cortisol levels – 24-hr urinary cortisol – 3 midnight/late-night salivary cortisol – Midnight serum cortisol – DHEAS (<40 mcg/dL) • Failure to suppress below 5.0 mcg/dL raises concern for cortisol excess 2.", + "tokenCount": 61, + "pageStart": 2, + "pageEnd": 2, + "hash": "3f9e7ec19beb6a3815afe199f75ed3caa084b57ddc0f70f49af14798131849f9" + }, + { + "text": "Screen for aldosteronoma Aldosterone level : Plasma Renin Activity (PRA) • Perform if patient has a history of hypertension or hypokalemia • Obtain mid-morning plasma aldosterone concentration and plasma renin activity – These must be drawn at the same time and should not be done with the DST • Divide the aldosterone level by the PRA to calculate the aldosterone :", + "tokenCount": 85, + "pageStart": 2, + "pageEnd": 2, + "hash": "329a6fedec37030b61b3718c99b055128048e10481eb0b7df8a6a29b347a783f" + }, + { + "text": "renin (ARR) • If the ARR is > 20, screen is POSITIVE or ABNORMAL for hyperaldosteronism • If aldosterone > 10 ng/dL AND renin < 1.0 ng/dL then screen is POSITIVE or ABNORMAL for hyperaldosteronism – Proceed to confirmatory testing with oral sodium load test, aldosterone suppression test or seated saline infusion test • If aldosterone < 10 ng/dL OR renin > 1.0 ng/dL, then screen is NEGATIVE or NORMAL for hyperaldosteronism • If aldosterone > 10 ng/dL AND renin > 1.0 ng/dL and is on a potentially interfering medication, then hold/replace medications for 4 weeks and repeat 3.", + "tokenCount": 163, + "pageStart": 2, + "pageEnd": 2, + "hash": "a3a7a89a79b6c4214c9e6bdf8f3f3c5e142a8334c96d3caadae12833e3eb2b0a" + }, + { + "text": "Screen for pheochromocytoma Plasma-free metanephrines • POSITIVE or ABNORMAL if elevated > 2x ULN • Elevations < 2x ULN may be false positives and should be considered equivocal • Elevations < 2x ULN and no classic signs of pheochromocytoma – Confirm with 24-hour urine metanephrines = less likely to be falsely positive • If mildly elevated or concern for false positive, stop medications:", + "tokenCount": 104, + "pageStart": 2, + "pageEnd": 2, + "hash": "dacf9c336510e37ac3cfab0d94dad5c57ae16a1306dadc6592efe121f7e4c630" + }, + { + "text": "– Tricyclic antidepressants – Phenoxybenzamine – Levodopa – Beta blockers – Labetalol – Amphetamines – Buspirone – Methyldopa – Chlorpromazine • Confirmatory testing = 24-hour urine metanephrines • Consider genetic testing in confirmed pheochromocytoma", + "tokenCount": 70, + "pageStart": 2, + "pageEnd": 2, + "hash": "00c31aad5838949bc50aa0f08788b70800bd1070a53d2e82d7b3a483bf671e00" + } +] \ No newline at end of file diff --git a/Adrenal Nodule information/JAMA Guidelines for Adrenalectomy.pdf_semantic.json b/Adrenal Nodule information/JAMA Guidelines for Adrenalectomy.pdf_semantic.json new file mode 100644 index 0000000000000000000000000000000000000000..660a4c24e23f23916f5fa4fa6262e4592f260552 --- /dev/null +++ b/Adrenal Nodule information/JAMA Guidelines for Adrenalectomy.pdf_semantic.json @@ -0,0 +1,856 @@ +[ + { + "text": "3% in patients without a history of malignancy and up to 8% in patients with a history of extra-adrenal malignancy. 8 Other features in addition to size should be considered when assess- ing risk of either a primary or secondary malignancy in an ad- renal incidentaloma (eTable 2 in the Supplement ).", + "tokenCount": 70, + "pageStart": 3, + "pageEnd": 3, + "hash": "611c0d9d5affa2a2fdac4a6ab955a48cba1c1c5805ea796b509054175be7e459" + }, + { + "text": "Recommendation 1.2. We recommend that all patients with an adrenal incidentaloma 1 cm or larger undergo biochemical testing for autonomous cortisol secretion. Patients with hy- pertension or hypokalemia also require biochemical evalua- tion for primary aldosteronism.", + "tokenCount": 55, + "pageStart": 3, + "pageEnd": 3, + "hash": "7a0343ca2f338fc48c275a7fedd589b31f4f9c0f56bf036e1fb2acf86ec2f63e" + }, + { + "text": "Patients with adrenal imaging findings that have noncontrast CT with HU greater than 10 should undergo evaluation for pheochromocytoma. (Strong recommendation, low-quality evidence.) Recommendation 1.3.", + "tokenCount": 46, + "pageStart": 3, + "pageEnd": 3, + "hash": "fff848405c1f3428f584ca1f5b68d5f8554aa6ef346a2d6ef79d40d1b0cbb040" + }, + { + "text": "We recommend that a primary ad- renal malignancy be considered in patients with an adrenal in- cidentaloma larger 4 cm and/or HU greater than 20 on non- contrast CT and in any patient younger than 18 years.", + "tokenCount": 49, + "pageStart": 3, + "pageEnd": 3, + "hash": "45b02e37a79371b58f246904248192a4a1a188d11299696ec18f021a1ae74940" + }, + { + "text": "We recommend that patients with a history of extra-adrenal ma- lignancy be recognized to be at increased risk for adrenal me- tastases. (Strong recommendation, low-quality evidence.) Most nonfunctional adrenal nodules with benign imaging characteristics remain stable in size 5,7,12 while up to 10% of ad- renal incidentalomas will grow 1 cm or more over 2 to 5 years of surveillance.", + "tokenCount": 87, + "pageStart": 3, + "pageEnd": 3, + "hash": "f4a214f8dc6a8c0a9363f58a723b982b854e38709e6c6306294f58f9fd0e50d8" + }, + { + "text": "13-15 Surgical resection may be considered for nodules that are larger than 2 cm at initial presentation and grow more than 1 cm by 12 months, while smaller nodules or those with less growth may undergo repeated short-interval imaging at 6 to 12 months.", + "tokenCount": 55, + "pageStart": 3, + "pageEnd": 3, + "hash": "99ab1086f56ec07327787a29ea9f4ff9219c8f167d261550b6e03d84c0962138" + }, + { + "text": "However, there are insufficient data to recommend specific criteria for nodule growth during sur- veillance that should prompt adrenalectomy. Topics and Questions in the Population, Intervention/Exposure, Comparison, and Outcome (PICO) Framework 1.", + "tokenCount": 50, + "pageStart": 3, + "pageEnd": 3, + "hash": "38b03945d065e8cebc1cd8c38cfd81a6c457ecff868cde5800457fc6f6646e96" + }, + { + "text": "Incidentalomas, myelolipomas, and cysts 1. In patients with an adrenal incidentaloma, does adrenal protocol computed tomography improve diagnostic accuracy for malignancy or pheochromocytoma compared with other imaging modalities?", + "tokenCount": 53, + "pageStart": 3, + "pageEnd": 3, + "hash": "1911d8373369e835215bab63b4e602335b71f60b3d5ef9ac8cd1d8e4e51775e9" + }, + { + "text": "In patients with an adrenal incidentaloma, should clinical and imaging characteristics influence the hormonal workup? In patients with an adrenal incidentaloma, what clinical and imaging characteristics increase the risk that malignancy is present? In patients with a nonfunctional adrenal incidentaloma, what are the outcomes during surveillance?", + "tokenCount": 62, + "pageStart": 3, + "pageEnd": 3, + "hash": "b7c719ec4d2089357e661bdd4498e26135df0691ef979f2e978ec3829da3551d" + }, + { + "text": "Does resection of a myelolipoma or an adrenal cyst improve quality of life compared with observation alone? Primary aldosteronism 1. In patients with primary aldosteronism (PA), does adrenalec- tomy compared with mineralocorticoid antagonist therapy alone improve related comorbidities and mortality?", + "tokenCount": 71, + "pageStart": 3, + "pageEnd": 3, + "hash": "57a39dc11abfdf2f244978b4129fe40dd27696e167f99e939cfb86749604c31c" + }, + { + "text": "In patients with PA and cross-sectional imaging consistent with a unilateral adenoma, does preoperative adrenal venous sampling increase the likelihood of a clinical or biochemical cure? In patients with PA due to unilateral disease, does laparo- scopic adrenalectomy improve health-related quality of life and/or reduce health care–related costs compared with medical management?", + "tokenCount": 74, + "pageStart": 3, + "pageEnd": 3, + "hash": "c92a58644395e17716be128d95f67e367429758f0277460654938a8524b00afe" + }, + { + "text": "Hypercortisolism 1. Do patients with mild autonomous cortisol secretion (MACS) who undergo laparoscopic adrenalectomy compared with conservative medical management have improvement in cardiometabolic comorbidities without major surgical (30-day) adverse events?", + "tokenCount": 53, + "pageStart": 3, + "pageEnd": 3, + "hash": "6bc4a2877d4c77a25312e59151ba9ca513d8164eade85a82d3643bf3d162eb3d" + }, + { + "text": "Do patients with Cushing syndrome and bilateral macronodu- lar hyperplasia who undergo unilateral laparoscopic adrenal- ectomy achieve biochemical remission of hypercortisolism when compared with patients treated with bilateral adrenalectomy? In patients with adrenocorticotropic hormone–dependent hypercortisolism, does bilateral laparoscopic adrenalectomy improve disease-free survival or mortality compared with pharmacologic management?", + "tokenCount": 86, + "pageStart": 3, + "pageEnd": 3, + "hash": "822b22aee09e487b0020c4b0594627330fdb0fe27e89e4dd3780b793e42c99bc" + }, + { + "text": "Is the incidence of postoperative adrenal insufficiency after unilateral adrenalectomy different between patients with overt Cushing syndrome vs those with MACS? Adrenocortical carcinoma 1. In patients with adrenocortical carcinoma (ACC), does treat- ment at a high-volume multidisciplinary center improve survival outcomes?", + "tokenCount": 67, + "pageStart": 3, + "pageEnd": 3, + "hash": "3888c1a331fe91f2eb0a71750f3c35bc878447ea650e42a6a45107f5732c48ac" + }, + { + "text": "In patients with ACC without evidence of distant metastatic disease at diagnosis, does operative technique affect survival? In patients with ACC and systemic disease at diagnosis, does resection of the primary tumor improve survival?", + "tokenCount": 40, + "pageStart": 3, + "pageEnd": 3, + "hash": "03dd3d3b1369bec3035483f2082ac065d7a354bec42e47c6cf4101d22d874c42" + }, + { + "text": "In patients with advanced ACC, what is the role of neoadju- vant therapy followed by resection vs surgery with or without adjuvant therapy? Metastasis to the adrenal gland 1.", + "tokenCount": 42, + "pageStart": 3, + "pageEnd": 3, + "hash": "a03a845c858b408f7c7ef3ed5ad8a11197a18bf29882465514048404b7292e94" + }, + { + "text": "In patients with an adrenal mass, does history of an extra- adrenal malignancy influence the hormonal evaluation? In a patient with a history of an extra-adrenal malignancy and an adrenal mass, when is image-guided needle biopsy recommended?", + "tokenCount": 56, + "pageStart": 3, + "pageEnd": 3, + "hash": "ded2487af766d1274a0925439f83f9e14fe19545eb7c0193be9ae0863aa916b4" + }, + { + "text": "In patients with an adrenal metastasis, does resection improve survival compared with systemic therapy alone? Pheochromocytoma and paraganglioma 1. In patients with pheochromocytoma and paraganglioma, how does selective α blockade affect perioperative hemodynamic stability when compared with nonselective blockade with phenoxybenzamine?", + "tokenCount": 78, + "pageStart": 3, + "pageEnd": 3, + "hash": "6d9d21375d7f5a1a7ee4c61fb123709e63bc3070929b9e7df793267d3df68a89" + }, + { + "text": "In patients with genetic mutations driving long-term develop- ment of bilateral pheochromocytomas, what is the impact of cortical-sparing adrenalectomy compared with bilateral total adrenalectomy on steroid dependence and disease recurrence?", + "tokenCount": 49, + "pageStart": 3, + "pageEnd": 3, + "hash": "ac90ad95a96e7eeef47952c6f64d2aba85a9d3a0ba9264bee41adceb04b6e2ec" + }, + { + "text": "In patients with metastatic pheochromocytoma and paragan- glioma, does surgical resection of primary disease improve survival compared with nonsurgical treatment? Technical aspects 1. In patients undergoing adrenalectomy, what is the benefit of minimally invasive surgery compared with open surgery on perioperative outcomes?", + "tokenCount": 65, + "pageStart": 3, + "pageEnd": 3, + "hash": "27a572f31dd7190adc3e83e21df9571cf32758be09858a28680a9c451a94005e" + }, + { + "text": "In patients who are appropriate candidates for minimally invasive adrenalectomy, does a retroperitoneal compared with a transperitoneal approach change perioperative outcomes? For surgeons performing adrenal surgery, does surgeon volume influence morbidity and mortality?", + "tokenCount": 50, + "pageStart": 3, + "pageEnd": 3, + "hash": "8e7992d452339be8f34c6d960531d967e2b17e7c081e7bfe90ba649880059800" + }, + { + "text": "In patients with adrenal tumors, what is the efficacy of radio- frequency ablation and stereotactic radiation compared with adrenalectomy? Research Original Investigation American Association of Endocrine Surgeons Guidelines for Adrenalectomy 872 JAMA Surgery October 2022 Volume 157, Number 10 (Reprinted) jamasurgery.com © 2022 American Medical Association.", + "tokenCount": 72, + "pageStart": 3, + "pageEnd": 3, + "hash": "4aabd3a82f267a3c08fccc2137dcdac48718f18e96c58d05737461bb9f4e7d1c" + }, + { + "text": "Downloaded from jamanetwork.com by University of Wisconsin -Madison user on 02/20/2026 Recommendation 1.4. We do not recommend routine scheduled follow-up of a nonfunctional adrenal nodule (size <4 cm) with benign imaging characteristics and noncontrast HU less than 10 because the risk of developing malignancy is very low.", + "tokenCount": 77, + "pageStart": 3, + "pageEnd": 4, + "hash": "663dccfeb8b3c54d0672820f76653a42e1753c12058e781f9d7cca8bcd862c08" + }, + { + "text": "Nodules from 1 to 4 cm with indeterminate imaging characteristics (such as noncontrast CT with HU >10) have a slightly increased risk of malignancy and should undergo at least 1 repeated image at 6 to 12 months to confirm stability.", + "tokenCount": 53, + "pageStart": 4, + "pageEnd": 4, + "hash": "efe852b1e11887078d899f112eff22464322197b7c0c8f0381ea657455fef873" + }, + { + "text": "Autonomous cortisol secretion is the most common hor- monal excess to develop during surveillance and thus may be reevaluated at a 2- to 5-year interval. (Strong recommenda- tion, low-quality evidence.) Adrenalmyelolipomasandcystshavecharacteristicimaging features.", + "tokenCount": 64, + "pageStart": 4, + "pageEnd": 4, + "hash": "d52062b642b1e338f45098e8c248ab2b122321d743473a48c793ba42bed71d0f" + }, + { + "text": "4 Resection may be considered for indeterminate imaging, symptomatic tumors due to mass effect, substantive growth on surveillance, or those that have hemorrhaged. Recommendation 1.5. We do not suggest resecting a my- elolipoma or adrenal cyst with pathognomonic imaging features to improve the patient’s quality of life unless there are symptoms of mass effect.", + "tokenCount": 82, + "pageStart": 4, + "pageEnd": 4, + "hash": "492310ccdb495da58ec1250b978fff23fa67584e5431546d122e21c8b482b997" + }, + { + "text": "(Weak recommendation, low- quality evidence.) 2. Primary Aldosteronism Primary aldosteronism (PA) has been reported in 3% to 10% of hypertensive patients. 16 Once PA is diagnosed, mineralo- corticoid antagonists can be used to effectively manage PA-related hypertension and hypokalemia.", + "tokenCount": 68, + "pageStart": 4, + "pageEnd": 4, + "hash": "fc6694df2947b057bac40fbf6ad4578f69ab08e16f2c3d968ce0659554b0fd16" + }, + { + "text": "Primary aldoste- ronism may be caused by an aldosterone-secreting adenoma, unilateral adrenal hyperplasia, or bilateral adrenal hyperpla- sia, and adrenal venous sampling (AVS) may be necessary for lateralization (eTable 3 in the Supplement ).", + "tokenCount": 67, + "pageStart": 4, + "pageEnd": 4, + "hash": "2fce7e4c79d8bd5b1f2e3c2c704ea7c9c164545cfa911326361962969bf06208" + }, + { + "text": "After adrenalec- tomy, the majority of patients with PA have either complete or partial clinical success, with less than 20% requiring the same or higher doses of medication postoperatively. Studies to date have assessed cost and quality-of-life outcomes after adrenalectomy via laparoscopy, and whether similar conclu- sions can be made using other minimally invasive surgical ap- proaches is not yet known.", + "tokenCount": 89, + "pageStart": 4, + "pageEnd": 4, + "hash": "ea2d2c52b00016c5866e853a0f802cb24ca47cdf4a016d56795cad4339911e8f" + }, + { + "text": "Recommendation 2.1. We recommend that patients un- dergo laparoscopic adrenalectomy for unilateral PA because they are more likely to use fewer medications with lower de- fined daily doses to achieve normalization of blood pressure and potassium levels and have lower risks of new-onset atrial fibrillation, chronic kidney disease, stroke, and all-cause mor- tality.", + "tokenCount": 79, + "pageStart": 4, + "pageEnd": 4, + "hash": "6d132c11f0231514db8738d2eb709909c1214213fa84f315c7db9027a578e5c8" + }, + { + "text": "(Strong recommendation, low-quality evidence.) Recommendation 2.2. We suggest that in patients 35 years and younger with cross-sectional imaging demonstrat- ing a unilateral adenoma and a normal contralateral gland, AVS may be deferred because adrenalectomy directed by CT imaging alone has a cure rate similar to adrenalectomy guided by AVS.", + "tokenCount": 74, + "pageStart": 4, + "pageEnd": 4, + "hash": "d98f68f1e2534203d206b16499510b7c30df1273d7ef89b9ab7ff52fa8fa4265" + }, + { + "text": "However, AVS should still be considered for all patients older than 35 years. (Weak recommendation, low-quality evidence.) Recommendation 2.3. We recommend laparoscopic adre- nalectomy for primary aldosteronism due to unilateral dis- ease because it improves quality of life and reduces health care–related costs.", + "tokenCount": 69, + "pageStart": 4, + "pageEnd": 4, + "hash": "0c40a02c8ee0b25f35b318f225e0e3bbab5f896a4df063948c2086c25b63be46" + }, + { + "text": "(Strong recommendation, low-quality evidence.) 3. Hypercortisolism Previously known as subclinical Cushing syndrome (CS), MACS has been reported in 0.2% to 2% of the general adult popula- tion and in 5% to 30% of patients with an adrenal inciden- taloma (eTable 3 in the Supplement ).", + "tokenCount": 74, + "pageStart": 4, + "pageEnd": 4, + "hash": "43f70c7def365062b698db9cb7d9d798075d1b5bb90322d6a3dc5f5a3c9c97c5" + }, + { + "text": "17 Although patients with MACS may lack the classical stigmata of hypercortisolism, they have a high prevalence of associated comorbidities such as obesity, arterial hypertension, type 2 diabetes, vertebral frac- tures, and cardiovascular morbidity and mortality.", + "tokenCount": 58, + "pageStart": 4, + "pageEnd": 4, + "hash": "a2fc1728a650b805a885886575befbb0d21f07d0417d75c17dae0eef123a9c53" + }, + { + "text": "18,19 Recommendation 3.1. We recommend that patients with MACS secondary to a unilateral adenoma undergo laparo- scopic adrenalectomy because of anticipated significant improvements in cardiometabolic comorbidities.", + "tokenCount": 47, + "pageStart": 4, + "pageEnd": 4, + "hash": "831627949389b08650ba2163d87e71ead6eaca1ceaeffe6b75cfcad3b374c9c4" + }, + { + "text": "(Strong rec- ommendation, moderate-quality evidence.) Bilateraladrenocorticotropichormone(ACTH)–independent CS can be due to either macronodular or micronodular adre- nal hyperplasia.", + "tokenCount": 55, + "pageStart": 4, + "pageEnd": 4, + "hash": "4840f3a4edd45241e8d3c7ffe152815d1e4b4cced18cf3a77a01e9ca4c0f7932" + }, + { + "text": "20,21 There has been growing interest in whether unilateral adrenalectomy of the larger gland may produce bio- chemical normalization of hypercortisolism in select pa- tients. While surgical morbidity and mortality are minimal 17 and resolution of hypercortisolism occurs in 84% to 100% of pa- tients, recurrence can be seen in 13.3% to 68% of patients at 4 years.", + "tokenCount": 87, + "pageStart": 4, + "pageEnd": 4, + "hash": "16e84622b4baf8e81eae999c9f2a678e2955e49441150164c269689f601a3e59" + }, + { + "text": "22,23 Recommendation 3.2. In patients with bilateral mac- ronodular hyperplasia, we suggest consideration of unilat- eral laparoscopic adrenalectomy in patients with CS as an at- tempt to achieve biochemical remission of hypercortisolism without causing permanent adrenal insufficiency.", + "tokenCount": 67, + "pageStart": 4, + "pageEnd": 4, + "hash": "d868765f190d35f42a7860e85ce29a09bf46ae73887d210631ec7a5432ee64e0" + }, + { + "text": "(Weak rec- ommendation, low-quality evidence.) ACTH-dependent CS results from pituitary Cushing dis- ease or an ectopic ACTH source. Although CS can be resolved in most patients with treatment of the primary source, a sub- set of patients experience persistent, symptomatic CS from in- curable pituitary disease or metastatic or occult ectopic ACTH production.", + "tokenCount": 84, + "pageStart": 4, + "pageEnd": 4, + "hash": "fe5bee6ca6e7debefb795773f09124feaf341f3e3529b189a7e00575617916b4" + }, + { + "text": "Modern surgical techniques permit most pa- tients who require bilateral adrenalectomy to be managed with laparoscopic surgery, and operative morbidity in these pa- tients is approximately 10% with surgical mortality at 3%.", + "tokenCount": 44, + "pageStart": 4, + "pageEnd": 4, + "hash": "9f0d90338a6069cde9d958ad42a83549b5496dc07bd57887628040e34967a893" + }, + { + "text": "24-26 Recommendation 3.3. We suggest that patients with mod- erate to severe ACTH-dependent hypercortisolism refractory to source control undergo bilateral laparoscopic adrenalec- tomy to ameliorate cortisol excess and improve disease-free survival and mortality.", + "tokenCount": 62, + "pageStart": 4, + "pageEnd": 4, + "hash": "925afa99b1f35afb27760a7a6cb65e609462eca48c67bb00adc06fcd55a34df8" + }, + { + "text": "Postoperative adrenal insufficiency is a life-threatening condition that should be prevented and promptly managed in patients undergoing adrenalectomy. Symptoms include fa- tigue, hypotension, anorexia, abdominal pain, weakness, syn- cope, back pain, nausea, vomiting, fever, and confusion.", + "tokenCount": 62, + "pageStart": 4, + "pageEnd": 4, + "hash": "d294211e1f9b5831483aed9d0377c3c3c708c31251587b6047b13b8254cdd349" + }, + { + "text": "27 (Weak recommendation, low-quality evidence.) Recommendation 3.4. The incidence of adrenal insuffi- ciency after unilateral adrenalectomy is nearly 100% in pa- tients with overt CS and about 60% in patients with MACS.", + "tokenCount": 54, + "pageStart": 4, + "pageEnd": 4, + "hash": "d5c5a21e6899c6f155b5b542e98fa5cfb464da8be22dbac9fffd52ef55c540e5" + }, + { + "text": "We recommend empirical postoperative glucocorticoid replace- ment therapy for all patients with overt CS after undergoing unilateral adrenalectomy. However, we r ecommend that in patients with MACS, postoperative day 1 morning cortisol or corticotropin stimulation testing could be used to determine the need for glucocorticoid replacement therapy (eTable 4 American Association of Endocrine Surgeons Guidelines for Adrenalectomy Original Investigation Research jamasurgery.com (Reprinted) JAMA Surgery October 2022 Volume 157, Number 10 873 © 2022 American Medical Association.", + "tokenCount": 117, + "pageStart": 4, + "pageEnd": 4, + "hash": "386b00dda3bd3ce64ded5905603ab0f31679070df3117b93d7493576380b5c3c" + }, + { + "text": "Downloaded from jamanetwork.com by University of Wisconsin -Madison user on 02/20/2026 in the Supplement ). (Strong recommendation, low-quality evidence.) 4. Adrenocortical Carcinoma Adrenocortical carcinoma is a rare cancer and complete sur- gical resection is the only potential curative therapy (eTable 3 in the Supplement ).", + "tokenCount": 78, + "pageStart": 4, + "pageEnd": 5, + "hash": "461f6eb58786e7c79f737d80850e36f3430ebd5e5c7494a0dc6c92411a8948bc" + }, + { + "text": "28 Given limited adjuvant therapies and the overall poor prognosis associated with recurrent ACC, com- plete resection to negative margins at the index operation is a key tenet of ACC management.", + "tokenCount": 40, + "pageStart": 5, + "pageEnd": 5, + "hash": "1e246b22272e5bd6ec58654d50f9815de94e868c77b1a55f7accf56fe9ac9df3" + }, + { + "text": "29 While radical surgery with en bloc resection and preservation of an intact tumor capsule is the standard of care for locoregionally invasive disease, the operative technique hinges on skill and experience. Recommendation 4.1.", + "tokenCount": 45, + "pageStart": 5, + "pageEnd": 5, + "hash": "b948f36ac8a57da1097e8436b22071b7b0b214e621a1675961f76306f76bfcf8" + }, + { + "text": "We recommend that patients with clinical and radiographic findings consistent with ACC should be treated at high-volume multidisciplinary centers to im- prove recurrence outcomes; data on overall survival are in- conclusive.", + "tokenCount": 41, + "pageStart": 5, + "pageEnd": 5, + "hash": "e630d536600f5fd9cf77217b2b6e8dbf54513719c0dd778e8c224f1fea9506dd" + }, + { + "text": "(Strong recommendation, low-quality evidence.) Recommendation 4.2. Regardless of operative approach, we recommend an en bloc radical resection with an intact cap- sule to microscopically negative (R0) margins because of im- proved survival.", + "tokenCount": 52, + "pageStart": 5, + "pageEnd": 5, + "hash": "262e4a4ab959a189432ebb6241aee15cd4f850b08a114ac960f17e9711b05446" + }, + { + "text": "Although open resection is preferred when ACC is suspected, the choice of operative approach should be based on the certainty of a complete R0 resection without tumor disruption. (Strong recommendation, low-quality evidence.) Approximately 22% to 35% of patients with ACC have evi- dence of distant metastatic disease at initial presentation. 29,30 Cases with oligometastatic but potentially resectable ACC pre- sent a challenge, as the benefits of primary resection and/or metastasectomy are incompletely understood.", + "tokenCount": 106, + "pageStart": 5, + "pageEnd": 5, + "hash": "bb776c54f9a27950224e56f00b0a92f9628efaa808af8c13c715f2bc27161e15" + }, + { + "text": "Careful pa- tient selection and clinical judgment should be integrated with the patient’s goals of care. Recommendation 4.3. We suggest that patients with sys- temic disease be offered resection of the primary tumor if all sites of disease are reasonably amenable to resection or local treatment and if performance status allows.", + "tokenCount": 68, + "pageStart": 5, + "pageEnd": 5, + "hash": "b68386c0cbd3bcaa37f93c6b6d5923514109b2918cfd1849806b4d645efe8e45" + }, + { + "text": "Surgery may also be considered in patients with hormone excess medically re- fractory to steroidogenic inhibition. (Weak recommenda- tion, low-quality evidence.) In ACC, the goal of systemic neoadjuvant therapy is pri- marily to reduce the burden of disease to facilitate later po- tential complete resection.", + "tokenCount": 67, + "pageStart": 5, + "pageEnd": 5, + "hash": "342efccfd421b6687dd9970ece0d1b7ecd4a2c56569147024e285e1963a4de4d" + }, + { + "text": "Although neoadjuvant therapy for advanced ACC has not been systemically evaluated, the ratio- nale for neoadjuvant treatment is extrapolated from the data on adjuvant therapy. Recommendation 4.4.", + "tokenCount": 45, + "pageStart": 5, + "pageEnd": 5, + "hash": "9239cc63714d358d864201d071a05cf4352a6ebd2a523de11fc4dfef5f7d5c7a" + }, + { + "text": "We recommend that neoadjuvant systemic therapy be administered for advanced ACC when R0 surgical resection is not initially feasible. We recommend up- front surgical intervention when R0 resection is possible. (Strong recommendation, low-quality evidence.) 5.", + "tokenCount": 51, + "pageStart": 5, + "pageEnd": 5, + "hash": "92fe805a8292e81c7268cd53063aaf7faa09b9805a40a5c624700ad4c35c3f48" + }, + { + "text": "Metastasis to the Adrenal Gland Adrenal metastases may have imaging features that make them potentially indistinguishable from other pathologies. Func- tional evaluation is imperative prior to biopsy, ablation, or re- section and should aim, at a minimum, to exclude excess hor- mone production.", + "tokenCount": 64, + "pageStart": 5, + "pageEnd": 5, + "hash": "df2a17bbef30b6d79d56dbf0804be84f3e4e6968b2b0530693d44f5e8f2ca8c3" + }, + { + "text": "If the indeterminate adrenal mass is the only site of potential metastatic disease and appears resectable in an otherwise fit operative candidate, surgical resection rather than biopsy may be considered for both diagnostic purposes and potential therapeutic benefit.", + "tokenCount": 48, + "pageStart": 5, + "pageEnd": 5, + "hash": "70d7e0d95d5c2f0006bd950b6c35229153b4014ee6ab4fbe26a574f8aac7c5f3" + }, + { + "text": "Recommendation 5.1. We recommend that a directed hor- monal evaluation should be performed in patients with an ad- renal mass regardless of history of extra-adrenal malignancy.", + "tokenCount": 40, + "pageStart": 5, + "pageEnd": 5, + "hash": "86310af75420788ba0ba84fc3aa5ce9a7c4faed982fc04c61a476a15af377ed3" + }, + { + "text": "(Strong recommendation, low-quality evidence.) Recommendation 5.2. We suggest that in the setting of a radiographically indeterminate mass, image-guided biopsy be rarely performed and reserved for patients in whom results would change overall disease management and that it be per- formed only after confirming lack of hormone excess.", + "tokenCount": 65, + "pageStart": 5, + "pageEnd": 5, + "hash": "b9556d07e109d49da12efb1f84477dfecf5e53af8d46c6115b7028726175168a" + }, + { + "text": "(Strong recommendation, low-quality evidence.) Adrenal metastasis commonly occurs in patients with ma- lignancy from the lung, kidney, breast, melanoma, and colon but may occur from many other primary sites.", + "tokenCount": 45, + "pageStart": 5, + "pageEnd": 5, + "hash": "eef4d353a4af01666f84ab446687a3d55423bce4be2a18f252ae424f40958e41" + }, + { + "text": "While there are currently no established criteria guiding patient selection for adrenal metastasectomy, consideration should be given to pa- thology, synchronous vs metachronous presentation, disease- free interval, and tumor size to help select appropriate surgi- cal candidates.", + "tokenCount": 54, + "pageStart": 5, + "pageEnd": 5, + "hash": "d9091a1d115fed3c8b7c1a836979d2f7b7c2034ceb90131ae6a8683d04ba464e" + }, + { + "text": "Adrenal metastasectomy may be more difficult because of reaction from systemic treatment but can be per- formed either open or minimally invasive with equivalent oncologic outcomes. Recommendation 5.3.", + "tokenCount": 41, + "pageStart": 5, + "pageEnd": 5, + "hash": "4f3acbe37331994ef45661226e7d555bdbbd15066d001a46bea988703544f4c4" + }, + { + "text": "We suggest that after multidisci- plinary review, resection may be offered to highly selected pa- tients to improve survival compared with systemic therapy alone. (Weak recommendation, low-quality evidence.) 6.", + "tokenCount": 44, + "pageStart": 5, + "pageEnd": 5, + "hash": "8f0eaf36b7a51575cd2bfcb37e60f622a66fdae78b7f273e9285acb9f9accb5f" + }, + { + "text": "Pheochromocytoma and Paraganglioma As recommended in the Endocrine Society clinic practice guideline for pheochromocytoma and paraganglioma (PPGL), initial biochemical testing for PPGLs should include measure- ment of plasma-free or urinary fractionated metanephrines and are typically more than 2 to 3 times the upper limit of normal in functional PPGLs.", + "tokenCount": 89, + "pageStart": 5, + "pageEnd": 5, + "hash": "f54396e6d7564c302d2d151f08b6a502ec0487addd318966b58f4d479cf1f365" + }, + { + "text": "31,32 Following the diagnosis, preopera- tive blockade for at least 7 days is routinely recommended to prevent dangerous perioperative hemodynamic instability. Recommendation 6.1. We recommend either selective or nonselective α blockade to safely prepare patients for surgical resection of PPGL, depending on the drug availability/cost, ex- perience, and preference of the care team.", + "tokenCount": 81, + "pageStart": 5, + "pageEnd": 5, + "hash": "440635cdbc2d5050bafe0a5459bc9c8c2e006c02362e192bcfb4878f6a388f1d" + }, + { + "text": "While there is no sig- nificant difference in morbidity or mortality between selective and nonselective α blockade, selective blockade (doxazosin, prazosin, terazosin) is associated with more intraoperative he- modynamic instability while nonselective blockade (phenoxy- benzamine) results in more postoperative hypotension.", + "tokenCount": 73, + "pageStart": 5, + "pageEnd": 5, + "hash": "c3f172b7268c49795447deee8884f30245995c4e45dc2300108ad54a5c1d891a" + }, + { + "text": "(Strong recommendation, moderate-quality evidence.) Pheochromocytomas (PCCs) and paragangliomas (PGLs) have the highest heritability of all adrenal tumors (about 40% are due to germline mutations), 33,34 and genetic testing is rec- ommended (eTable 3 in the Supplement ).", + "tokenCount": 73, + "pageStart": 5, + "pageEnd": 5, + "hash": "74e258671c535a3c7527a7444f816c335b4e2a2d977777ac5d6f7471270ce452" + }, + { + "text": "In the presence of bilateral or familial PCC, cortical-sparing adrenalectomy has been successfully used to preserve adrenal cortical tissue, pre- venting lifelong adrenal insufficiency. Studies report steroid dependency rates between 9% and 30% with recurrence rates from 9% to 30%.", + "tokenCount": 60, + "pageStart": 5, + "pageEnd": 5, + "hash": "7527a06201975e06e9912e8c3c4d02267a2f0bc15e9d7445af6173ca20be4100" + }, + { + "text": "35,36 While there are benefits to cortical- Research Original Investigation American Association of Endocrine Surgeons Guidelines for Adrenalectomy 874 JAMA Surgery October 2022 Volume 157, Number 10 (Reprinted) jamasurgery.com © 2022 American Medical Association.", + "tokenCount": 54, + "pageStart": 5, + "pageEnd": 5, + "hash": "52b12de2bae72600673ef2237d4d2e84c662290ffdbb3435f557bf7b18cc7ce5" + }, + { + "text": "Downloaded from jamanetwork.com by University of Wisconsin -Madison user on 02/20/2026 sparing adrenalectomy, considerations must include the in- creased technical difficulty and risk of recurrence in the adrenal remnant, which could necessitate a reoperative adre- nalectomy.", + "tokenCount": 63, + "pageStart": 5, + "pageEnd": 6, + "hash": "380838bf0e10bd19c9bae074dafd9803d10bb212e8e51048abd4ce58d5a09236" + }, + { + "text": "If an attempt at cortical-sparing adrenalectomy in- creases concern for tumor disruption or incomplete resec- tion, it may not be appropriate. Recommendation 6.2. Because of the decreased rate of ste- roid dependence, we recommend consideration of cortical- sparing adrenalectomy in patients with bilateral PCCs if tech- nically feasible.", + "tokenCount": 74, + "pageStart": 6, + "pageEnd": 6, + "hash": "a0b89cee560db9a3e644de4313973d22fcc61ccbc29e5d283a45c905d0274629" + }, + { + "text": "However, the pa tient’s goals of care and a higher risk of recurrent pheochromocytoma should also be con- sidered. (Strong recommendation, low-quality evidence.) Approximately 2% to 25% of PCCs are metastatic, as com- pared with 2% to 60% of PGLs, and several studies suggest a sur- vival benefit associated with resection of the primary tumor in the presence of metastatic disease.", + "tokenCount": 98, + "pageStart": 6, + "pageEnd": 6, + "hash": "b72e3523630183ab42e733b26fb4eee6a8ff1e42fff3c3a72e92d214b227d328" + }, + { + "text": "However, more data are needed before potential positive effects of surgery, such as de- creasing symptoms of catecholamine excess and improving re- sponsetosystemicradiotherapies,canbeevaluatedandvalidated.", + "tokenCount": 49, + "pageStart": 6, + "pageEnd": 6, + "hash": "d7c8de9aad486587e10c0f401c9a38b77fb338306c71c4ee06d5b708e004071e" + }, + { + "text": "Recommendation 6.3. We suggest that in selected cases of metastatic PPGLs, resection of the primary tumor may be performed to improve overall survival. Patients should be care- fully evaluated by a multidisciplinary care team to determine if the benefits of resection of the primary tumor outweigh the risks.", + "tokenCount": 64, + "pageStart": 6, + "pageEnd": 6, + "hash": "3678b8ff87f19f0210df120ecbd5aa46240c061bd0ebbe8cccb3d390b74dda93" + }, + { + "text": "(Weak recommendation, low-quality evidence.) 7. Technical Aspects Adrenalectomy may be technically accomplished using either open or minimally invasive techniques via one of several ap- proaches (eTable 5 in the Supplement ).", + "tokenCount": 45, + "pageStart": 6, + "pageEnd": 6, + "hash": "203aedc297b297de5b13a3eaf5ed62c4f9427e20554e58f5f7aecb30afd885c6" + }, + { + "text": "Minimally invasive ad- renalectomy has become accepted as the gold-standard ap- proach for most small benign adrenal pathology because of multiple studies demonstrating decreased pain, shorter hos- pitalizations, and more rapid recovery compared with open adrenalectomy.", + "tokenCount": 54, + "pageStart": 6, + "pageEnd": 6, + "hash": "708ab692be697349b17b36d2184f9496c07891aa0cd9deb0502765840a4f09ee" + }, + { + "text": "37,38 There have been no prospective random- ized trials comparing laparoscopic to open adrenalectomy. Both laparoscopic transabdominal adrenalectomy and posterior ret- roperitoneal adrenalectomy (PRA) are effective and safe mini- mally invasive approaches.", + "tokenCount": 60, + "pageStart": 6, + "pageEnd": 6, + "hash": "9ed6771f1c3eda823257c1dbffa5ab873661614e4bd19b20f6b1ed63a7121705" + }, + { + "text": "Some studies suggest less pain and faster recovery after PRA, and in patients with extensive ab- dominal surgical history and/or bilateral tumors, PRA offers additional advantages (eTable 6 in the Supplement ).", + "tokenCount": 42, + "pageStart": 6, + "pageEnd": 6, + "hash": "b3a9a33006fd4296aa35d08159601fe01ef994a358237b9c2364527c3bf6be8f" + }, + { + "text": "Recommendation 7.1. When patient and tumor character- istics are appropriate, we recommend minimally invasive ad- renalectomy over open adrenalectomy because of improved perioperative morbidity.", + "tokenCount": 40, + "pageStart": 6, + "pageEnd": 6, + "hash": "77f80668471edf7004a0e9e90836f2062fbde9763e1978a2212f8c1c24bb996c" + }, + { + "text": "(Strong recommendation, low- quality evidence.) Recommendation 7.2. We recommend either a retroperito- neal or transperitoneal approach because of similar periopera- tive outcomes.", + "tokenCount": 43, + "pageStart": 6, + "pageEnd": 6, + "hash": "19880ddd92a047418415da083faa9513ca1f2ba161533f244496f8c0c6beaa12" + }, + { + "text": "The choice of approach should be determined by surgeon expertise and guided by tumor and patient character- istics. (Strong recommendation, moderate-quality evidence.) Several definitions of what would be a high volume for an adrenal surgeon have been proposed, ranging from 4 to 7 an- nual adrenalectomies.", + "tokenCount": 63, + "pageStart": 6, + "pageEnd": 6, + "hash": "04232d560f4110948ef59bad5839f8583662713af814460fb3f307cf3c421bd0" + }, + { + "text": "A threshold of 6 or more adrenal resec- tions per year was shown in assessment of the National Inpa- tient Sample to be associated with improved patient outcomes, including lower rates of complications, reduced in-hospital mortality, decreased cost of care, and shorter hospital stay.", + "tokenCount": 58, + "pageStart": 6, + "pageEnd": 6, + "hash": "c85a878250942376eefae84695b37e2701cd4f9bda06883cdd2706b0c133d7db" + }, + { + "text": "39 Since not all patients have access to high-volume adrenal sur- geons, lower-volume surgeons should exercise judgment and careful patient selection to provide safe care at their own cen- ter vs seeking referral or consultation with a more experi- enced adrenal surgeon when appropriate.", + "tokenCount": 59, + "pageStart": 6, + "pageEnd": 6, + "hash": "58c5a5622c0814748cc32c61cf6d7d255086febb39da53b6f6a8535d14744eea" + }, + { + "text": "Recommendation 7.3. We recommend that adrenalec- tomy be preferentially performed by a high-volume adrenal sur- geon to optimize outcomes, including lower rates of morbid- ity and mortality.", + "tokenCount": 46, + "pageStart": 6, + "pageEnd": 6, + "hash": "d2f9b58f5e3bc5a87c08ed5b6213d5c36baf0b08a8e7d9191c710895dad4dd5b" + }, + { + "text": "(Strong recommendation, moderate quality evidence.) The utility of percutaneous ablation, mainly with radio- frequency ablation, and stereotactic body radiation therapy for the destruction of hormonally active and inactive tumors and adrenal metastasis has been investigated in small retrospec- tive studies.", + "tokenCount": 60, + "pageStart": 6, + "pageEnd": 6, + "hash": "37286cdf8bd6613001c3c65ca7e1e950a920336d5e5449ad35df06d8448481f3" + }, + { + "text": "The studies suffer from small sample sizes and heterogeneity. Recommendation 7.4. We conditionally suggest ablation and stereotactic radiation not be used as an alternative to adrenalectomy for patients with adrenal lesions because there are inadequate data to support these modalities.", + "tokenCount": 54, + "pageStart": 6, + "pageEnd": 6, + "hash": "dea750eb62d7325f452b52eb180fafbf348eb9be0e16ffdbbf9c2a2f7b98773c" + }, + { + "text": "Sur- geons should be involved in the decision-making early in the treatment algorithm. (Weak recommendation, low-quality evidence.) Strengths and Limitations The study is limited in some sections by the paucity of strong evidence-based data available in the English literature.", + "tokenCount": 57, + "pageStart": 6, + "pageEnd": 6, + "hash": "eba98fa00c1747d8c53741eddfad6959c0bb1860335f988a402f25361bef06d2" + }, + { + "text": "In ad- dition, the PICO format (Population, Intervention/Exposure, Comparison, and Outcome) for comparing outcomes limited the sample size for which recommendations were crafted. How- ever, the strength of the article lies in the extensive review and rigorous attention to bias, strength of the literature that was reviewed, and the comprehensive considerations made by a diverse group of experts in the field.", + "tokenCount": 80, + "pageStart": 6, + "pageEnd": 6, + "hash": "6f23de19faf63571abacad1b745c62ea472057b17ce779f12c85fcd8fc83e72a" + }, + { + "text": "Conclusions We provide 26 evidence-based recommendations with clini- cally meaningful data to primarily assist surgeons with peri- operative adrenal care. Clinicians from multiple disciplines and patients may also find these recommendations useful.", + "tokenCount": 44, + "pageStart": 6, + "pageEnd": 6, + "hash": "e2bf79afb93efa81180f681c1bb7a4ec38eb31d4b310484ac6f3d6f84c74a098" + }, + { + "text": "We highlight topics that have low-quality data or little evidence available and propose these topics as opportunities for fur- ther research. ARTICLE INFORMATION Accepted for Publication: April 30, 2022. Published Online: August 17, 2022. 10.1001/jamasurg.2022.3544 Author Affiliations:", + "tokenCount": 63, + "pageStart": 6, + "pageEnd": 6, + "hash": "cc0fb31ae7a231c27e37f468cf0781fa8f9d27fb91001d300d3af5667bf03e1f" + }, + { + "text": "Division of Endocrine Surgery, University of Pittsburgh, Pennsylvania (Yip); Department of Surgery, University of California, San Francisco (Duh); Department of Surgery, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia (Wachtel); Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston (Jimenez); Department of Surgery, American Association of Endocrine Surgeons Guidelines for Adrenalectomy Original Investigation Research jamasurgery.com (Reprinted) JAMA Surgery October 2022 Volume 157, Number 10 875 © 2022 American Medical Association.", + "tokenCount": 130, + "pageStart": 6, + "pageEnd": 6, + "hash": "4b7a602a1c826d1e4d76b877186e397406e0d8df3fe4ab02dab5dc94ec3adbcd" + }, + { + "text": "Downloaded from jamanetwork.com by University of Wisconsin -Madison user on 02/20/2026", + "tokenCount": 23, + "pageStart": 6, + "pageEnd": 6, + "hash": "a24152b115a5667bb82733b63d71a65fc79599230d688ef2a4c1db33bb496ace" + }, + { + "text": "Section of Endocrine Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois (Sturgeon); Department of Surgery, University of Kentucky College of Medicine, Lexington (C. Lee); National Institute for Medical Sciences and Nutrition Salvador Zubirán, Mexico City, Mexico (Velázquez-Fernández); Center for Endocrine Surgery, Cleveland Clinic, Cleveland, Ohio (Berber); Department of Internal Medicine, University of Michigan, Ann Arbor (Hammer); Department of Cell & Developmental Biology, University of Michigan, Ann Arbor (Hammer); Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor (Hammer); Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota (Bancos); Department of Surgery, Department of Internal Medicine, Columbia University College of Physicians and Surgeons, New York, New York (J. A. Lee); Department of Radiology and Imaging Sciences, National Institutes of Health Clinical Center, Bethesda, Maryland (Marko); Division of Endocrine Surgery, Johns Hopkins Medicine, Baltimore, Maryland (Morris-Wiseman); Division of Surgical Oncology, Department of Surgery, Eastern Virginia Medical School, Norfolk (Hughes); Department of General Surgery, UCLA David Geffen School of Medicine, Los Angeles, California (Livhits); Department of Preventive Medicine, College of Medicine, Chosun University, Gwangju, Korea (Han); Department of Surgery, University of Virginia, Charlottesville (Smith); Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio (Wilhelm); Department of Pathology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio (Asa); Division of Endocrine & Minimally Invasive Surgery, Department of Surgery, Weill Cornell Medical College, New York– Presbyterian Hospital, New York (Fahey); Division of Endocrine and Metabolic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota (McKenzie); Department of Surgery, Gastric and Mixed Tumor Service, Memorial Sloan Kettering Cancer Center, New York, New York (Strong); Section of Surgical Endocrinology, Department of", + "tokenCount": 449, + "pageStart": 7, + "pageEnd": 7, + "hash": "dbf0ad7a9f3f5e8bc43924875184b80d4f3f3116162c7108d0b219c6e9105ff4" + }, + { + "text": "Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston (Perrier). Author Contributions : Drs Yip and Perrier had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Yip, Jimenez, C. Lee, Velázquez-Fernández, Berber, Bancos, J. Lee, Hughes, Han, Smith, Wilhelm, Fahey, McKenzie, Perrier. Acquisition, analysis, or interpretation of data: Duh, Wachtel, Jimenez, Sturgeon, C. Lee, Velázquez-Fernández, Hammer, Bancos, J. Lee, Marko, Morris-Wiseman, Hughes, Livhits, Han, Smith, Asa, Fahey, McKenzie, Strong, Perrier. Drafting of the manuscript: Yip, Duh, Wachtel, Jimenez, Sturgeon, C. Lee, Velázquez-Fernández, Berber, Bancos, J. Lee, Morris-Wiseman, Hughes, Livhits, Han, Smith, Fahey, McKenzie, Strong, Perrier. Critical revision of the manuscript for important intellectual content: Duh, Wachtel, Jimenez, Sturgeon, C. Lee, Velázquez-Fernández, Berber, Hammer, Bancos, J. Lee, Marko, Morris-Wiseman, Hughes, Livhits, Han, Smith, Wilhelm, Asa, Fahey, McKenzie, Strong, Perrier. Statistical analysis: Yip, Velázquez-Fernández, J. Lee, Livhits, McKenzie. Administrative, technical, or material support: Yip, Jimenez, Velázquez-Fernández, Marko, Hughes, Han, Wilhelm, Fahey, McKenzie, Perrier. Supervision: Duh, Jimenez, Sturgeon, Velázquez-Fernández, Berber, Hammer, Hughes, Fahey, McKenzie, Strong,", + "tokenCount": 450, + "pageStart": 7, + "pageEnd": 7, + "hash": "e37dc2b7042a9d5524828782291667d5874dc70ae34a6c8ed80dcdac7eef2825" + }, + { + "text": "Perrier. Conflict of Interest Disclosures: Dr Wachtel reported grants from the National Institutes of Health (NIH), National Center for Advancing Translational Sciences (KL2 TR001879), during the conduct of the study. Dr Jimenez reported research support from Lantheus Pharmaceuticals, Progenics, Exelixis, MSD, and Pfizer and serving on an advisory board for HRA Pharma and Pfizer during the conduct of the study. Dr Berber reported consulting for Medtronic, Aesculap, and Ethicon outside the submitted work. Dr Hammer reported being a founder of and consultant for Vasaragen, having patents for diagnostics via Vasaragen and the University of Michigan, and being the editor or associate editor of two textbooks outside the submitted work. Dr Bancos reported grants from the NIH and fees to her institution from HRA Pharma, Corcept, Lantheus, Recordati, Spruce, Sparrow, and Adrenas outside the submitted work. Dr Asa reported serving as an advisor for Leica Biosystems, Ibex Medical Analytics, and Iron Mountain outside the submitted work. Dr Fahey reported being a consultant and investor in Mediflix Inc. No other disclosures were reported. Additional Contributions: The Adrenalectomy Guidelines Committee acknowledges the support and dedication of all contributors for the voluntary time and diligence of acquiring the detailed data and constructing the manuscript. In addition, we thank the American Association of Endocrine Surgeons (AAES) membership for their careful review of the manuscript and insightful feedback. We are also grateful for the National Adrenal Disease Foundation (NADF) for representing the voice of our patients as we constructed these guidelines. Many thanks to Yasmin J. Khawaja, MA, Department of Surgical Oncology, MD Anderson Cancer Center, for orchestrating the committee’s activities and her excellent administrative support and reference management. Written permission to include names has been obtained. No compensation was received by any of the individuals who worked on this manuscript. Additional Information: The International Association of Endocrine Surgeons (IAES), the American Association of Clinical Endocrinology (AACE), and the Society of", + "tokenCount": 450, + "pageStart": 7, + "pageEnd": 7, + "hash": "34f444e933ac168747f4db8708e2576d2279bcf561e975e6eb7d4576d160146c" + }, + { + "text": "Abdominal Radiology’s Adrenal Neoplasm Disease Focused Panel have fully endorsed the guidelines. REFERENCES 1 . Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol . 2011;64(4):401-406. doi: 10.1016/j. jclinepi.2010.07.015 2 . Fassnacht M, Arlt W, Bancos I, et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol . 2016;175 (2):G1-G34. doi: 10.1530/EJE-16-0467 3 . 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Differences in outcomes of bilateral adrenalectomy in patients with ectopic ACTH producing tumor of known and unknown origin.", + "tokenCount": 43, + "pageStart": 8, + "pageEnd": 8, + "hash": "1abf15b721d2798b2538fe173356644587e4f16aa353b433438163a0be666a2d" + }, + { + "text": "Am J Surg . 2021;221(2): 460-464. 10.1016/j.amjsurg.2020.08.047 26 . Thompson SK, Hayman AV, Ludlam WH, Deveney CW, Loriaux DL, Sheppard BC.", + "tokenCount": 57, + "pageStart": 8, + "pageEnd": 8, + "hash": "66f72f1517af0733f25aff466089480d1bf7fbbb846a8f3c449b79ebe3c1e6dc" + }, + { + "text": "Improved quality of life after bilateral laparoscopic adrenalectomy for Cushing’s disease: a 10-year experience. Ann Surg . 2007;245(5):790-794.", + "tokenCount": 40, + "pageStart": 8, + "pageEnd": 8, + "hash": "8ddd41e11d3bf2be6f2cb70c8a7c3d7a19308c0494f657c3a297baeb20a42c02" + }, + { + "text": "10.1097/01.sla.0000251578.03883.2f 27 . 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Laparoscopic adrenalectomy: the optimal surgical approach. J Laparoendosc Adv Surg Tech A . 2001;11 (6):409-413. 10.1089/10926420152761941 39 . Anderson KL Jr, Thomas SM, Adam MA, et al. Each procedure matters: threshold for surgeon volume to minimize complications and decrease cost associated with adrenalectomy. Surgery . 2018; 163(1):157-164.", + "tokenCount": 184, + "pageStart": 8, + "pageEnd": 8, + "hash": "ce7648416e34060dd59968ea848b56dedad33684e7ebe69ddae9040cdca779b0" + }, + { + "text": "10.1016/j.surg.2017.04.028 Invited Commentary Importance of a Multidisciplinary and Comprehensive Approach to Management of Adrenal Tumors Tracy S. Wang, MD, MPH; Carmen C.", + "tokenCount": 47, + "pageStart": 8, + "pageEnd": 8, + "hash": "a56dd9028f78037eeac033784fca518ccc9819ce8844e93e300ec5f167b89e71" + }, + { + "text": "Solórzano, MD The American Association of Endocrine Surgeons Guidelines for Adrenalectomy, published in this issue of JAMA Surgery , represent a series of 26 carefully composed recommenda- tions on the surgical management of patients with adrenal disease.", + "tokenCount": 53, + "pageStart": 8, + "pageEnd": 8, + "hash": "08977bf3d128c53210db72973394c05ec75c4d3c824b8227ae9b30b14ef15011" + }, + { + "text": "1 The authors are to be congratulated for this compre- hensive update, which focuses on 7 areas of clinical concern to the practicing adrenal surgeon. We would like to highlight the recommendations for a com- prehensive biochemical evaluation of patients with inciden- tally identified adrenal nodules more than 1 cm on cross- sectional imaging (recommendations 1.1-1.3) and emphasize the need for a multidisci- plinary approach to adrenal tumors.", + "tokenCount": 100, + "pageStart": 8, + "pageEnd": 8, + "hash": "b947644760fd9f021a60464526e646488bf86d0f0dfcf6e4dd05c6ddfd25720f" + }, + { + "text": "A systemwide algo- rithm for adrenal incidentalomas, including standardized ter- minology in the radiological assessment for evaluation and re- ferral to a multidisciplinary clinic (staffed by endocrinology and adrenal surgeons) at our institution(s), has resulted in an increase in the number of patients who have appropriate evalu- ation of adrenal incidentalomas; this anecdotal experience is supported by others.", + "tokenCount": 89, + "pageStart": 8, + "pageEnd": 8, + "hash": "9fc3cfbcd807dc584c318450ee358791873007736d678a1e8d4b09f15e5c100f" + }, + { + "text": "2-4 We encourage adrenal surgeons to lead the implementation of similar processes and the multidisci- plinary discussion of patients with adrenal tumors including those being considered for unconventional treatments (rec- ommendation 7.4), a point emphasized by the authors through- out these guidelines.", + "tokenCount": 60, + "pageStart": 8, + "pageEnd": 8, + "hash": "86fdda45022bb434a88ded685add4b541e6fd2c47e8c0e6030e3e570b3b6d547" + }, + { + "text": "Multidisciplinary care is particularly important in deter- mining the appropriate follow-up, both radiographic and bio- chemical, in patients who have nonfunctional adrenal tu- mors with benign imaging characteristics.", + "tokenCount": 42, + "pageStart": 8, + "pageEnd": 8, + "hash": "8e83d258c011b61818ae1c47e37b30139a05f90fd1741fb25cc8963016055f96" + }, + { + "text": "While the authors do not recommend routine scheduled follow-up in these pa- tients (recommendation 1.4), due to the low risk of malig- nancy and low incidence of developing hormonal excess, the level of evidence is “low quality” and the follow-up remains Related article page 870 American Association of Endocrine Surgeons Guidelines for Adrenalectomy Original Investigation Research jamasurgery.com (Reprinted) JAMA Surgery October 2022 Volume 157, Number 10 877 © 2022 American Medical Association.", + "tokenCount": 110, + "pageStart": 8, + "pageEnd": 8, + "hash": "7f816528a02347b4fbd3bbc1a82639737a54bbe1a2726fb0a79ffbcc490c59e7" + }, + { + "text": "Downloaded from jamanetwork.com by University of Wisconsin -Madison user on 02/20/2026", + "tokenCount": 23, + "pageStart": 8, + "pageEnd": 8, + "hash": "a24152b115a5667bb82733b63d71a65fc79599230d688ef2a4c1db33bb496ace" + } +] \ No newline at end of file diff --git a/Adrenal Nodule information/Primary Aldosteronism- An Endocrine Society Clinical Practice Guideline.pdf_semantic.json b/Adrenal Nodule information/Primary Aldosteronism- An Endocrine Society Clinical Practice Guideline.pdf_semantic.json new file mode 100644 index 0000000000000000000000000000000000000000..2fa50f4859b641a79077f6e2a2a9b01b06fa9d18 --- /dev/null +++ b/Adrenal Nodule information/Primary Aldosteronism- An Endocrine Society Clinical Practice Guideline.pdf_semantic.json @@ -0,0 +1,5357 @@ +[ + { + "text": "endocrine.org/clinical-practice-guidelines/methodology ( 10 ). The Endocrine Society follows the GRADE approach ( 11 ) ( Tables 1 and 2 ), which includes EtD frameworks to ensure all important criteria are considered when making recommenda - tions ( 14", + "tokenCount": 56, + "pageStart": 3, + "pageEnd": 3, + "hash": "304bbcc9aab59bb1868f6c6c4142f27380c3e386a497c49f51e09d1c2934a0d6" + }, + { + "text": "The process was facilitated by the GRADEpro Guideline Development Tool (GRADEpro GDT) ( 15 ). The GDP consisted of content experts representing the following clin - ical specialties: endocrinology, general internal medicine, genet - ics, hypertension specialists, epidemiology, and a patient representative. Members were identified by the Endocrine Society Board of Directors and the Clinical Guidelines Committee and were vetted according to the Endocrine Society ’ s conflict-of-interest policy, which was followed through - out the guideline process to manage and mitigate conflicts of interest. Detailed disclosures of panel members and the manage - ment strategies implemented during the development process can be found in Appendix A . In addition, the group included a clinical practice guideline methodologist from the Mayo Evidence-Based Practice Center, who led the team that conducted the systematic reviews, and a methodologist from the Endocrine Society, who advised on methodology and moderated the application of the EtD framework and development of the recommendations. A group of 2 to 3 GDP members were assigned to lead each guideline question. The 10 clinical questions addressed in this guideline were prioritized from an extensive list of potential questions through a survey of the panel members and discus - sion. The Mayo Evidence-Based Practice Center conducted a systematic review for each question and, when available, pro - duced GRADE evidence profiles that summarized the body of evidence for each question and the certainty of the evidence (Murad in press", + "tokenCount": 296, + "pageStart": 3, + "pageEnd": 3, + "hash": "b76f730a1689a1b2d6c4b6f5909414b68aa523a43e9c5aa29eebc6e166945edb" + }, + { + "text": "The systematic searches for evidence were conducted in February 2022 and updated in October 2024. In parallel with the development of the evidence summaries, the GDP members searched and summarized research evi - dence related to each question (generally observational stud - ies) and to other EtD criteria, such as individuals ’ values and preferences, cost and resources required, cost- effectiveness, feasibility, acceptability, and the potential im - pact on health equity. Research evidence summaries noted in the EtD frameworks were compiled using standardized ter - minology templates for clarity and consistency ( 16 ). During 2 in-person panel meetings and a series of video conferences, the GDP judged the balance of benefits and harms, in addition to the other EtD criteria, to determine the direction and strength of each recommendation ( 16-18 ) ( Tables 1 and 2", + "tokenCount": 170, + "pageStart": 3, + "pageEnd": 3, + "hash": "998c5218b463bbc4bad8888ace1745819b03833151eba4b78cd67f791aacfdfb" + }, + { + "text": "The draft recommendations were posted publicly for external peer review and internally for Endocrine Society members, and the draft guideline manuscript was reviewed by the Society ’ s Clinical Guidelines Committee, representatives of any co- sponsoring organizations, a representative of the Society ’ s Board of Directors, and an Expert Reviewer. Revisions to the guideline were made based on submitted comments and ap - proved by the Clinical Guidelines Committee, the Expert Reviewer, and the Board of Directors. Finally, the guideline Table 1. GRADE certainty of evidence classifications Certainty of evidence Interpretation High ⊕⊕⊕⊕ There is high confidence that the true value of the estimate of interest is on one side of a threshold of interest or within a specific range. Moderate ⊕⊕⊕ O There is moderately confidence that the true value of the estimate of interest is on one side of a threshold of interest or within a certain range. The true value of the estimate may deviate slightly from the target of the certainty rating (i.e. may possibly fall in a different range). Low ⊕⊕ OO There is low confidence that the true value of the estimate of interest is on one side of a threshold of interest or within a certain range. The true value of the estimate may deviate from the target of the certainty rating (i.e. likely fall in a different range", + "tokenCount": 287, + "pageStart": 3, + "pageEnd": 3, + "hash": "343b1a580e3348d35c186273941b362e81403a34d4411904b131cd421e4aee04" + }, + { + "text": "Very Low ⊕ OOO There is very-low confidence that the true value of the estimate of interest is on one side of a threshold of interest or within a certain range. The true value of the estimate may deviate significantly from target of the certainty rating (i.e. probably fall in a different range). Reprinted with permission from Schünemann HJ, Brożek J, Guyatt GH, Oxman AD. GRADE Handbook. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach. Updated October 2013. Adapted with permission from Neumann I, Schünemann H (Editors", + "tokenCount": 137, + "pageStart": 3, + "pageEnd": 3, + "hash": "a45868581c24be6c0d489bf9eda007de39b222d91cc0f524ad9824d821cecec8" + }, + { + "text": "The GRADE Book version 1.0 (updated September 2024). The GRADE Working Group ( 12 Table 2. GRADE strength of recommendation classifications and interpretation Strength of recommendation Criteria Interpretation by individuals Interpretation by health care clinicians Interpretation by policy makers 1: Strong recommendation for or against Desirable consequences CLEARLY OUTWEIGH the undesirable consequences in most settings (or vice versa). Most individuals in this situation would want the recommended course of action, and only a small proportion would not. Most individuals should follow the recommended course of action. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. The recommendation can be adopted as policy in most situations. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. 2: Conditional recommendation for or against Desirable consequences PROBABLY OUTWEIGH undesirable consequences in most settings (or vice versa", + "tokenCount": 190, + "pageStart": 3, + "pageEnd": 3, + "hash": "c29b91a36ee95385fcfa1780f9adeb2d2bfb3953e7ce077ef8138378bb9e4e4b" + }, + { + "text": "The majority of individuals in this situation would want the suggested course of action, but many would not. Decision aids may be useful in helping individuals make decisions consistent with their individual risks, values, and preferences. Clinicians should recognize that different choices will be appropriate for each individual and that clinicians must help each individual arrive at a management decision consistent with the individual’s values and preferences. Policy-making will require substantial debate and involvement of various stakeholders. Performance measures should assess whether decision making is appropriate. Adapted from Schünemann HJ et al Blood Adv, 2018; 2(22):3198-3225. © The American Society of Hematology, published by Elsevier ( 13 ). The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 2455 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 205, + "pageStart": 3, + "pageEnd": 3, + "hash": "436aa7ec9f0e9ce3d09b13066dc3e325506c1db805a5c99de20f029725b7f6aa" + }, + { + "text": "manuscript was reviewed before publication by the Journal of Clinical Endocrinology and Metabolism’s publisher ’ s reviewers. This guideline will be reviewed annually to assess the state of the evidence and determine if any developments warrant an update to the guideline.", + "tokenCount": 52, + "pageStart": 4, + "pageEnd": 4, + "hash": "4b129bfdb894d3f07e0ffcc4477b6ea29fbeb77f6d71e1584d3dbdf59656d14b" + }, + { + "text": "List of Recommendations Question 1. Should care that includes primary aldosteron - ism screening be applied to all individuals with hypertension, compared with care without screening? Recommendation 1 In all individuals with hypertension, we suggest screening for primary aldosteronism (PA) (2 | ⊕⊕ OO).", + "tokenCount": 68, + "pageStart": 4, + "pageEnd": 4, + "hash": "08f6ce1f9a65b03cf39d75df2ac1addb6423e3842c47a711b7b0f156659e6879" + }, + { + "text": "Technical remarks: • This is a conditional recommendation, with imple - mentation depending on contextual factors such as available resources, local expertise, and health - care system capacity, which may affect feasibility and prioritization.", + "tokenCount": 43, + "pageStart": 4, + "pageEnd": 4, + "hash": "353246c15cf33061fe098c1830a11dfc8f3b7aeb1575a9c46e59b8df2359d2eb" + }, + { + "text": "• This recommendation emphasizes care that is in - formed and guided by screening, with a positive screening result serving as the critical first step in the care process for individuals with PA. • PA screening includes measurement of serum/plas - ma aldosterone concentration and plasma renin (concentration or activity) with determination of the aldosterone to renin ratio (ARR).", + "tokenCount": 76, + "pageStart": 4, + "pageEnd": 4, + "hash": "d58bbec72c3ec9dfd4fd5b8355515d9a3d85a89306789c4be373961a31ed828f" + }, + { + "text": "Potassium is also assessed—not for screening itself—but to aid in the accurate interpretation of aldosterone (refer to Question 3). Question 2. Should primary aldosteronism–specific therapy (medical or surgical) vs nonspecific antihypertensive ther - apy be used in individuals with primary aldosteronism?", + "tokenCount": 71, + "pageStart": 4, + "pageEnd": 4, + "hash": "5fdba542b5dd2eafcf78991475580bbcd182739b03c76bd7bf5b0dd27458accb" + }, + { + "text": "Recommendation 2 In individuals with hypertension and primary aldos - teronism (PA), we suggest PA-specific therapy (med - ical or surgical) (2 | ⊕⊕ OO).", + "tokenCount": 45, + "pageStart": 4, + "pageEnd": 4, + "hash": "7fbce537e46bf0449a07a26e1e5561553e69bcdba32ec2d93d5e7f153f22e06c" + }, + { + "text": "Technical remarks: • In individuals with lateralizing PA who are not sur - gical candidates or do not desire surgery and in in - dividuals with bilateral PA, medical treatment with mineralocorticoid receptor antagonists (MRAs) should be considered preferable over nonspecific antihypertensive therapy.", + "tokenCount": 62, + "pageStart": 4, + "pageEnd": 4, + "hash": "f70a8d934ef752d31abd52859a0ff493037ce03b1257b0f7467212fc1ddec323" + }, + { + "text": "• In individuals with lateralizing PA who are surgical candidates and desire surgery, unilateral adrenalec - tomy should be considered preferable over non - specific antihypertensive therapy. Question 3. Should aldosterone (serum/plasma, or urine), re - nin (concentration or activity), and the aldosterone to renin ratio vs hypokalemia (unprovoked or diuretic-induced) be used for screening for primary aldosteronism in individuals with hypertension?", + "tokenCount": 104, + "pageStart": 4, + "pageEnd": 4, + "hash": "55b43102085e958a2b363a65c4b4e16a6f312cba456d0bd7f37ff746226871c4" + }, + { + "text": "Recommendation 3 In individuals with hypertension, we suggest primary aldosteronism (PA) screening with serum/plasma al - dosterone concentration and plasma renin (concen - tration or activity) (2 | ⊕⊕ OO).", + "tokenCount": 56, + "pageStart": 4, + "pageEnd": 4, + "hash": "747ed5a7342e9190001ffe151c3c42f7dcc3a1a7543d24f3db58cef249a88344" + }, + { + "text": "Technical remarks: • Screen for PA by measuring serum/plasma aldos - terone and plasma renin (concentration or activity) in the morning with individuals seated and avoid - ing dietary sodium restriction during the few days prior to screening.", + "tokenCount": 51, + "pageStart": 4, + "pageEnd": 4, + "hash": "a74466a92f9ab277e68b50c1e20855c949f8a13ce84fb63e2afc245e8a1a1898" + }, + { + "text": "Potassium should be measured alongside renin and aldosterone—not for screen - ing itself but to aid in the accurate interpretation of aldosterone—as low potassium may lead to a falsely low aldosterone.", + "tokenCount": 44, + "pageStart": 4, + "pageEnd": 4, + "hash": "fc149b8a03a1215dbca1de2fbfd1212298ecc62fa385053a24af85b78138b536" + }, + { + "text": "• If screening results are negative and the patient has hypokalemia, potassium should be corrected to within the laboratory reference range and screen - ing should be repeated. • Manage interfering medications depending on individual safety and feasibility.", + "tokenCount": 45, + "pageStart": 4, + "pageEnd": 4, + "hash": "1a74118704473e3faaff8fe5d3299644a97f0e385d0af583ddfeb84a31a128c0" + }, + { + "text": "The Guideline Development Panel outlined both minimal- withdrawal and no-withdrawal strategies of inter - fering medications before screening ( Tables 6 and 7 , Fig. • A positive screen meets both of the following con - ditions in most circumstances:", + "tokenCount": 50, + "pageStart": 4, + "pageEnd": 4, + "hash": "efab828b487c5f8a7eece3cbf88846e740f254dfa9e0e24ebcb25adcd5befdb2" + }, + { + "text": "Renin is low/suppressed (hallmark of diagno - sis) and aldosterone is inappropriately high relative to renin: indicative of PA if plasma renin activity (PRA) is ≤ 1 ng/mL/h or direct renin con - centration (DRC) is ≤ 8.2 mU/L AND serum/plas - ma aldosterone concentration is ≥ 10 ng/dL ( ≥ 277 pmol/L) when measured by immuno - assay or ≥ 7.5 ng/dL ( ≥ 208 pmol/L) when meas - ured by liquid chromatography–tandem mass spectrometry (LC-MS/MS) 2.", + "tokenCount": 144, + "pageStart": 4, + "pageEnd": 4, + "hash": "78d78a03bdf2c7af68c06130d5e6d68dc259fdd0b9169481f7c423e71c7a8d36" + }, + { + "text": "Elevated aldosterone to renin ratio (ARR): indica - tive of PA if the aldosterone [ng/dL] to PRA [ng/ mL/h] ratio is > 20 or aldosterone [pmol/L] to DRC [mU/L] ratio is > 70 when aldosterone is measured by immunoassay; the ARR indicative of PA is about 25% lower when aldosterone is measured by LC-MS/MS).", + "tokenCount": 103, + "pageStart": 4, + "pageEnd": 4, + "hash": "2f7eb8a29a1cb9ea31037ffdadf9a7e750fbfafd6fb7fdc49064ffcb2b7cdb19" + }, + { + "text": "( Fig. 1 and Table 5 for ARR cut points for differing assays and units). • The aldosterone, renin, and ARR values above are provided for guidance. However, as with many diagnostic tests based on continuous variables, the sensitivity and specificity depend on the se - lected threshold.", + "tokenCount": 63, + "pageStart": 4, + "pageEnd": 4, + "hash": "8e281b9a56735923e5dc1d3fdccf391571219581151bc53890eea281ab2a9ac8" + }, + { + "text": "Aldosterone and renin levels are further influenced by individual variability, local 2456 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 77, + "pageStart": 4, + "pageEnd": 4, + "hash": "424ac00a7f7f5d66deaa998e6c3ccb4869434ffc20a5d424c2bf1798973937a7" + }, + { + "text": "laboratory assays, and other factors. Where possible, clinicians should rely on local laboratory cut points, as assays may vary. No cut point is perfect—each carries a trade-off between false positives and false negatives.", + "tokenCount": 47, + "pageStart": 5, + "pageEnd": 5, + "hash": "4b629d75ea6ade5f102eec9c58ed4b172b739e9551f059c64ab0eccabc341f7a" + }, + { + "text": "Therefore, results should be interpreted within the context of the patient’s pretest probabil - ity for PA, along with potential interfering medica - tions and conditions. • If the individual’s initial screen is negative and fac - tors are present that could have led to a false- negative result (eg, hypokalemia or medications), the test should be repeated on a different day, preferably after correcting hypokalemia (where present) and withdrawing interfering medica - tions if safe and feasible (for 4 weeks for mineralo - corticoid receptor antagonists [MRAs], epithelial Figure 1.", + "tokenCount": 130, + "pageStart": 5, + "pageEnd": 5, + "hash": "f1206744bc535219450cf4334319aeea000e6b13e0edc6ca6e93fdfb0cd8e6a8" + }, + { + "text": "How to screen for PA in individuals with hypertension. This figure diagrams the process of screening for PA in individuals with hypertension. For individuals whose screening indicates likely PA, the next steps are diagrammed in Fig.", + "tokenCount": 41, + "pageStart": 5, + "pageEnd": 5, + "hash": "1b333a2528d51a20c0d45c88b6af896d7323a97157d63f1e39a92115d444486e" + }, + { + "text": "2 , Algorithm for the Management of Adults with Hypertension in Whom PA is Likely Based on Aldosterone, Renin, and ARR. *Blood is obtained in seated position in the morning; ideally without venous stasis (release tourniquet after venipuncture and wait at least 5 seconds before withdrawing blood) to avoid factitious rises in potassium.", + "tokenCount": 76, + "pageStart": 5, + "pageEnd": 5, + "hash": "b001fd0260842343ac64c5f4ced40da52b7ceb5cac1e885d9d4bdb67991f2794" + }, + { + "text": "**The aldosterone, renin, and ARR values provided in this figure and in greater detail in Table 5 are for guidance. However, as with many diagnostic tests based on continuous variables, the sensitivity and specificity depend on the selected threshold.", + "tokenCount": 50, + "pageStart": 5, + "pageEnd": 5, + "hash": "fe228b2a7e98690afcf5508053d64489509d0101071af8cc872e7e6a9de69907" + }, + { + "text": "Aldosterone and renin levels are further influenced by individual variability, local laboratory assays, and other factors. Where possible, clinicians should rely on local laboratory cut points, as assays may vary. No cut point is perfect—each carries a trade-off between false positives and false negatives.", + "tokenCount": 60, + "pageStart": 5, + "pageEnd": 5, + "hash": "80de2c357e7e808e1efd5a69532ed8c05c2f3503b460e3fa609e1477f626593c" + }, + { + "text": "Therefore, results should be interpreted within the context of the patient’s pretest probability for PA, along with potential interfering medications and conditions. ***Consider potential false positive induced by β -adrenergic blockers when aldosterone < 15 ng/dL ( < 415 pmol/L) by immunoassay, < 10 ng/dL ( < 277 pmol/L) by LC-MS/MS.", + "tokenCount": 85, + "pageStart": 5, + "pageEnd": 5, + "hash": "ad5e9d892023607f4f814a38eef0ea494948df1495e5ca962cd90f9a3608d903" + }, + { + "text": "# Drospirenone in OCPs is an MRA. ## Amiloride and triamterene are ENaC inhibitors. Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II – receptor blocker; CCB, calcium-channel blocker; DRC, direct renin concentration; ENaC, epithe - lial sodium-channel; HRT, hormone-replacement therapy; LC-MS/MS:", + "tokenCount": 105, + "pageStart": 5, + "pageEnd": 5, + "hash": "8895046e76e9196cf2b4e2af396fe99199d1bbccdb1444f69bcdf13339a463a7" + }, + { + "text": "liquid chromatography – tandem mass spectrometry; MRA, mineralocorticoid antagonist; OCP, oral contracep - tive; PRA, plasma renin activity; SGLT2, sodium-glucose cotransporter 2.", + "tokenCount": 55, + "pageStart": 5, + "pageEnd": 5, + "hash": "0edcd2bb79f79148eb82fc426529caf7a592d3dc0b656b87214d67287dc3259e" + }, + { + "text": "The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 2457 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 62, + "pageStart": 5, + "pageEnd": 5, + "hash": "e23c2c5c354a4051f6ec4423b3fbee05472af7b10adbc2d4c2eb3d6117d5f8f4" + }, + { + "text": "sodium-channel [ENaC] inhibitors [eg, amiloride, triamterene], and other diuretics; and 2 weeks for angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptor blockers [ARBs]), which raise renin or lower aldosterone.", + "tokenCount": 67, + "pageStart": 6, + "pageEnd": 6, + "hash": "1ca5394d0b3d4000653225759253a59ed3d5f2c5b2de1bc7dbd0efd46467b1f3" + }, + { + "text": "For the most ac - curate determination of potassium, measure plas - ma potassium in blood collected slowly with a syringe and needle (preferably not using a vacuum-sealed blood collection tube to minimize the risk of spuriously raising potassium).", + "tokenCount": 51, + "pageStart": 6, + "pageEnd": 6, + "hash": "ccb330deddfa1246fab2137c9d87ecef50173c8b0754f964e4402dff21e566c0" + }, + { + "text": "During collection, avoid fist clenching, wait at least 5 sec - onds after tourniquet release (if used) to achieve in - sertion of needle, and ensure separation of plasma from cells within 30 minutes of collection.", + "tokenCount": 49, + "pageStart": 6, + "pageEnd": 6, + "hash": "13f5c3185477b8c11b3738dea6a3c52a0c5a86575479447b894c9055594e4b7a" + }, + { + "text": "• If the individual’s initial screen is negative and the pretest probability of PA is moderate to high (eg, hypokalemia and/or resistant hypertension) or re - nin is suppressed with aldosterone of 5 to 10 ng/ dL (138 to 277 pmol/L) by immunoassay, the test should be repeated on a different day.", + "tokenCount": 78, + "pageStart": 6, + "pageEnd": 6, + "hash": "baeb230258c5553c998d723a16339f4b9ca067ac97b5713aca88218335dae181" + }, + { + "text": "• If the individual’s initial screen is positive, but they are receiving medications (eg, β -adrenergic blockers and centrally acting α 2 -agonists [eg, clonidine, α -methyldopa]) that can lower renin and thereby cause false-positive results, the test should be repeated after withdrawing those medications for 2 weeks if it is safe and feasible.", + "tokenCount": 79, + "pageStart": 6, + "pageEnd": 6, + "hash": "2fb1504fa50c312c394509a806869f223e979c188297bd4b07ffeff147664f4b" + }, + { + "text": "Consider po - tential false positives induced by β -adrenergic blockers when aldosterone is 10 to 15 ng/dL (277-416 pmol/L) by immunoassay or 7.5 to 10 ng/dL (208-277 pmol/L) by LC-MS/MS; if aldos - terone is above these concentrations, PA is likely despite being on β -adrenergic blockers.", + "tokenCount": 90, + "pageStart": 6, + "pageEnd": 6, + "hash": "2fb9d3c0d8a315dc7b85c7077618fd0c5e230e02be24d04ea67111338d7f16fc" + }, + { + "text": "• If screening hypertensive patients with chronic kidney disease, renin decreases proportionately to nephron loss, except in cases where there is re - nal ischemia from renal artery stenosis where re - nin will be elevated.", + "tokenCount": 48, + "pageStart": 6, + "pageEnd": 6, + "hash": "2a3f336d029d7c76cd1f07cd94f04fd6f02522c5fb133d7945bbbf85a35bc509" + }, + { + "text": "Aldosterone can also be elevated in chronic kidney disease, leading to overall increases in false-positive testing. • If all initial screening is negative, consider re- screening in the future if a patient develops:", + "tokenCount": 42, + "pageStart": 6, + "pageEnd": 6, + "hash": "71548dd2375ddcfebcf4ceca61f8fd5ecb31e1242d1111839701973b7103f96d" + }, + { + "text": "⚬ Unexplained worsening of hypertension or re - sistant hypertension ⚬ New spontaneous or diuretic-induced hypokalemia ⚬ Atrial fibrillation in the absence of structural heart disease or hyperthyroidism Question 4.", + "tokenCount": 54, + "pageStart": 6, + "pageEnd": 6, + "hash": "e2f743a646d07aa07ff03f1ed41da224ab78e1c27f90431d92a9d04bf83fc651" + }, + { + "text": "Should care guided by aldosterone suppression testing vs no aldosterone suppression testing be used in individuals with positive primary aldosteronism screen before initiating primary aldosteronism–specific therapy (medical or surgical)?", + "tokenCount": 45, + "pageStart": 6, + "pageEnd": 6, + "hash": "a6c9344d348ac6fa64019c55b4f86dd7041d49998dd0c21336ffc5c43b4fd2b3" + }, + { + "text": "Recommendation 4 In individuals who screen positive for primary aldos - teronism (PA), we suggest aldosterone suppression testing in situations when screening results suggest an intermediate probability for lateralizing PA and in - dividualized decision making confirms a desire to pur - sue eligibility for surgical therapy (2 | ⊕ OOO).", + "tokenCount": 68, + "pageStart": 6, + "pageEnd": 6, + "hash": "dd549ff965030dfa20f96fffb6f6c6a3c0eecfd5f700172a567335095f80f8c9" + }, + { + "text": "Technical remarks: Situations in which aldosterone suppression testing may be helpful include: • In individuals with an intermediate probability of having lateralizing PA who are willing and able to undergo surgical adrenalectomy ( Fig. Situations in which aldosterone suppression testing is not required prior to initiating PA-specific therapy in - clude ( Fig.", + "tokenCount": 69, + "pageStart": 6, + "pageEnd": 6, + "hash": "de9829a4ad6a085d90822e60fe0f800684974340206cd675475a12893ee24e6a" + }, + { + "text": "• In individuals with resistant hypertension or hyper - tension with hypokalemia and overt biochemical evidence of renin-independent aldosterone produc - tion (plasma renin activity [PRA] < 0.2 ng/mL/h or dir - ect renin concentration [DRC] < 2 mU/L and plasma aldosterone concentration > 15 ng/dL [ > 416 pmol/L] via liquid chromatography–tandem mass spectrom - etry [LC-MS/MS] assay or > 20 ng/dL [ > 554 pmol/L] via immunoassay), aldosterone suppression testing is not recommended due to the risk of false-negative results, which may exceed the risk of false-positive screening results.", + "tokenCount": 158, + "pageStart": 6, + "pageEnd": 6, + "hash": "aec71a25f40bbc7261eab770e8b75263734dd09ff1b4d3cde83d2c4a23aa9dde" + }, + { + "text": "• Individuals unwilling or unable to pursue adrenal ven - ous sampling and adrenalectomy can be empirically treated with mineralocorticoid receptor antagonists (MRAs) based on screening results, without aldoster - one suppression testing.", + "tokenCount": 49, + "pageStart": 6, + "pageEnd": 6, + "hash": "de4b5e299bce143190e713d296f873eeed80014af1ae05b321b8d063d358b262" + }, + { + "text": "Aldosterone suppression testing may still provide value in some cases for fur - ther documenting the diagnosis. • Aldosterone suppression testing is unnecessary in individuals from families with germline mutations associated with familial hyperaldosteronism.", + "tokenCount": 44, + "pageStart": 6, + "pageEnd": 6, + "hash": "93ad14d42f63377f722617129390c548875fda5d3f7c264bcb2df6d127e6e26e" + }, + { + "text": "Genetic screening is recommended for all first- degree relatives of individuals with familial hyper - aldosteronism and for individuals with young- onset PA ( < 20 years) to enable early diagnosis and treatment.", + "tokenCount": 42, + "pageStart": 6, + "pageEnd": 6, + "hash": "d5c3ccd3693074907227df980d24122a284bb82b1805b1b35eeccb5fa787d919" + }, + { + "text": "• Aldosterone suppression testing can also be avoided if the likelihood of lateralizing PA is so low that pursuing a formal diagnosis of PA is not justifiable (eg, normokalemia + plasma/serum al - dosterone <∼ 11ng/dL [ <∼ 305 pmol/L] [immuno - assay] or <∼ 8 ng/dL [ <∼ 222 pmol/L] [LC-MS/MS]).", + "tokenCount": 95, + "pageStart": 6, + "pageEnd": 6, + "hash": "7b8e102b8b19be22be5027afa3635f8af545bd03ed3490ab8ce7e193c4b1d93d" + }, + { + "text": "Question 5. Should primary aldosteronism–specific medical therapy vs surgical therapy be used in individuals with di - agnosed primary aldosteronism? Recommendation 5 In individuals with primary aldosteronism (PA), we suggest medical therapy or surgical therapy with the choice of therapy based on lateralization of aldoster - one hypersecretion and candidacy for surgery (2 | ⊕ OOO).", + "tokenCount": 87, + "pageStart": 6, + "pageEnd": 6, + "hash": "19539fcae65641c9fedd7163821dd6f3a7aff5ac6d02647e86070731a110602e" + }, + { + "text": "2458 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 62, + "pageStart": 6, + "pageEnd": 6, + "hash": "0847dce07676910eb157eefe7afeb64c26dfc6df9ec67d746f587da03801e1af" + }, + { + "text": "Technical remarks: • Surgical therapy by total unilateral adrenalectomy, usually by the laparoscopic approach, is mainly of - fered to individuals with lateralizing PA who choose to pursue the surgical option ( Fig.", + "tokenCount": 44, + "pageStart": 7, + "pageEnd": 7, + "hash": "93b88fe52a4baccb3fd1dd316500d8081f0234a993b866e700153d0b932f6392" + }, + { + "text": "• Lifelong medical therapy that includes a min - eralocorticoid receptor antagonist (MRA) is usu - ally offered to individuals with bilateral PA or lateralization status unknown (refer to Question 6 for definition of lateralization) and to those who are not surgical candidates or who decline the surgical option ( Fig.", + "tokenCount": 67, + "pageStart": 7, + "pageEnd": 7, + "hash": "8d5034c3901b0c3582f5777982ee3dcdfd084be3c4c9c6f45626c91bea7a6c29" + }, + { + "text": "• Individuals with mild PA typically have bilateral disease and may bypass adrenal venous sampling (AVS), proceeding directly to medical manage - ment, as outlined in the diagnostic algorithm ( Fig. • Individuals with multiple comorbidities who may not be good surgical candidates may also proceed directly to medical therapy ( Fig.", + "tokenCount": 63, + "pageStart": 7, + "pageEnd": 7, + "hash": "e3cf6405415877e74c5fdde756819010b80ea7559c899da6376e143a13d8e353" + }, + { + "text": "Question 6. Should care guided by adrenal lateralization with computed tomography scanning and adrenal venous sampling vs computed tomography scanning alone be used for deciding treatment approach in individuals with primary aldosteronism?", + "tokenCount": 44, + "pageStart": 7, + "pageEnd": 7, + "hash": "bf35ac57bfac6dbaf1f03e0bafee0aac5ac0543b679f0f629754b84e1e537965" + }, + { + "text": "Recommendation 6 In individuals with primary aldosteronism (PA) consid - ering surgery, we suggest adrenal lateralization with computed tomography (CT) scanning and adrenal ven - ous sampling (AVS) prior to deciding the treatment ap - proach (medical or surgical) (2 | ⊕⊕ OO).", + "tokenCount": 74, + "pageStart": 7, + "pageEnd": 7, + "hash": "5c035d8c50f864d42b6ff222a60b5932811c7d261013d4ead1ad27f84847d08d" + }, + { + "text": "Technical remarks: • Individuals with PA who desire and are candidates for adrenalectomy should undergo AVS in order to reliably differentiate lateralizing from bilateral forms. Figure 2. Algorithm for the management of adults with hypertension in whom PA is likely based on aldosterone, renin, and ARR.", + "tokenCount": 61, + "pageStart": 7, + "pageEnd": 7, + "hash": "64c73cea99b0d6886d6f6142c93d93e8962f08d4b8d8c6f3577ccbd082f84ce6" + }, + { + "text": "Patients who are likely to have PA, but have no desire for surgical adrenalectomy, or have contraindications to undergoing surgery, can be offered MRA therapy without further testing. MRA therapy is highly effective in PA.", + "tokenCount": 48, + "pageStart": 7, + "pageEnd": 7, + "hash": "30f78239a52c653a7c81e316b5235d18a0cb5927bba6ddabe22975a8359bbbd0" + }, + { + "text": "In addition, in studies of hypertensive individuals, MRAs have been consistently shown to be superior to alternative medication classes at lowering BP when renin is low or when the ARR is high ( 19 - 22 ).", + "tokenCount": 43, + "pageStart": 7, + "pageEnd": 7, + "hash": "ed4c1c736ec75acfd600b2c7c8586fc5e237909d4b4cda277cb97b24b9cd5a7c" + }, + { + "text": "For patients who are interested in the possibility of, and capable of undergoing, unilateral adrenalectomy, probabilistic and shared decision making should be pursued. When the probability of lateralizing PA is low, patients can be offered MRA therapy without further testing.", + "tokenCount": 52, + "pageStart": 7, + "pageEnd": 7, + "hash": "10ba3a57779a78f76157856773fd5c2818c98cf43e6cde80a8a804a2a87db243" + }, + { + "text": "When the probability of lateralizing PA is high, cross-sectional adrenal imaging with CT and AVS can be pursued to adjudicate the possibility of lateralizing PA. When the probability of lateralizing PA is intermediate, or uncertain, shared decision making is advised.", + "tokenCount": 53, + "pageStart": 7, + "pageEnd": 7, + "hash": "d801996fa5e5a65550e74b5c8036b7c953760395ca48216298b68b61c817be5f" + }, + { + "text": "When possible, aldosterone suppression testing may be considered to steer the direction of management in individuals willing and able to undergo testing. In interpreting the aldosterone suppression test one should consider the possibility of false negatives ( 23 - 27 ).", + "tokenCount": 47, + "pageStart": 7, + "pageEnd": 7, + "hash": "58f908f7363f6d5e99b15290c8572cf942fd91a9958b9a1bdb4c301ddfdec171" + }, + { + "text": "When aldosterone suppression testing is not available or desired, MRA therapy can be initiated. Approximate values for aldosterone and renin are provided for guidance. *See Fig. Initiating and Following MRA Therapy.", + "tokenCount": 47, + "pageStart": 7, + "pageEnd": 7, + "hash": "2842dba33bb857dd2066ca62dd28e963273ddc5c6c176e65bee5b64183600b34" + }, + { + "text": "# False negatives may occur, may be impacted by local study conditions, and should be considered when deciding on whether to proceed to AVS testing. Abbreviations: HTN, hypertension; CVA, cerebrovascular accident; MRA, mineralocorticoid antagonist.", + "tokenCount": 58, + "pageStart": 7, + "pageEnd": 7, + "hash": "da6862ce24a6c85791712af7a763d7b3c1cc1ed80b5394561272e07d2b4849cb" + }, + { + "text": "The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 2459 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 62, + "pageStart": 7, + "pageEnd": 7, + "hash": "771330464051be72366d58089a6ecf118e4fab6d6a0c67a41ec1d7531ef1ea98" + }, + { + "text": "• A potential exception is when the diagnosis of uni - lateral aldosterone-producing adenoma (APA) is so likely that AVS could be considered unnecessary (eg, individual age < 35 years with marked PA with hypokalemia and a > 1.0-cm unilateral adrenal ad - enoma on CT scanning).", + "tokenCount": 70, + "pageStart": 8, + "pageEnd": 8, + "hash": "d7e6e58bfc37510ae5fd20b2d42a3df6115ee4d7130504a369e370335b946798" + }, + { + "text": "Question 7. Should suppressed renin vs unsuppressed renin be used in individuals with primary aldosteronism receiv - ing primary aldosteronism–specific medical therapy? Recommendation 7 In individuals with primary aldosteronism (PA) receiv - ing PA-specific medical therapy whose hypertension is not controlled and renin is suppressed, we suggest increasing PA-specific medical therapy to raise renin (2 | ⊕ OOO).", + "tokenCount": 95, + "pageStart": 8, + "pageEnd": 8, + "hash": "ab65fad68a5304e78369f11012a210ca88cfd4a4edca85a466a1a4a0782b3070" + }, + { + "text": "Technical remarks: • This recommendation applies to individuals with PA receiving aldosterone-directed medical ther - apy whose blood pressure (BP) remains high. Uncertainty remains as to whether titrating aldosterone-directed medical therapy to raise re - nin when BP is controlled is efficacious.", + "tokenCount": 60, + "pageStart": 8, + "pageEnd": 8, + "hash": "6ed41a07937da2376e9e8e6df2d91a4de69f155f7fe330e422afdc75d2784e89" + }, + { + "text": "• The panel does not specify a renin level to target but rather advises titration of aldosterone-directed medical therapy to a rise in renin from pretreat - ment baseline. Question 8.", + "tokenCount": 41, + "pageStart": 8, + "pageEnd": 8, + "hash": "7b6e49fcfe8cae0377dd65827d58e5ad1dace987cd0feda36d561f2ece55172f" + }, + { + "text": "Should a dexamethasone suppression test vs no dexamethasone suppression test be used in individuals with primary aldosteronism and adrenal adenoma? Recommendation 8 In individuals with primary aldosteronism (PA) and adrenal adenoma, we suggest a dexamethasone sup - pression test (2 | ⊕ OOO).", + "tokenCount": 80, + "pageStart": 8, + "pageEnd": 8, + "hash": "c023696b64c746ebb230d2628347df454a68f8257ad561a2c65e4a741effc1ca" + }, + { + "text": "Technical remarks: • A dexamethasone suppression test should be per - formed, and a positive test should prompt further evaluation for Cushing syndrome as detailed in the Endocrine Society Clinical Practice Guidelines.", + "tokenCount": 41, + "pageStart": 8, + "pageEnd": 8, + "hash": "eeade8cf123500c945870cc417a236d5e49d695e9036fc46aa7670469113715f" + }, + { + "text": "• For the 1-mg overnight dexamethasone suppres - sion test, 1 mg dexamethasone is taken orally at 23:00 to 24:00 with serum cortisol measured at 08:00 to 09:00 the next morning.", + "tokenCount": 53, + "pageStart": 8, + "pageEnd": 8, + "hash": "5fa30271643d972272d1d306048505e890ad4c8f47fde0c7ee1e038413f5392a" + }, + { + "text": "A serum cortisol > 1.8 μ g/dL (50 nmol/L) suggests autonomous cor - tisol secretion (ACS). • For individuals with mild autonomous cortisol se - cretion, measuring plasma metanephrine during adrenal venous sampling may help lateralize both aldosterone and cortisol secretion, although fur - ther research is needed.", + "tokenCount": 73, + "pageStart": 8, + "pageEnd": 8, + "hash": "410fb87eddf750a6fa39cdf0c3aca36314691d53420aaac370ede795d432f565" + }, + { + "text": "It will also be important to measure early morning cortisol following adrenal surgery and prepare for a period of pos - sible glucocorticoid insufficiency. Question 9. Should spironolactone vs other mineralocorticoid receptor antagonists be used for primary aldosteronism– specific medical therapy?", + "tokenCount": 65, + "pageStart": 8, + "pageEnd": 8, + "hash": "50462a0eea8821f6ded511df86fcffd6cc9a1ee629989a6a0a4d9d1825f25ba0" + }, + { + "text": "Recommendation 9 In individuals with primary aldosteronism (PA) receiv - ing PA-specific medical therapy, we suggest spirono - lactone over other mineralocorticoid receptor antagonists (MRAs) due to its low cost and wide - spread availability (2 | ⊕ OOO).", + "tokenCount": 65, + "pageStart": 8, + "pageEnd": 8, + "hash": "39d411304e887558c5d584c919dea90c644d7bdafa2e64f29821a8ce5a0f6942" + }, + { + "text": "Technical remarks: • The recommendation is driven by the availability and low cost of spironolactone vs other MRAs; how - ever, all MRAs, when titrated to equivalent poten - cies, are anticipated to have similar efficacy in treating PA.", + "tokenCount": 54, + "pageStart": 8, + "pageEnd": 8, + "hash": "0182bbf47445fd24cdf2e50932004c63269e146d4290a67cb47c68c0f2893567" + }, + { + "text": "MRAs with greater mineralocorticoid re - ceptor specificity and fewer androgen/progesterone receptor-mediated side effects may be preferred. • When initiating an MRA, consider hypertension severity for dosing and potential discontinuation of other antihypertensive medications ( Fig.", + "tokenCount": 60, + "pageStart": 8, + "pageEnd": 8, + "hash": "392552f04773ce9eb4ee8df1daabe263a334b5f738641dee3015e877fcd3956a" + }, + { + "text": "• Monitor potassium, renal function, renin (concen - tration or activity), and blood pressure response during follow-up to guide MRA dose titration. Question 10. Should epithelial sodium-channel inhibitors vs mineralocorticoid receptor antagonists (steroidal and nonsteroidal) be used for medical treatment of primary aldosteronism?", + "tokenCount": 74, + "pageStart": 8, + "pageEnd": 8, + "hash": "4ac50ccf2243cdcc9e38f674fae1e06f5be2b689165622cf9fedbfc465be9500" + }, + { + "text": "Recommendation 10 For individuals with primary aldosteronism (PA) re - ceiving PA-specific medical therapy, we suggest us - ing mineralocorticoid receptor antagonists (MRAs) rather than epithelial sodium-channel (ENaC) inhibi - tors (amiloride, triamterene) (2 | ⊕ OOO).", + "tokenCount": 79, + "pageStart": 8, + "pageEnd": 8, + "hash": "db502fde25b4b38958da79f88c4b6d16ace1ab78ecad02ecefd16af6b6cabc60" + }, + { + "text": "Technical remark: • The recommendation (see Fig. 3 ) does not apply to clinical conditions in which spironolactone is contra - indicated (eg, hyperkalemia, advanced renal impair - ment, or pregnancy) or if a non-spironolactone MRA were indicated for other non-PA indications (eg, heart failure).", + "tokenCount": 72, + "pageStart": 8, + "pageEnd": 8, + "hash": "db2bff426e742c44fabd9ae96ab1b1bdfa50d88f7855917e29ecd2a5392ba59e" + }, + { + "text": "2460 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 62, + "pageStart": 8, + "pageEnd": 8, + "hash": "feb152cab39243e15f3183a9b09c85f718bfba088bec486fbec4d8ae81737943" + }, + { + "text": "Figure 3. Initiating and following MRA therapy. This is a general guide and there is a wide range of inter-patient responsiveness to varying doses of MRA. The process of MRA initiation and titration is expected to be multi-step for many patients; each MRA adjustment is followed by an assessment of both BP and biochemical response, then re-entering the treatment algorithm as appropriate.", + "tokenCount": 81, + "pageStart": 9, + "pageEnd": 9, + "hash": "230f55499ca7fbeec6caad74a1b90d651ef5ffe8f14229ceccc133f92b5c4ec3" + }, + { + "text": "The primary goal of therapy is control of BP. The secondary goal of therapy is achievement of normokalemia. Measurement of renin (as a marker of MR blockade) may assist in the process of MRA dose titration for achieving these goals and possibly reducing other non-MRA antihypertensive drugs.", + "tokenCount": 65, + "pageStart": 9, + "pageEnd": 9, + "hash": "7e7b21487e2bebff8f7c61035b28ad5aaf54bbb410196861840ac757892b857e" + }, + { + "text": "Clinicians may start at a relatively low dose MRA (spironolactone 12.5-25 mg/d or eplerenone 25 mg daily or twice daily). Medically complex or frail individuals and those in whom MRA–drug interactions (eg, with an ACE inhibitor or ARB) are possible may need careful monitoring.", + "tokenCount": 71, + "pageStart": 9, + "pageEnd": 9, + "hash": "2bdd651b26838f65d9fd25ccf9eb49a1e91ce1cefe3491a6d566b659341d5fde" + }, + { + "text": "For individuals with more severe PA, especially if profound hypokalemia is present, a higher initial dose could be considered (spironolactone 50 mg/d or eplerenone 50 mg twice daily).", + "tokenCount": 44, + "pageStart": 9, + "pageEnd": 9, + "hash": "9e9de7a3c4f3e3ea8865db6e34d0f50a6589bf0ced364e218620219d9a5f6fbf" + }, + { + "text": "All individuals should get routine measurement of serum electrolytes, renal function, and renin within 2 to 3 months of starting MRA therapy; more fre - quent serial measurements may be needed in those with prior severe hypokalemia or renal impairment.", + "tokenCount": 51, + "pageStart": 9, + "pageEnd": 9, + "hash": "63106d5b813b558677cb4578c25e2f519e9108476cd45ece550f0c4f1309a640" + }, + { + "text": "Some panelists recommend enquiring about dietary sodium or measuring 24-hour urine sodium at baseline and periodically throughout follow-up as a means of tracking dietary salt restriction; a target of < 85.5 mmol/d sodium is recommended (representing < 5 g/d salt intake) ( 6 ).", + "tokenCount": 60, + "pageStart": 9, + "pageEnd": 9, + "hash": "4e85f216a67861c041d70366141e4eb2ae6795d379596b1e1e43f60cc99552c4" + }, + { + "text": "MRA dose changes to target BP control should occur at 8- to 12-week intervals, and the full drug effect may take up to 3 months in more severe PA forms ( 28 ). Typical doses required to de-suppress renin are variable and likely higher than doses used as empiric add-on for resistant hypertension ( 29 ) ( 30 ); most individuals will achieve renin de-suppression with spironolactone doses (or spironolactone dose equivalents) between 50 and 100 mg/day.", + "tokenCount": 106, + "pageStart": 9, + "pageEnd": 9, + "hash": "1799dc7af1ba978dae2c480e90ff28dad87c85131d766f3d38cc99c8848a7df8" + }, + { + "text": "Spironolactone may be increased in 25- to 50-mg increments, and eplerenone in 25- to 100-mg increments. With each MRA dose change, repeat elec - trolytes, renal function, and renin 2 to 3 months later is recommended.", + "tokenCount": 60, + "pageStart": 9, + "pageEnd": 9, + "hash": "8ee45be7fadf7ea565c9b807caffdae49ae5cedcd8024567e3bdfa4ba05c0ac9" + }, + { + "text": "When possible, consider off-titration of other anti-hypertensives. Once renin is de-suppressed, and if further BP reduction is required, other non-MRA antihypertensives should be added or uptitrated.", + "tokenCount": 53, + "pageStart": 9, + "pageEnd": 9, + "hash": "ba9d473de25cad919adb29831c8788bff1cc9a21cf588abf4f334bfd768ac3e3" + }, + { + "text": "If blood pressure is controlled on MRA monotherapy, there is insufficient evidence to suggest further MRA dose increases in response to low renin levels alone. Normalization of serum potassium usually occurs, even with lower-dose MRAs, in the first 3 to 5 days, so it is reasonable to reduce or discontinue any potassium supplements at day 2 to 4 of MRA initiation in all but the most severe hypokalemic cases.", + "tokenCount": 88, + "pageStart": 9, + "pageEnd": 9, + "hash": "88bc4c832bb14cf0f9853012c1968847391f560180830b462a77bdf62bb12ac4" + }, + { + "text": "Individuals who do require ongoing potassium supplementation require frequent careful monitoring of potassium. Dietary salt restriction is a critical part of determining response to MRA therapy ( 31 ); individuals should be explicitly instructed on and assisted with dietary salt reduction strategies.", + "tokenCount": 46, + "pageStart": 9, + "pageEnd": 9, + "hash": "390afcff40de21de50435d83802c6cd1e67e7721130ab45db8ef67cb9c74608d" + }, + { + "text": "An ongoing high-salt diet is a very common reason for apparent nonresponse to MRA therapy. The glomerular filtration rate (GFR) may decrease in individuals with PA on introduction of PA-targeted medical therapy or with successive titration of MRA ( 32 , 33 ).", + "tokenCount": 61, + "pageStart": 9, + "pageEnd": 9, + "hash": "eb5da16193a0b656051f84d4a61abdacf1c5598e06536a9e1d3a6879417899a7" + }, + { + "text": "The time course of change may be over days to weeks and, in most cases, represents a marker of treatment efficacy as opposed to adverse effect. The natural history of an appropriate treatment-induced decrease in GFR is usually one of eventual long-term stability, anticipating a renal- sparing effect of effective MRA therapy ( 32 , 33 ).", + "tokenCount": 68, + "pageStart": 9, + "pageEnd": 9, + "hash": "d661624d898c2ac898e4fab2d1c2efdc69c53cf15c1ed5d3a9707005df4d70bf" + }, + { + "text": "If renal function progressively declines, consider referring to nephrology and discontinuing ACE inhib - itors or ARBs. Gynecomastia from spironolactone is dose-related and may appear as early as 1 to 2 months into therapy but more commonly after ≥ 6 months of treat - ment.", + "tokenCount": 63, + "pageStart": 9, + "pageEnd": 9, + "hash": "27c0f0b11a43955d21df0a43785b7588f81d809db22801609543e411f3a93009" + }, + { + "text": "In some cases (especially in younger males) a dose reduction to ≤ 50 mg per day resolves gynecomastia. Some men may request a switch to a more selective MRA such as eplerenone or other new MRA agents; amiloride is an alternative option (see Question 10).", + "tokenCount": 63, + "pageStart": 9, + "pageEnd": 9, + "hash": "bc44f0058a07bdaf6c8363e6537ad8d0f195fd2f70d97896e04b8a448142d33c" + }, + { + "text": "This almost always allows com - plete resolution of the gynecomastia if it has not already progressed to advanced size. Routine follow-up after MRA dose optimization should generally consist of blood pressure monitoring, along with annual measures of potassium and kidney function.", + "tokenCount": 54, + "pageStart": 9, + "pageEnd": 9, + "hash": "dff7be9894bfa8a04a684d5b122a2faea0abfef659deeb1ce5656635808f00ae" + }, + { + "text": "Patients with chronic kidney disease or other risk factors for impaired renal function/electrolyte disorders (eg, combination MRA and ACE inhibitor/ARB drugs) should undergo biochemical monitoring more frequently.", + "tokenCount": 40, + "pageStart": 9, + "pageEnd": 9, + "hash": "7e7274adc2df10986445523de074975a3d30d615b3c7b74a30100a305b6a4c22" + }, + { + "text": "Routine repeat renin measures are not necessary unless re- entering the MRA titration algorithm due to incomplete BP/potassium control. The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No.", + "tokenCount": 48, + "pageStart": 9, + "pageEnd": 9, + "hash": "eec1842fd9e1372eb8af56854a0338024a0d605b91f001466d56ec5959bd44f6" + }, + { + "text": "9 2461 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 42, + "pageStart": 9, + "pageEnd": 9, + "hash": "18b59af0a8c9416584b02447917a0c00eda56b739a3b9b603f4e79e36a965b73" + }, + { + "text": "Who Should be Screened for Primary Aldosteronism? Background Primary aldosteronism (PA) is the most common endo - crine cause of secondary hypertension with an estimated prevalence of 5% to 14% of individuals with hyperten - sion seen in primary care ( 34-36 ) and up to 30% in refer - ral centers ( 37-39 ).", + "tokenCount": 78, + "pageStart": 10, + "pageEnd": 10, + "hash": "5dd5c77fe5ac07bdbcb8541f1c690a7e2f87a22a4dde4139e964e7176f55e792" + }, + { + "text": "PA is particularly prevalent in individuals with specific clinical characteristics or co - morbid conditions ( Table 3 ). PA is characterized by excessive production of aldosterone ( 49 ), leading to higher blood pressure (BP), renal injury, and an elevated risk of stroke, atrial fibrillation, and other cardio - vascular diseases ( 1 , 2 ).", + "tokenCount": 67, + "pageStart": 10, + "pageEnd": 10, + "hash": "de373bfff7e96fb1edc6f36e63859216785570e33abeb7c7784751c05d2f4564" + }, + { + "text": "Detection of PA allows the use of spe - cific treatments — such as mineralocorticoid receptor antagonists (MRAs), or adrenalectomy for those with lateral - izing disease — that can effectively control BP, correct hypo - kalemia, and reduce cardiovascular risk ( 7-9 ) Despite the potential benefits of treatment, PA remains underdiagnosed, in part due to limited screening in routine clinical practice ( 50 , 51 ).", + "tokenCount": 91, + "pageStart": 10, + "pageEnd": 10, + "hash": "76b23061be3c82f3beed30db7e58523be1970e2dbda70cc9bf656bac040b4a46" + }, + { + "text": "Many individuals with PA, even those with high-risk features, such as resistant hypertension and hypokalemia ( 52 ), are never identified, leading to subopti - mal management of their hypertension and cardiovascular risk.", + "tokenCount": 44, + "pageStart": 10, + "pageEnd": 10, + "hash": "a75715036e12f753622fa4494c3133592851389696aaf5e6bf38a33bd9eb0d94" + }, + { + "text": "Expanding PA screening to all hypertensive individuals could increase the detection rate, allowing more individuals to benefit from targeted therapies and potentially reducing long-term cardiovascular risks. However, the benefits of widespread screening must be weighed against certain challenges.", + "tokenCount": 46, + "pageStart": 10, + "pageEnd": 10, + "hash": "bbed7351376bc9f6020e95e1b45cbfba91c90cdac63dcaa60c926110b56f9b14" + }, + { + "text": "The accuracy of screening tests, such as aldosterone concentration, renin concentration or activity, and the aldosterone to renin ratio (ARR), is influ - enced by various factors, including medication use, dietary so - dium intake, and test conditions.", + "tokenCount": 55, + "pageStart": 10, + "pageEnd": 10, + "hash": "a47b2a7b788f471d53c3efc37b275c326d47f7b833ba80c1be129e3d3aa4c783" + }, + { + "text": "False positives can occur, resulting in unnecessary aldosterone suppression testing or even inappropriate PA treatment in individuals without the condition. Access to diagnostic and subtyping tests and the availability of specialized treatments may also undermine the feasibility of universal screening unless alternative strat - egies are proposed.", + "tokenCount": 55, + "pageStart": 10, + "pageEnd": 10, + "hash": "d2bf85dc13be60c87051213e4cdc4b23cc3f26c34fe9465fbf69be2b1471820a" + }, + { + "text": "Therefore, the guideline addresses the question of whether care with PA screening should be implemented for all individ - uals with hypertension. Question 1. Should care that includes primary aldosteron - ism screening be applied to all individuals with hyperten - sion, compared with care without screening?", + "tokenCount": 60, + "pageStart": 10, + "pageEnd": 10, + "hash": "5692228c7e7cc4aaf85671943984ab9191f2d0749e54ca69b900a65d9ed69b09" + }, + { + "text": "Recommendation 1 In all individuals with hypertension, we suggest screening for primary aldosteronism (PA) (2 | ⊕⊕ OO). Technical remarks: • This is a conditional recommendation, with imple - mentation depending on contextual factors such as available resources, local expertise, and health - care system capacity, which may affect feasibility and prioritization.", + "tokenCount": 77, + "pageStart": 10, + "pageEnd": 10, + "hash": "2681ecaf6e9c8054080e0208399875205a1420d3c9120bdd54e42cead0ffc2c2" + }, + { + "text": "• This recommendation emphasizes care that is in - formed and guided by screening, with a positive screening result serving as the critical first step in the care process for individuals with PA. • PA screening includes measurement of serum/plas - ma aldosterone concentration and plasma renin (concentration or activity) with determination of the aldosterone to renin ratio (ARR).", + "tokenCount": 76, + "pageStart": 10, + "pageEnd": 10, + "hash": "d58bbec72c3ec9dfd4fd5b8355515d9a3d85a89306789c4be373961a31ed828f" + }, + { + "text": "Potassium is also assessed—not for screening itself—but to aid in the accurate interpretation of aldosterone (refer to Question 3). Summary of the Evidence The meta-analysis results, a detailed summary of the evidence and Evidence to Decision (EtD) tables can be found online at:", + "tokenCount": 61, + "pageStart": 10, + "pageEnd": 10, + "hash": "1371561f47763752445bfe62d4e07f6e001804593fcfd7c40774feb1eb238a95" + }, + { + "text": "https:/ /guidelines.gradepro.org/profile/goKsLjFSyDQ . Table 3. Prevalence of primary aldosteronism in different subgroups Setting Prevalence Reference Hypertension in Primary Care 5.9% (range, 3.2-14.0) ( 34 - 36 , 39 ) Hypertension in referral centers 7.2% (range, 0.7-21.9) ( 39 ) Hypertension in young adults (ages 18-40 years) 16.2% ( 39 ) a Grade 1 hypertension 3.9%-15.7% ( 23 , 34 ) a Grade 2 hypertension 9.7%-21.6% ( 23 , 34 , 37 ) a Grade 3 hypertension 11.9%-19% ( 34 , 37 ) Resistant hypertension 11.3%-29.1% ( 23 , 40 - 42 ) Hypertension and hypokalemia 28.1% ( 43 ) Hypertension and adrenal incidentaloma 4.4% (range, 0.4-24.6%) ( 44 ) Hypertension and atrial fibrillation b 42.5% ( 45 ) Hypertension and type 2 diabetes mellitus 11.3%-19.1% ( 46 , 47 ) Abbreviations:", + "tokenCount": 272, + "pageStart": 10, + "pageEnd": 10, + "hash": "f531cabf8ad1db5ca5605671af02012b90a9aeb12984272ba90eb84f2f33048b" + }, + { + "text": "DBP, diastolic blood pressure; SBP, systolic blood pressure. a Grades 1, 2, and 3 hypertension refer to the classification of the 2023 European Society of Hypertension guideline ( 48 ). Grade 1, SBP 140-159 mmHg and/or DBP 90-99 mmHg; grade 2, 160-179 mmHg and/or DBP 100-109 mmHg; grade 3, SBP ≥ 180 mmHg and/or DBP ≥ 110 mmHg.", + "tokenCount": 111, + "pageStart": 10, + "pageEnd": 10, + "hash": "b3fa881b48c24eac76b0f9d96d21915d5735c46a80def5ee7fa85a8378be086d" + }, + { + "text": "b If unexplained by structural heart disease and other conditions like hyperthyroidism. 2462 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 78, + "pageStart": 10, + "pageEnd": 10, + "hash": "da8487649b66b763c44a9d9aed56c095d4c77f2de1f20e38ba29e6939a46b227" + }, + { + "text": "Benefits and Harms The panel voted for the following patient-important outcomes for Question 1 decision making: 1) percent of individuals achiev - ing BP control, 2) number of antihypertensive agents, 3) dosage of antihypertensive agents, 4) systolic BP (SBP) level, 5) major ad - verse cardiovascular events (MACEs), 6) atrial fibrillation, 7) stroke, 8) ischemic heart disease, 9) heart failure, 10) cardiovas - cular mortality, 11) all-cause mortality, and 12) adverse events.", + "tokenCount": 126, + "pageStart": 11, + "pageEnd": 11, + "hash": "f22ed874809c29ae34a6ecbe7a426a132f3318cde54e1750b10ae5f5b17bf4d7" + }, + { + "text": "The commissioned systematic review ( 53 ) identified a single retrospective observational study ( 51 ) that showed that screening for PA was associated with a significantly lower SBP over time. The authors reported that of 269 010 US veter - ans with apparent treatment-resistant hypertension, only 1.6% were tested for PA with a concomitant measurement of blood aldosterone concentration and either plasma renin activity (PRA) or direct renin concentration (DRC).", + "tokenCount": 92, + "pageStart": 11, + "pageEnd": 11, + "hash": "50c4dce6e33a5afeee76f60fed0d5e658d6d3eb3ea8d824aecb0319bcfbe9a9a" + }, + { + "text": "Testing for PA was associated with a 4-fold higher likelihood of initi - ating treatment with an MRA. Individuals who underwent PA testing also had an average 1.47-mmHg lower SBP over time compared with those not tested.", + "tokenCount": 50, + "pageStart": 11, + "pageEnd": 11, + "hash": "792bce4e7b0723b26836d53412f0e68fdacfebf7c64526ba8485818e7a2bb079" + }, + { + "text": "Certainty of evidence for the outcome of BP control is low due to the nonrandomized nature of the study and indirectness. The panel did not identify any head-to-head studies comparing screening vs no screening for the outcomes of interest.", + "tokenCount": 49, + "pageStart": 11, + "pageEnd": 11, + "hash": "75aadcdb899987e18fb3340eb33bd449fcc434f8e744f678e2b55cd6957873a4" + }, + { + "text": "Due to the limited availability of studies directly evaluating the comparative effectiveness and potential harms of screen - ing, this recommendation relies on indirect evidence. The pan - el used a guideline screening framework that considers multiple factors required to justify screening ( 54 ).", + "tokenCount": 47, + "pageStart": 11, + "pageEnd": 11, + "hash": "5038ae3c8621d7d44f50445ff2a1544f8ceedafe8cce6c466b9de98909ef354c" + }, + { + "text": "The panel also adopted a framework based on Wilson and Jungner ’ s principles of screening ( 55 ). This framework, as relevant to screening for PA, is detailed in Table 4 . PA is recognized as an important health problem.", + "tokenCount": 46, + "pageStart": 11, + "pageEnd": 11, + "hash": "c67678152e9b658f35eab879ae2ed13fac76ed73a9ccb2b0702267baf3c67b55" + }, + { + "text": "It is com - mon, affecting 5% to 14% of hypertensive individuals in the primary care population and up to 30% in referral centers ( 34 , 38 , 35 , 36 ). Untreated PA confers a higher risk of cardio - vascular complications, with a meta-analysis of 31 studies showing an increased risk of stroke, coronary artery disease, atrial fibrillation, and heart failure for individuals with PA compared with BP-matched primary hypertension ( 2 ).", + "tokenCount": 94, + "pageStart": 11, + "pageEnd": 11, + "hash": "f61bf13fd6d8e6201e6dc2a0faeb6ab4dee3d9835e3f6c9e92c1c88d113bc908" + }, + { + "text": "While the natural history of PA is not fully understood, due to the general lack of screening from a young age, multiple studies provide evidence that elevated aldosterone concentra - tion, especially in the presence of low renin concentration or activity, is associated with increased risk of hypertension and cardiovascular events over time.", + "tokenCount": 62, + "pageStart": 11, + "pageEnd": 11, + "hash": "a69b621aeba210c50a996c1727fb565a4156a5904b69df2e0afa30915c5dfaa9" + }, + { + "text": "For example, data from the Framingham Heart Study demonstrate that individuals with aldosterone levels in the higher quartiles of the normal distri - bution are more prone to develop hypertension or to have an increase in BP during the follow-up period than individuals with lower aldosterone levels ( 56 ).", + "tokenCount": 61, + "pageStart": 11, + "pageEnd": 11, + "hash": "e254fdd7099a3aa49ac455a01ba9a07931ca593dc3f01082d4892bb670dc1b7f" + }, + { + "text": "Furthermore, higher aldos - terone levels predict the development of chronic kidney disease and microalbuminuria ( 57 ). The effect of aldosterone on hypertension development is more evident in individuals with low renin (ie, those with a higher ARR) ( 58 , 59 ), with the ratio being associated with incident hypertension in differ - ent population studies ( 58 , 60 , 61 ).", + "tokenCount": 79, + "pageStart": 11, + "pageEnd": 11, + "hash": "fdeb082bc9a31f5800bee108345372c569c8eaf9eb68f0c35ab17ae3df82e30e" + }, + { + "text": "Renin-independent aldos - teronism (with low renin), in contrast to renin-dependent aldosteronism, is associated with higher cardiovascular risk ( 62 ). The ARR in healthy individuals also correlates with vas - cular stiffness ( 63 ).", + "tokenCount": 56, + "pageStart": 11, + "pageEnd": 11, + "hash": "0148dc87c71d932799a3979ad89f5ab10c10309c090cdac2164e12e38ea8d08f" + }, + { + "text": "These data were replicated in a Canadian population ( 64 ), which showed that, independent of BP, a bio - chemical phenotype of subclinical PA is negatively associated with cardiovascular health, including greater arterial stiffness, Table 4.", + "tokenCount": 44, + "pageStart": 11, + "pageEnd": 11, + "hash": "688756893281b22af2b08fcc9158c713113886d47ba9924c2813282f035a1a87" + }, + { + "text": "Evidence for the recommendation of primary aldosteronism screening Importance The condition should be an important health problem. PA is a frequent cause of secondary hypertension. PA, independent of blood pressure, is associated with increased mortality and morbidity if untreated.", + "tokenCount": 50, + "pageStart": 11, + "pageEnd": 11, + "hash": "f5d23aecae2521d0e496b15f2b0a904fbac74af6fc6570bca0409ee6e7d2ad56" + }, + { + "text": "Natural History The condition being screened for should have a natural history that is understood and a recognized latent period. Individuals with PA develop organ damage and cardiovascular events if left untreated. Difference in Management Individuals with a positive screening test would receive different care than those with a negative test.", + "tokenCount": 54, + "pageStart": 11, + "pageEnd": 11, + "hash": "588f5c82766a4b5258d47299166429df894fe725a98bbaaa4e56a3e0c286b28a" + }, + { + "text": "Individuals with a positive screening test are candidates for PA-targeted therapy. Available Treatment Effective treatment should be available for the condition that improves outcomes if administered earlier than when the condition is clinically apparent.", + "tokenCount": 40, + "pageStart": 11, + "pageEnd": 11, + "hash": "446bc14dcd5ebb2b072f00a0a287b4ed052a1cd53c9e5608ad5f3b1672ddf1d5" + }, + { + "text": "Specific medical therapies are available and effective. Also, adrenalectomy for lateralizing subtypes of PA is effective. PA-specific therapies reduce the rate of cardiovascular complications. Novel therapies are under investigation.", + "tokenCount": 40, + "pageStart": 11, + "pageEnd": 11, + "hash": "0a829e503b6f174211a0748807b9d04bcdfcc11d4da9fc7305c1194b75fc1915" + }, + { + "text": "Difference in Outcomes Improvement in outcomes based on management according to screening results outweighs harms of screening. Individuals with PA display a significant benefit from targeted treatment, with the possibility of cure in those with surgically resectable lateralizing adrenal disease.", + "tokenCount": 51, + "pageStart": 11, + "pageEnd": 11, + "hash": "2eeef7f882afca4f2bf4dff62d7313c093ff2fb26b546b275f78e2c4690a9448" + }, + { + "text": "Individuals with potentially false-positive results are not exposed to harm if treated with aldosterone-blocking drugs since they also proved effective in individuals with primary hypertension. Careful selection for individuals undergoing AVS should be made to avoid unnecessary invasive procedures.", + "tokenCount": 50, + "pageStart": 11, + "pageEnd": 11, + "hash": "0f3c28a51ff8f4e6bf6ae3851dcac4ab09cd4f13112bf203e10a168142f83ec3" + }, + { + "text": "Harms associated with screening are minimal as we provide pathways for screening that involve no or minimal withdrawal of current antihypertensive medications. Accuracy Certainty of evidence for a sufficient accuracy of the test is high or moderate. Screening tests are sufficiently accurate.", + "tokenCount": 51, + "pageStart": 11, + "pageEnd": 11, + "hash": "21c50219c9d9ab19d952be25154c5c79d8be65cf18f4520b1432164e7405c7c2" + }, + { + "text": "False-negative results may be observed in mild forms or may be caused by variability in aldosterone concentration; aldosterone suppression testing can help to confirm PA. Other Considerations Screening should be cost-effective, acceptable to individuals, and feasible to implement.", + "tokenCount": 53, + "pageStart": 11, + "pageEnd": 11, + "hash": "b9a6c7ae1dffb1d0afa7f6ae3607e4bdcf0bd2998ca062f04bab3c3888dce56f" + }, + { + "text": "Screening for PA is cost-effective, convenient, and accepted by the individuals. Feasibility depends on collaboration between general practitioners, specialists, laboratories, and referral centers. The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No.", + "tokenCount": 55, + "pageStart": 11, + "pageEnd": 11, + "hash": "33a664c78288327f653a947f51a572bf0616b35357d79cdd4c8cd9fe47a8a56a" + }, + { + "text": "9 2463 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 42, + "pageStart": 11, + "pageEnd": 11, + "hash": "7fd38e059d9c92baf3e37bd2006542b0bb626a7d2707092fa1d34a671d479b15" + }, + { + "text": "adverse cardiac remodeling, and incident hypertension. In the ARIC study ( 65 ), low renin and high aldosterone levels are as - sociated with cardiac structural and functional alterations. Even in adults as young as 27 years of age, aldosterone concen - trations or the ARR have been found to correlate with left ven - tricular mass index ( 66 ).", + "tokenCount": 78, + "pageStart": 12, + "pageEnd": 12, + "hash": "62543e6ca1c48b274ac1782d3f5dad0298addbb5f2e325c17948e8f12feeb93a" + }, + { + "text": "Management is different if PA screening is incorporated, or not, into the care of individuals with hypertension. In the ab - sence of specific recommendations for PA screening with measurement of aldosterone and renin in all individuals with hypertension, this blood test is rarely done ( 50 , 51 ).", + "tokenCount": 58, + "pageStart": 12, + "pageEnd": 12, + "hash": "363ef64119cebe18d417db9fa8627373c5e9e91d2807dc80738798d32b871b05" + }, + { + "text": "In a Canadian population of 1 million hypertensive individuals, fewer than 1% had been screened for PA ( 67 ), and an Australian primary care study reported that aldosterone was only measured 66 times over 1.5 million primary care patient encounters during a 16-year period ( 68 ).", + "tokenCount": 57, + "pageStart": 12, + "pageEnd": 12, + "hash": "c11f20377a00955732ae2984686d3c4f8e8d7aa4b04d637f1f8f37b55e1bf193" + }, + { + "text": "Similar rates of low detection have been observed in the United States and Europe ( 50 , 51 ). Without the screening blood test, PA is almost im - possible to diagnose due to the absence of specific symptoms and signs other than high BP.", + "tokenCount": 47, + "pageStart": 12, + "pageEnd": 12, + "hash": "a5083221b7e4a682d8a1eb7d70eac01fc902ae82de0ab0aa812e033414c1fa11" + }, + { + "text": "Lack of diagnosis or delayed Table 5. PA screening: ARR cut points according to aldosterone and renin assay and unit measurements Renin Aldosterone concentration measured by immunoassay Aldosterone concentration measured by LC-MS/MS ≥ 10 ng/dL ≥ 277 pmol/L ≥ 7.5 ng/dL ≥ 208 pmol/L Plasma renin activity ≤ 1 ng/mL/h > 20 > 555 > 15 > 416 ≤ 12.9 pmol/L/min > 1.55 > 43 > 1.16 > 32 ≤ 0.28 ng/L/s > 71 > 2000 > 53 > 1500 DRC ≤ 5.2 ng/L > 4.0 > 111 > 2.8 > 82 ≤ 8.2 mU/L > 2.5 > 70 > 1.8 > 52 The aldosterone, renin, and aldosterone to renin ratio (ARR) values above are provided for guidance.", + "tokenCount": 198, + "pageStart": 12, + "pageEnd": 12, + "hash": "83a347a6c96f27abb639fdceea3d1e726ee7bd78200d5e6430d7e297a286402e" + }, + { + "text": "However, as with many diagnostic tests based on continuous variables, the sensitivity and specificity depend on the selected threshold. Aldosterone and renin levels are further influenced by individual variability, local laboratory assays, and other factors.", + "tokenCount": 44, + "pageStart": 12, + "pageEnd": 12, + "hash": "4a8ca65b6809015d8e9dd698f473f96bb7e10c4fd71c08d63f2cad74a8f572c4" + }, + { + "text": "Where possible, clinicians should rely on local laboratory cut points, as assays may vary. No cut point is perfect—each carries a trade-off between false positives and false negatives. Therefore, results should be interpreted within the context of the patient’s pretest probability for primary aldosteronism (PA), along with potential interfering medications and conditions.", + "tokenCount": 73, + "pageStart": 12, + "pageEnd": 12, + "hash": "cb1ef2eb38448522f747caddbc9c964a57bd9f8e106fd4542328a1e0213922c0" + }, + { + "text": "The AAR values are not bolded. Abbreviations: DRC, direct renin concentration; LC-MS/MS, liquid chromatography–tandem mass spectrometry. Table 6.", + "tokenCount": 42, + "pageStart": 12, + "pageEnd": 12, + "hash": "e4df3f91a7a0501181095ddaa905d69c60c4eaa3fae6ce69040ca2e53a50d336" + }, + { + "text": "Managing interfering antihypertensive medications during PA screening and interpretation of aldosterone, renin, and ARR Management strategy Medication to withdraw Timeline of withdrawal Replacement antihypertensive agents Interpretation of negative screen Interpretation of positive screen No medication withdrawal None − − Possible false negative if moderate to high pretest probability Repeat screen on different day with minimal- or full-medication withdrawal strategy Possible false positive if individual taking β -adrenergic blockers or centrally acting α 2 -agonists (clonidine, α -methyldopa) Repeat screen after withdrawing these medications Minimal medication withdrawal Stop MRAs and ENaC inhibitors (amiloride, triamterene) 4 weeks before testing Hydralazine a α 1 -adrenergic blockers Non-dihydropyridine CCBs Moxonidine Possible false negative if moderate to high pretest probability Repeat screen on different day with full withdrawal strategy If pretest probability is low, then likely true negative Likely true positive Proceed to algorithm ( Fig. 2 ) Stop β -adrenergic blockers and centrally acting α 2 -agonists (clonidine, α -methyldopa) 2 weeks before testing Ideal full medication withdrawal Stop MRAs, ENaC inhibitors (amiloride, triamterene), and other diuretics 4 weeks before testing Hydralazine a α 1 -adrenergic blockers Non-dihydropyridine CCBs Moxonidine Possible false negative if moderate to high pretest probability Repeat screen on different day.", + "tokenCount": 315, + "pageStart": 12, + "pageEnd": 12, + "hash": "61a604ebdd1474d731c669340b4da2c765250a50039ab1fdfe572136f2682ae6" + }, + { + "text": "If repeat is negative, then likely true negative If pretest probability is low, then likely true negative Likely true positive Proceed to algorithm ( Fig. 2 ) β -adrenergic blockers ACE inhibitors ARBs Dihydropyridine CCBs Centrally acting α 2 -agonists (clonidine, α -methyldopa) SGLT2 inhibitors 2 weeks before testing Abbreviations:", + "tokenCount": 83, + "pageStart": 12, + "pageEnd": 12, + "hash": "5f2465565a034e0943fbbc15455a8b16272ed7c0fb9cf7f5341298f99954d953" + }, + { + "text": "ACE, angiotensin-converting enzyme; ARB, angiotensin II–receptor blocker; CCB, calcium-channel blocker; ENaC, epithelial sodium-channel, MRA, mineralocorticoid antagonist; SGLT2, sodium-glucose cotransporter 2.", + "tokenCount": 68, + "pageStart": 12, + "pageEnd": 12, + "hash": "a5d8343f709b9126c7ddf0d767cfdd0bd7e37bf21cda5fabed913b831a846d1b" + }, + { + "text": "a Ideally individuals receiving hydralazine should also be administered a negative chronotropic agent such as verapamil slow release to avoid reflex tachycardia. 2464 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No.", + "tokenCount": 54, + "pageStart": 12, + "pageEnd": 12, + "hash": "b1a463d6922e91c296c61cbd99ad96791c27dc1bd890b21057600f94d43bccc9" + }, + { + "text": "9 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 40, + "pageStart": 12, + "pageEnd": 12, + "hash": "86d3541f16c4cf3f3990fa58d424f397068a88b4c212a690d7cd989da5201309" + }, + { + "text": "diagnosis of PA is associated with poor BP control, high bur - den of symptoms, and poor quality of life (QOL) ( 3 , 4 ) and re - sults in increased morbidity and mortality ( 1 , 2 , 7 , 69 ). Once diagnosed, PA has specific treatment that differs from that of primary hypertension. The source of excess aldosterone from a unilateral adrenal adenoma can be removed surgically, leading to a potential cure of hyperaldosteronism, or the actions of aldosterone can be specifically blocked by MRAs. The ele - vated risk of cardiovascular events is ameliorated in individuals with PA treated with unilateral adrenalectomy or sufficient dose of an MRA ( 7", + "tokenCount": 148, + "pageStart": 13, + "pageEnd": 13, + "hash": "61162eb574255a334d2029d9c5c84d1daafec022b649a44fe09323abd88a4be3" + }, + { + "text": "Numerous studies demonstrate that spe - cific treatment is able to improve cardiovascular and renal out - comes in individuals with PA (see Question 2 ( 7-9 , 32 ). This highlights the importance of early detection of individuals with PA who can benefit from targeted medical or surgical treatment that would not be applied if individuals remained un - diagnosed and instead treated as having primary hypertension. Early screening for PA has also been demonstrated to be cost-effective in studies from Japan, China, and Australia ( 70-72", + "tokenCount": 100, + "pageStart": 13, + "pageEnd": 13, + "hash": "a4eb4a8d31c7aba2ee1200aeae556f7d6745110a56367ebecb106cbb23487126" + }, + { + "text": "It is also favored by primary care clinicians ( 73 ) and desired by patients ( 74 ). The screening test for PA has varying diagnostic accuracy, depending on the decision threshold adopted by individual centers. By the nature of screening, the threshold is usually set lower to permit high sensitivity at the expense of lower spe - cificity (ie, more false-positive results) ( 75", + "tokenCount": 75, + "pageStart": 13, + "pageEnd": 13, + "hash": "9c69371a1099392db67f789aa28731acb0160c4df744cee6b259a010836be9bd" + }, + { + "text": "A false-positive screening blood test could lead to a cascade of unnecessary investigations, but PA can generally be excluded by the next diagnostic step with aldosterone suppression testing. However, even if the individual is initiated on an MRA on the basis of a false-positive screening test, MRA treatment may still benefit individuals with an elevated ARR (typically due to a low or suppressed renin) for a few reasons. First, a systematic review and meta-analysis demonstrated that MRAs are superior to rou - tine antihypertensive therapy (eg, angiotensin-converting en - zyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]) in treating low-renin hypertension, which is the typical diagno - sis given to individuals with suspected PA who do not meet cur - rent diagnostic criteria for PA ( 76 ). Second, 20% of individuals with a positive ARR screening test but a negative aldosterone suppression test (ie, false-positive screening test) may develop PA over time ( 77", + "tokenCount": 215, + "pageStart": 13, + "pageEnd": 13, + "hash": "7aa18d285cbdf05028131410b0e8d61d51956bdddef0d8625a439affb32c0834" + }, + { + "text": "Third, low renin levels and high ARRs are predictors of BP response to MRA treatment, even in individuals without a formal diagnosis of PA ( 19 ). Evidence to Decision Factors As described in the Introduction, the panel also used the Evidence to Decision (EtD) framework for this and all subse - quent Questions, to consider broader factors such as stake - holder values and preferences (including insights from clinical experts and patient representatives), costs and resour - ces required, cost-effectiveness, acceptability, feasibility, and the potential impact on health equity. PA screening requires commonly available and relatively low-cost laboratory tests (aldosterone and renin measure - ments", + "tokenCount": 139, + "pageStart": 13, + "pageEnd": 13, + "hash": "165e852c00f3ec7714115fcfe72a078f18e284d78a60c201f08ff2366653e862" + }, + { + "text": "However, downstream testing — such as aldosterone suppression tests, adrenal imaging, and adrenal vein sampling (AVS) — introduces significant additional costs and is not uni - versally available, particularly in resource-limited settings. While initial screening is affordable at the individual level, im - plementation of universal screening will increase overall healthcare system costs due to follow-up testing, specialist re - ferrals, and potential surgical interventions. Screening for PA in the general hypertensive population has been shown to be cost-effective in health economic studies conducted in Japan, Australia, and China. The favorable cost- effectiveness is largely driven by the reduction in long-term complications associated with untreated PA. While upfront screening costs are higher when applied broadly compared to targeted screening of high-risk groups, modeling studies demonstrate that screening remains below commonly ac - cepted willingness-to-pay thresholds. In addition to general population studies, cost-effectiveness has been demonstrated in specific high-risk groups, such as individuals with resistant hypertension or those with obstructive sleep apnea, where screening prevents cardiovascular complications and reduces long-term healthcare expenditures. The degree of cost- effectiveness, however, varies across healthcare settings. For the impact of screening on equity, the panel considered that PA is underdiagnosed globally, particularly in under - served populations and minority groups, contributing to health disparities in hypertension-related outcomes. Limited access to screening, confirmatory testing, and specialized care — especially in rural and resource-poor settings — delays diagnosis and treatment. PA screening may reduce disparities by improving detection; however, inequities could be exacer - bated if follow-up services, such as subtype diagnosis and AVS, remain inaccessible to disadvantaged populations. The Table 7. Medications that interfere with PA screening and their effects on aldosterone and renin Effect on renin or aldosterone Medication Lower renin β -adrenergic blockers, central acting α 2 -agonists (clonidine, α -methyldopa), NSAIDs Combined estrogen and progesterone-containing OCPs and HRT decrease DRC (impact on PRA described below) Raise renin MRAs, diuretics including", + "tokenCount": 448, + "pageStart": 13, + "pageEnd": 13, + "hash": "9b113f59d112fec8956a86ed1b92ecfd7526f7a4bb94b7d0917f597314d262f7" + }, + { + "text": "ENaC inhibitors (amiloride, triamterene), ARBs, ACE inhibitors, SGLT2 inhibitors Combined estrogen and progesterone-containing OCPs and HRT increase PRA (impact on DRC described above) Drospirenone blocks the MR and thus increases PRA and DRC Lower aldosterone ARBs, ACE inhibitors, β -adrenergic blockers, central α 2 -agonist (clonidine, α -methyldopa) Raise aldosterone Diuretics a , MRAs Combined estrogen and progesterone-containing OCPs and HRT Drospirenone Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin II–receptor blocker; CCB, calcium-channel blocker; DRC, direct renin concentration; HRT, hormone-replacement therapy; MRA, mineralocorticoid antagonist; NSAID, nonsteroidal anti-inflammatory drug; OCP, oral contraceptive; PRA, plasma renin activity; SGLT2, sodium-glucose cotransporter 2; ENaC, epithelial sodium-channel. a By promoting natriuresis, diuretics (including MRAs) may induce a rise in aldosterone secondary to a rise in renin/angiotensin II. In the case of thiazide or loop diuretics, however, this may be mitigated by the development of hypokalemia (which inhibits aldosterone production). The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 2465 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 381, + "pageStart": 13, + "pageEnd": 13, + "hash": "edb86e75bee80c72f271f418d4ec72e48cc9b98b49160a6c63a44b3e8791f4a9" + }, + { + "text": "panel judged the impact on equity as mixed, taking into ac - count pragmatic treatment pathways provided in Fig. 2 that permit targeted treatment for PA without extensive testing. The panel judged that acceptability of PA screening will vary among providers.", + "tokenCount": 46, + "pageStart": 14, + "pageEnd": 14, + "hash": "c86f00a3ee750d919ad2fcb4d4ddc693cc5cbd11f4e6dec418957709c1ba89a0" + }, + { + "text": "Primary care clinicians, in particular, may have lower acceptance due to limited awareness of PA, difficulties interpreting results in patients on interfering med - ications, and concerns about the complexity and availability of subtype testing.", + "tokenCount": 42, + "pageStart": 14, + "pageEnd": 14, + "hash": "25f5efe2ce047d9e6fe619c127e47e8fb32f09e37dfc8d5aae7c4dd293b9b4c6" + }, + { + "text": "Some also view medication washout as burdensome or potentially risky. In contrast, screening is gen - erally well-accepted by patients, especially at the time of initial hypertension diagnosis. However, provider hesitancy could limit implementation, particularly in settings with high work - loads or limited specialist access.", + "tokenCount": 61, + "pageStart": 14, + "pageEnd": 14, + "hash": "dd68054d026c03b1433cdfe893714560210966d997ac438959eb8483d42fcb35" + }, + { + "text": "The panel judged that the feasibility of PA screening will vary by setting and stakeholder perspective. While screening relies on simple, widely available biochemical tests and is tech - nically feasible, implementation has remained low.", + "tokenCount": 41, + "pageStart": 14, + "pageEnd": 14, + "hash": "2b63c4efc29eb27e3de370d7372e4f3a7475229eb7f0dd980017de1247ed2ff5" + }, + { + "text": "This is Table 8.", + "tokenCount": 5, + "pageStart": 14, + "pageEnd": 14, + "hash": "7cae95a3fc55218385eee406a8870c388c8f232f71236568d81a7f60a6793199" + }, + { + "text": "Description of the most commonly used aldosterone suppression tests Aldosterone suppression test Resource requirements Protocol Metrics Interpretations Comments Oral sodium suppression test Low Individuals are instructed to consume 4-5 g of sodium per day for 3-4 days Collect 24-h urine collection on final day of high sodium intake Measure urinary aldosterone, sodium, creatinine 24-h urine sodium should ideally be > 200 mEq/ 24 hours 24-h urine creatinine is used to assess adequacy of urine collection 24-h urine aldosterone < 10 mcg/nmol/24 hours makes PA unlikely ( 84 ) Oral sodium can be consumed via sodium chloride tablets or sodium rich foods Because hypokalemia may cause false-negative interpretations, serum potassium should be normalized before the study protocol Interpretation of results is probabilistic and lacks evidence to recommend a precise diagnostic threshold ( 23 ) Protocol can be conducted in the ambulatory setting Captopril challenge test Moderate After sitting for 1 hour, blood is drawn to mark t = 0 Individuals are then given 50 mg of captopril and remain seated for 2 hours following administration Blood should be drawn at t = 2 hours to complete the study Measure plasma aldosterone and renin at t = 0 and t = 2h In the context of a post-captopril suppressed renin ( < 1.0 ng/mL/h or < 10 mU/L), a 2-h post-captopril plasma aldosterone level < 277 pmol/L (10 ng/dL) by immunoassay or < 203 pmol/L (7.5 ng/dL) by LC-MS/MS makes PA unlikely ( 84 ) ( 112 ) Many individuals with hypertension are actively treated with ACE inhibitors or ARBs; plasma aldosterone and renin values measured after taking these routinely prescribed medications may serve as a proxy for the captopril challenge test Interpretation of results should be considered to be probabilistic as the evidence to support a singular diagnostic threshold is not firm ( 26 ) Protocol requires an in-person visit and space and staff to accommodate the procedures Saline suppression test Moderate After sitting for 1 hour, blood should be drawn to mark t =", + "tokenCount": 450, + "pageStart": 14, + "pageEnd": 14, + "hash": "4c819262183d02ce54449630c0ff637087aff67289ea1491a1aa6727448970cc" + }, + { + "text": "0 Two liters of normal saline are infused over 4 hours (500 mL/h for 4 hours), while maintaining a seated position, after which blood should be drawn Measure plasma aldosterone and serum potassium at t = 0 and t = 4 hours Plasma aldosterone < 162 pmol/L (5.8 ng/dL) via LC-MS/MS assay makes PA unlikely Plasma aldosterone < 217 pmol/L (7.8 ng/dL) via immunoassay assay makes PA unlikely ( 84 , 100 , 102 , 113 ) Because hypokalemia may cause false-negative interpretations, serum potassium should be normalized before the study protocol Interpretation of results should be considered to be probabilistic as the evidence to support a singular diagnostic threshold is not firm ( 25 ) Protocol requires an in-person visit, space and staff to accommodate the procedures, and IV infusion of saline Protocol should not be performed if baseline BP is uncontrolled, or in patients at high risk for pulmonary edema (such as in heart failure or advanced chronic kidney disease) Abbreviations:", + "tokenCount": 221, + "pageStart": 14, + "pageEnd": 14, + "hash": "fba71dac275d7dfe02393c3994a07b41f2145914f6efdddda658f085324dde9c" + }, + { + "text": "ACE, angiotensin-converting enzyme; ARB, angiotensin II–receptor blocker; IV, intravenous. 2466 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No.", + "tokenCount": 51, + "pageStart": 14, + "pageEnd": 14, + "hash": "bdb9ae440567da1549a8b3795d201105bf0f72722056e73fee124dd768d91221" + }, + { + "text": "9 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 40, + "pageStart": 14, + "pageEnd": 14, + "hash": "86d3541f16c4cf3f3990fa58d424f397068a88b4c212a690d7cd989da5201309" + }, + { + "text": "likely due more to the complexity of prior diagnostic algo - rithms than to challenges with performing the tests them - selves. The current guideline offers suggestions for more pragmatic and feasible approaches to PA testing and treat - ment ( Figs.", + "tokenCount": 48, + "pageStart": 15, + "pageEnd": 15, + "hash": "5d416f37f1b0a0f3b72ef06c137b24d37c5fcddfc6c25af064c0f0963f1b74a4" + }, + { + "text": "1 - 3 ). Justification for the Recommendation The panel suggests PA screening for individuals with hyperten - sion based on the high prevalence of PA, its underdiagnosis, and the potential to reduce cardiovascular morbidity and mortal - ity through targeted treatment.", + "tokenCount": 53, + "pageStart": 15, + "pageEnd": 15, + "hash": "538a06d4ce7892c9f843ce2ad43b18f9cf61bda2aee26e0e7972257991b11b80" + }, + { + "text": "However, this is a conditional recommendation, reflecting important limitations in the evi - dence base. The certainty of evidence for both benefits and harms is low, primarily due to reliance on indirect data and observational studies.", + "tokenCount": 43, + "pageStart": 15, + "pageEnd": 15, + "hash": "c30856f74fb482a5833883fb8d31ad7b00c02e4f1ac918ddbe24b745dcc35af2" + }, + { + "text": "While existing evidence suggests improved BP control and reduced long-term complications with screening, the mag - nitude of benefit remains uncertain. No direct comparative studies between screening and no screening were identified for critical clinical outcomes.", + "tokenCount": 42, + "pageStart": 15, + "pageEnd": 15, + "hash": "f84a618ab05f788d50ac1e3d48bba8d309ca35d3524b9cfb59380e8050454cb6" + }, + { + "text": "Despite these limitations, the panel judged that the potential benefits of early detection and specific treatment for PA likely outweigh potential harms, including false-positive results and unnecessary downstream testing. In making this decision, the panel placed high value on offering patients the opportunity for evaluation and identification of an endocrine etiology for hypertension — one that is treated differently from primary hypertension and that offers the possibility of cure in cases of lateralizing PA.", + "tokenCount": 84, + "pageStart": 15, + "pageEnd": 15, + "hash": "8c1e4137213a201a37d500484eafb3df30ae38ab3e6eeea5b8bddd1dc8774dc2" + }, + { + "text": "The panel also acknowledged feasibility concerns, particular - ly the burden on healthcare systems and specialist services, espe - cially in primary care and resource-limited settings. Therefore, the recommendation emphasizes that implementation should be context-sensitive, depending on available resources, local ex - pertise, and healthcare system capacity.", + "tokenCount": 62, + "pageStart": 15, + "pageEnd": 15, + "hash": "6e2960b2eafa927a088d3245846d614283c7b8459aabf545e61cb9403231930d" + }, + { + "text": "It also underscores the need for additional guidance to help clinicians interpret and manage screening results, especially when interfering medica - tions are present. Ultimately, this conditional recommendation supports screening to improve PA detection and treatment but leaves room for adaptation based on local resources, feasibility, and priorities.", + "tokenCount": 56, + "pageStart": 15, + "pageEnd": 15, + "hash": "01cc50bf5e3844a7d4c92c6b6e0c827f0e252262fe91dd05fd7ec279487e0402" + }, + { + "text": "The panel judged that, on balance, the likely benefits outweigh the harms but that the recommendation should be applied flexibly. Implementation Considerations This is a conditional recommendation, and its implementation will vary depending on contextual factors at both the health - care system and clinician-patient levels.", + "tokenCount": 56, + "pageStart": 15, + "pageEnd": 15, + "hash": "ad989305bd9dbabad13d591c9ff797a5ca366d643c4b2a21bc27536b83576481" + }, + { + "text": "Health system–level considerations When healthcare systems consider implementing this condi - tional recommendation, they must weigh several intercon - nected factors that will shape feasibility, sustainability, and equity. Expanded PA screening may improve detection but will also introduce system-level demands that vary depending on resources, infrastructure, and workforce capacity.", + "tokenCount": 65, + "pageStart": 15, + "pageEnd": 15, + "hash": "dfff4396131299dfb946629122761c761d5cdf192201df211d60b03e45c8e87a" + }, + { + "text": "Key considerations include: Resource availability. Availability of laboratories to conduct aldosterone, renin, and potassium testing, as well as capacity for downstream evaluations such as aldosterone suppression testing, adrenal imaging, or AVS, varies widely.", + "tokenCount": 49, + "pageStart": 15, + "pageEnd": 15, + "hash": "1e6d90e1679e6422e0e4562e1bf5e63878a956086812c1ad425dd4d76dbfe170" + }, + { + "text": "In settings where advanced diagnostics or specialist services are limited, al - ternative approaches — such as empiric MRA therapy following a positive screening result — may be appropriate. Table 9. Key indices and cutoffs for adrenal vein sampling interpretation AVS index Index formula Cutoff values Diagnostic significance Selectivity index (SI) [cortisol] AV /[cortisol] IVC Unstimulated > 1.4 to 3 Indication of successful AV cannulation Cosyntropin-stimulated > 5 Lateralization index (LI) ([aldosterone]/[cortisol]) highAV / ([aldosterone]/[cortisol]) lowAV Unstimulated or cosyntropin-stimulated ≥ 4 Distinguishes lateralizing from bilateral PA Contralateral suppression index (CSI) ([aldosterone]/[cortisol]) lowAV / ([aldosterone]/[cortisol]) IVC Unstimulated or cosyntropin-stimulated < 1 Consistent with suppressed aldosterone production by the contralateral adrenal gland Abbreviations:", + "tokenCount": 226, + "pageStart": 15, + "pageEnd": 15, + "hash": "5292342b82cf352e94c4b3b47314adedb1c6b1113dee1715d79b0219018f97ff" + }, + { + "text": "AV, adrenal vein; highAV, adrenal vein measurement from the dominant adrenal; IVC, inferior vena cava; lowAV, adrenal vein measurement from the nondominant adrenal gland.", + "tokenCount": 44, + "pageStart": 15, + "pageEnd": 15, + "hash": "b49af2629f94c772e9640c932dab1d02ab1b9cc99e633aa7149eefc4a5fb1378" + }, + { + "text": "Table 10. Comparisons of MRA and ENaC inhibitors a Drug Typical starting dose in PA Possible maximum dose in PA b Usual cost Spironolactone 12.5-25 mg/d 200 mg/d $ Eplerenone 25-50 mg twice daily 200 mg twice daily $$-$$$ Finerenone c Unknown; 10-20 mg/d unknown $$$$ Amiloride 5-10 mg/d 40 mg/d $ Triamterene d 50-100 mg/d 300 mg/d $ a Data are very limited, mostly from observational studies using fixed doses in hypertension, uncertain outcomes and titration protocols.", + "tokenCount": 136, + "pageStart": 15, + "pageEnd": 15, + "hash": "da3e8cd525bddba0ae6a9a40e6d850abcb290267d042f7219115a7c1eee80fd8" + }, + { + "text": "b Specialist consultation recommended if doses above these ranges appear to be necessary. c Data are very limited in PA individuals. d Often supplied as combination with hydrochlorothiazide. The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No.", + "tokenCount": 55, + "pageStart": 15, + "pageEnd": 15, + "hash": "82e9c982836c1b882502772661e276dc035f7c1d3446edf6a510da7a23cf222a" + }, + { + "text": "9 2467 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 42, + "pageStart": 15, + "pageEnd": 15, + "hash": "e8e11f785fa281d050c5634348ab021b6fc714f45ea43efb4872f8dd22a7eb7f" + }, + { + "text": "Infrastructure and workflow integration. The ability to inte - grate PA screening into existing hypertension care pathways will depend on clinical workflow structures and system-level coordination between primary care and specialty services. This includes managing referrals, follow-up testing, and treat - ment decisions following abnormal results. Financial and equity considerations. Widespread screening may increase healthcare costs, particularly when considering downstream diagnostics and treatment.", + "tokenCount": 79, + "pageStart": 16, + "pageEnd": 16, + "hash": "0fd2ee117843dbc75c87111282c182a5d7d8abfda8a7df9dd02f30c855137543" + }, + { + "text": "Equity concerns are particularly relevant in rural and underserved regions, where infrastructure may be lacking and specialist access is limited. Mitigating strategies could include developing regional refer - ral hubs, streamlining diagnostic algorithms, or creating context-sensitive care pathways that balance feasibility and effectiveness.", + "tokenCount": 55, + "pageStart": 16, + "pageEnd": 16, + "hash": "b8e8b9ede20109540a8ffb175f02e3accd25c61767b9a3aa8b5b1921d9e56367" + }, + { + "text": "Provider training and system support. Successful implemen - tation requires investment in education for primary care clini - cians and other front-line providers on PA screening protocols, including management of interfering medications and appropriate referral thresholds.", + "tokenCount": 47, + "pageStart": 16, + "pageEnd": 16, + "hash": "f32983a8ec9c195d5e10063d6c32099c162ca51aa1a549862915a7a00362828a" + }, + { + "text": "Clinician- and patient-level considerations and implementation tools At the clinician and patient level, implementation is shaped by knowledge, attitudes, and available decision-support tools. Clinicians may be hesitant to adopt screening due to limited familiarity with PA, perceived testing complexity, or concerns about managing false positives and interpreting results in pa - tients on interfering therapies.", + "tokenCount": 72, + "pageStart": 16, + "pageEnd": 16, + "hash": "4f6657680709f1cb6c1de57660a413280f881dab6dd46f6e52cea9b14a3e01db" + }, + { + "text": "To address this, the guideline provides practical tools — including Figs. 1 and 2 — to stream - line clinical decision making, guide result interpretation, and clarify pathways for management or referral based on patient characteristics and available resources.", + "tokenCount": 45, + "pageStart": 16, + "pageEnd": 16, + "hash": "0e6ea77b554062dfa2144e9e631d0f22dd54abc0c8fcf2e49024bfac9dac02bb" + }, + { + "text": "Additional implementation considerations include: • Some panel members consider every hypertensive individ - ual with low renin levels as affected by PA. Despite almost all individuals with PA having low renin concentration or activity, a number of individuals with low renin do not have PA (eg, individuals with high salt intake or Liddle syndrome), hence a nonsuppressed aldosterone concen - tration should be required together with low renin to con - sider the individuals at risk of PA.", + "tokenCount": 100, + "pageStart": 16, + "pageEnd": 16, + "hash": "9390dfd7c664d782e78a0b6bf5919e34978ee5be3a29c63e27a449d9c7374489" + }, + { + "text": "• The recommendation is applicable to individuals older than age 16 years. Pediatric individuals should be consid - ered to have a positive screening test at an ARR cutoff lower than for adults ( 78 , 79 ).", + "tokenCount": 43, + "pageStart": 16, + "pageEnd": 16, + "hash": "fe2f976ee1f615ec2c8bf8fdf90805560a4030edd9361f8cc1df1c34b9dbc40d" + }, + { + "text": "The interpretation of aldos - terone and renin levels and the ARR and subsequent man - agement is also different in pregnant individuals due to pregnancy-related changes in the renin – angiotensin – al - dosterone system (RAAS) ( 80 , 81 ).", + "tokenCount": 59, + "pageStart": 16, + "pageEnd": 16, + "hash": "aae6316e01cbc06fc80fb5eaff0c3d15d32173d6b2398838d4c0ee23df9711f1" + }, + { + "text": "Individuals with con - comitant heart failure may have unsuppressed renin levels, and diagnosis requires expert input. Elderly pa - tients with hypertension and patients with concomitant renal failure are more likely to have a low renin and in - creased ARR.", + "tokenCount": 57, + "pageStart": 16, + "pageEnd": 16, + "hash": "c895c8c76328093c40d21e567a16ad95c2f720575da22109be6fbfbad495cad5" + }, + { + "text": "The approach for subsequent investigations or pragmatic therapy with MRA should be weighed in in - dividual evaluation. • Screening tests should be performed by primary care clini - cians or by specialists in an outpatient setting.", + "tokenCount": 44, + "pageStart": 16, + "pageEnd": 16, + "hash": "30bdc53a2f0e0ac51af7d16dd212e31ed459f17f11acffa18aea160084f55951" + }, + { + "text": "Referral to specialized centers should be considered for aldosterone suppression testing, and, if positive, further subtyping to differentiate lateralizing from bilateral forms of PA. Research Considerations Current gaps in knowledge call for further research in the fol - lowing areas:", + "tokenCount": 53, + "pageStart": 16, + "pageEnd": 16, + "hash": "7a542dbe1297aacd1c30e51df7755af9970532a5b94562ac8b06626ef2fda1a6" + }, + { + "text": "• Determining the benefit of MRA treatment (vs other non - specific antihypertensive treatments) in individuals with an increased ARR but a negative aldosterone suppression test • Determining the efficacy of nonsteroidal MRAs and aldos - terone synthase inhibitors compared with spironolactone in individuals with PA and in those with low renin or an elevated ARR who do not meet the current diagnostic cri - teria for PA • Evaluating the efficacy and cost of novel strategies for screening outside the ARR (eg, steroid profiling, omic sig - natures, clinical scores, and machine-learning methods ( 82 , 83 ) • Conducting a gold-standard prospective randomized con - trolled trial (RCT) in which individuals with newly diag - nosed PA are randomized to treatment with standard medical therapy vs PA-specific medical therapy in order to assess cardiovascular outcomes (however, for ethical reasons, this study is not likely to be undertaken) Treatment of Primary Aldosteronism:", + "tokenCount": 212, + "pageStart": 16, + "pageEnd": 16, + "hash": "069d234aa40897ecc3de2c1293678921a92b3c516449ce00d8697e6242fa644a" + }, + { + "text": "Specific vs Nonspecific Therapies Background Specific therapies directed against aldosterone excess are available: treatment with mineralocorticoid receptor antago - nists (MRAs) and, if appropriate, unilateral adrenalectomy ( 84 , 85 ).", + "tokenCount": 52, + "pageStart": 16, + "pageEnd": 16, + "hash": "70abc9a0977d39e8a5d6e3742c4f6984bc293fbdbe6e79b211cc6e004bc8a288" + }, + { + "text": "If those therapies result in better outcomes than non - specific antihypertensive therapy, encouraging their imple - mentation among hypertensive individuals with PA is appropriate. Question 2. Should primary aldosteronism–specific therapy (medical or surgical) vs nonspecific antihypertensive ther - apy be used in individuals with primary aldosteronism?", + "tokenCount": 75, + "pageStart": 16, + "pageEnd": 16, + "hash": "a570ee040c444328f5b74268fd0aa61ec8dd89d61b6612c70517e6398980632b" + }, + { + "text": "Recommendation 2 In individuals with hypertension and primary aldos - teronism (PA), we suggest PA-specific therapy (med - ical or surgical) (2 | ⊕⊕ OO).", + "tokenCount": 45, + "pageStart": 16, + "pageEnd": 16, + "hash": "7fbce537e46bf0449a07a26e1e5561553e69bcdba32ec2d93d5e7f153f22e06c" + }, + { + "text": "Technical remarks: • In individuals with lateralizing PA who are not sur - gical candidates or do not desire surgery, and in in - dividuals with bilateral PA, medical treatment with MRAs should be considered preferable over non - specific antihypertensive therapy.", + "tokenCount": 54, + "pageStart": 16, + "pageEnd": 16, + "hash": "65df59607bf895a932455e6f3b26c29adfdaff5f567fa004d6aabc100420d4aa" + }, + { + "text": "• In individuals with lateralizing PA who are surgical candidates and desire surgery, unilateral adrena - lectomy should be considered preferable over nonspecific antihypertensive therapy. 2468 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No.", + "tokenCount": 57, + "pageStart": 16, + "pageEnd": 16, + "hash": "d6daefba20d130d7852c939712749f1da08710f009d3d0bfac785069300b2231" + }, + { + "text": "9 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 40, + "pageStart": 16, + "pageEnd": 16, + "hash": "86d3541f16c4cf3f3990fa58d424f397068a88b4c212a690d7cd989da5201309" + }, + { + "text": "Summary of the Evidence The meta-analysis results, a detailed summary of the evidence and Evidence to Decision (EtD) tables can be found online at https:/ /guidelines.gradepro.org/profile/LGYDlKeCN6A .", + "tokenCount": 54, + "pageStart": 17, + "pageEnd": 17, + "hash": "a356dbbaab61ef67f8e266f642f1606a3885b53195f0447fbfb1b293da20849a" + }, + { + "text": "Benefits and Harms The panel voted for the following patient-important outcomes for Question 2 decision making: 1) percent of individuals achieving blood pressure (BP) control, 2) number of antihy - pertensive agents, 3) dosage of antihypertensive agents, 4) sys - tolic BP (SBP) level, 5) major adverse cardiovascular events (MACEs), 6) atrial fibrillation, 7) stroke, 8) ischemic heart dis - ease, 9) heart failure, 10) cardiovascular mortality, 11) all- cause mortality, and 12) adverse events.", + "tokenCount": 124, + "pageStart": 17, + "pageEnd": 17, + "hash": "2834f1338d917afe55c7f696bec9c100f0896c48cb3393754c51f6d7910b0437" + }, + { + "text": "Our systematic review yielded only 2 studies, both of which were observational in nature. One ( 4 ) showed that (a) all indi - viduals who underwent unilateral adrenalectomy displayed complete biochemical resolution of PA at 6-month follow-up assessment; (b) individuals receiving an MRA showed a reduc - tion of SBP and diastolic BP (DBP) without a significant in - crease in antihypertensive treatment; (c) individuals with primary hypertension treated with nonspecific antihyperten - sive agents showed SBP and DBP reductions at 6 months but with increased treatment.", + "tokenCount": 128, + "pageStart": 17, + "pageEnd": 17, + "hash": "723e14c00939c757d796bec80cb511264f11a3a813203b4c5470b3b04226bcc3" + }, + { + "text": "Due to the limited availability of studies directly evaluating the comparative effectiveness and potential harms of PA-specific treatment vs nonspecific hypertension management, this recom - mendation also relies on indirect evidence. This indirect evidence derived from noncomparative observational studies.", + "tokenCount": 51, + "pageStart": 17, + "pageEnd": 17, + "hash": "b86decd9df761eb13ce1259e2590b285f7ca259f5438f7180e8927edde80c2cb" + }, + { + "text": "Individuals with PA who are not receiving PA-specific therapy demonstrate higher rates of cardiovascular, cerebrovascular, and renal com - plications than do individuals with primary hypertension and an otherwise similar risk profile ( 1 , 2 ).", + "tokenCount": 46, + "pageStart": 17, + "pageEnd": 17, + "hash": "01539a10db24d36fdc717cf1643c0d6f0744228d68034e176b5f9a1fbc180c3c" + }, + { + "text": "This excess risk is abro - gated, and quality of life (QOL) improved following the institu - tion of PA-specific medical or surgical treatment ( 7 , 86 ). Individuals with PA who undergo surgery demonstrate a lower rate of cardiovascular and cerebrovascular complications than do matched individuals (based on BP and cardiovascular risk profile) with primary hypertension ( 7 ).", + "tokenCount": 75, + "pageStart": 17, + "pageEnd": 17, + "hash": "a5311fddfde7d715e200d52444a2df36aecb453a4df2f5d64af74f7c0a352f63" + }, + { + "text": "Individuals with bilateral PA undergoing sufficient MRA therapy to unsuppress renin, dis - play a similar (rather than higher) risk to matched individuals with primary hypertension, whereas individuals treated with MRA therapy in doses that are insufficient to unsuppress renin still display increased risk ( 7 ).", + "tokenCount": 60, + "pageStart": 17, + "pageEnd": 17, + "hash": "64c88d03c0d9e692f6ea89bdc1dc763871ea4c29d8de2ba9f6bb90d0f61e4150" + }, + { + "text": "PA-specific treatment is associated with significant BP re - duction ( 7 , 86 ), which, in turn, is expected to result in a re - duced rate of cerebrovascular, cardiovascular, and renal events.", + "tokenCount": 46, + "pageStart": 17, + "pageEnd": 17, + "hash": "d0999eadc18c5fa8496e7ef82831c5dda4142fce06bc3fa8bc3fd91762813fa5" + }, + { + "text": "Furthermore, individuals with PA display lower rates of adverse events after diagnosis and initiation of PA-specific treatment than before diagnosis when the treatment is with general antihypertensive drugs ( 87 , 88 ). In summary, this indirect evidence shows that institution of specific treatment (medical or surgical) in individuals with PA re - sults in a significant improvement of hypertension control.", + "tokenCount": 72, + "pageStart": 17, + "pageEnd": 17, + "hash": "5324c19a209298b2996c68a2d8692b206da3a3f0e677a0d4621a7bc017bb9560" + }, + { + "text": "BP normalization occurs in a significant proportion of those who undergo surgery for lateralizing forms of PA ( 89 ). Furthermore, therapies (medical or surgical) that directly target the increased al - dosterone in PA reduce the excess cardiovascular, cerebrovascu - lar, and renal complications associated with PA.", + "tokenCount": 61, + "pageStart": 17, + "pageEnd": 17, + "hash": "2806b17da6afe88f550a313eb93e4c540e019214a56f27554f470035f0c47a95" + }, + { + "text": "Spironolactone ’ s dose-dependent side effects (including gyne - comastia, erectile dysfunction, and menstrual irregularities) limit the efficacy and tolerability of this medication in PA.", + "tokenCount": 42, + "pageStart": 17, + "pageEnd": 17, + "hash": "686ec4ebf28f5622082420134497793eddc6d645cdbf2ca11249bb8600876022" + }, + { + "text": "However, newer MRAs, such as eplerenone, have a much lower side effect profile (see Recommendation 9). Surgical therapy re - quires skilled surgeons and adequate postsurgical care to minim - ize surgical complications.", + "tokenCount": 48, + "pageStart": 17, + "pageEnd": 17, + "hash": "6d118c6933fef2ba4feedfde43fba7437eb99935034187c71f4861e1df000a3e" + }, + { + "text": "Evidence to Decision Factors • Costs of medical therapy are minor (in the case of spirono - lactone) to moderate depending on the medication used, whereas costs of surgical therapy vary. • Three health economic studies in Japan, Australia, and China demonstrated cost-effectiveness of screening for PA in the general hypertensive population.", + "tokenCount": 66, + "pageStart": 17, + "pageEnd": 17, + "hash": "e8396f5fa201220357597aac860093fdf6ac137971c5469e5cd2dfaaf333dee1" + }, + { + "text": "Cost-effectiveness was mainly due to a decrease in lifelong complications and their associated costs in individuals with PA who re - ceived PA-specific therapy compared with those who did not receive therapies targeting PA ( 70-72 ).", + "tokenCount": 45, + "pageStart": 17, + "pageEnd": 17, + "hash": "b1ec7b7b26550b8ca5cdf824e1be69444c8a3c7d8879763d1823baaf5334c865" + }, + { + "text": "• Surgical therapy requires skilled surgeons and adequate postsurgical care and has economic consequences for individuals. • Medical therapy requires individualized titration and sur - veillance through regular follow-up visits. In areas where these resources are available, the intervention should be feasible.", + "tokenCount": 53, + "pageStart": 17, + "pageEnd": 17, + "hash": "762a7e0876a8239b4379589caa3414368263be4dbd0cf1df2355a649879e53c4" + }, + { + "text": "• Specific medical or surgical treatment of PA should be ac - cepted by individuals since it represents targeted therapy, improved hypertension control (and sometimes cure), im - proved QOL, and a reduction in the complications associ - ated with PA.", + "tokenCount": 50, + "pageStart": 17, + "pageEnd": 17, + "hash": "d2440c80c240fd3c0838f1eb8537b2e5ac38cf737826f2f2f09713960c050fe6" + }, + { + "text": "• While PA-specific therapy is likely to be acceptable to pri - mary care clinicians, the steps required to identify individ - uals with PA who are candidates for specific surgical or medical treatment may reduce acceptance (and, hence, up - take) because of:", + "tokenCount": 55, + "pageStart": 17, + "pageEnd": 17, + "hash": "79cceda27862b530a3e7dede3b947e8b9a08bcbaf684a0bd0379e1934ad4d581" + }, + { + "text": "lack of knowledge of prevalence and complications of PA; 2. lack of familiarity with implementing and interpreting screening tests; 3. lack of familiarity with using MRAs; and 4. costly, invasive, and challenging procedures associated with subtype diagnosis (lateralizing vs bilateral adrenal aldosterone production) for individuals contemplating potential unilateral adrenalectomy.", + "tokenCount": 70, + "pageStart": 17, + "pageEnd": 17, + "hash": "c9ddaa104caf8a88f06060fd550e61b8c79e95c114ff5781aa5f912a20e858dc" + }, + { + "text": "• Finally, the diagnosis of PA and treatment with MRA should be affordable in most clinical settings. Subtype diagnosis, especially when using adrenal vein sampling (AVS), and access to surgical intervention may be limited in some settings.", + "tokenCount": 47, + "pageStart": 17, + "pageEnd": 17, + "hash": "e7b09da3094417df94bebaf07e0090ef523f97ebeb557ab894e97c7109025f04" + }, + { + "text": "After years of implementation with high fidelity, equity will probably be increased. Justification for the Recommendation Aldosterone excess has adverse cardiovascular and renal effects that go above and beyond the effects of hypertension, leading to a higher rate of cardiovascular and renal complications in indi - viduals with PA compared with individuals with primary hyper - tension matched for BP levels.", + "tokenCount": 72, + "pageStart": 17, + "pageEnd": 17, + "hash": "da39cd658cee1761eabb7d12f8176898103f9dd6c57fc3065c0b204fc34dcc46" + }, + { + "text": "Unilateral adrenalectomy in individuals with lateralizing forms of PA often leads to cure of hypertension, and surgically treated individuals demonstrate a lower rate of cardio- and cerebrovascular complications than do matched (for BP and cardiovascular risk profile) individuals with primary hypertension.", + "tokenCount": 54, + "pageStart": 17, + "pageEnd": 17, + "hash": "cd10b45a9de4bb0ebd8a801ac1baadb0acff58e46bf8dcfe325c84f26b92ddb1" + }, + { + "text": "Individuals with PA treated with MRAs in sufficient doses to unsuppress renin demonstrate a similar (rather than higher) risk to matched individuals with pri - mary hypertension. While the certainty of evidence is low, indir - ect data from noncomparative cohorts support the intervention, The Journal of Clinical Endocrinology & Metabolism , 2025, Vol.", + "tokenCount": 75, + "pageStart": 17, + "pageEnd": 17, + "hash": "a433acd764e8a440c6c6ab994c9ff00e5824536bb0aa6f831ceb1be8245ad7e9" + }, + { + "text": "110, No. 9 2469 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 46, + "pageStart": 17, + "pageEnd": 17, + "hash": "91835c40a1d339a40d79d14167a0850fc2b83d48b2294533f66766dea59ec75c" + }, + { + "text": "as the benefits observed with all therapies for PA are likely to outweigh the associated harms. The panel also considered the economic implications of PA-specific therapies. While medical therapy has negligible costs, surgical treatment is associated with higher and variable costs depending on the country and health care system. Nonetheless, cost-effectiveness analyses generally favor PA-specific therapies. The panel concluded that the accept - ability and feasibility of implementing these therapies depend on available resources and clinical expertise. Given the overall certainty of the evidence regarding bene - fits and harms and recognizing that the implementation of PA-specific therapies varies by context, the panel issued a con - ditional recommendation for the use of PA-specific therapies over nonspecific antihypertensive treatments. This recommen - dation reflects the balance of evidence, contextual considera - tions, and resource variability across different settings. The risk of MRA side effects can be minimized by commencing at low doses (eg, 12.5-25 mg of spironolactone daily) and increas - ing the dose gradually (eg, every 2-3 months or sooner if clinically indicated) as required to control BP (see Question 9. Table 10 , Fig. 3 ). Measurement of renin during MRA titration can assist in treatment decision making, but this is less straightforward if the individual is on other medications that affect renin levels (see Question 7", + "tokenCount": 281, + "pageStart": 18, + "pageEnd": 18, + "hash": "d719863b37f755eb4e2aae46f2f49a00611637877525e5f36669b8f1513383ff" + }, + { + "text": "Research Considerations Current gaps in knowledge call for further research in the fol - lowing areas: • Assessing health equity after implementation of this recommendation • Assessing efficacy and safety of newer nonsteroidal MRAs and aldosterone synthase inhibitors in the medical treat - ment of PA and developing new medications • Conducting comparative effectiveness studies to assess PA-specific therapies (both medical and surgical) against nonspecific antihypertensive treatments in diverse clinical contexts and subgroups • Studying the barriers to widespread adoption of PA-specific therapies, including clinician knowledge gaps, individual preferences, and logistical challenges as - sociated with identifying lateralizing vs bilateral aldoster - one production and treatment access • Establishing large, diverse, and prospective cohorts to moni - tor long-term outcomes of PA-specific therapies, including cardiovascular and renal events, QOL, and cost-effectiveness • Investigating disparities in access to PA-specific diagnostic and therapeutic interventions, particularly in low- resource settings and regions with limited access to AVS, surgical expertise, and newer medications Screening for Primary Aldosteronism in Individuals With Hypertension Background Screening for primary aldosteronism (PA) allows for early identification and treatment, which can improve patient out - comes (Question 1). Several strategies exist for PA screening, with the most used approach being the measurement of aldos - terone and renin (concentration or activity) and calculation of the aldosterone to renin ratio (ARR", + "tokenCount": 306, + "pageStart": 18, + "pageEnd": 18, + "hash": "9bdb4e1a5b68a110415e1eb181d140f5c0a314e07f4fdc0b3a8b6db1bc9791cc" + }, + { + "text": "This method may be more sensitive than relying solely on hypokalemia, as hypo - kalemia is present in only a minority of PA individuals (9%-37%), and many individuals with PA have normal potas - sium levels ( 90 ). Aldosterone and renin testing can identify normokalemic individuals with PA, expanding detection to a broader hypertensive population. However, there are practical challenges to using aldoster - one and renin for screening. The accuracy of these measure - ments can be influenced by medications, dietary sodium, and sampling conditions, which may lead to false positives or negatives. Additionally, the availability and cost of testing could limit the feasibility of widespread screening. In contrast, hypokalemia is simpler to detect, but screening for hypokal - emia may miss many cases of PA, especially milder forms of the disease. Given these considerations, the guideline evaluates whether measuring aldosterone and renin (including ARR) is a better strategy for screening for PA compared with relying on the detec - tion of hypokalemia alone in individuals with hypertension. Question 3. Should aldosterone (serum/plasma, or urine), renin (concentration or activity), and the aldosterone to renin ratio vs hypokalemia (unprovoked or diuretic- induced) be used for screening for primary aldosteronism in individuals with hypertension? Recommendation 3 In individuals with hypertension, we suggest primary aldosteronism (PA) screening with serum/plasma al - dosterone concentration and plasma renin (concen - tration or activity) (2 | ⊕⊕ OO", + "tokenCount": 348, + "pageStart": 18, + "pageEnd": 18, + "hash": "c6c5da43979150a8ba4873096ae0c290dd3a89d9e5e823563b004b6874c8013e" + }, + { + "text": "Technical remarks: • Screen for PA by measuring serum/plasma aldos - terone and plasma renin (concentration or activity) in the morning with individuals seated and avoid - ing dietary sodium restriction during the few days prior to screening. Potassium should be measured alongside renin and aldosterone— not for screen - ing itself, but to aid in the accurate interpretation of aldosterone—as a low potassium may lead to a falsely low aldosterone. • If screening results are negative and the patient has hypokalemia, potassium should be corrected to within the laboratory reference range and screening should be repeated. • Manage interfering medications depending on in - dividual safety and feasibility. The Guideline Development Panel (GDP) outlined both minimal- withdrawal and no-withdrawal strategies of inter - fering medications before screening ( Tables 6 and 7 , Fig. 1 ). • A positive screen meets both of the following con - ditions in most circumstances: 1. Renin is low/suppressed (hallmark of the diag - nosis) and aldosterone is inappropriately high relative to renin: indicative of PA if plasma renin 2470 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 300, + "pageStart": 18, + "pageEnd": 18, + "hash": "ec1bfb80dedded74790ab5c09328f27c1c3758eceb01f393440fad641fa67c2a" + }, + { + "text": "activity (PRA) is ≤ 1 ng/mL/h or direct renin con - centration (DRC) is ≤ 8.2 mU/L AND serum/plas - ma aldosterone concentration is ≥ 10 ng/dL ( ≥ 277 pmol/L) when measured by immuno - assay or ≥ 7.5 ng/dL ( ≥ 208 pmol/L) when meas - ured by liquid chromatography–tandem mass spectrometry (LC-MS/MS) 2.", + "tokenCount": 107, + "pageStart": 19, + "pageEnd": 19, + "hash": "173d0d7654d0b7406c35e2eac718a79ed5ddd2b8f190c7094e74ffc7e58b010b" + }, + { + "text": "Elevated aldosterone to renin ratio (ARR): indi - cative of PA if the aldosterone [ng/dL] to PRA [ng/mL/h] ratio is > 20 or aldosterone [pmol/L] to DRC [mU/L] ratio is > 70 when aldosterone is measured by immunoassay; the ARR indica - tive of PA is about 25% lower when aldosterone is measured by LC-MS/MS) ( Fig.", + "tokenCount": 110, + "pageStart": 19, + "pageEnd": 19, + "hash": "900fa82f6a697d5dfdef908baf41be4d08e180b9c48cd126fb14ed8eac29dd4f" + }, + { + "text": "1 and Table 5 show ARR cut points for differing assays and units) • The aldosterone, renin, and ARR values above are provided for guidance. However, as with many diagnostic tests based on continuous variables, the sensitivity and specificity depend on the se - lected threshold.", + "tokenCount": 60, + "pageStart": 19, + "pageEnd": 19, + "hash": "a2085468391323eb450b53b04019640a2dc33426a8af5a39dcb07ecf074935ed" + }, + { + "text": "Aldosterone and renin levels are further influenced by individual variability, local la - boratory assays, and other factors. Where pos - sible, clinicians should rely on local laboratory cut points, as assays may vary.", + "tokenCount": 48, + "pageStart": 19, + "pageEnd": 19, + "hash": "d28e1d3d916edc301b653541145bcaa7474e5ef358ce9d0eeadf77518d9ec9e1" + }, + { + "text": "No cut point is perfect—each carries a trade-off between false positives and false negatives. Therefore, results should be interpreted within the context of the pa - tient’s pretest probability for PA, along with poten - tial interfering medications and conditions.", + "tokenCount": 55, + "pageStart": 19, + "pageEnd": 19, + "hash": "8b40a75ef0ccda792d156a59cdd73bc0cb9443aec225d1b74dc284d49265f714" + }, + { + "text": "• If the individual’s initial screen is negative and fac - tors are present that could have led to a false- negative result (eg, hypokalemia or medications), the test should be repeated on a different day, pref - erably after correcting hypokalemia (where pre - sent) and withdrawing interfering medications if it is safe and feasible (for 4 weeks for mineralocor - ticoid receptor antagonists (MRAs), epithelial sodium-channel [ENaC] inhibitors [eg, amiloride, triamterene], and other diuretics, and 2 weeks for angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptor blockers [ARBs]), which raise renin or lower aldosterone.", + "tokenCount": 160, + "pageStart": 19, + "pageEnd": 19, + "hash": "65edf2b04cf544b8e3378d048268129f625b61b79325c0cf5651054dae2ff3d3" + }, + { + "text": "For the most ac - curate determination of potassium, measure plas - ma potassium in blood collected slowly with a syringe and needle (preferably not using a vacuum-sealed blood collection tube to minimize the risk of spuriously raising potassium).", + "tokenCount": 51, + "pageStart": 19, + "pageEnd": 19, + "hash": "ccb330deddfa1246fab2137c9d87ecef50173c8b0754f964e4402dff21e566c0" + }, + { + "text": "During collection, avoid fist clenching, wait at least 5 sec - onds after tourniquet release (if used) to achieve insertion of needle, and ensure separation of plas - ma from cells within 30 minutes of collection.", + "tokenCount": 48, + "pageStart": 19, + "pageEnd": 19, + "hash": "be84b08e6246e9c8fa89975f7c97e0f0d8a153180bd6a6363756b81ebac1173a" + }, + { + "text": "• If the individual’s initial screen is negative and the pretest probability of PA is moderate to high (eg, hypokalemia and/or resistant hypertension) or renin is suppressed with aldosterone of 5 to 10 ng/dL (138 to 277 pmol/L) by immunoassay, the test should be repeated on a different day.", + "tokenCount": 76, + "pageStart": 19, + "pageEnd": 19, + "hash": "a99c199acb147a6f5bd955552b9840efc7f289138869efe0bebdf64af9405a95" + }, + { + "text": "• If the individual’s initial screen is positive, but they are receiving medications (eg, β -adrenergic block - ers and centrally acting α 2 -agonists [eg, clonidine, α -methyldopa]) that can lower renin and thereby cause false-positive results, the test should be repeated after withdrawing those medications for 2 weeks if it is safe and feasible.", + "tokenCount": 82, + "pageStart": 19, + "pageEnd": 19, + "hash": "32971f19ac23c08f01d00e6c7c97418ff7dd108a44eede0ce58d867571275bef" + }, + { + "text": "Consider po - tential false positives induced by β -adrenergic blockers when aldosterone is 10 to 15 ng/dL (277-416 pmol/L) by immunoassay or 7.5 to 10 ng/dL (208-277 pmol/L) by LC-MS/MS; if aldos - terone is above these concentrations, PA is likely despite being on β -adrenergic blockers.", + "tokenCount": 90, + "pageStart": 19, + "pageEnd": 19, + "hash": "2fb9d3c0d8a315dc7b85c7077618fd0c5e230e02be24d04ea67111338d7f16fc" + }, + { + "text": "• If screening hypertensive patients with chronic kidney disease, renin decreases proportionately to nephron loss, except in cases where there is re - nal ischemia from renal artery stenosis where re - nin will be elevated.", + "tokenCount": 48, + "pageStart": 19, + "pageEnd": 19, + "hash": "2a3f336d029d7c76cd1f07cd94f04fd6f02522c5fb133d7945bbbf85a35bc509" + }, + { + "text": "Aldosterone can also be elevated in chronic kidney disease, leading to overall increases in false-positive testing. • If all initial screening is negative, consider re- screening in the future if a patient develops:", + "tokenCount": 42, + "pageStart": 19, + "pageEnd": 19, + "hash": "71548dd2375ddcfebcf4ceca61f8fd5ecb31e1242d1111839701973b7103f96d" + }, + { + "text": "⚬ Unexplained worsening of hypertension or re - sistant hypertension ⚬ New spontaneous or diuretic-induced hypokalemia ⚬ Atrial fibrillation in the absence of structural heart disease or hyperthyroidism Summary of the Evidence The meta-analysis results, a detailed summary of the evidence and Evidence to Decision (EtD) tables can be found online at https:/ /guidelines.gradepro.org/profile/qFJ3iuy78Bw .", + "tokenCount": 106, + "pageStart": 19, + "pageEnd": 19, + "hash": "102597128c546e801a62df180c898f1ed39328c8baee9f7d6521349c30267781" + }, + { + "text": "Benefits and Harms The panel voted for the following patient-important outcomes for Question 3 decision making: 1) accuracy of PA detection, 2) detection of lateralizing PA, and 3) adverse events.", + "tokenCount": 42, + "pageStart": 19, + "pageEnd": 19, + "hash": "7bf92f9153f278bfdb4cae0bca2db76d3699596ec8fe84bd46acb169d5877e1d" + }, + { + "text": "The systematic review found no studies that directly com - pared detection rates for PA among individuals screened by serum or plasma potassium levels vs those screened by meas - uring serum/plasma aldosterone and renin.", + "tokenCount": 44, + "pageStart": 19, + "pageEnd": 19, + "hash": "ffc24a7a5ef858bb0c2d228a35530aef953305104c54cf37da39e6d7085dc358" + }, + { + "text": "Therefore, we relied on indirect evidence on the frequency and accuracy of PA detection from observational studies among those with hypertension and hypokalemia vs hypertension and normokalemia. In a retrospective evaluation of the diagno - sis of PA from 5 continents, after the widespread use of the ARR as a screening test in individuals with hypertension, identification of PA increased 5- to 15-fold ( 90 ).", + "tokenCount": 83, + "pageStart": 19, + "pageEnd": 19, + "hash": "f115ab1c66a47aa8b24454faa010b49d247dae6f9240955830773fcdf69ced41" + }, + { + "text": "Only be - tween 9% and 37% of individuals had hypokalemia. Three other prospective studies totaling 5797 individuals re - ferred to hypertension centers or from primary care settings reported that only 25% to 30% of those with confirmed PA had hypokalemia ( 34 , 37 , 91 ).", + "tokenCount": 63, + "pageStart": 19, + "pageEnd": 19, + "hash": "07b0aadba35060217c7fc4df9e441f7070d735bccbba92cf6274dc118e0f6bcb" + }, + { + "text": "The ARR was effective at screening for PA, and most cases were ultimately diagnosed with bilateral PA. The presence of hypokalemia is associated with more severe forms of PA and is more common in the lat - eralizing subtype.", + "tokenCount": 49, + "pageStart": 19, + "pageEnd": 19, + "hash": "eeb6e7734bc14f99854e620db67d61628a63620547241ea6f3a0c4ffbbe54274" + }, + { + "text": "Nevertheless, in a study of 95 individuals with lateralizing PA, more than 90% had suppressed renin preoperatively ( 92 ). In contrast, 62% to 67% had hypokal - emia requiring potassium supplementation preoperatively, suggesting that relying on hypokalemia to detect PA would miss a substantial percentage of individuals with surgically curable PA.", + "tokenCount": 74, + "pageStart": 19, + "pageEnd": 19, + "hash": "be3d6703ae7ca189a76c6a940e0e0ce3a0a8cb0fda3f1b7a48d6abf86b86fa7f" + }, + { + "text": "The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 2471 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 62, + "pageStart": 19, + "pageEnd": 19, + "hash": "456a8f714cb83fb3b428d780aced61e80808f3dd368fa779fd3391a1f1a1643c" + }, + { + "text": "Although the evidence demonstrated that a large proportion of individuals with PA do not have hypokalemia, and thus the ARR would be more sensitive than the presence of hypokal - emia, these data were indirect and were mostly derived from selected populations of individuals referred to hypertension centers.", + "tokenCount": 58, + "pageStart": 20, + "pageEnd": 20, + "hash": "d7f4c6d1bcd026555c65f04005524894041147330b1a61c1b723a11b2f406c6d" + }, + { + "text": "Therefore, the level of certainty was low. In addition to increasing case detection, the ability of the ARR to limit false positives and negatives was another import - ant consideration. The accuracy of detection of PA using ARR has inherent variability as assays, screening conditions, and pa - tient populations are heterogenous, which can affect the screen - ing test ’ s sensitivity and specificity.", + "tokenCount": 79, + "pageStart": 20, + "pageEnd": 20, + "hash": "aa9c30f2dfeb106f2c20d862e0df909323f508c97938c579158b220f25789613" + }, + { + "text": "A meta-analysis of 9 studies (974 individuals) determined that the sensitivity and specificity of the aldosterone to PRA and aldosterone to DRC ratios were reasonable and improved when interfering medications were withdrawn ( 93 ).", + "tokenCount": 46, + "pageStart": 20, + "pageEnd": 20, + "hash": "ddf6286c0d2b07d92d311f92dc011804af8b76e94660d20da5f54febd28177ce" + }, + { + "text": "Regarding false negatives, in a study of 216 in - dividuals with PA with at least 2 aldosterone levels drawn (MRAs were withdrawn prior to testing, but other interfering medications permitted), a lower aldosterone concentration cut point of 10 ng/dL was associated with false-negative rates for PA screening of 14.3% for a single aldosterone measure - ment, and 4.6% for 2 aldosterone measurements ( 94 ).", + "tokenCount": 92, + "pageStart": 20, + "pageEnd": 20, + "hash": "73822c7de2bb5bef238ba2b4527e0c8bb3c155ba1a9366eeb9104ed5905c892d" + }, + { + "text": "Although one meta-analysis ( 95 ) demonstrated good overall ac - curacy, significant variability precludes a single standard cutoff for detecting PA, and false negatives may result. Evidence to Decision Factors • The GDP considered that measuring aldosterone and re - nin has low cost and resource implications, making this an attractive screening tool in most regions.", + "tokenCount": 68, + "pageStart": 20, + "pageEnd": 20, + "hash": "d7d0199e179991d461bab0cab8350d5015b30cc91483ca1e93dd42873860262d" + }, + { + "text": "• Cost studies across multiple countries indicate low cost of the aldosterone, renin, and potassium measurements. • Three health economic studies in Japan, Australia, and China demonstrated cost-effectiveness of screening for PA in the general hypertensive population, mainly due to reduced costs of lifelong complications related to un - treated PA ( 70 , 71 , 72 ).", + "tokenCount": 71, + "pageStart": 20, + "pageEnd": 20, + "hash": "195147b3df2d1f2a486fc4359082b6e9ab0a2aed5d13a19641975879cceb1f77" + }, + { + "text": "• The GDP expects that measuring aldosterone and renin should not have a significant impact on health equity, with the caveat that current access to PA screening and to specialists in PA to interpret findings for manage - ment varies.", + "tokenCount": 45, + "pageStart": 20, + "pageEnd": 20, + "hash": "99d3f8fc75eba52c14c94223081269eef7d7fa34f7fee7482d973a40ca117dc8" + }, + { + "text": "• Although not well studied, available evidence suggests that those living in rural areas and far from tertiary care centers are less likely to be screened with aldosterone and renin ( 51 , 96 ).", + "tokenCount": 40, + "pageStart": 20, + "pageEnd": 20, + "hash": "fe651bdf28251aa015dfa01b814536e976dd593946a39491bea0898ca12c6699" + }, + { + "text": "With increased clinician and public awareness, testing should increase in these areas. • A significant barrier to screening is the lack of feasibility of aldosterone and renin testing by clinicians. Complex test - ing requirements, in particular withdrawal of interfering medications prior to testing and selecting specific subpopu - lations for screening, underlie some of the poor detection rates ( 97 ).", + "tokenCount": 75, + "pageStart": 20, + "pageEnd": 20, + "hash": "0da733d5940af28ddb50d1568739eae2378d7f1378db7a61175d23970cac017e" + }, + { + "text": "Although withdrawing interfering medications is associated with more consistent and increased accuracy of the ARR, several studies indicated that the ARR re - tained reasonable accuracy with minimal withdrawal or no withdrawal of interfering medications ( 98 , 99 ).", + "tokenCount": 44, + "pageStart": 20, + "pageEnd": 20, + "hash": "5fb3a932bf4836196ebfb98a3be07e2bc413c1a0129c42df2a9a3f694d68ea1b" + }, + { + "text": "• The GDP considered that screening for PA in individuals with newly diagnosed hypertension with an estimated prevalence of PA of 2% to 6% prior to medication initi - ation would be feasible, facilitate widespread screening, and limit false negatives or positives.", + "tokenCount": 48, + "pageStart": 20, + "pageEnd": 20, + "hash": "177998048dbab35d79addcc69ed46b22cb0a3b6251822deb978f16da71e66571" + }, + { + "text": "• As described in technical remarks, Fig. 1 , and Tables 5 and 6 , the GDP created a pathway for clinicians to test individuals on antihypertensive medications with minimal or no withdrawal of interfering medications.", + "tokenCount": 42, + "pageStart": 20, + "pageEnd": 20, + "hash": "8995330ca034248b6229144b6e7ae5c435e5de9b6cf5d77751c4c880a3b0f9ad" + }, + { + "text": "Justification for the Recommendation Screening with serum/plasma aldosterone and renin was se - lected over hypokalemia as the global screening tool for de - tecting PA based on indirect evidence that PA is more common than previously appreciated and that most individu - als with PA do not have hypokalemia.", + "tokenCount": 72, + "pageStart": 20, + "pageEnd": 20, + "hash": "6b1eabd09edb38b00dac707f8eb0f4674a661cd3d65cf08310c96c1ca0feb5b3" + }, + { + "text": "Limiting screening to individuals with hypokalemia would miss many cases requir - ing PA-specific therapy, some with potential for cure, and they would remain at increased risk of cardiovascular and renal events.", + "tokenCount": 42, + "pageStart": 20, + "pageEnd": 20, + "hash": "3e7983c971c13913546c6664c06b1ae8cf3a6dc5380bb56a638deb5ccde8e348" + }, + { + "text": "However, screening with serum/plasma aldosterone and renin has notable limitations. The accuracy is variable and depends on assay type; can be influenced by individual so - dium intake/volume status, medications ( Tables 6 and 7 ), and other factors; and has inherent intra-individual variability.", + "tokenCount": 61, + "pageStart": 20, + "pageEnd": 20, + "hash": "c64168c6bfa09a259029a1bfd7e4c726634a47529ca705f32d3105ce055f70b6" + }, + { + "text": "Despite these limitations, it is a more sensitive screening tool than hypokalemia, has reasonable accuracy overall with or without interfering medications, and is widely available across regions at low cost. Given the poor uptake of screening for PA and missed op - portunity to provide targeted treatment for individuals with PA, the GDP developed several implementation strategies to facilitate aldosterone/renin screening in primary care settings.", + "tokenCount": 81, + "pageStart": 20, + "pageEnd": 20, + "hash": "02a494bec08ce474ebc66c39970c6f9ba604c138b598642a73b82b9b3e43acae" + }, + { + "text": "Screening with aldosterone and renin in individuals with newly diagnosed hypertension prior to medication start is highly feasible with a more straightforward interpretation. Withdrawing a minimum set of interfering medications or not withdrawing them are also screening options for individ - uals on antihypertensive therapy and should improve the practicality of PA screening especially when medication with - drawal is not practical or safe.", + "tokenCount": 79, + "pageStart": 20, + "pageEnd": 20, + "hash": "de7755f8a76daa0cd045aacb44988ac0acc56fe281297fa7bb9b5709f4a68867" + }, + { + "text": "Other approaches for screening include only screening renin or measuring 24-hour urinary excretion of aldosterone. However, these strategies do not have sufficient evidence or cost-effectiveness data to justify their use for widespread screening.", + "tokenCount": 45, + "pageStart": 20, + "pageEnd": 20, + "hash": "097c33155e28c87f923b258b0c96aaaca9ee8904c9c92aa25f24d72068dcd398" + }, + { + "text": "Also, some individuals with low renin do not have PA (ie, those with high sodium diet or Liddle syndrome); thus, to be diagnosed with PA, individuals should have both a suppressed renin and a nonsuppressed aldosterone.", + "tokenCount": 50, + "pageStart": 20, + "pageEnd": 20, + "hash": "550eebabe30e87f7da2b5f44dcd6ea3decf3b3872863b6528f2c45b0e1ba6e5b" + }, + { + "text": "Implementation Considerations Given that case detection is currently so low ( 67 ), and detect - ing cases of PA would lead to targeted therapy that would im - prove BP control and cardiovascular morbidity, and cure hypertension in some cases, high priority was given to increas - ing the sensitivity of case detection while maintaining reason - able specificity.", + "tokenCount": 67, + "pageStart": 20, + "pageEnd": 20, + "hash": "5b7b3473bbfedb79c2b522efd4982689bd46b581f2195fa8551a966641b62c57" + }, + { + "text": "Research Considerations Current gaps in knowledge call for further research in the fol - lowing areas: • Conducting prospective studies to refine the thresholds for the ARR and absolute aldosterone concentration across diverse patient populations and laboratory assays, par - ticularly those using LC-MS/MS for aldosterone measurement 2472 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol.", + "tokenCount": 81, + "pageStart": 20, + "pageEnd": 20, + "hash": "21c020b1945af70a7c763e28dbe483abfb8ae2db073d700b1b61767a2d4e04cc" + }, + { + "text": "110, No. 9 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 44, + "pageStart": 20, + "pageEnd": 20, + "hash": "838dd5eb379613452959448b60e11bc1b5cf46655c5056a0432c7ee39628472d" + }, + { + "text": "• Investigating novel or other methods of screening for PA, including development of new biomarkers (see Question 4) and assessing 24-hour urine aldosterone • Investigating the impact of medication withdrawal proto - cols on false-positive and false-negative rates and develop - ing standardized approaches for testing under real-world conditions, such as minimal or no medication withdrawal Role of Aldosterone Suppression Testing Background The recommended approach to diagnosing PA has generally been a two-step process involving an initial “ screening ” step (using a plasma/serum aldosterone and renin with calculation of the aldosterone to renin ratio [ARR]) followed by a second “ confirmatory ” step to either confirm or exclude the diagnosis (using an aldosterone suppression test). However, the value of the confirmatory aldosterone suppression test remains uncer - tain because it is still unclear whether performing an aldoster - one suppression test significantly improves the detection of PA or reduces false-positive results following an initial positive screening.", + "tokenCount": 212, + "pageStart": 21, + "pageEnd": 21, + "hash": "a7ce6c8343f8e2bbffa7555cd8684347b42da86131ab4075d001f513285076e6" + }, + { + "text": "It is also unclear whether this additional step has any direct impact on important clinical outcomes, such as im - proved BP control or reduced cardiovascular risk, after treat - ment with either medical or surgical interventions for PA, and prediction of lateralizing PA.", + "tokenCount": 49, + "pageStart": 21, + "pageEnd": 21, + "hash": "643b65ac2e7258f5048edd2e0d2240515a9c1c39177bf0abbca37ff7240a5bb5" + }, + { + "text": "Given these uncertainties, the guideline addresses whether care guided by aldosterone sup - pression testing should be used in individuals with a positive PA screening result, before initiating further diagnostic steps and/or specific treatment for PA, or if treatment can proceed without confirmatory testing.", + "tokenCount": 54, + "pageStart": 21, + "pageEnd": 21, + "hash": "3bfc66ae435d2577ea0d1167e94650d3445f83d2d03eccf94f4e4384f38ab708" + }, + { + "text": "Question 4. Should care guided by aldosterone suppression testing vs no aldosterone suppression testing be used in individuals with a positive primary aldosteronism screen before initiating primary aldosteronism–specific therapy (medical or surgical)?", + "tokenCount": 49, + "pageStart": 21, + "pageEnd": 21, + "hash": "73d6a5ac1b3656053e114101bdc3382fa90130c116133a94fe2e6ffd1f4bab09" + }, + { + "text": "Recommendation 4 In individuals who screen positive for primary aldos - teronism (PA), we suggest aldosterone suppression testing in situations when screening results suggest an intermediate probability for lateralizing PA and in - dividualized decision making confirms a desire to pur - sue eligibility for surgical therapy (2 | ⊕ OOO).", + "tokenCount": 68, + "pageStart": 21, + "pageEnd": 21, + "hash": "dd549ff965030dfa20f96fffb6f6c6a3c0eecfd5f700172a567335095f80f8c9" + }, + { + "text": "Technical remarks: Situations in which aldosterone suppression testing may be helpful include: • In individuals with an intermediate probability of having lateralizing PA who are willing and able to undergo surgical adrenalectomy ( Fig. Situations in which aldosterone suppression testing is not required prior to initiating PA-specific therapy include ( Fig.", + "tokenCount": 66, + "pageStart": 21, + "pageEnd": 21, + "hash": "120c98894e5d12c74596610de354081d4c38d8fd2c46bc1837c740f89e1b6d9b" + }, + { + "text": "• In individuals with resistant hypertension or hyper - tension with hypokalemia and overt biochemical evi - dence of renin-independent aldosterone production (direct renin concentration [DRC] < 2 mU/L or plasma renin activity [PRA] < 0.2 ng/mL/h and plasma aldos - terone concentration > 20 ng/dL [ > 554 pmol/L] via immunoassay or > 15 ng/dL [ > 416 pmol/L] via liquid chromatography–tandem mass spec - trometry [LC-MS/MS] assay), aldosterone sup - pression testing is not recommended due to the risk of false-negative results, which may ex - ceed the risk of false-positive screening results.", + "tokenCount": 165, + "pageStart": 21, + "pageEnd": 21, + "hash": "a2d71d7184e955afcb6274634cd9b29f90ed9a911a5cc77872e6ca02042b007c" + }, + { + "text": "• Individuals unwilling or unable to pursue adrenal venous sampling (AVS) and adrenalectomy can be empirically treated with mineralocorticoid receptor antagonists (MRAs) based on screening results with - out aldosterone suppression testing.", + "tokenCount": 50, + "pageStart": 21, + "pageEnd": 21, + "hash": "cde7aa3572a4c0f7e41c0cd608bf962d9d06060fb089f23efb8688941d33609d" + }, + { + "text": "Aldosterone suppression testing may still provide value in some cases for further documenting the diagnosis. • Aldosterone suppression testing is unnecessary in individuals from families with germline mutations associated with familial hyperaldosteronism.", + "tokenCount": 42, + "pageStart": 21, + "pageEnd": 21, + "hash": "e05c3b06adace2cf93908d504bae861d3b0b12d3d28a0f15b88dbcb47bae31e1" + }, + { + "text": "Genetic screening is recommended for all first- degree relatives of individuals with familial hyper - aldosteronism and for individuals with young- onset PA ( < 20 years) to enable early diagnosis and treatment.", + "tokenCount": 42, + "pageStart": 21, + "pageEnd": 21, + "hash": "d5c3ccd3693074907227df980d24122a284bb82b1805b1b35eeccb5fa787d919" + }, + { + "text": "• Aldosterone suppression testing can also be avoided if the likelihood of lateralizing PA is so low that pursuing a formal diagnosis of PA is not justifiable (eg, normokalemia + plasma/serum al - dosterone <∼ 11 ng/dL [ <∼ 305 pmol/L] [immuno - assay] or <∼ 8 ng/dL [ <∼ 222 pmol/L] [LC-MS/MS]).", + "tokenCount": 95, + "pageStart": 21, + "pageEnd": 21, + "hash": "26d8030b48c02b4256c01b896ddcae7e5335b55b759efb41e1624be30e0fbe21" + }, + { + "text": "Summary of the Evidence The meta-analysis results, a detailed summary of the evidence and Evidence to Decision (EtD) tables can be found online at https:/ /guidelines.gradepro.org/profile/DF0l5-vIoxI .", + "tokenCount": 55, + "pageStart": 21, + "pageEnd": 21, + "hash": "9afcd6fce234d0b4f807aad579e5a184e51410b657b74144c001b12f68a8eeca" + }, + { + "text": "Benefits and Harms The panel voted for the following patient-important outcomes for Question 4 decision making: 1) accuracy of PA detection, 2) detection of lateralizing PA, 3) percent of individuals achieving blood pressure (BP) control, 4) number of antihy - pertensive agents, 5) dosage of antihypertensive agents, 6) sys - tolic BP (SBP) level, and 7) adverse events (eg, for medications, invasive procedures, surgery, aldosterone suppression tests).", + "tokenCount": 105, + "pageStart": 21, + "pageEnd": 21, + "hash": "5047cd91cbd72e6779e7782c2b3660be8131ea7ef3d1fcc9aaa0c7c67fd18544" + }, + { + "text": "We found no RCTs that addressed this question. Likewise, no prospective and head-to-head studies are available evaluat - ing the value of aldosterone suppression testing, in addition to screening results, on treatment outcomes in PA.", + "tokenCount": 50, + "pageStart": 21, + "pageEnd": 21, + "hash": "987272c9380e70869293ad25e69b0b6ea0536ef1bf6b9057b99f030046ffe512" + }, + { + "text": "Therefore, the panel ’ s recommendation relied primarily on evidence derived from retrospective observational studies. The systematic re - view found only one study (retrospective observational study) that was included ( 24 ).", + "tokenCount": 40, + "pageStart": 21, + "pageEnd": 21, + "hash": "89b90bc03506bdc19e1bc7ce63761e4635f219c660ae9a27528eb6796e72bc1e" + }, + { + "text": "Cornu et al showed that when con - ducting the saline suppression test (performed in the supine position) in individuals with high-probability features of PA, all of whom underwent AVS, even very low post-saline aldos - terone levels ( < 139 pmol/L or 5 ng/dL) could not definitively exclude lateralizing PA ( 24 ). Similarly, another study showed that lateralizing PA could be detected in 15% of individuals with a post-supine saline suppression test aldosterone below 10 ng/dL ( 25 ); in general, the degree of nonsuppressibility in this study correlated with the likelihood of lateralization of The Journal of Clinical Endocrinology & Metabolism , 2025, Vol.", + "tokenCount": 154, + "pageStart": 21, + "pageEnd": 21, + "hash": "cee0cd04c68afe1a35ee0b1f4f8e0ba8a22e8d4ec0bedde323dbafeab1b4b25f" + }, + { + "text": "110, No. 9 2473 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 46, + "pageStart": 21, + "pageEnd": 21, + "hash": "c58ad43e4cf60bf2f65c31815691b519687c86a93c4c892e8e692703ab5f8688" + }, + { + "text": "AVS, thereby providing a desirable prognostic value. However, the choice of protocol and aldosterone assay are factors that can modify the interpretation of the results. For example, the sensitivity of the saline suppression test at pre - dicting the fludrocortisone suppression test has been shown to be superior when conducted in the seated position vs the su - pine position ( 100 ).", + "tokenCount": 78, + "pageStart": 22, + "pageEnd": 22, + "hash": "c6d672eb6e18a5db58cb5987e4ae1c4f824f1c986cf0c93f7336d0f71de1bfba" + }, + { + "text": "Moreover, the use of modern LC-MS/MS aldosterone assays yield lower aldosterone values than trad - itional immunoassays, thereby warranting a re-assessment of aldosterone interpretations for virtually all aldosterone suppression tests ( 101-105 ).", + "tokenCount": 58, + "pageStart": 22, + "pageEnd": 22, + "hash": "4b6e2f02beb54158aecaa40229a12ad88366fa2b0c067ad0f60b7634285cfdcd" + }, + { + "text": "Two systematic reviews and meta-analyses ( 106 , 107 ), in - cluding 55 and 31 studies respectively, concluded that the ac - curacy of aldosterone suppression tests in confirming PA was overestimated and that the number of missed cases (false- negative interpretations) may exceed the number of overdiag - noses (false-positive interpretations) ( 106 ).", + "tokenCount": 74, + "pageStart": 22, + "pageEnd": 22, + "hash": "21e489b98d1f174dc0bff45d65a1ad1b750c68e0195a935a28241f93f1b47133" + }, + { + "text": "These results were attributed to inflation of diagnostic accuracy due to biased se - lection of individuals with very high probabilities of having PA. One study reported the anecdotal experience of a hyper - tension referral center abandoning the use of aldosterone sup - pression tests entirely from the diagnostic cascade for individuals with high-probability features of PA (ie, hyperten - sion with a high ARR or hypertension with hypokalemia) over a period of 6 years (2005-2011) ( 108 ).", + "tokenCount": 102, + "pageStart": 22, + "pageEnd": 22, + "hash": "0a6505eb87ac75b7e361c5496f065ee95448b99a3735c2a5e2774974fa84c775" + }, + { + "text": "When using just the screening aldosterone and renin values to guide subsequent decisions, the authors estimated that less than 3% of individ - uals were at risk of a false-positive diagnostic interpretation.", + "tokenCount": 42, + "pageStart": 22, + "pageEnd": 22, + "hash": "9885ae4328751b730430021561b0bd1306c480c76d2cb38aa1fe496dbaa926db" + }, + { + "text": "False-negative determinations after an aldosterone suppres - sion test in individuals with high-probability features of PA is considered to be a substantial undesired effect ( 23-26 ).", + "tokenCount": 41, + "pageStart": 22, + "pageEnd": 22, + "hash": "96596093b8dd6b6616bdfc9be15c4a10c00ea492d554748c22ce783352862486" + }, + { + "text": "If al - dosterone suppression testing is used to enhance knowledge of lateralization and AVS use, the risk of undesirable effects is low. However, a negative aldosterone suppression test does not preclude the option of commencing specific medical therapy for PA, which has shown to be effective in individuals with low-renin hypertension and renin-independent aldoster - one production even when they do not meet the formal diag - nostic criteria for PA ( 19-22 ).", + "tokenCount": 97, + "pageStart": 22, + "pageEnd": 22, + "hash": "52cacdf3c6b6a34a98410ce4017dadf3d163d996c248fb6465ae0960accb442b" + }, + { + "text": "For example, in one study evaluating the captopril challenge test, aldosterone-directed therapy was highly effective at improving biochemical and clinical outcomes even for patients that did not meet the for - mal diagnostic criteria for PA ( 26 ).", + "tokenCount": 47, + "pageStart": 22, + "pageEnd": 22, + "hash": "8d399496cef27c08e077fc94145d7a5b08c2b445994bcaad83aa166cb51136c2" + }, + { + "text": "Evidence to Decision Factors • An aldosterone suppression test is cost-effective in the long term, particularly if it assists in identifying lateralizing forms of PA that might guide curative surgery. The cost and resources will depend on the test used.", + "tokenCount": 49, + "pageStart": 22, + "pageEnd": 22, + "hash": "c44bac75af70c22211c5ab15b55be1ac8cb1f1848f4e0b08140472b7f7de06bd" + }, + { + "text": "• Although no specific studies address this aspect, aldoster - one suppression testing appears acceptable by clinicians with expertise in PA, as well as by patients. In a limited-resource setting, conducting aldosterone suppres - sion testing may be less acceptable. • Aldosterone suppression testing can be prohibitively costly or resource-intensive in certain places. As a re - sult, many parts of the world favor aldosterone suppres - sion tests that are less expensive and resource-intensive, whereas other resource-rich institutions rely on more la - borious and costly aldosterone suppression tests.", + "tokenCount": 124, + "pageStart": 22, + "pageEnd": 22, + "hash": "fd69c031793a7c2d5e2f4ce82ee6d5574585392dec371415d8b4308ab9c9ade3" + }, + { + "text": "This discrepancy further adds to implications for equitable health care delivery. Justification for the Recommendation At least 10 aldosterone suppression testing protocols have been described and used to confirm or exclude PA, 4 of which are wide - ly recommended by prior major society guidelines ( 84 , 109-111 ), and each with their own unique thresholds to interpret a confirm - ation, or exclusion, of a PA diagnosis.", + "tokenCount": 81, + "pageStart": 22, + "pageEnd": 22, + "hash": "7c38883ec153915c88963e5c415c3fc794e553afe2502378d4df60d360997caa" + }, + { + "text": "These tests include, but are not limited to, fludrocortisone suppression, oral sodium suppres - sion, supine and seated saline infusion, captopril challenge, losar - tan, dexamethasone-captopril-valsartan, intravenous (IV) furosemide upright, oral furosemide, and posture stimulation tests.", + "tokenCount": 79, + "pageStart": 22, + "pageEnd": 22, + "hash": "f8b3d50bc6f4644eaf32b9bc2efea1bd584d91334d3025dc1b81f3dabb440650" + }, + { + "text": "Given the heterogeneity and lack of standardization across these tests, the ability to provide general recommendations for their implementation and interpretation is limited. Table 8 de - scribes the 3 most widely used aldosterone suppression tests. Aldosterone suppression testing has traditionally been used to confirm or exclude the diagnosis of PA.", + "tokenCount": 60, + "pageStart": 22, + "pageEnd": 22, + "hash": "496e8692b08d09af02fe04134f5517e41bc736ac7817530c42403e7acaaa4f9c" + }, + { + "text": "Limitations of using al - dosterone suppression testing as a diagnostic metric include that the numerous protocols are not calibrated against one another, and each has diagnostic thresholds that are not validated against a gold standard.", + "tokenCount": 40, + "pageStart": 22, + "pageEnd": 22, + "hash": "d30d7bf3ba8ca20d5c04a15569e63cd4bb93ff17c10965d55958257b587b14a7" + }, + { + "text": "The summary of many studies suggests that a sin - gle optimal threshold for most aldosterone suppression tests does not exist and that over-reliance on these tests may result in erro - neous exclusion of PA cases rather than increased accuracy of diagnosis.", + "tokenCount": 51, + "pageStart": 22, + "pageEnd": 22, + "hash": "1d77087cece664360dec0b47ef0968d0a33e5e8751865257dbab960e1399f485" + }, + { + "text": "The balance of evidence ( 106 , 107 ) suggests that the quality of evidence to support the accuracy of this practice is low, particularly in relation to confidently excluding the diagno - sis. However, if testing results that fall below protocol thresholds are interpreted as implying nonlateralizing PA or low-renin hyper - tension and prompting initiation of MRA therapy ( 25 , 26 , 100 ), the use of aldosterone suppression testing could serve as both a diagnostic and therapeutic tool.", + "tokenCount": 98, + "pageStart": 22, + "pageEnd": 22, + "hash": "a5f95cd7a6b3634218e912c73b34d9aa3e89c35caf6dfa0cccd0284e6f58bf51" + }, + { + "text": "The caveat for this approach is the implicit assumption that a positive PA screen indicates a high pretest probability for PA. Some studies suggest that the results of aldosterone sup - pression testing predict the general likelihood that an indi - vidual may have lateralizing PA (ie, greater inability to suppress aldosterone indicates greater likelihood of lateral - izing PA) ( 25 , 100 ), thus providing clinicians with probabil - istic information on when to refer for AVS or when to forego AVS in favor of targeted medical therapy.", + "tokenCount": 111, + "pageStart": 22, + "pageEnd": 22, + "hash": "3bd917df3d17db8b31aae793df9f45ec09a7cb17ccecf66ada091ff53f52c50a" + }, + { + "text": "Caveats to this ap - proach include its lack of quantifiable metrics to guide such interpretations, supporting data are not uniformly available for all suppression tests/protocols, and high-quality com - parative effectiveness studies to assess whether other bio - markers may have similar predictive power are also lacking.", + "tokenCount": 62, + "pageStart": 22, + "pageEnd": 22, + "hash": "40c8dbd9886266e7bba105bb1f29e57eb0ec551b4f02248138047f9daea8186d" + }, + { + "text": "Nevertheless, this approach may help some clini - cians streamline referrals for AVS, especially when this re - source is not readily available, for those who need it and spare those who do not.", + "tokenCount": 42, + "pageStart": 22, + "pageEnd": 22, + "hash": "ab0c6affe8b4d7992a5156232589095d20f2247d0c7842d5d6ccb16600d8c563" + }, + { + "text": "Given the low certainty in the trade-offs between benefits and harms of aldosterone suppression testing, along with considera - tions regarding the costs, resource requirements, and expertise needed to perform it, as well as its feasibility, acceptability, and equity implications, the panel suggests conducting aldoster - one suppression testing in individuals with an intermediate probability for lateralizing PA who desire to pursue eligibility for surgical therapy ( Fig.", + "tokenCount": 86, + "pageStart": 22, + "pageEnd": 22, + "hash": "67c973f9801e9ed7ce0f49e33daf28cdf873a12cd1cc21d31a2954db99f21776" + }, + { + "text": "Aldosterone suppression testing can be performed without stopping or changing antihyperten - sive medications as long as renin is low; when treatment with MRAs has been initiated and renin is no longer low, it is advised that these medications be stopped, and aldosterone suppression testing be performed only when renin is low again.", + "tokenCount": 68, + "pageStart": 22, + "pageEnd": 22, + "hash": "fa5ac6adeac1ca36d03ce995948e969ba015842611257ef9e5f5396fc8e95650" + }, + { + "text": "2474 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 62, + "pageStart": 22, + "pageEnd": 22, + "hash": "47a5c47dcab931d9320d400b1ad6449000faa2a81ea506c35993a6f915bef825" + }, + { + "text": "Comments The use of aldosterone suppression testing in individuals with a positive PA screen may best serve individuals and clinicians by providing them with a probabilistic framework to deter - mine the optimal treatment pathway ( Fig.", + "tokenCount": 42, + "pageStart": 23, + "pageEnd": 23, + "hash": "fc0d1cac207f7cb1a9644049a03c142f408e3f871488f3906a538fb7fe81d9c4" + }, + { + "text": "The evidence for the outcomes of the percentage of individuals achieving BP control and detection of lateralizing PA following aldoster - one suppression testing was very low. However, conducting relatively safe testing to prognosticate the value of undergoing AVS (and determining the next therapeutic steps) would likely be valuable to individuals.", + "tokenCount": 63, + "pageStart": 23, + "pageEnd": 23, + "hash": "0b3ec1c9885ccf8e8de6029d32861133b14a812cc7404c9312a3d6d15320dee5" + }, + { + "text": "In resource-constrained settings, aldosterone suppression testing may be difficult to implement, considering the lack of evidence for major outcomes. Research Considerations Current gaps in knowledge call for further research in the fol - lowing areas: • Prospective, randomized, comparative outcome studies:", + "tokenCount": 57, + "pageStart": 23, + "pageEnd": 23, + "hash": "a8832fc71185d02571de35a80915db8580395e3a435f75f039f2768027e639da" + }, + { + "text": "The lack of a gold-standard diagnostic to define PA is one of the main reasons why aldosterone suppression tests are not uniformly calibrated to one another or validated against a central benchmark. As a result, most available evidence provides low-quality information to reliably ad - judicate whether the use of aldosterone suppression test - ing is superior to no aldosterone suppression testing.", + "tokenCount": 76, + "pageStart": 23, + "pageEnd": 23, + "hash": "815acd93ab1861a3577de0aaea2e0159fa1ab59afa14e57b8ffab18fcf33c53d" + }, + { + "text": "Prospective studies, employing randomization to each ap - proach, and evaluating clinical efficacy outcomes are needed to robustly assess whether the practice of aldoster - one suppression testing adds value in selecting the correct individuals for localization procedures and targeted treat - ment, and improves outcomes.", + "tokenCount": 56, + "pageStart": 23, + "pageEnd": 23, + "hash": "aaca23c05e8e8899de13b1e4c26cfb2e6f39e755c83ed8518a9a36d980eae414" + }, + { + "text": "• New diagnostic biomarkers: Novel cutting-edge omics tech - nologies together with the application of artificial intelligence (AI) for disease prediction hold potential for the development of more effective biomarkers to diagnose PA.", + "tokenCount": 43, + "pageStart": 23, + "pageEnd": 23, + "hash": "1ca96d9f6c77e36da7792c25bf219580bc191b396e0aa0ef9fc35232ec1a5281" + }, + { + "text": "Besides the im - proved diagnostic performance of plasma or urinary steroid profiling to diagnose PA ( 82 , 114 ), a recent approach using multi-omics data, including plasma miRNAs, plasma cat - echol O-methylated metabolites, plasma steroids, urinary steroid metabolites, and plasma small metabolites, integrated by machine learning, was able to correctly diagnose PA with high sensitivity and specificity distinguishing them from indi - viduals with primary hypertension or other forms of endo - crine hypertension ( 83 ).", + "tokenCount": 102, + "pageStart": 23, + "pageEnd": 23, + "hash": "bdc20e7a4204e0394e51bd6664a26d859a654cc9dbf050d50543e35322350f90" + }, + { + "text": "This and similar approaches, combining clinical data with biologic profiles, may provide better performances to diagnose PA and potentially lateraliz - ing PA, thereby possibly eliminating the need for aldosterone suppression tests in the future.", + "tokenCount": 43, + "pageStart": 23, + "pageEnd": 23, + "hash": "d7c04cffbedaeb92a4ff97d7115301f28522ea3c2036fa725ee5e213020b5819" + }, + { + "text": "Medical Therapy vs Surgical Therapy for Individuals With Primary Aldosteronism Background Effective prevention of excess cardiovascular and cerebrovascular risk in individuals with primary aldosteronism (PA) involves tar - geted therapies for lateralizing and bilateral forms of the disease.", + "tokenCount": 54, + "pageStart": 23, + "pageEnd": 23, + "hash": "8b23144c16381b3861b9f4839ef2e87434678a6740567f6049390c8751d80e5d" + }, + { + "text": "For individuals with bilateral disease and those who do not desire or are not a candidate for surgery, lifelong pharmacotherapy with a mineralocorticoid receptor antagonist (MRA) is the standard ap - proach.", + "tokenCount": 43, + "pageStart": 23, + "pageEnd": 23, + "hash": "2a79c80e2d4c0473d287aadee924f2dab3c682b6ec2ca9683e956a4905de450f" + }, + { + "text": "In contrast, surgical intervention is typically recommended for individuals with lateralizing PA who wish to pursue this op - tion. However, surgical intervention requires adrenal venous sam - pling (AVS) to confirm lateralization, a procedure that demands significant expertise and specialized resources, often limited to ter - tiary care centers.", + "tokenCount": 65, + "pageStart": 23, + "pageEnd": 23, + "hash": "8136b1f9543470950de50f35c25d1a6eda9cea2f286a94cf75b2430f7d75e636" + }, + { + "text": "These challenges highlight the need to balance the benefits and feasibility of medical vs surgical treatments. Considering these factors, the panel formulated this question to de - termine the best management strategy for individuals with PA.", + "tokenCount": 40, + "pageStart": 23, + "pageEnd": 23, + "hash": "4a42d928248ccac73c9df82a5373fb220363da7ecf9c7851c38505567e548c4d" + }, + { + "text": "Question 5. Should primary aldosteronism–specific medical therapy vs surgical therapy be used in individuals diag - nosed with primary aldosteronism? Recommendation 5 In individuals with primary aldosteronism (PA), we sug - gest medical therapy or surgical therapy with the choice of therapy based on lateralization of aldosterone hypersecretion and candidacy for surgery (2 | ⊕ OOO).", + "tokenCount": 88, + "pageStart": 23, + "pageEnd": 23, + "hash": "9c772a7bada23dca1af781f272b2ffe648f40b208af582d441b9e32e7f3b4806" + }, + { + "text": "Technical remarks ( Fig. • Surgical therapy by total unilateral adrenalec - tomy, usually by the laparoscopic approach, is mainly offered to individuals with lateralizing PA who choose to pursue the surgical option ( Fig.", + "tokenCount": 46, + "pageStart": 23, + "pageEnd": 23, + "hash": "560696bbb5b6deaee9c1f2516e339d33e835a9f5c3af682f2292f905680a82c2" + }, + { + "text": "• Lifelong medical therapy that includes an MRA is usually offered to individuals with bilateral PA or lateralization status unknown (refer to Question 6 for definition of lateralization) and to those who decline the surgical option or who are not surgical candidates ( Fig.", + "tokenCount": 52, + "pageStart": 23, + "pageEnd": 23, + "hash": "49f985df835768a2a6dfb76d68687d59a10d4bcd6ab9d6fd3365adc98d6344b0" + }, + { + "text": "• Individuals with mild PA typically have bilateral disease and may bypass AVS, proceeding directly to medical management ( Fig. • Individuals with multiple comorbidities who may not be good surgical candidates may also proceed directly to medical therapy ( Fig.", + "tokenCount": 48, + "pageStart": 23, + "pageEnd": 23, + "hash": "e274efb4e0914a21a0b99895a9e75e7cf246e4c6390edcd2babc66bae753e5dc" + }, + { + "text": "Summary of the Evidence The meta-analysis results, a detailed summary of the evidence and Evidence to Decision (EtD) tables can be found online at https:/ /guidelines.gradepro.org/profile/FT5oNrFmGsY .", + "tokenCount": 55, + "pageStart": 23, + "pageEnd": 23, + "hash": "617767a776160e24d69d5841a94e5c5cf931bb7b2b7a622c4b14d855ba87737c" + }, + { + "text": "Benefits and Harms The panel voted for the following patient-important outcomes for Question 5 decision making: 1) percent of individuals achieving blood pressure (BP) control, 2) number of antihy - pertensive agents, 3) dosage of antihypertensive agents, 4) sys - tolic BP (SBP) level, 5) major adverse cardiovascular events (MACEs), 6) atrial fibrillation, 7) stroke, 8) ischemic heart dis - ease, 9) heart failure, 10) cardiovascular mortality, 11) all- cause mortality, and 12) adverse events.", + "tokenCount": 124, + "pageStart": 23, + "pageEnd": 23, + "hash": "0e4a1f17d21b1bbbaddf924602f031f8794f2ccda05c3eba636e2c7ab8afff4a" + }, + { + "text": "Systematic review metadata ( 53 ) from 4 randomized con - trolled trials (RCTs) enrolling 669 individuals with PA (mean age 52.6 years, 28.7% females) and from 52 comparative obser - vational studies with 17 893 individuals with PA (mean age 52.6 years, 46.9% females) were included for evidence synthesis.", + "tokenCount": 77, + "pageStart": 23, + "pageEnd": 23, + "hash": "fc697149662cf3a78f47229794fa768f5b9a99bca1a8d2a29174099fe6f52661" + }, + { + "text": "The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 2475 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 62, + "pageStart": 23, + "pageEnd": 23, + "hash": "63a2f3bcfd914e370fad86fe531cb157b0f725a2811c8c245a364e480a55f129" + }, + { + "text": "No significant differences between medical and surgical man - agement were identified for hypertension remission. However, a meta-analysis ( 53 ) of 20 observational studies, including 3209 individuals with PA, showed an association of lower long-term efficacy in achieving BP control with PA-specific medical ther - apy compared with surgical therapy (odds ratio [OR]: 0.333; 95% CI: 0.202-0.550). Additionally, long-term SBP levels were higher with medical management in an analysis of 42 ob - servational studies ( 53 ) of 10 286 persons with PA mean differ - ence (MD: 4.811; 95% CI: 3.327-6.294 Observational studies also indicate that medical treatment for PA is associated with a higher number of antihypertensive agents (21 studies, 4998 individuals) and higher dosage of antihypertensive agents (8 studies, 1409 individuals) com - pared with surgical intervention (MD: 1.339; 95% CI: 1.136-1.542; MD: 1.855; 95% CI: 1.400-2.309, respectively) ( 53 ). The higher number of antihypertensive agents with med - ical treatment was supported by a review of clinical trials in - cluding 425 persons with PA (MD: 1.348; 95% CI: 0.866-1.830) ( 115-117 ), and the higher dosage of antihyper - tensive agents associated with medical vs surgical manage - ment persisted in an analysis based on lateralizing disease only (MD: 1.733; 95% CI: 1.160-2.306", + "tokenCount": 342, + "pageStart": 24, + "pageEnd": 24, + "hash": "d9720c53a1a8ff992dd6838b8cc2f7518be5a8ea7678be0e6578cf055171783b" + }, + { + "text": "The systematic review ( 53 ) assessed the comparative efficacy of medical vs surgical management for cardiovascular risk. No statistically significant differences were found between the 2 treatment modalities for ischemic heart disease, atrial fibrilla - tion, MACEs, and cardiovascular mortality. However, com - pared with surgical therapy, review of observational studies indicated medical management had an increased risk of stroke (OR: 1.821; 95% CI: 1.144-2.898). The increased risk for heart failure and all-cause mortality persisted in a review of metadata based on lateralizing PA only (OR: 2.182; 95% CI: 1.38-3.452 and OR: 2.082; 95% CI: 1.124-3.855, respective - ly", + "tokenCount": 162, + "pageStart": 24, + "pageEnd": 24, + "hash": "6e2ee63f265b92491fe01fe5c3ff621999892df1628a782fe9c18c2c63fca2ee" + }, + { + "text": "One cohort study reported that MRA therapy compared with adrenalectomy had a higher risk of mortality, major car - diac or cardiovascular events, and combined new-onset atrial fibrillation with mortality ( 118 ). However, this increased risk might be mitigated with adequate mineralocorticoid receptor blockade based on unsuppressed renin activity ( 9", + "tokenCount": 73, + "pageStart": 24, + "pageEnd": 24, + "hash": "6ffb7a8a305fad5fa00fb7107575ad71cd480c4cee48b858c838ae0b4f7f257f" + }, + { + "text": "Due to off-target androgen receptor antagonism and pro - gesterone receptor agonism, spironolactone has dose- dependent side effects of gynecomastia and sexual dysfunction in men and menstrual irregularities in women ( 116 , 119-121 ). The meta-analysis of a systematic review of 2 observational studies estimated significantly higher medication-related ad - verse events with medical therapy compared to surgical ther - apy (OR: 29.853; 95% CI: 3.726-239.166) ( 123", + "tokenCount": 109, + "pageStart": 24, + "pageEnd": 24, + "hash": "e4eabaf7670585504eaf9aef0afd399f1d2dbdf6fd03d03de0c32f4baa9dfb15" + }, + { + "text": "Of note, fewer side effects were associated with eplerenone than spir - onolactone, consistent with eplerenone ’ s greater specificity for the mineralocorticoid receptor ( 122 ). While the antihyper - tensive efficacy of eplerenone was lower than that of spirono - lactone, the eplerenone doses studied were about one-third less potent than the spironolactone doses. Therefore, the panel concluded that the balance of effects favor surgery, depending on lateralization of aldosterone hy - persecretion, individual choice, and suitability for surgery. Refer to Question 6 for a definition of lateralization. Evidence to Decision Factors • Medical treatment is cheaper and requires fewer resources ( 124", + "tokenCount": 153, + "pageStart": 24, + "pageEnd": 24, + "hash": "bd11f1840ab55402304bbe393673e77af46bf041d21195f3f4418092e8b1026f" + }, + { + "text": "However, in an individual with PA and a remaining life expectancy of 25.4 years or more, surgery was esti - mated as the least costly strategy in the long-term due to the decreased risk of PA-associated adverse events ( 125 ). • MRAs are readily available, including in resource-poor settings, whereas surgery requires additional resources. • MRA treatment is equitable and independent of socioeconom - ic status with no significant inequality of outcomes ( 126", + "tokenCount": 93, + "pageStart": 24, + "pageEnd": 24, + "hash": "461ada6e9885b70ea3ccdc0ffffcbbdce28533a83d4614bc64d562c7c784ad02" + }, + { + "text": "• MRA therapy is often preferred by health care clinicians due to its accessibility and low cost. However, individual adherence to spironolactone is lower compared with other antihypertensive medications, possibly related to its anti- androgen and progestogenic side effects. • Adherence may improve with the use of more selective MRAs, such as eplerenone and potentially finerenone ( 127-129 ). • Adrenalectomy appeals to individuals seeking a definitive cure for hypertension. Justification for the Recommendation Based on the systematic review and indirect evidence, the panel provided a recommendation for either medical therapy or surgical intervention for the treatment of PA. This recommendation is based on the observed benefits of surgical treatment, including lower SBP, more effective BP control, reduced risk of stroke, fewer MACEs, lower inci - dence of heart failure, decreased need for antihypertensive medications, improved quality of life (QOL), and lower all- cause mortality. While medical therapy with MRAs showed less favorable outcomes overall, the excess risk of hard out - comes might be mitigated by monitoring treatment re - sponse based on an increase in renin rather than the BP response alone ( 9 ) (refer to Question 7", + "tokenCount": 251, + "pageStart": 24, + "pageEnd": 24, + "hash": "87f3d664694e2fe8342e0dee3244214a73c9110e9f0c50dfb5f8916b8d073dc2" + }, + { + "text": "However, individ - uals often favor surgical therapy due to the possibility of avoiding lifelong medical therapy, overall QOL improve - ments, limited pharmacologic treatment options, and side effects of some MRAs (eg, spironolactone). Thus, surgical treatment is generally preferred by individuals with lateral - izing PA and may offer superior outcomes, but the choice between surgical and medical management should be based on individual characteristics, preferences, and the specific presentation of the disease. For a definition of lateralization, refer to Question 6. Comments Individuals managed either medically or surgically should be monitored according to clinical and biochemical outcomes and to ensure clinical safety as recommended by international expert consensuses and in Questions 7 and 9 ( 85 , 86", + "tokenCount": 149, + "pageStart": 24, + "pageEnd": 24, + "hash": "7a9e3d45f3b5e1bb9c155830a6df2ce07f7b5610028c25db54b9b936d8fae93f" + }, + { + "text": "Postsurgical outcomes partly depend on successful AVS and the availability of skilled adrenal surgeons, which might be limited outside specialized centers. Preoperative morbidity and length of stay are more favorable in high- volume centers ( 130 ). Adrenalectomy is mainly performed by a laparoscopic ap - proach, but open adrenalectomy can be considered under spe - cific conditions (eg, in individuals who have had multiple prior laparotomies", + "tokenCount": 89, + "pageStart": 24, + "pageEnd": 24, + "hash": "1ec45beecc2c0dffc21738abbb5a79e1d9a862a870c3268c7d6a9ba8e24508d5" + }, + { + "text": "Individuals with bilateral PA in whom medical therapy is not well-tolerated or effective can be considered for unilateral adrenalectomy although evidence regarding clinical effective - ness in those situations is limited ( 131-133 ). 2476 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 106, + "pageStart": 24, + "pageEnd": 24, + "hash": "54a082d6c10949458478cae8337cc1b4ffcf0a679d46798495a044d674604264" + }, + { + "text": "Research Considerations Further research is necessary to investigate the protective ef - fects of aldosterone synthase – inhibitor therapy as well as oth - er strategies like adrenal ablation and tailored approaches for milder forms of PA.", + "tokenCount": 49, + "pageStart": 25, + "pageEnd": 25, + "hash": "c6ee3a44af81373fd72779397cb1736681c65632eb2a4982df1a1f2a4b4d725f" + }, + { + "text": "Role of Adrenal Venous Sampling and Computed Tomography Scanning in Determining Lateralization of Primary Aldosteronism Background Cross-sectional imaging (eg, computed tomography [CT] or magnetic resonance imaging [MRI]) has limitations in the evaluation of individuals with primary aldosteronism (PA) because it cannot determine the functional activity of adrenal glands.", + "tokenCount": 78, + "pageStart": 25, + "pageEnd": 25, + "hash": "1f9d74e09be05e678e0fd32ce4d6a4c9b55ee5a87004b28b47bb11dc883b65d6" + }, + { + "text": "This can result in misclassification as lateralizing or bilateral PA, especially in those with bilateral adrenal hyper - plasia or nonfunctional adrenal nodules. While adrenal ven - ous sampling (AVS) can improve diagnostic accuracy and guide treatment decisions, its limited availability raises the question of whether its use significantly improves outcomes compared with CT scanning alone. This guideline question addresses whether care guided by adrenal lateralization us - ing both CT scanning and AVS should be preferred over CT scanning alone for directing the treatment approach in individuals with PA.", + "tokenCount": 111, + "pageStart": 25, + "pageEnd": 25, + "hash": "3e659ddb1b14b5ecbf5f69eac85ba6db8aff88adef52bcec3a10336fa1fbb45f" + }, + { + "text": "Question 6. Should care guided by adrenal lateralization with computed tomography scanning and adrenal venous sampling vs computed tomography scanning alone be used for deciding treatment approach in individuals with primary aldosteronism?", + "tokenCount": 44, + "pageStart": 25, + "pageEnd": 25, + "hash": "bf35ac57bfac6dbaf1f03e0bafee0aac5ac0543b679f0f629754b84e1e537965" + }, + { + "text": "Recommendation 6 In individuals with primary aldosteronism (PA) con - sidering surgery, we suggest adrenal lateralization with computed tomography (CT) scanning and ad - renal venous sampling (AVS) prior to deciding the treatment approach (medical or surgical) (2 | ⊕⊕ OO).", + "tokenCount": 70, + "pageStart": 25, + "pageEnd": 25, + "hash": "2f916068e04191edc8ecc9c34f404ade1ba795500f64769304d55f7422e2ec0b" + }, + { + "text": "Technical remarks • Individuals with PA who desire and are candidates for adrenalectomy should undergo AVS in order to reliably differentiate lateralizing from bilateral forms. • A potential exception is when the diagnosis of uni - lateral aldosterone-producing adenoma (APA) is so likely that AVS could be considered unneces - sary (eg, individual age < 35 years with marked PA with hypokalemia and > 1.0-cm unilateral ad - renal adenoma on CT scanning).", + "tokenCount": 104, + "pageStart": 25, + "pageEnd": 25, + "hash": "f9ee8f2f03d0b69b8509041dfb42ddd71b38edaf64e2dd97127d0d0375093b58" + }, + { + "text": "Summary of the Evidence The meta-analysis results, a detailed summary of the evidence and Evidence to Decision (EtD) tables can be found online at https:/ /guidelines.gradepro.org/profile/FL6i3ZvDYXg .", + "tokenCount": 56, + "pageStart": 25, + "pageEnd": 25, + "hash": "9770e540c9b2185c5139e7bff8255b84afdb4c5e6704fac7938f82061bc197ac" + }, + { + "text": "Benefits and Harms The panel voted for the following patient-important outcomes for Question 6 decision making: 1) detection of lateralizing PA, 2) biochemical cure rate post-adrenalectomy, 3) percent of individuals achieving blood pressure (BP) control, 4) num - ber of antihypertensive agents, 5) dosage of antihypertensive agents, 6) systolic BP (SBP) level, and 7) adverse events.", + "tokenCount": 94, + "pageStart": 25, + "pageEnd": 25, + "hash": "123402dfc519f11db6cb58acc3eede973b59f02934aaf9b0e1e6f658f264a688" + }, + { + "text": "A systematic review of 38 studies including 950 individuals reported that when AVS was used as the criterion standard test for the diagnosis of lateralizing PA, CT/MRI misdiag - nosed the cause of PA in 37.8% of individuals ( 134 ).", + "tokenCount": 52, + "pageStart": 25, + "pageEnd": 25, + "hash": "a380054ac0c54c62f59552e357fab68f61f14c355655f24536a79225c0aebf25" + }, + { + "text": "Several retrospective studies reported low-level concordance between CT scanning alone and CT scanning plus AVS ( 89 , 135 , 136 ). In individuals who were biochemically cured after surgery with AVS-based management, CT/MRI alone correctly de - tected lateralizing PA in 58.6% ( 135 ) and 64% of cases ( 89 ).", + "tokenCount": 72, + "pageStart": 25, + "pageEnd": 25, + "hash": "9262bde8cddebdcf0754cfa382b9ccc759e9915b5d84e0842bd65908a263a8e6" + }, + { + "text": "These studies highlight the limitations of adrenal CT in the diagnosis of unilateral aldosterone-producing adenomas (APAs). Small unilateral APAs may not be visible on CT, leading to misinterpretation as normal adrenal glands.", + "tokenCount": 47, + "pageStart": 25, + "pageEnd": 25, + "hash": "bb7ab4ba9a1f1a06a59dbafd1e315e7c1172ca12052d95093e048c51fcb15b95" + }, + { + "text": "Conversely, appar - ent microadenomas on CT might actually be areas of hyperplasia, making unilateral adrenalectomy inappropriate. Furthermore, nonfunctioning unilateral adrenal macroadenomas, which are common in individuals older than age 35 years, cannot be distin - guished from APAs on CT.", + "tokenCount": 64, + "pageStart": 25, + "pageEnd": 25, + "hash": "f8bebd7ed76a6c85aa66b90f757da1a03424cdc45e333e9b23e5271dd78e4bb6" + }, + { + "text": "Therefore, to address the performance of adrenal lateraliza - tion with CT scanning plus AVS vs CT scanning alone for the management of PA, the systematic review ( 53 ) identified one randomized controlled trial (RCT) ( 117 ) enrolling 200 indi - viduals with PA (mean age 53.1 years; 21.7% female) and 29 comparative observational studies with 8375 participants (mean age 50.4 years; 48.8% female).", + "tokenCount": 96, + "pageStart": 25, + "pageEnd": 25, + "hash": "4fc7158f1e61a0f7f5b103e8e971ff4ccdc49dc9d41d3c8981b80f46bae86ab2" + }, + { + "text": "Data from the RCT alone did not show differences in inten - sity of antihypertensive medications, BP control, or biochem - ical remission after 1-year of follow-up.", + "tokenCount": 42, + "pageStart": 25, + "pageEnd": 25, + "hash": "705bab8c8e07f5bafa00c53a6ee089b6f4c29c3eee7b93bf07ffe2667527fa02" + }, + { + "text": "Meta-analysis of 4 observational studies including 1070 individuals with PA indi - cated that compared with AVS-based management, CT scan - ning alone may be associated with lower postoperative biochemical cure (odds ratio [OR]:", + "tokenCount": 48, + "pageStart": 25, + "pageEnd": 25, + "hash": "4d4c84deb8eb6c7d235df55211f8bdc53ce17bf6b37b89ada49e0f1fcfb6592f" + }, + { + "text": "0.266; 95% CI: 0.103-0.690) ( 89 , 137-139 ). Otherwise, comparable out - comes were observed between AVS- and CT-based manage - ment approaches for the detection of lateralizing PA, achieving BP control, number or dosage of antihypertensive medications, and SBP levels.", + "tokenCount": 70, + "pageStart": 25, + "pageEnd": 25, + "hash": "4cd0ce7c1caded2f4e3b7296fbeb4714c685a5acbc19a6d5a4a569f4262bb921" + }, + { + "text": "Additionally, an observational, retrospective, multicenter study reported an overall adrenal vein rupture during 0.61% of AVS procedures, with an inverse correlation between rupture incidence and the radiologist ’ s experience in performing AVS studies ( 140 ).", + "tokenCount": 50, + "pageStart": 25, + "pageEnd": 25, + "hash": "56e3ce808844fa2e9d28db1f58405c4675d898f68277ecb4be77eddefa30f36d" + }, + { + "text": "Evidence to Decision Factors • Resource requirements for AVS include training and time of expert interventional radiologists, accurate laboratory measurements, and interpretation of AVS results ( 141 ). • One RCT reported increased average health care costs for individuals undergoing AVS ( 117 ), but decision-tree mod - eling and incremental cost-effectiveness ratios (ICERs) based on quality-adjusted life years (QALYs) report that AVS-based care is more cost-effective ( 124 , 142 ).", + "tokenCount": 102, + "pageStart": 25, + "pageEnd": 25, + "hash": "849b5413cd2b4b63de8e6e2a2d60b2abc6fbf10aceb5311e3027550cab29d626" + }, + { + "text": "• AVS has low feasibility to implement due to the require - ment for a highly trained interventional radiologist and other additional resources and is probably less acceptable The Journal of Clinical Endocrinology & Metabolism , 2025, Vol.", + "tokenCount": 47, + "pageStart": 25, + "pageEnd": 25, + "hash": "af57fd811d11efb101a3c48d2ba4e5ae1262fd9c4d4116b096f81c855c30a8ff" + }, + { + "text": "110, No. 9 2477 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 46, + "pageStart": 25, + "pageEnd": 25, + "hash": "f73430633d76b17a671c8b43dfa4e302d2eb3193613a9c1c06897cabfeff103a" + }, + { + "text": "to care clinicians who do not have local or regional access to a center that performs AVS with a high bilateral adrenal vein cannulation success rate. • AVS might be unacceptable to some individuals unwilling to undergo an invasive procedure but should be accept - able to individuals who want to achieve hypertension cure and avoid both noncurative surgery based on CT findings alone and lifetime pharmacotherapy.", + "tokenCount": 76, + "pageStart": 26, + "pageEnd": 26, + "hash": "3ae1d2f6336315aac9d935e42ddf0c67063565478e189300f571d8285592f968" + }, + { + "text": "• AVS has higher costs relative to CT-guided care, is not wide - ly available in most countries, and is offered only in highly specialized centers and not at all in resource-poor countries.", + "tokenCount": 41, + "pageStart": 26, + "pageEnd": 26, + "hash": "4fc8b3789096cdb7e633d871f499840be6cc0a59687e0e7af3fe927a904851d3" + }, + { + "text": "• Although AVS is more accurate than cross-sectional imaging, it is substantially more costly and difficult to implement. • Individuals with PA prioritize the accurate detection of surgically treatable forms; therefore, AVS is acceptable and desired by those who favor a cure of PA over lifelong mineralocorticoid receptor antagonist (MRA) therapy.", + "tokenCount": 69, + "pageStart": 26, + "pageEnd": 26, + "hash": "316eab1c5648541c81fdf91bba158d71b51ea85867d276c7b5de5372f075fbc8" + }, + { + "text": "Justification for the Recommendation The panel recommended that for individuals diagnosed with PA who are candidates for surgical intervention, the treatment approach should be guided by adrenal lateralization using both CT scanning and AVS.", + "tokenCount": 41, + "pageStart": 26, + "pageEnd": 26, + "hash": "a161125e82420ef75be14e5f498d61f13d5754a0d55fc8caa41f48b3946614d1" + }, + { + "text": "This recommendation is based primarily on indirect evidence, and partially supported by dir - ect evidence, highlighting the low detection rate of lateralizing PA with CT scanning alone compared with combined CT scanning and AVS.", + "tokenCount": 40, + "pageStart": 26, + "pageEnd": 26, + "hash": "ad7accc9dee53c6ff76cefa34fea86eb1769bcdbfa441674455167b733ca2df5" + }, + { + "text": "Also considered was the value that clini - cians place on the accuracy of aldosterone lateralization be - cause it leads to successful surgical outcomes in those individuals who want to pursue a surgical cure.", + "tokenCount": 41, + "pageStart": 26, + "pageEnd": 26, + "hash": "81d56ebdbf96e3f4ddc6c3f3db1ecc9575fbb86e676f8b27db0bf542b7a988a8" + }, + { + "text": "CT (or MRI) cannot assess the functional activity of adrenal glands and may misclassify individuals, particularly those with bilat - eral adrenal hyperplasia or nonfunctional adrenal nodules.", + "tokenCount": 42, + "pageStart": 26, + "pageEnd": 26, + "hash": "1440e270d92bc062c0ee7233bf4b7e16476d05ec495ba9914d92d343f7e2e814" + }, + { + "text": "Thus, in individuals who are surgical candidates, an addition - al localization step is needed, and the most accurate currently available option is AVS. Although a prospective randomized trial reported no appar - ent outcome differences between CT-based and cosyntropin- stimulated AVS-based management ( 117 ), several caveats need to be considered.", + "tokenCount": 67, + "pageStart": 26, + "pageEnd": 26, + "hash": "74afd67d56d928e8f3fdb3c797e4c78ef2cdadace3d3459330c7050ce55dc23e" + }, + { + "text": "For example, medication and BP out - come data at 1 year after intervention were pooled from the surgical and medically managed individuals in each arm of the study, which failed to recognize that MRA treatment is a “ surgical equivalent.", + "tokenCount": 46, + "pageStart": 26, + "pageEnd": 26, + "hash": "056a5aa81bdd9a8daf74a31fe166edc5053ff45ff39ab275cbcb647b199621a6" + }, + { + "text": "” The study was not powered to detect outcome differences in those individuals treated only with sur - gery based on CT vs AVS. Additional issues with this study in - cluded the selection bias toward more florid forms of PA, which limited its generalizability, and a suboptimal selectivity index cutoff for AVS ( > 3:1 with a cosyntropin infusion- stimulated protocol) that may have led to surgical manage - ment in individuals with bilateral adrenal disease in the AVS-based care cohort.", + "tokenCount": 109, + "pageStart": 26, + "pageEnd": 26, + "hash": "7c139454f1ad3f5a9fedbb80dbc668c54f5d0d84b50f570fb78ec2b6d581b75d" + }, + { + "text": "In addition, 5 of the 92 individuals in the CT-based management group had apparent unilateral adrenal disease on CT scan but were not managed surgically. Implementation Strategies AVS success rates depend on the experience of the operators and thus performance in centers with high expertise is recom - mended ( 143 ).", + "tokenCount": 61, + "pageStart": 26, + "pageEnd": 26, + "hash": "e5552de4e6c1cce519b0957aaee2935014b87bc1485c07dee0f4a082dcdb9e29" + }, + { + "text": "Most centers use radiographic contrast administration dur - ing AVS to help localize the adrenal veins. Contrast administration carries a risk of a contrast allergy reaction, as does contrast-enhanced adrenal CT.", + "tokenCount": 42, + "pageStart": 26, + "pageEnd": 26, + "hash": "50a53fe7362f1c449029af391052fd55c78d70a8361ba0ebd83ac6575bdd3d53" + }, + { + "text": "A contrast allergy may ne - cessitate the use of cosyntropin for AVS for those individuals treated with exogenous corticosteroids for contrast-associated allergic reaction prevention ( 144 ). Three protocols have been used successfully for AVS: Unstimulated sequential or simultaneous bilateral AVS; 2. Unstimulated sequential or simultaneous bilateral AVS followed by bolus cosyntropin-stimulated sequential or simultaneous bilateral AVS; and 3. Continuous cosyntropin infusion with sequential bilat - eral AVS.", + "tokenCount": 107, + "pageStart": 26, + "pageEnd": 26, + "hash": "8e3631aff58597d9db0af5399480832ecef873c667d8ea1a658f8096c4173dd2" + }, + { + "text": "Simultaneous bilateral AVS is difficult to per - form and is not used at most centers ( 145,146 ). Many groups advocate the use of continuous cosyntropin infusion during AVS to minimize stress-induced fluctuations in aldosterone secretion during nonsimultaneous (sequential) AVS, maximize the gradient in cortisol from adrenal vein to inferior vena cava and thus confirm successful sampling of the adrenal vein, and maximize the secretion of aldosterone from an APA and thus avoid the risk of sampling during a rela - tively quiescent phase of aldosterone secretion ( 85 , 147-149 ).", + "tokenCount": 130, + "pageStart": 26, + "pageEnd": 26, + "hash": "1354869a7b6f5cd3ec821efca208f99555d441cd6dfd2ed6ab8153419b95eee1" + }, + { + "text": "However, there is a lack of consensus on the use of cosyntro - pin stimulation to assess for lateralization ( 150 ). Aldosterone and cortisol concentrations are measured in the blood from all 3 sites (right and left adrenal veins and in - ferior vena cava [IVC]).", + "tokenCount": 60, + "pageStart": 26, + "pageEnd": 26, + "hash": "474188e1f0e0312a87195a7a36bb4cd5d3ac4e2c71b4866568b9fcfb50984223" + }, + { + "text": "The IVC sample may be obtained from veins that are even more peripheral (eg, external iliac vein) ( 141 ). All of the blood samples should be assayed at 1:1, 1:10, and 1:50 dilutions; absolute values and accurate la - boratory assays for cortisol and aldosterone are essential for successful interpretation of the AVS data.", + "tokenCount": 79, + "pageStart": 26, + "pageEnd": 26, + "hash": "232689154c4b1c0b0b106a9faf1087c0b532447efc359e0abd66354ff7777250" + }, + { + "text": "The interpretation of AVS results relies on several key indi - ces and their corresponding cutoff values, which help deter - mine the success of the sampling procedure and the lateralization of aldosterone excess ( Table 9 ).", + "tokenCount": 45, + "pageStart": 26, + "pageEnd": 26, + "hash": "2465744ff71d2e0f9bf83af0edc7568049dadcc9c98834e03a72943f091918bc" + }, + { + "text": "The cortisol con - centrations from the adrenal veins and IVC are used to confirm successful cannulation of both adrenal veins. With cosyntropin protocols, an adrenal vein to IVC cortisol ratio (referred to as the selectivity index ) of more than 5:1 is required to be confi - dent that the adrenal veins were successfully catheterized ( 141 ).", + "tokenCount": 80, + "pageStart": 26, + "pageEnd": 26, + "hash": "3968f1d754572a79ce57a4e68489b688b90f6eb85a2abd05c2a8a08cfb4a0cb4" + }, + { + "text": "When cosyntropin is not used, a selectivity index of more than 1.4 to 3.0 is a threshold that has been used to verify successful catheterization ( 150-152 ).", + "tokenCount": 41, + "pageStart": 26, + "pageEnd": 26, + "hash": "c2612dd45c255f761372adb2a19ac70621fa734c9555a7fb5fc9f4bb8f266302" + }, + { + "text": "Use of intraprocedural cortisol measurement has been shown to improve bilateral ad - renal vein catheterization success rates ( 153 ). Dividing the right and left adrenal vein aldosterone concentra - tions by their respective cortisol concentrations corrects for dilu - tional effects of the inferior phrenic vein flowing into the left adrenal vein and, if suboptimally sampled, of IVC flow into the right adrenal vein catheter.", + "tokenCount": 93, + "pageStart": 26, + "pageEnd": 26, + "hash": "6574779ad8519879f16bdfdeac0718830ed759f6a59e22666e7b50813613ea8d" + }, + { + "text": "These are termed cortisol-corrected al - dosterone ratios . With unstimulated or continuous cosyntropin administration, clinicians use a cutoff of the cortisol-corrected al - dosterone ratio from high-side to low-side of more than 4:1 (re - ferred to as the lateralization index ) to indicate lateralizing aldosterone excess ( 85 ); a lateralization index less than 3:1 sug - gests bilateral aldosterone hypersecretion.", + "tokenCount": 99, + "pageStart": 26, + "pageEnd": 26, + "hash": "3759ee51a9368b9ccf5151b433df33d5827da5fb41e4d391ac56832d29f95001" + }, + { + "text": "Individuals with a lat - eralization index between 3:1 and 4:1 may have either lateralizing or bilateral disease, and the AVS results must be cau - tiously interpreted in conjunction with the clinical setting, CT scan, and the contralateral suppression of aldosterone secretion.", + "tokenCount": 62, + "pageStart": 26, + "pageEnd": 26, + "hash": "ba6ccb908ad7aa09dfcf59d4b65704a50c95b7490b4a03dcc26794878ff4bb15" + }, + { + "text": "2478 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 62, + "pageStart": 26, + "pageEnd": 26, + "hash": "72580a1bb7eea39d0b93eeda12ea01e51b1c9702f4e54a646c02dee0a56c2d81" + }, + { + "text": "Although the use of cosyntropin clearly improves the selectivity index, there is debate on its impact on accurate lateralization. In a retrospective cohort study of 340 patients with primary al - dosteronism, bilateral simultaneous AVS was performed before and after the administration of cosyntropin ( 154 ).", + "tokenCount": 62, + "pageStart": 27, + "pageEnd": 27, + "hash": "adf2e745749762237bce00551ca47116af994873efcac2c4d410682f579f815d" + }, + { + "text": "Using a lateral - ization index of > 4:1, there was a 19% discordance rate between pre- and post-cosyntropin data sets. More than half (64%) of the discordance was due to apparent lateralizing adrenal disease prior to cosyntropin administration that was reinterpreted as bilateral disease after cosyntropin ( 154 ).", + "tokenCount": 76, + "pageStart": 27, + "pageEnd": 27, + "hash": "d0d5ca50db13207ffaf50a3109d920c60eaa2a5b6fafc69b4cedab13bb42b700" + }, + { + "text": "In the same publication, the au - thors reported that 10 of 11 similar studies that they reviewed demonstrated either no change or a decrease in lateralization rates following cosyntropin stimulation. Most studies have found no difference in post-adrenalectomy outcomes with or without cosyntropin-stimulated AVS ( 151 , 154 , 155 ) while others found that the post-cosyntropin lateralization index correlated better with positive postoperative clinical outcomes than the unstimu - lated lateralization index ( 156 ).", + "tokenCount": 107, + "pageStart": 27, + "pageEnd": 27, + "hash": "ad28357dbeb7d41d034f00e478f6ec9493ca5d1c90a81f7ab5fb49bfe676a5de" + }, + { + "text": "Finally, in most individuals with lateralizing disease, with cosyntropin-stimulated AVS, the aldosterone to corti - sol ratio from the nondominant adrenal vein is lower than the aldosterone to cortisol ratio in the IVC, termed the contralateral suppression index ( 157 ). When AVS is per - formed without cosyntropin stimulation, and the aldoster - one concentration from the nondominant adrenal is divided by the IVC aldosterone concentration, a cutoff of < 2.15 correlates with postoperative clinical outcomes ( 158 ).", + "tokenCount": 120, + "pageStart": 27, + "pageEnd": 27, + "hash": "81df5cbdab7c1afb809d632c41b802fd55233399092e12069c488c5e6acb4a91" + }, + { + "text": "Use of the contralateral suppression index remains controver - sial and more work is required to validate this and other in - dices of lateralization. Comments For accurate interpretation of AVS, it is important that serum potassium concentration is normal and renin is suppressed.", + "tokenCount": 55, + "pageStart": 27, + "pageEnd": 27, + "hash": "1337af921e894b1673c71c3e7d884d7dd49d2cfa8f874560f9f57d5898e905ee" + }, + { + "text": "It is also important that blood pressure is well controlled, and this may necessitate the use of antihypertensive agents. Antihypertensive agents (eg, diuretics, angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], or MRAs) do not interfere with AVS as long as renin is low ( 159 , 160 ).", + "tokenCount": 83, + "pageStart": 27, + "pageEnd": 27, + "hash": "7c6169d31bd805e06ca02e784e8e475e6686efa4b9fc4cbd2740b0f8f10caaa2" + }, + { + "text": "If renin is not suppressed, changes in the antihypertensive program should be considered before AVS. Drugs that have minimal effect on renin may include selective α 1 -receptor antagonists (eg, doxazosin, terazosin, prazosin) and long-acting dihydropyridine (eg, amlodipine, felodipine) or non-dihydropyridine calcium-channel blockers (eg, verap - amil, diltiazem).", + "tokenCount": 108, + "pageStart": 27, + "pageEnd": 27, + "hash": "7e78ab8415e29df9b498acfdc70182728cd447f8aaff5c0b66012801fef7ef34" + }, + { + "text": "There are 4 exceptions to the suggested requirement for AVS prior to surgery: • Most young individuals (eg, age < 35 years) who have marked PA (eg, spontaneous hypokalemia, plasma aldosterone con - centration > 30 ng/dL [ > 832 pmol/L] by immunoassay or > 22.5 ng/dL [ > 624 pmol/L] by liquid chromatography – tan - dem mass spectrometry [LC-MS/MS], and suppressed renin), and a unilateral adrenal mass with radiologic features consist - ent with a cortical adenoma on adrenal CT scan.", + "tokenCount": 133, + "pageStart": 27, + "pageEnd": 27, + "hash": "b886faf9df8f950779bfc250e8fb1a43826d1967030ceb72fc0d9a6bbf5fb95b" + }, + { + "text": "Adrenal in - cidentalomas are very uncommon in individuals aged < 35 years (0.28%) ( 161 ), and marked PA is usually associated with a CT-detectable adrenal nodule ( 162-164 ).", + "tokenCount": 47, + "pageStart": 27, + "pageEnd": 27, + "hash": "4f5d97c69c09276f708efb766009c3bf5b6bdd89939c0dd797d0d0698f01be38" + }, + { + "text": "Thus, in young individuals (eg, age < 35 years) with marked PA and a > 1.0-cm unilateral adrenal nodule on CT, unilateral adre - nalectomy without prior AVS can be considered.", + "tokenCount": 47, + "pageStart": 27, + "pageEnd": 27, + "hash": "0398f5773cce60dee1a179ff2bb51b0f72d692256c5938e3909f91a0e191213b" + }, + { + "text": "• Individuals with a unilateral adrenal macroadenoma ( > 1 cm) who have both PA and clinically important corti - sol secretory autonomy. The source of clinically important cortisol secretory autonomy is the unilateral adrenal mac - roadenoma, and a localization study (eg, AVS) is not needed.", + "tokenCount": 65, + "pageStart": 27, + "pageEnd": 27, + "hash": "18263f36f7442dc7551ce073545c1ccb0af87e72912b415625affda0c5c5dc6e" + }, + { + "text": "• Individuals with familial hyperaldosteronism (types I-IV). These autosomal-dominant disorders are each linked to specific germline pathogenic variants ( 165 , 166 ). These in - dividuals have bilateral adrenal disease, and AVS is not re - quired (Question 4.) Adrenalectomy is usually not indicated in individuals with familial PA.", + "tokenCount": 75, + "pageStart": 27, + "pageEnd": 27, + "hash": "a37068ead67118858bb466680ca72de382c0d554d689b36a07ffdef2e43a4d10" + }, + { + "text": "• Individuals with primary bilateral macronodular adrenal hyperplasia (PBMAH) who have excessive production of both cortisol and aldosterone ( 167 ). These individuals have bilateral adrenal disease, and AVS is not required.", + "tokenCount": 48, + "pageStart": 27, + "pageEnd": 27, + "hash": "5378388ea182606a21038d3ca6ad6c68ece219e494403c6e3fe084a7884ff382" + }, + { + "text": "Research Considerations One of the long-term goals for subtype evaluation is to decrease the reliance on specialized interventional radiologists for AVS. Positron emission tomography (PET)-based imaging with aldos - terone synthase – specific molecules is under investigation as a method to identify whether excess adrenal aldosterone production is lateralizing or bilateral ( 168-170 ).", + "tokenCount": 78, + "pageStart": 27, + "pageEnd": 27, + "hash": "d8812e724481867a15f640797683a0445c2c2ef94f8679d81afd9c7cb9e0f749" + }, + { + "text": "A recent study showed that pretreatment with dexamethasone converts 11 C-metomidate from a nonselective ligand for CYP11B1 and CYP11B2 into an in vivo selective CYP11B2 ligand ( 171 ).", + "tokenCount": 54, + "pageStart": 27, + "pageEnd": 27, + "hash": "d21c4b13c0658eb22d0331e43a9d4a13178ba9030ce2f05699dcfeafaec47e9b" + }, + { + "text": "In 93 patients with PA and CT-detected adrenal nodules who were treated surgically, dexamethasone-suppressed 11 C-metomidate PET-CT was nonin - ferior to AVS in diagnosing lateralizing PA ( 171 ).", + "tokenCount": 55, + "pageStart": 27, + "pageEnd": 27, + "hash": "d273d56b170d48febe6ad76fafc7f6f7fa04b2313bea6c0a93295216adaa12f4" + }, + { + "text": "In addition, the C-X-C chemokine receptor 4 (CXCR4) is a G protein-coupled transmembrane receptor overexpressed in APAs and exhibits low to undetectable expression levels in normal adrenal tissues and nonfunctional adenomas ( 172 ).", + "tokenCount": 62, + "pageStart": 27, + "pageEnd": 27, + "hash": "132da3c5c365acfc230caaf0d791bda109cfa690393076e4b02491f011873e85" + }, + { + "text": "68 Ga-pentixafor is a radionuclide imaging ligand specifically targeting CXCR4 ( 173 ). In 63 patients with PA who were treated surgically, 68 Ga-pentixafor PET-CT was noninferior to AVS in diagnosing lateralizing PA ( 174 ).", + "tokenCount": 63, + "pageStart": 27, + "pageEnd": 27, + "hash": "b0802b80969b3debc3963d884c5266a8b69fcd2cfe81cace9060b8f33e5a0467" + }, + { + "text": "Suppressed vs Unsuppressed Renin in Individuals With Primary Aldosteronism Receiving Primary Aldosteronism–Specific Medical Therapy Background Although aldosterone-directed medical therapy has been shown to be beneficial in primary aldosteronism (PA), the op - timal approach to dosing and surveillance is uncertain.", + "tokenCount": 66, + "pageStart": 27, + "pageEnd": 27, + "hash": "9e33c5ea745ad7fd93e0743b199d7cc0bd735bc8fa4a7cdf70fac0ef7b8d0432" + }, + { + "text": "Whether renin should be used to guide treatment has been considered in prior studies and by consensus groups. The premise of using renin as a biomarker of PA-specific medical therapy stems from the general knowledge of the physiology of endocrine hormone excess (ie, decline in hormone excess or activity is reflected in a rise of the proximal regulatory hor - mone).", + "tokenCount": 73, + "pageStart": 27, + "pageEnd": 27, + "hash": "d3ee2862a091b47bfa11b1ea2d62306ea8a6d8f644832d27c44ce6396c92d33f" + }, + { + "text": "Since PA is characterized and diagnosed by aldoster - one production despite suppression of renin and angiotensin II, a rise in renin induced by aldosterone-directed medical therapy should reflect the reversal of PA pathophysiology that may portend improved clinical outcomes ( 175 ).", + "tokenCount": 58, + "pageStart": 27, + "pageEnd": 27, + "hash": "331ad25492d3b0e523b6cc6533e0c6e630b38d4e1e1d592eb9ba98a2d70a70b5" + }, + { + "text": "Question 7. Should suppressed renin vs unsuppressed renin be used in individuals with primary aldosteronism receiving primary aldosteronism–specific medical therapy? The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No.", + "tokenCount": 56, + "pageStart": 27, + "pageEnd": 27, + "hash": "b3ca32f9ad3872916567a2a7d279c62989edbe1a5509d66f297bd2f7bd29bacd" + }, + { + "text": "9 2479 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 42, + "pageStart": 27, + "pageEnd": 27, + "hash": "1898fe2ca73c448dc16d4b090ce77830dd9e5338298df00741d363a825d27b20" + }, + { + "text": "Recommendation 7 In individuals with primary aldosteronism (PA) receiv - ing PA-specific medical therapy whose hypertension is not controlled and renin is suppressed, we suggest increasing PA-specific medical therapy to raise renin (2 | ⊕ OOO).", + "tokenCount": 56, + "pageStart": 28, + "pageEnd": 28, + "hash": "a000cb20019f307e3c2c3781295271f2a7cf7f7b92a47716b8aec956702a403b" + }, + { + "text": "Technical remarks: • This recommendation applies to individuals with PA receiving aldosterone-directed medical ther - apy whose blood pressure (BP) remains high. Uncertainty remains as to whether titrating aldosterone-directed medical therapy to raise re - nin when BP is controlled is efficacious.", + "tokenCount": 60, + "pageStart": 28, + "pageEnd": 28, + "hash": "6ed41a07937da2376e9e8e6df2d91a4de69f155f7fe330e422afdc75d2784e89" + }, + { + "text": "• The panel does not specify a renin level to target but rather advises titration of aldosterone-directed medical therapy to a rise in renin from pretreat - ment baseline. Summary of the Evidence The meta-analysis results, a detailed summary of the evidence and Evidence to Decision (EtD) tables can be found online at https:/ /guidelines.gradepro.org/profile/EHqkK_8QHm8 .", + "tokenCount": 94, + "pageStart": 28, + "pageEnd": 28, + "hash": "0a5e354fc3d4cb6298ac90f5c33918ccbc8f90cd0c00833c6e1e3b6ba5e23a6b" + }, + { + "text": "Benefits and Harms The panel voted for the following patient-important outcomes for Question 7 decision making: 1) percent of individuals achiev - ing BP control, 2) number of antihypertensive agents, 3) dosage of antihypertensive agents, 4) systolic BP (SBP) level, 5) major ad - verse cardiovascular events (MACEs), 6) atrial fibrillation, 7) stroke, 8) ischemic heart disease, 9) heart failure, 10) cardiovas - cular mortality, 11) all-cause mortality, and 12) adverse events.", + "tokenCount": 126, + "pageStart": 28, + "pageEnd": 28, + "hash": "296b7c9fd52b46f9f1a560600f3ec687ad5bdd09b5b3a59c4211814f7aea303b" + }, + { + "text": "Our systematic review ( 53 ) identified 11 studies that evaluated the impact of increasing renin with aldosterone-directed medical therapy when compared with persistently suppressed renin. When compared with unsuppressed renin, suppressed renin dur - ing aldosterone-directed medical therapy was associated with in - creases in mortality; risk for stroke, atrial fibrillation, and hypokalemia; and number of antihypertensive medications.", + "tokenCount": 91, + "pageStart": 28, + "pageEnd": 28, + "hash": "31123174a3a72a4817663750d6b30ee3eb9838e3236a270dd88fee6bd6622e8a" + }, + { + "text": "There were no statistically significant differences in MACEs (eg, ischemic heart disease, heart failure) in the meta-analysis. In indi - vidual retrospective cohort studies, a rise in renin to a level higher than 1.0 ng/mL/h was associated with lower risk for MACEs when compared with persistently suppressed renin ( 7 , 69 ).", + "tokenCount": 79, + "pageStart": 28, + "pageEnd": 28, + "hash": "7536e5b954b36c373a36724c95a5aeb2b4313131001fa1ffb2d56dc7fa97dca0" + }, + { + "text": "In this regard, the addition of renin measurements does not pose a substantial increase in resource utilization. However, the add - itional costs of measuring renin may be a limiting factor or pro - hibitive to some clinicians and increase health disparities.", + "tokenCount": 51, + "pageStart": 28, + "pageEnd": 28, + "hash": "2618825437f5f191d97eb23e4bbbd3ac312805faee4df298d5419381c21e0abf" + }, + { + "text": "In balance, targeting a rise in renin may be associated with a lower risk of death, stroke, and atrial fibrillation, but the pooled analysis did not demonstrate statistically significant re - duction in the risk for MACEs.", + "tokenCount": 49, + "pageStart": 28, + "pageEnd": 28, + "hash": "29c59d8d0e89726fb57d29bf065089bbab97133d571687deb3964ce8a67be0dd" + }, + { + "text": "Evidence to Decision Factors • No studies were found that assessed the cost-effectiveness of targeting renin in PA-directed medical therapy. • There is an obligate cost associated with measuring renin and measuring it frequently during longitudinal care.", + "tokenCount": 47, + "pageStart": 28, + "pageEnd": 28, + "hash": "8e7819fe5ace5456800c513f91e50ca90c858a9231a5df501c49cf367bcf1de7" + }, + { + "text": "• If the studies suggesting that increasing renin with min - eralocorticoid receptor antagonist (MRA) therapy can mitigate some of the risk for incident cardiovascular and kidney disease are confirmed or validated, the additional cost of measuring renin is likely to be cost-effective.", + "tokenCount": 57, + "pageStart": 28, + "pageEnd": 28, + "hash": "233584b16ff9c5dcd8d92e945f81ae23a762469893f8de7cc6951d51fe54e064" + }, + { + "text": "• No studies were found that assess the impact of targeting renin in PA-directed therapy on health equity. • As stated, the costs of measuring renin, in addition to the standard longitudinal follow-up and monitoring for med - ical therapy for PA, may be a limiting factor for some clini - cians (specifically in areas where this test is not readily available).", + "tokenCount": 78, + "pageStart": 28, + "pageEnd": 28, + "hash": "ab04c68e8b81763118f83d458e8dd565f457587dc98aac81dbf588a9856347ef" + }, + { + "text": "• No research evidence was identified for acceptability by the health care workers or feasibility. • Measurement of renin to guide medical therapy is likely feas - ible at most centers that routinely treat individuals with PA.", + "tokenCount": 43, + "pageStart": 28, + "pageEnd": 28, + "hash": "f2bae773447153078e7d99b89517f06b8c4d50d9c5212c8f23cb14e4b5753cb6" + }, + { + "text": "Justification for the Recommendation Because the pathophysiology of PA in most individuals man - ifests with suppressed renin, a rise in renin with MRA therapy serves as a biomarker indicating a restoration of physiology (ie, sufficient mineralocorticoid receptor [MR] blockade and reduction in extracellular volume) ( 175 ).", + "tokenCount": 69, + "pageStart": 28, + "pageEnd": 28, + "hash": "02ecfa9be8eafc502d69ef21fdc71e43a2702935e945191fdb6e081ba27e4045" + }, + { + "text": "The summary of sev - eral observational studies suggests that this practice is associ - ated with statistically lower risks of death and atrial fibrillation as well as a lower number of antihypertensive med - ications and risk for hypokalemia.", + "tokenCount": 54, + "pageStart": 28, + "pageEnd": 28, + "hash": "5d6098c88c55ea9efb4f0116e6a63eaa9ecfff4a64f101f5c938d1e829ff8e96" + }, + { + "text": "Importantly, the primary clinical objective of MRA therapy remains normalizing BP with the fewest number of medications (and normalizing po - tassium, when applicable); however, achieving a rise in renin is suggested as an additional objective that reflects a better prognosis ( 175 ).", + "tokenCount": 57, + "pageStart": 28, + "pageEnd": 28, + "hash": "498c0a4e698035c12386c3b26341235cde140e9c4e0a26546d74a3e730e58d39" + }, + { + "text": "Caveats to this approach include that this evidence stems from observational studies susceptible to bias and residual confounding, that there is no direct evidence to dictate what renin threshold to target as optimal, that this approach may not be possible or feasible or necessary in all individuals, that there are different methods to measure renin (activity and concentration) and no consensus on which one is more accurate, and that intensification of MRA therapy to achieve this objective may induce more adverse effects.", + "tokenCount": 95, + "pageStart": 28, + "pageEnd": 28, + "hash": "350f1cb4f6c6f1dc070bb406cade2b2ad4fc7cbe0c55c6ee10b654328fbd0f79" + }, + { + "text": "For these rea - sons, we suggest focusing on dose intensification of MRA therapy to raise renin, particularly in individuals whose BP is not controlled. Once BP is controlled, non-MRA medica - tions can be lowered or removed, when possible, thus allow - ing further increases of MRA dosing and attempts to raise renin ( Fig.", + "tokenCount": 75, + "pageStart": 28, + "pageEnd": 28, + "hash": "b1941c24fbb2308673bfff88ebff4b7144d395cb1af2c840d3be95115b623451" + }, + { + "text": "Furthermore, interpretation of renin levels may be hampered in individuals concomitantly receiving other medications that affect renin levels (eg, β -adrenergic blockers that lower renin or renin – angiotensin – aldosterone system [RAAS] inhibitors that may raise renin in synergy with MRAs).", + "tokenCount": 66, + "pageStart": 28, + "pageEnd": 28, + "hash": "e71c12f8ceb00a1343beee635c36422da8ccb687b878e90f22553991c6bc3fc7" + }, + { + "text": "Rather than targeting a specific renin thresh - old, we suggest that the observation that renin has in - creased from its pretreatment baseline should provide some reassurance of treatment efficacy. Consistent with this recommendation, a recent large international consen - sus group endorsed targeting a rise in renin when imple - menting aldosterone-directed medical therapy to a level higher than 1.0 ng/mL/h (plasma renin activity [PRA]) or 10 mU/L (direct renin concentration [DRC]) ( 85 ).", + "tokenCount": 115, + "pageStart": 28, + "pageEnd": 28, + "hash": "aa2a998c8a56f76655e9ab6ad6b8d67eddac512af9984bb6fbabbce8644c5e50" + }, + { + "text": "2480 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 62, + "pageStart": 28, + "pageEnd": 28, + "hash": "6e627c7ffc7dd4636f1c2f7c1aafc6d6bc4160d62b49b2cbce5cd470b6c3ebdf" + }, + { + "text": "Comments Special populations: • Individuals with hyperkalemia/chronic kidney disease (CKD) stage 3 and above: Achieving an increase in renin with MRA therapy is challenging in individuals with CKD.", + "tokenCount": 46, + "pageStart": 29, + "pageEnd": 29, + "hash": "5a8316aad4ed892e3d481eff43843034576fa7291c6b99ed4d0a723ec645eaed" + }, + { + "text": "The ability to produce and secrete renin may be im - paired with advanced CKD and higher MRA doses, which may increase the risk for hyperkalemia. As such, targeting an increase in renin in CKD may not always be a feasible or practical clinical objective.", + "tokenCount": 58, + "pageStart": 29, + "pageEnd": 29, + "hash": "3d447b34be3bf3fcdd12451f6c4507ac167b13b885163eb8a1f57056efa73919" + }, + { + "text": "However, since the nonsteroidal MRA finerenone has been shown to reduce adverse cardiovascular and kidney outcomes in 3 large randomized controlled trials (RCTs) of individ - uals with diabetes and CKD or heart failure ( 176-178 ), it is reasonable to treat individuals with PA and CKD with MRAs as long as serum potassium is monitored.", + "tokenCount": 74, + "pageStart": 29, + "pageEnd": 29, + "hash": "580f798a65cd2e080175cb89280adaa51877f0cad9f55761a9ce1d8bdce9155a" + }, + { + "text": "When encountering hyperkalemia in CKD, the use of concur - rent diuretics, sodium-glucose cotransporter (SGLT2) in - hibitors, and patiromer/novel potassium binders have all been shown to mitigate the risk of MRA-induced hyper - kalemia in RCTs ( 179 , 180 ).", + "tokenCount": 79, + "pageStart": 29, + "pageEnd": 29, + "hash": "8ae7d34f1cdf38f0244f7d5e91c009aad7006634e9b1c782b7b29bad1a3c3c7c" + }, + { + "text": "• Individuals taking medications that influence renin: The use of some concurrent medications may confound the in - terpretation of renin. β -Adrenergic blockers can lower re - nin secretion; therefore, individuals on high doses may not manifest an increase in renin with MRAs.", + "tokenCount": 59, + "pageStart": 29, + "pageEnd": 29, + "hash": "81aad8d7c912a858030fd1a77d66b42270fb3284bd127025d886086cba33c0a5" + }, + { + "text": "High dietary so - dium intake can lower renin, whereas a sodium-restricted diet can increase renin ( 181 ); however, most of the global population consumes a relatively high dietary sodium con - tent known to expand intravascular volume and put downward pressure on renin.", + "tokenCount": 56, + "pageStart": 29, + "pageEnd": 29, + "hash": "4c8d277ea3631d6c7c157d74a0ef9b0b03b1f578439c1ba61a50c7add6286254" + }, + { + "text": "The use of angiotensin- converting enzyme [ACE] inhibitors/angiotensin receptor blockers [ARBs] and diuretics can raise renin and thereby potentially confound the isolated effect attributable to MRA therapy.", + "tokenCount": 47, + "pageStart": 29, + "pageEnd": 29, + "hash": "4e90d42225fc700f28f959e558d6a693cdada3f6dad8418207312ac750fbfa22" + }, + { + "text": "Research Considerations Current gaps in knowledge call for further research in the fol - lowing area: • Conducting prospective, randomized, controlled studies with surrogate outcomes (eg, cardiac imaging, vascular dynamics) and hard outcomes to robustly assess the effi - cacy of targeting a rise in renin with aldosterone-directed medical therapy Dexamethasone Suppression Testing in Individuals With Primary Aldosteronism and an Adrenal Adenoma Background Assessing cortisol production is considered routine practice in individuals with an adrenal adenoma due to the increased car - diometabolic risks of excess cortisol exposure.", + "tokenCount": 123, + "pageStart": 29, + "pageEnd": 29, + "hash": "8e3cc316ab2db0c30f5e441d644303906d7e5b258e9117b2ef9cd899196c6555" + }, + { + "text": "In individuals with primary aldosteronism (PA), 24-hour urine steroid metabolome studies and dexamethasone suppression tests in - dicate that autonomous cortisol secretion (ACS) is not uncom - mon.", + "tokenCount": 46, + "pageStart": 29, + "pageEnd": 29, + "hash": "d5c201c0cbede5dc1c0d6c3f260462580e0bef9a57ec253a2c2fef417d58a3b9" + }, + { + "text": "Furthermore, excess cortisol production in individuals with PA may affect interpretation of AVS results and/or lead to postoperative glucocorticoid deficiency in those with aden - omas co-secreting aldosterone and cortisol.", + "tokenCount": 48, + "pageStart": 29, + "pageEnd": 29, + "hash": "a4fc86ffac7bd9fd393e774291787ba700b823c889e780da5740eaaeaad5d4ec" + }, + { + "text": "Question 8. Should a dexamethasone suppression test vs no dexamethasone suppression test be used in individuals with primary aldosteronism and adrenal adenoma? Recommendation 8 In individuals with primary aldosteronism (PA) and adrenal adenoma, we suggest a dexamethasone sup - pression test (2 | ⊕ OOO).", + "tokenCount": 83, + "pageStart": 29, + "pageEnd": 29, + "hash": "885af86625175e69d709f58513b2b6e3980a1b4cde19de41c12a3fa846a4fc35" + }, + { + "text": "Technical remarks • A dexamethasone suppression test should be per - formed, and a positive test should prompt further evaluation for Cushing syndrome as detailed in the Endocrine Society Clinical Practice Guidelines.", + "tokenCount": 40, + "pageStart": 29, + "pageEnd": 29, + "hash": "34cf79dc34bf58093b5bfeeaa13364883d90977d65d80a362205c0749c6125e1" + }, + { + "text": "• For the 1-mg overnight dexamethasone suppres - sion test, 1 mg dexamethasone is taken orally at 23:00 to 24:00 with serum cortisol measured at 08:00 to 09:00 the next morning.", + "tokenCount": 53, + "pageStart": 29, + "pageEnd": 29, + "hash": "5fa30271643d972272d1d306048505e890ad4c8f47fde0c7ee1e038413f5392a" + }, + { + "text": "A serum cortisol > 1.8 μ g/dL (50 nmol/L) suggests autonomous cor - tisol secretion (ACS). • For individuals with mild ACS, measuring plasma metanephrine during adrenal venous sampling (AVS) may help lateralize both aldosterone and cor - tisol secretion although further research is needed.", + "tokenCount": 72, + "pageStart": 29, + "pageEnd": 29, + "hash": "f90a9bd28e9b6c8c8114bb88f2268baaa0ec36ad02cf06daf28fffa73c0e8a19" + }, + { + "text": "It will also be important to measure early morning cortisol following adrenal surgery and prepare for a period of possible glucocorticoid insufficiency. Summary of the Evidence The meta-analysis results, a detailed summary of the evidence and Evidence to Decision (EtD) tables can be found online at https:/ /guidelines.gradepro.org/profile/vRFNnZpoKZY .", + "tokenCount": 85, + "pageStart": 29, + "pageEnd": 29, + "hash": "21c63e6ab87a83e5388b1437c01c970cbccffd95e6f17bba03f3ff3c0ddca581" + }, + { + "text": "Benefits and Harms The panel voted for the following patient-important outcomes for Question 8 decision making: 1) postoperative adrenal in - sufficiency, 2) ACS detection, 3) false lateralization, 4) AVS accuracy and 5) adverse events.", + "tokenCount": 54, + "pageStart": 29, + "pageEnd": 29, + "hash": "b59e3a88afae0297a375a05b5263175047a089a085f445ed46de7b25d0e40d81" + }, + { + "text": "As the systematic review did not identify any studies that directly address this question, additional relevant studies were evaluated. A number of retrospective cohort studies reported that ap - proximately 5% to 15% of individuals with PA have ACS as defined by a positive 1-mg dexamethasone suppression test with a cortisol concentration more than 1.8 μ g/dL (50 nmol/ L) ( 182-186 ).", + "tokenCount": 84, + "pageStart": 29, + "pageEnd": 29, + "hash": "4ae0e825a79b95dd0d628f4118fe929f8b41033598aefd110bc49a532e2ebc90" + }, + { + "text": "A more recent systematic review of 16 studies published between 2000 and 2020, with data from 2862 indi - viduals with PA, reported a prevalence of 5% to 27% ( 187 ).", + "tokenCount": 41, + "pageStart": 29, + "pageEnd": 29, + "hash": "78fbe8f258463bbac2cdf283c2339c6e7f9a7a573183cd34b59de4958bab50d2" + }, + { + "text": "Studies have also reported increased cardio-metabolic-renal complications in individuals with PA and concurrent cortisol excess. The adverse consequences include worse glucose tolerance and diabetes ( 188-191 ), higher left ven - tricular mass index ( 192 ), more cardiovascular events ( 189 , 193 ), osteopenia/osteoporosis ( 189 , 194 ), and renal dysfunction ( 195 ).", + "tokenCount": 75, + "pageStart": 29, + "pageEnd": 29, + "hash": "e79ecdef3b4884faec99c7750e8f284073df1e3ad1bc13a7431cc6f8df6813d4" + }, + { + "text": "In individuals with PA who undergo AVS, studies indicate that ACS may complicate the interpretation of adrenal vein se - lectivity and lateralization of aldosterone production. Excess cortisol secretion may lead to lateralization of cortisol to The Journal of Clinical Endocrinology & Metabolism , 2025, Vol.", + "tokenCount": 62, + "pageStart": 29, + "pageEnd": 29, + "hash": "3daf036b5a859d72cb545495dea1541b20b20952e97f71e880ac88ede8796fc3" + }, + { + "text": "110, No. 9 2481 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 46, + "pageStart": 29, + "pageEnd": 29, + "hash": "625007eba728d52f68f3c4258b9b4ef8a15691c2d2a58fcb7b1a6d45c9198170" + }, + { + "text": "one side with underestimation of aldosterone production, as reflected by the aldosterone to cortisol ratio, on the same side ( 182 , 196 , 197 ). Cortisol production on the contralateral side may be suppressed and lead to the false assessment of in - adequate adrenal vein cannulation ( 196 ).", + "tokenCount": 63, + "pageStart": 30, + "pageEnd": 30, + "hash": "0c167b499b20669161cde0423fc8f65780b52d667e57e967f50f0864f144304e" + }, + { + "text": "Current evidence suggests that measurement of plasma metanephrine, which displays minimum fluctuation during stress and a higher adrenal to peripheral gradient compared to cortisol ( 198 , 199 ), is useful in these cases to assess selectivity and lateralization.", + "tokenCount": 48, + "pageStart": 30, + "pageEnd": 30, + "hash": "c896b51a3ffaa21a1b990da6335d26ff353532053d24888fb16cc039cad87ff9" + }, + { + "text": "Suggested thresholds include selectivity index > 12 and lateral - ization index > 4 where metanephrine replaced cortisol in the assessment of selectivity and lateralization ( 197 , 199-203 ).", + "tokenCount": 40, + "pageStart": 30, + "pageEnd": 30, + "hash": "c8539a647eb253268a8cad38e09c2bc0c23d8eed0dd5d1d40757987b28732bb9" + }, + { + "text": "However, issues with selectivity of adrenal vein catheteriza - tion and lateralization of aldosterone production have not been reported in all studies ( 183 ), possibly because AVS inter - pretation was mainly affected in individuals with post- dexamethasone cortisol more than 5 ug/dL (138 nmol/L) ( 204 ).", + "tokenCount": 72, + "pageStart": 30, + "pageEnd": 30, + "hash": "15f0f86d7fe26e6416b5b335d09cf88f1e7185635f31aae504f48f934622cef9" + }, + { + "text": "One study suggested that AVS performance under co - syntropin stimulation, instead of during unstimulated condi - tions, may overcome the need to measure metanephrines for the assessment of selectivity and lateralization ( 197 ).", + "tokenCount": 50, + "pageStart": 30, + "pageEnd": 30, + "hash": "eaae133feaaa4c68d3d100f08975f6c4da1b31166b747d41cf36af7c035e4632" + }, + { + "text": "For those with concurrent PA and ACS, surgical resection of the adrenal adenoma may lead to postoperative glucocorticoid insufficiency. A study of 108 individuals who underwent unilat - eral adrenalectomy for a range of reasons reported that 50% of those with concurrent PA and hypercortisolism (n = 12) devel - oped adrenal insufficiency requiring glucocorticoid replace - ment for a median period of 0.8 months ( 205 ).", + "tokenCount": 104, + "pageStart": 30, + "pageEnd": 30, + "hash": "3a4b0ebbe90a08cd1301f68f3d3be795cdc649d321aa58f3cec5e714d8c83292" + }, + { + "text": "The potential undesirable effect of performing a 1-mg dexa - methasone suppression test may be related to false-positive or false-negative results. False-positive results may lead to unneces - sary further investigations, although 24-hour urinary free corti - sol and midnight salivary cortisol are noninvasive and relatively accessible tests.", + "tokenCount": 72, + "pageStart": 30, + "pageEnd": 30, + "hash": "bcb86f4f9498d46911004efb5f313bbb833b3df687df1493e7b322f9cd11ab28" + }, + { + "text": "More invasive testing would only be conducted if multiple screening tests are positive. The dexamethasone sup - pression test is considered the most sensitive screening test, and false negatives are uncommon. A meta-analysis demonstrated a sensitivity of 98.6% (96.9%-99.4%), specificity of 90.6% (86.4%-93.6%), positive likelihood ratio of 10.5 (7.2-15.3), and negative likelihood ratio of 0.016 (0.007-0.035) ( 206 ).", + "tokenCount": 111, + "pageStart": 30, + "pageEnd": 30, + "hash": "eddfdab3a0e42176152a3f7f7bf9f1cabda0e30cc1717346b98288d94eb5db02" + }, + { + "text": "False-positive results can occur due to failure to correctly take dexamethasone, interfering medications such as anticonvulsants and other CYP3A4 inducers that increase dexamethasone deg - radation, and malabsorption of dexamethasone ( 207 ).", + "tokenCount": 61, + "pageStart": 30, + "pageEnd": 30, + "hash": "a7cc58a42e4c3a9ff77a488f18db91f29909df44912545084a50ef0a00fbd09e" + }, + { + "text": "This is - sue can be resolved with serum dexamethasone measurement. A range of other conditions may cause false-positive results, in - cluding oral estrogen use, obesity, major depression, alcohol use disorder, and acute illnesses.", + "tokenCount": 49, + "pageStart": 30, + "pageEnd": 30, + "hash": "bd5b2813af0d9ba98995065cd215f5319bc123316104fde6b9605bd0f61b7044" + }, + { + "text": "These are covered by guidelines for Cushing syndrome ( 208 ). Evidence to Decision Factors • The potential benefits obtained from doing a 1-mg dexa - methasone suppression test outweigh the potential harms, as outlined.", + "tokenCount": 43, + "pageStart": 30, + "pageEnd": 30, + "hash": "2844ed3c18ce5e57a8fb19c7c64d0e3cd2cca7b079a607b7f599f7340e03b7a6" + }, + { + "text": "• The dexamethasone suppression test requires minimal re - sources, which include dexamethasone tablets and a blood test for plasma cortisol concentration, and it is widely available worldwide. • We did not find any published studies on the cost- effectiveness of conducting a 1-mg dexamethasone sup - pression test.", + "tokenCount": 69, + "pageStart": 30, + "pageEnd": 30, + "hash": "5fed8ef0343fa41fe87348e15037eecd490b821b45dad7fd9487ffc4491dbd1d" + }, + { + "text": "However, it is known to be a relatively cheap and commonly ordered test in endocrinology. • If the result is abnormal, 2 follow-up tests (24-hour urin - ary free cortisol and midnight salivary cortisol) are also accessible and inexpensive.", + "tokenCount": 55, + "pageStart": 30, + "pageEnd": 30, + "hash": "c3733e566b8119329ac94724259746788f212e9f328b8c882322d57a87f0f3a6" + }, + { + "text": "• Furthermore, an understanding of normal adrenal cortisol secretion will reduce confounding in the interpretation of AVS results. Repeating AVS due to uninterpretable results is much more expensive ( ∼ $2000-3000 USD) than doing a 1-mg dexamethasone suppression test ( ∼ $20) and plan - ning AVS accordingly.", + "tokenCount": 71, + "pageStart": 30, + "pageEnd": 30, + "hash": "33317616521375ba36ea49a5c8f4dd59956ccf0a6f10428098bc1894df4c020d" + }, + { + "text": "• Individuals rarely decline the dexamethasone suppression test in clinical practice. They may occasionally experience adverse effects from the dexamethasone, but these effects are transient, as the dose of dexamethasone is low and the medication is given only once.", + "tokenCount": 55, + "pageStart": 30, + "pageEnd": 30, + "hash": "2f29d70df6dabe2aee12f1ad0669ac07ee39a08df087fbe35311913f6374ce46" + }, + { + "text": "Justification for the Recommendation The panel based its recommendation on evidence demonstrat - ing that ACS is not uncommon in individuals with PA and can be detected by dexamethasone suppression testing. Having ACS may lead to adverse cardiometabolic consequences, com - plicate the interpretation of AVS results, and predispose the individual to postoperative adrenal insufficiency following unilateral adrenalectomy.", + "tokenCount": 81, + "pageStart": 30, + "pageEnd": 30, + "hash": "be779cef54498793c71bf7a677669f665874dac08141c43c4532bf08d22c5946" + }, + { + "text": "The potential for harm from doing the dexamethasone suppression test is low and relates mainly to unnecessary investigations for Cushing syndrome. Therefore, the panel concluded that the balance of effects probably favors the intervention and that the test is feasible, accessible, and cost-effective.", + "tokenCount": 55, + "pageStart": 30, + "pageEnd": 30, + "hash": "31dc098a4d2d8b1decba36d23a7f3887f816da039be519be3fe61fd5597608c5" + }, + { + "text": "Comments Individuals with adrenally mediated, overt Cushing syndrome and unilateral adrenal adenoma may proceed to surgery, with - out AVS, to remove the source of excess cortisol. Research Considerations Current gaps in knowledge call for further research in the fol - lowing areas:", + "tokenCount": 56, + "pageStart": 30, + "pageEnd": 30, + "hash": "0a6355cf78e6e51670f912f6e6cd9a9cb9ae8be20212225272a8353c0d0aaa7e" + }, + { + "text": "• Determining the prevalence of mild autonomous cortisol excess, as indicated by an abnormal 1-mg dexamethasone suppression test, in individuals with PA who do not have an adrenal adenoma • Evaluating the role of adrenal and peripheral vein meta - nephrine for assessing selectivity and lateralization with the goal of improving guidelines on AVS interpretation in individuals with ACS • Prospectively evaluating dexamethasone suppression test results and their correlation with AVS and surgical out - comes to establish cortisol cutoffs that guide the need for specific care during AVS (eg, measurement of adrenal vein metanephrine) and the need for perioperative gluco - corticoid administration Medical Treatment for Individuals With Primary Aldosteronism:", + "tokenCount": 155, + "pageStart": 30, + "pageEnd": 30, + "hash": "210488ee580f599e2487ba005843aa12318ba9649c6fbda5fd018d4c2d66c2d5" + }, + { + "text": "Spironolactone vs Other Mineralocorticoid Receptor Antagonists Medical therapy for primary aldosteronism (PA) will likely become the central issue in PA care over the next decade as PA becomes more widely recognized ( 209 ).", + "tokenCount": 50, + "pageStart": 30, + "pageEnd": 30, + "hash": "53bcfedacf386a15e6fd266c8b19f1b29359ea4013770b5c318f48b68d780fd1" + }, + { + "text": "Modern PA series already show that, with expanded PA screening, an increasing majority of PA cases are nonsurgical, bilateral adrenal 2482 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol.", + "tokenCount": 43, + "pageStart": 30, + "pageEnd": 30, + "hash": "6714b007755e2c41df2ace3c8e5fe17a99b46a9b038235cd06ff48e4377a0d65" + }, + { + "text": "110, No. 9 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 44, + "pageStart": 30, + "pageEnd": 30, + "hash": "838dd5eb379613452959448b60e11bc1b5cf46655c5056a0432c7ee39628472d" + }, + { + "text": "hypersecretory states ( 210 ). Further, lack of access to AVS ne - cessitates guidance on specific MRA selection. Question 9. Should spironolactone vs other mineralocortic - oid receptor antagonists be used for primary aldosteron - ism–specific medical therapy?", + "tokenCount": 62, + "pageStart": 31, + "pageEnd": 31, + "hash": "be346e9e67911d31e5692aefddceaaeccaac498d9784016fae1ba2ddebc82b5a" + }, + { + "text": "Recommendation 9 In individuals with primary aldosteronism (PA) receiv - ing PA-specific medical therapy, we suggest spironolac - tone over other mineralocorticoid receptor antagonists (MRAs) due to its low cost and widespread availability (2 | ⊕ OOO).", + "tokenCount": 63, + "pageStart": 31, + "pageEnd": 31, + "hash": "9a752123230cc34a69ebc51ba0ec0dda3fc0c6e17450d2900d373bbc17855249" + }, + { + "text": "Technical remarks: • The recommendation is driven by the availability and low cost of spironolactone vs other MRAs; however, all MRAs, when titrated to equivalent po - tencies, are anticipated to have similar efficacy in treating PA.", + "tokenCount": 51, + "pageStart": 31, + "pageEnd": 31, + "hash": "cab1b5e3f815e9085542d4d861cf3601b6584bb93566e5440776b31959b661c9" + }, + { + "text": "MRAs with greater mineralocorticoid receptor (MR) specificity and fewer androgen/ progesterone receptor-mediated side effects may be preferred. • When initiating MRAs, consider hypertension se - verity for dosing and potential discontinuation of other antihypertensive medications ( Fig.", + "tokenCount": 60, + "pageStart": 31, + "pageEnd": 31, + "hash": "b83223165a40f6e3a89269fdee527d27d53ffc3bf0903654db0f5c76e8393b96" + }, + { + "text": "• Monitor potassium, renal function, renin (concentra - tion or activity), and blood pressure (BP) response during follow-up to guide MRA dose titration. Summary of the Evidence The meta-analysis results, a detailed summary of the evidence and Evidence to Decision (EtD) tables can be found online at https:/ /guidelines.gradepro.org/profile/FUa-5ocTKo4 .", + "tokenCount": 91, + "pageStart": 31, + "pageEnd": 31, + "hash": "fbc31ef1a748d5f6bd8cd387781924f87d9e7e36a5de3354648b5aba8ea4b27d" + }, + { + "text": "Benefits and Harms The panel voted for the following patient-important outcomes for Question 9 decision making: 1) percent of individuals achieving BP control, 2) number of antihypertensive agents, 3) dosage of antihypertensive agents, 4) systolic BP (SBP) level, 5) control of hypokalemia, 6) quality of life (QOL), and 7) adverse events.", + "tokenCount": 86, + "pageStart": 31, + "pageEnd": 31, + "hash": "f725db347a27c6035e17307927cf864c4af10bd1ceee29e959e214c6e3dd4140" + }, + { + "text": "The systematic review ( 53 ) identified 3 relevant randomized controlled trials (RCTs) ( 122 , 211 , 212 ), (n = 229) and 1 com - parative observational study (n = 188) with an equal distribu - tion of women and men ( 29 ).", + "tokenCount": 57, + "pageStart": 31, + "pageEnd": 31, + "hash": "13ac3a92cac18923c462acb4379c2bd061981f6644a95c270ac38e2bc6cc43d7" + }, + { + "text": "The meta-analysis concluded that eplerenone, compared with spironolactone, was associated with a higher number of antihypertensive agents and dosage of antihypertensive agents.", + "tokenCount": 40, + "pageStart": 31, + "pageEnd": 31, + "hash": "ac9b50cebccbd4ab8045c1aeaf5e9ae0f75e8181ffa4c71322ee52339ceeb838" + }, + { + "text": "However, the doses of the medications were not renin-guided to ensure dose-equivalent MR blockade. There were no statistically significant differences in achieving BP control, control of hypokalemia, and SBP level.", + "tokenCount": 45, + "pageStart": 31, + "pageEnd": 31, + "hash": "f64aeb1eed64b1938432251a03be2f3200032c3a760ea1980a91ee644dfcc6dd" + }, + { + "text": "Data from the direct evidence were insufficient to inform on broad issues of ad - verse events or QOL, although increased female breast pain and male gynecomastia were reported with spironolactone use.", + "tokenCount": 43, + "pageStart": 31, + "pageEnd": 31, + "hash": "ce39ac0ce2e095fa37e3b24ed9a4522965547f92336f5266ee2559bd676aa029" + }, + { + "text": "After completion of the systematic review, but prior to publication of these guidelines, a new study comparing short-term finerenone and low-dose spironolactone in PA was published demonstrating comparable blood pressure – lowering efficacy and effects upon serum potassium and renin concentration ( 213 ).", + "tokenCount": 57, + "pageStart": 31, + "pageEnd": 31, + "hash": "5ee8b57e1ae4a166a8f51335817c23d1817f6caf8c37b03ad89ddc23fb86261b" + }, + { + "text": "Spironolactone has far greater ability to block androgen ac - tion and affect progesterone action than does eplerenone. As this may be relevant to the issue of individual tolerability, the Guideline Development Panel (GDP) considered indirect evi - dence in the form of studies reporting use other than for a PA indication.", + "tokenCount": 72, + "pageStart": 31, + "pageEnd": 31, + "hash": "c357e89a03646d0131b0baaad9a13e748b84e8985263fe5036ad6499e9652cc3" + }, + { + "text": "Two systematic reviews/meta-analyses were found that compared spironolactone with eplerenone or canrenone ( 214 , 215 ). One meta-analysis of 14 studies and including 3745 individuals using spironolactone for non-PA indications showed a male gynecomastia incidence rate of 7.9% vs 0.6% among placebo users (OR:", + "tokenCount": 80, + "pageStart": 31, + "pageEnd": 31, + "hash": "faad465ff311b3e9f4be5c20e53e5d1d203350bb299eda02eaaabc0f6cb525d3" + }, + { + "text": "8.39 [5.02-13.99]), although this was still less than that observed in users of anti-androgens or ris - peridone ( 214 ). Among users of MRAs or placebo for heart fail - ure, spironolactone had a relative odds of 8.44 (3.9-18.2) vs eplerenone 0.77 (0.31-1.88) for male gynecomastia ( 215 ).", + "tokenCount": 99, + "pageStart": 31, + "pageEnd": 31, + "hash": "2acb7208d5156bae1783df7406edbf893af73176194d9b12f8d7e771534d28fc" + }, + { + "text": "Evidence to Decision Factors • Studies specifically comparing spironolactone vs other MRAs in medical PA treatment were few in number, small in size, and judged to be low quality. All used surrogate outcomes (eg, BP changes or serum potassium levels), typically ascer - tained after short treatment intervals.", + "tokenCount": 62, + "pageStart": 31, + "pageEnd": 31, + "hash": "49ab341f1d1ef0297864e3b4001febc0e96516f6c0fa896baf487a8a873f11f5" + }, + { + "text": "Heterogeneity and un - balanced baseline characteristics in study PA individuals (severe vs mild or mixed PA, lateralizing vs bilateral PA, hypo- or eukalemia) limited the interpretability of meta- analysis.", + "tokenCount": 45, + "pageStart": 31, + "pageEnd": 31, + "hash": "c9cb3ca322e90e58eea5adf98d28311a411dfe1c7b60372d276ba8afdd3e6fb1" + }, + { + "text": "MR-blocking potencies of various MRA agents were not routinely built into treatment protocols, and non - equivalent drug doses were sometimes compared. Dose titra - tion was not uniformly part of the study designs, and, even if so, titration schemes generally did not reflect modern (ie, renin-guided) titration paradigms or BP targets.", + "tokenCount": 74, + "pageStart": 31, + "pageEnd": 31, + "hash": "a7c25de699ab101c2d0b0c16c500f94f8f36fa63e6f7c108cef7b11030ad811b" + }, + { + "text": "• In order to proceed despite the evidence gaps, the GDP agreed to make the following 5 assumptions as part of the EtD process: ⚬ Each MRA, titrated appropriately, by blocking the MR, likely has an equal chance of eventually achieving the same degree of BP and potassium control in individ - uals with PA.", + "tokenCount": 68, + "pageStart": 31, + "pageEnd": 31, + "hash": "a9e9f5d3ed904680e49dbacf2a359491e5500ee95c1fd766356d20ce5eced7aa" + }, + { + "text": "⚬ Each MRA, once titrated to equivalent MR blockade, likely has an equal chance of permitting discontinu - ation of other antihypertensives. ⚬ Rates of adverse events may differ between the MRAs. ⚬ QOL differences may be explained by adverse event rates.", + "tokenCount": 63, + "pageStart": 31, + "pageEnd": 31, + "hash": "c17382d29a2e7d5801e817e0b2c485d5405c7754876572eb65ee4c0606ecf478" + }, + { + "text": "⚬ QOL differences may exist outside of adverse event oc - currences but would need appropriately designed head-to-head comparisons of sufficient duration to detect. • Expected costs of medical therapy were considered in de - tail by the GDP, although high-quality cost-effectiveness modeling data in PA specifically is scarce ( Table 10 ).", + "tokenCount": 70, + "pageStart": 31, + "pageEnd": 31, + "hash": "99deeca00b30fe9a0a9113c5a24422719bc464b93c144cc9521ffb290181e586" + }, + { + "text": "• It was acknowledged that available studies focused on ex - pected costs would not necessarily translate to all individu - als and countries, even among high-resource health systems. • It was also noted that modeling cost-effectiveness in a PA setting would be highly complex and difficult to perform without high-quality, dose-equivalent MRA comparison studies to rely on.", + "tokenCount": 77, + "pageStart": 31, + "pageEnd": 31, + "hash": "e57b1c15df4e4d8233e37403174b05688963cc210b3d9166af819afb8b7616e8" + }, + { + "text": "The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 2483 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 62, + "pageStart": 31, + "pageEnd": 31, + "hash": "80506c2b509b18042b4a99b8c3015ed2771175d34b7ff4f2cea13fa4f3bd0262" + }, + { + "text": "• Additionally, with PA diagnosed at young or middle ages, a lifetime model must include very long-term costs of ther - apy balanced against the long-term cost trajectory of re - duced disease burden.", + "tokenCount": 43, + "pageStart": 32, + "pageEnd": 32, + "hash": "cead323670dc189c2bf027d0336e72f69ce704c17e2b882c06d0d9d7f0715bf7" + }, + { + "text": "• Nonetheless, attempts at cost estimates in other cardiovas - cular conditions ( 216-218 ) consistently demonstrate markedly lower costs for spironolactone vs eplerenone; newer MRA drugs will likely have the highest costs.", + "tokenCount": 49, + "pageStart": 32, + "pageEnd": 32, + "hash": "dfcf86ef3ac579e3bbb0c8bdf32b27850e7b2ef55f12229b0251d32c23d8af0f" + }, + { + "text": "• In cost-modeling studies of PA diagnosis and therapy, giv - en the lifelong requirement for MRA treatment in those who do not receive surgery, the cost of medication is ex - pected to rapidly dominate the cost inputs for all but the oldest individuals.", + "tokenCount": 54, + "pageStart": 32, + "pageEnd": 32, + "hash": "d81d2d07ab2ef3122d9345389121b9dae4a21192dd464ba23044056017afc76e" + }, + { + "text": "• The GDP made specific note of the individual concerns about tolerability and side effect risk, recognizing the im - portant role of individual preference in choice of MRA, beyond cost considerations alone. Justification for the Recommendation Although legitimate individual concerns about tolerability of spironolactone exist, there is no scientific basis in studies of medical efficacy to recommend an alternative MRA as first- line therapy to replace spironolactone.", + "tokenCount": 89, + "pageStart": 32, + "pageEnd": 32, + "hash": "c01ee0ab8102b2d6eab6d0d5d063af2843c40b3e910d1bfa963fc8edcc9dd5b8" + }, + { + "text": "Cost considerations or risk of unwanted anti-androgen effects may be secondary concerns and are likely highly significant when comparing spironolactone vs other MRAs. Shared decision making with individual patients allows for use of a non- spironolactone MRA in PA treatment where desired.", + "tokenCount": 58, + "pageStart": 32, + "pageEnd": 32, + "hash": "7d014cc1f503d3dbdf80c7897d3bc59ce867e5ff369453a37a120f106ab3dd5f" + }, + { + "text": "Comments A recent international consensus document regarding the spe - cific targets and means of implementing optimized MRA ther - apy has been published ( 85 ). As new evidence for new MRAs in PA emerges, recommendations may require updating, al - though major differential cost considerations may continue to dominate for many years.", + "tokenCount": 61, + "pageStart": 32, + "pageEnd": 32, + "hash": "862c73af0dca915285fe6c050336f1716600eb20ec9306cb24d193f9d8b73178" + }, + { + "text": "Research Considerations Current gaps in knowledge call for further research in the fol - lowing areas: • Evaluating aldosterone synthase inhibitors with appropri - ately designed PA-specific research studies to determine their optimal position within a PA treatment framework; ongoing trials of MRA drugs such as esaxerenone and al - dosterone synthase inhibitors such as dexfadrostat should help clarify relative efficacies in PA therapies both as monotherapy and in combination • Specifically studying PA with individual-relevant hard clinical endpoints • Designing and studying more complex treatment para - digms including surgical or procedural-based debulking strategies with and without adjuvant medical therapy Implementation Considerations Expanded PA screening in hypertensive individuals is expected to increase diagnosis rates, requiring greater access to additional tests such as adrenal computed tomography (CT) scans and ad - renal venous sampling (AVS).", + "tokenCount": 181, + "pageStart": 32, + "pageEnd": 32, + "hash": "86e6656bf0b7f4a910d92517476b2d7a81d25be801c66590bd4864b5e624342b" + }, + { + "text": "These demands may challenge health care systems with limited resources, where access to speci - alized equipment, expertise, and follow-up care could be uneven. In such settings, pathways involving direct medical treatment, such as initiating MRAs based on screening results alone, may be considered when further testing is not feasible.", + "tokenCount": 63, + "pageStart": 32, + "pageEnd": 32, + "hash": "22f3a98ca8e6477af49a7abcaad0184696f0f484e0d83c300b39f88d9b05bfa7" + }, + { + "text": "Variability in resources across settings highlights potential in - equities, with rural and low-resource areas facing the greatest barriers. Practical adaptations, such as simplified diagnostic algorithms or regional hubs for specialized care, could miti - gate these challenges.", + "tokenCount": 49, + "pageStart": 32, + "pageEnd": 32, + "hash": "3e4f9261074042373efaf169fd61eba8db3f7ae149a4fa6defcc820b4271b157" + }, + { + "text": "Broader implementation will depend on embedding PA screening within existing hypertension management frameworks, supported by education for clini - cians and individuals, and ongoing monitoring to ensure ben - efits reach all populations equitably.", + "tokenCount": 43, + "pageStart": 32, + "pageEnd": 32, + "hash": "a1b4d427a75800c515ecba88cd1fb7a2b5f1b57da0239c8762a8e0a6758fb3f2" + }, + { + "text": "To support the adoption of this recommendation and address challenges in implemen - tation, the guideline offers PA screening and management al - gorithms as practical tools ( Figs. 1 - 3 ).", + "tokenCount": 41, + "pageStart": 32, + "pageEnd": 32, + "hash": "360aceb022a1fa592bb2f33529383e025b91949f68980f40127b4a21c2bfaeda" + }, + { + "text": "Medical Therapy With Epithelial Sodium-Channel Inhibitors vs Mineralocorticoid Receptor Antagonists (Steroidal and Nonsteroidal) for Individuals With Primary Aldosteronism Background With increased screening and diagnosis of primary aldosteronism (PA), the need for medical treatment will continue to grow ( 209 ).", + "tokenCount": 67, + "pageStart": 32, + "pageEnd": 32, + "hash": "0fdd6623b65f4e7a76016bd55a08d4552a71c42fd0bc9f5384e0f036ca379ff1" + }, + { + "text": "The most commonly used and targeted medical treatments are mineralocorticoid receptor antagonists (MRAs), which are gener - ally widely available and inexpensive. For individuals who cannot tolerate MRAs (eg, due to effects on androgen or progesterone re - ceptors), a lower-cost, second-line option such as epithelial sodium-channel (ENaC) inhibitors may be a consideration.", + "tokenCount": 83, + "pageStart": 32, + "pageEnd": 32, + "hash": "57a121665a0e60f31fc4fdab7e345af8de4dd35e981a5f341252175f6ae4a324" + }, + { + "text": "PA is often associated with resistant or refractory hypertension ( 219 ). The significance of aldosterone in resistant hypertension is supported by studies demonstrating that aldosterone synthase inhibitors reduce blood pressure (BP) in treatment-resistant hypertension ( 220 ).", + "tokenCount": 49, + "pageStart": 32, + "pageEnd": 32, + "hash": "acaa57eb7eafda6b05f5d3bec5f8a982de4dcd7b43b60fefd89a58010e9a05ae" + }, + { + "text": "In PA, renal sodium reabsorption is increased, leading to vol - ume expansion and higher BP. The increased sodium reabsorp - tion is due to aldosterone-mediated activation of renal mineralocorticoid receptors (MRs) and consequent increased ex - pression and activation of the renal ENaCs ( 221 ).", + "tokenCount": 70, + "pageStart": 32, + "pageEnd": 32, + "hash": "dc42b82c76482445c55751c0f119546241549a55b15c4ec854524f8eeacb5604" + }, + { + "text": "Increased ENaC activity leads to increased sodium reabsorption and potas - sium excretion in the distal convoluted nephron. ENaC is a major regulator of sodium excretion during feedback regulation of BP by the renin – angiotensin – aldosterone system (RAAS) ( 221 , 222 ).", + "tokenCount": 68, + "pageStart": 32, + "pageEnd": 32, + "hash": "e316438ad1f3cf98ca45ceec2b489205f707459793e95c2c8c7c494cf0353f6b" + }, + { + "text": "End-organ damage in individuals with PA is more severe than in individuals with primary hypertension, and includes left ven - tricular hypertrophy, cardiac fibrosis, arterial stiffness, tubuloin - terstitial fibrosis, microalbuminuria, and microvascular damage ( 2 , 223 , 224 ).", + "tokenCount": 63, + "pageStart": 32, + "pageEnd": 32, + "hash": "7e1fff44392b5e30474e499927ed95832537bd8897ed13bad7f47fb9b3570fe4" + }, + { + "text": "ENaCs are also expressed in the cardiovascular system, and their activation promotes cardiovascular fibrosis, vascular dysfunction, and arterial stiffening ( 222 , 225 ). Reducing effects of excess aldosterone by blocking MRs or inhibiting ENaC activation could attenuate PA-induced hyper - tension, sodium reabsorption, and cardiovascular damage.", + "tokenCount": 70, + "pageStart": 32, + "pageEnd": 32, + "hash": "051ae5aecff30d643681c0939959789ab81dbb4b29e5210b004a528187a88057" + }, + { + "text": "This suggests the potential utility of ENaC inhibitors like ami - loride and triamterene in the treatment of individuals with PA. Question 10. Should epithelial sodium-channel inhibitors vs mineralocorticoid receptor antagonists (steroidal and nonsteroidal) be used for medical treatment of primary aldosteronism?", + "tokenCount": 70, + "pageStart": 32, + "pageEnd": 32, + "hash": "959d60a0d846ffe9b95efb09f9f72812cd6577bc9f302d1dda6e4f689f54c142" + }, + { + "text": "2484 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 62, + "pageStart": 32, + "pageEnd": 32, + "hash": "67a93d39ed14cbe73db0a48bcfb9c1464f43c2b441acf82b25b422cfa435f320" + }, + { + "text": "Recommendation 10 For individuals with primary aldosteronism (PA) receiv - ing PA-specific medical therapy, we suggest using min - eralocorticoid receptor antagonists (MRAs) rather than epithelial sodium-channel (ENaC) inhibitors (amiloride, triamterene) (2 | ⊕ OOO).", + "tokenCount": 76, + "pageStart": 33, + "pageEnd": 33, + "hash": "041829af4d08e7242c71bfb568f9f70365b0008072a18b0f947d1fbfcf321fd1" + }, + { + "text": "Technical remark: • The recommendation (see Fig. 3 ) does not apply to clinical conditions in which spironolactone is contra - indicated (eg, hyperkalemia, advanced renal impair - ment, or pregnancy) or if a non-spironolactone MRA were indicated for other non-PA indications (eg, heart failure).", + "tokenCount": 72, + "pageStart": 33, + "pageEnd": 33, + "hash": "db2bff426e742c44fabd9ae96ab1b1bdfa50d88f7855917e29ecd2a5392ba59e" + }, + { + "text": "Summary of the Evidence The meta-analysis results, a detailed summary of the evidence and Evidence to Decision (EtD) tables can be found online at https:/ /guidelines.gradepro.org/profile/CssZc_4Ppmg .", + "tokenCount": 55, + "pageStart": 33, + "pageEnd": 33, + "hash": "cdffa6c72e7310e06560153e5e9a80d1edfaf4d5405702952f6db5a8fe522c5d" + }, + { + "text": "Benefits and Harms The panel voted for the following patient-important outcomes for Question 10 decision making: 1) percent of individuals achieving BP control, 2) number of antihypertensive agents, 3) dosage of antihypertensive agents, 4) systolic BP (SBP) level, 5) adverse car - diovascular events (MACEs), 6) atrial fibrillation, 7) stroke, 8) is - chemic heart disease, 9) heart failure, 10) cardiovascular mortality, 11) all-cause mortality, and 12) adverse events.", + "tokenCount": 120, + "pageStart": 33, + "pageEnd": 33, + "hash": "072a781b851d308970c09c98e0d886c5127852a964cb7c52c411cb172412faa1" + }, + { + "text": "The systematic review did not find any studies directly com - paring ENaC inhibitors vs MRAs in the medical treatment of PA, although a few studies compared ENaC inhibitors and spironolactone (but not eplerenone) in resistant hypertension.", + "tokenCount": 54, + "pageStart": 33, + "pageEnd": 33, + "hash": "3da7f1c4e0959c9c8aa4f7144652c9df155118152a6d6e5700cc6c21530a9841" + }, + { + "text": "Because most individuals with resistant hypertension have PA, we used these studies as indirect evidence of hyperaldosteron - ism ( 40 , 164 ). The largest study was a sub-study of the PATHWAY-2 study, which was a randomized, double-blind crossover trial in individuals with resistant hypertension ( 19 ).", + "tokenCount": 63, + "pageStart": 33, + "pageEnd": 33, + "hash": "b10a35714e2675ac2f127265060126ace883b8a17d1b8664656c3e1e9ebfb307" + }, + { + "text": "Results showed similar BP-lowering effects of spironolactone and amiloride. In the spironolactone, amiloride, losartan, and thiazide (SALT) double-blind crossover trial in individuals with low-renin hypertension and elevated aldosterone to re - nin ratio (ARR), spironolactone and high-dose amiloride had similar antihypertensive effects ( 226 ). Several smaller studies also demonstrated that amiloride and spironolac - tone were similarly effective at lowering BP in individuals with resistant hypertension ( 227-229 ). In individuals with hypertension and supranormal aldosterone secretion, effects of spironolactone were better than those of amiloride ( 230 ). In low-renin hypertension, BP-lowering effects of spirono - lactone and a hydrochlorothiazide/triamterene combination were similar ( 231 ). In volume-dependent hypertension, spir - onolactone and triamterene reduced BP, with spironolac - tone having greater effects ( 232 ).", + "tokenCount": 232, + "pageStart": 33, + "pageEnd": 33, + "hash": "60e7147feed74d71ea1869cd6c3803708fadc2e2cde80a0c97078a3aaa5d9895" + }, + { + "text": "Together, these studies in resistant hypertension suggest ENaC inhibitors as a viable substitute for spironolactone when spironolactone is not tolerated ( 233 , 234 ). Beyond similar antihypertensive effects, both amiloride and spironolactone equally improved quality of life (QOL) in individuals with PA ( 234 , 5 ).", + "tokenCount": 73, + "pageStart": 33, + "pageEnd": 33, + "hash": "97d71837aae14c220cc5c98d85d8f1ac9434edeb85340a52518f15028d5c9d82" + }, + { + "text": "Amiloride may be an effective antihypertensive drug in indi - viduals with PA. However, whether the effects are superior or not to MRAs is unknown because head-to-head trials compar - ing them in PA are lacking.", + "tokenCount": 54, + "pageStart": 33, + "pageEnd": 33, + "hash": "7c716430e8d1777effab778d9ed1cd9d81316c03957073781b8cbb7a87028a9a" + }, + { + "text": "In a small clinical study in individ - uals with PA, low-dose amiloride controlled BP within 1 to 4 weeks of initiation, with effects sustained for up to 20 years ( 227 ).", + "tokenCount": 42, + "pageStart": 33, + "pageEnd": 33, + "hash": "3b399d475419602f2f79f52434a8ceca3c89f7d791e9e6fa7770680778fc92fd" + }, + { + "text": "This was associated with improved vascular function (pulse-wave velocity-indicating cardiac output, vascular re - sistance, and arterial stiffness) and no cardiovascular events. Amiloride at higher doses corrected hypokalemia and normal - ized BP in individuals with PA ( 228 ).", + "tokenCount": 60, + "pageStart": 33, + "pageEnd": 33, + "hash": "a77a9860f4ae7d0a6072a0dfe61e52415cc4e30b2eaa755ec98eeef2210d2f0a" + }, + { + "text": "A major assumption (as required with reliance on indirect evidence) is that both ENaC inhibitors and MRAs would like - ly yield equivalent clinical outcomes based on observations that they probably yield similar BP reductions in a PA popula - tion.", + "tokenCount": 48, + "pageStart": 33, + "pageEnd": 33, + "hash": "8484401ab96e0d76feca66f8c8357998c60a5e168a5108f0d075e250884288c9" + }, + { + "text": "However, ENaC inhibitors do not block aldosterone dir - ectly; therefore, the impact of ENaC inhibitors and MRAs on aldosterone-specific end-organ injury may differ.", + "tokenCount": 42, + "pageStart": 33, + "pageEnd": 33, + "hash": "96b76ed5d21a299c8c9ed9386d8b8ac4638f490f880e8dfe8ca5e79a7f1ba975" + }, + { + "text": "Evidence to Decision Factors • Cost-effectiveness data do not exist for ENaC inhibitors in medical PA treatment. However, cost estimates in the United States demonstrated equally low prices for equipo - tent amiloride and spironolactone.", + "tokenCount": 51, + "pageStart": 33, + "pageEnd": 33, + "hash": "f6df0d9ee07f0aa00b037b7bb65f2fad5115b16ab689befd44bdc058e211c9d2" + }, + { + "text": "• Accordingly, amiloride as an alternative to spironolactone may be cost-neutral. (See Question 9 for discussion of cost-effectiveness of spironolactone.) • Since the clinical impact (BP-lowering) of ENaC inhibitors is the same as spironolactone and given their similar low costs, similar cost-effectiveness is expected from any fu - ture model using ENaC inhibition.", + "tokenCount": 92, + "pageStart": 33, + "pageEnd": 33, + "hash": "f91d8c00602e94b7c9ea028223418bd65aee50bca9bbfe2ce23d5d2f49030807" + }, + { + "text": "• Cost neutrality may be especially relevant in Black individ - uals who are more likely to have low-renin hypertension ( 231 ). Some evidence exists that a significant proportion of these individuals may also have a Liddle-syndrome-type biochemical phenotype, which is strongly responsive to ENaC inhibitors ( 235 ).", + "tokenCount": 65, + "pageStart": 33, + "pageEnd": 33, + "hash": "991d0b8b9d8d3006b49606ab20e753f8bcc306e88ac90b1598d1ea9ad8f1de14" + }, + { + "text": "• Accordingly, inclusion of ENaC inhibitors as an option for low-renin/PA hypertension could increase health equity. Justification for the Recommendation Although the evidence is limited and indirect, amiloride seems to be as effective as spironolactone in reducing BP in individuals with resistant hypertension, which the Guideline Development Panel (GDP) used as a surrogate of PA.", + "tokenCount": 80, + "pageStart": 33, + "pageEnd": 33, + "hash": "7065d6bbcf75e759179b2ce6438a231424764e416615edc6323bbe5a1d338ec2" + }, + { + "text": "Both drugs are low cost and both improve QOL. In addition to a lack of direct clinical evidence to recommend the ENaC amiloride over the MRA spironolactone as first- line therapy, questions remain as to whether amiloride would offer all the same benefits as an MRA.", + "tokenCount": 65, + "pageStart": 33, + "pageEnd": 33, + "hash": "3951e43d7380abfd5cf459450ef860df79b780225718768e511a16b40ac5ca19" + }, + { + "text": "There is some justification that MRA should be the preferred treat - ment in PA based on a small study of 10 individuals with hypertension and supranormal aldosterone secretion in which spironolactone (400 mg/day) had greater BP-lowering ef - fects than did amiloride (40 mg/day) as well as on the clear evidence that MRAs are effective in PA (see Question 9). When spironolactone is not tolerated and other MRAs are not available, amiloride may be an alternative therapy in the management of PA.", + "tokenCount": 123, + "pageStart": 33, + "pageEnd": 33, + "hash": "3f6f10e661a06b0400f908f21d36504f60b0c6dd405534e30279ad5380b79eb1" + }, + { + "text": "The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 2485 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 62, + "pageStart": 33, + "pageEnd": 33, + "hash": "b23793cd00055ca31411eaee5d32dd88ffe43fe95c27672ee165a1862ffcb3d8" + }, + { + "text": "Comments and Future Research Considerations Many gaps in knowledge need to be addressed through robust clinical studies before ENaC inhibitors could be considered a replacement, or add-on therapy, to MRAs, including:", + "tokenCount": 41, + "pageStart": 34, + "pageEnd": 34, + "hash": "8af57a9c4bb624080832e06efb4ae1791cfeab1867cbbae5e264f33063fd68e2" + }, + { + "text": "• Comparing ENaC inhibitors vs MRAs in PA • Studying the potential long-term effects of ENaC inhibi - tors on end-organ damage in PA, including cardiac, vascu - lar, and renal fibrosis • Considering diverse populations of PA, including those who are salt-sensitive Acknowledgments The Endocrine Society and the Guideline Development Panel thank Marie McDonnell, MD, and Roma Gianchandani, MD, who served as Clinical Guidelines Committee chairs during the development of this clinical practice guideline.", + "tokenCount": 109, + "pageStart": 34, + "pageEnd": 34, + "hash": "7646f4c76b34521b99f2de03812a73ae10ed3d931db0bf4acd3eefb002bc56c6" + }, + { + "text": "The panel thanks Endocrine Society staff including Maureen Corrigan, MA, Elizabeth York, MPH, Laura Mitchell, MA, and Emma Goldberg, PhD, for their expert guidance and assistance with all aspects of guideline develop - ment.", + "tokenCount": 46, + "pageStart": 34, + "pageEnd": 34, + "hash": "d0126f40ab64c82e5ffcd4d673a906815beebf4d502dac83ae10439bf394760c" + }, + { + "text": "We also thank the numerous contributors from the Mayo Evidence-Based Practice Center, especially Magdoleen Farah, MBBS, for their contribution in conduct - ing the evidence reviews for the guideline.", + "tokenCount": 40, + "pageStart": 34, + "pageEnd": 34, + "hash": "cc0143f49e4175d4a8b97350a829b9e0ed24f3e75a0d5879b48b571252aa9a1b" + }, + { + "text": "We are grateful to Robert Carey, MD, for his contributions to this guideline and to the field. Funding Funding for the development of this guideline was provided by The Endocrine Society. No other entity provided financial support.", + "tokenCount": 43, + "pageStart": 34, + "pageEnd": 34, + "hash": "783195cda9ffd9914d645065974645b4cb42e957ac979d0b357b2d92c1a13591" + }, + { + "text": "Disclaimer The Endocrine Society ’ s clinical practice guidelines are devel - oped to be of assistance to endocrinologists by providing guidance and recommendations for particular areas of practice. The guidelines should not be considered as an all-encompassing approach to individual care and not inclu - sive of all proper approaches or methods, or exclusive of others.", + "tokenCount": 72, + "pageStart": 34, + "pageEnd": 34, + "hash": "848f964763c9686536fdf6cf0ad268f8978e16fd2506f83d17525051370214b9" + }, + { + "text": "The guidelines cannot guarantee any specific outcome or successful treatment, nor do they establish a standard of care. The guidelines are educational tools, not medical advice, and are not intended to dictate the treatment of a particular individual.", + "tokenCount": 43, + "pageStart": 34, + "pageEnd": 34, + "hash": "fc2e6040c7b202f1f85c74c4f677dfc7ae6ab4c5038e2a0619fe084817496a3d" + }, + { + "text": "Treatment decisions must be made based on the in - dependent judgment of health care clinicians and each per - son ’ s individual circumstances. The Endocrine Society makes every effort to present accurate and reliable informa - tion, and this guideline reflects the best available data and understanding of the science of medicine at the time the guide - line was prepared.", + "tokenCount": 70, + "pageStart": 34, + "pageEnd": 34, + "hash": "28cbf4a65b56509fd5fc0bba2ef5566cf261afc5b9529991185689358656dad1" + }, + { + "text": "The results of future studies may require revisions to the recommendations in this guideline to reflect new data. This publication is provided “ as is ” and the Society makes no warranty, express or implied, regarding the accuracy and reliability of these guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose, title, or noninfringement of third- party rights.", + "tokenCount": 78, + "pageStart": 34, + "pageEnd": 34, + "hash": "b2296addf6f3fc2029964c41aa5bfb479ef0022d010026098875268a017d6357" + }, + { + "text": "The Society, its officers, directors, members, em - ployees, and agents (including the members of the Guideline Development Panel) shall not be liable for direct, indirect, special, incidental, or consequential damages, including the interruption of business, loss of profits, or other monetary damages, regardless of whether such damages could have been foreseen or prevented, related to this publication or the use of, inability to use, results of use of, or reliance on the information contained herein, based on any legal theory what - soever and whether or not there was advice on the possibility of such damages.", + "tokenCount": 122, + "pageStart": 34, + "pageEnd": 34, + "hash": "2dd66c0ad0884efba5a45ce0e692752bd7b71ad4c307cf5a2075c9e18835e7d7" + }, + { + "text": "Appendix A. Guideline Development Panel makeup, roles, and management plans Summary • Total number of Guideline Development Panel (GDP) members = 13 • Percentage of total GDP members with relevant (or poten - tially relevant) COI = 31% Individual Disclosures, Conflicts, and Management Strategies Chair:", + "tokenCount": 66, + "pageStart": 34, + "pageEnd": 34, + "hash": "b2ef40aa652bbfc5a6b184a8f1699526f4c70b6de0ec57366b9d4661e6c3ce6b" + }, + { + "text": "Gail K. Adler, MD, PhD Brigham and Women ’ s Hospital Expertise: Adult endocrinology Disclosures (2021-2025): • National Institutes of Health, Research Funding (various topics) • Tersus Life Sciences, LLC, Research Funding (insulin sen - sitivity and lipogenesis) • American Heart Association, Member of Programming Committee for Hypertension Scientific Conference 2018-2022 Role Name Relevant COI?", + "tokenCount": 95, + "pageStart": 34, + "pageEnd": 34, + "hash": "721a599e32391b75ae0eea9ad5a905b1e3fa848eb46abceff3a442d4744b7cbf" + }, + { + "text": "Representative Chair Gail Adler No Co-Chair Michael Stowasser No Members Ricardo Correa Yes AACE Nadia Khan No ISH Gregory Kline No Michael McGowan No PAF Paolo Mulatero Yes ESH Rhian Touyz No AHA Anand Vaidya Yes Tracy Williams No ESE Jun Yang No William Young Yes Maria Christina Zennaro No Methodologists M.", + "tokenCount": 81, + "pageStart": 34, + "pageEnd": 34, + "hash": "1cb17a1a4c435824c74a0337264f17dc7261b97e9e5435ada6e000062842df9b" + }, + { + "text": "Hassan Murad No Juan P. Brito No Abbreviations: AACE, American Association of Clinical Endocrinology; AHA, American Heart Association; COI, conflict of interest; ESE, European Society of Endocrinology; ESH, European Society of Hypertension; ISH, International Society of Hypertension; PAF, Primary Aldosteronism Foundation.", + "tokenCount": 82, + "pageStart": 34, + "pageEnd": 34, + "hash": "20e66429f9eb0c3d8bb7224e493764f91ff9c254d1e7923ab81ad14f3b3312b0" + }, + { + "text": "2486 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 62, + "pageStart": 34, + "pageEnd": 34, + "hash": "30609cbe4901d3c294c19e8d0e97f339f347ca7f32fc0aeb5e68a610029680bd" + }, + { + "text": "• Paris-Cardiovascular Research Center (PARCC) INSERM U970, France, Member of Scientific Advisory Board 2012-2022 Open Payments Database: https:/ /openpaymentsdata.cms. gov/physician/1040596 Assessment and Management: • No COI relevant to this CPG. • No management required. Co-Chair: Michael Stowasser, MBBS, FRACP, PhD University of Queensland Expertise: Adult endocrinology Disclosures (2021-2025): • Springer, Editor-in-Chief for Journal of Human Hypertension Open Payments Database: n/a Assessment and Management: • No COI relevant to this CPG. • No management required. Ricardo Correa, MD Cleveland Clinic Expertise: Adult endocrinology Disclosures (2022-2025):", + "tokenCount": 171, + "pageStart": 35, + "pageEnd": 35, + "hash": "46329738d35441805c8fca5464e51469a617889e390259030d2a4b92ec7a147c" + }, + { + "text": "• Dynamed • American Medical Association IMG section • American Federation of Medical Research • Association of Program Director of Endocrinology • Maricopa Medical Association • ModernaTX, Consulting • Ascendis Pharma, Speaker • Neurocrine Biosciences, Consulting • NovoNordisk, Consulting • Boehringer Ingelheim (Boehringer Ingelheim manufactures and markets Micardis ® (telmisartan), Micardis HCT ® (telmisartan and hydrochlorothiazide), and Twynsta ® (telmisartan and amlodipine) and is developing vicadro - stat, an aldosterone synthetase inhibitor.), Consulting Pfizer (Pfizer manufactures and markets aldosterone antagonist and Aldactone ® (spironolactone) and the anti-hypertensive agents Accupril ® (quinapril HCl), Accuretic ® (quinapril HCl/ hydrochlorothiazide), Norvasc ® (amlodipine) and Minipress ® (prazosin hydrochloride).), Consulting Open Payments Database:", + "tokenCount": 236, + "pageStart": 35, + "pageEnd": 35, + "hash": "0a8e7d92242b8795c3278524cbdabc441a92a6da537dc099e2843155d7d767f9" + }, + { + "text": "https:/ /openpaymentsdata.cms.gov/ physician/1323034 Assessment and Management: • Dr. Correa was assessed at the initiation of guideline develop - ment of having no industry relationship relevant to the guide - line.", + "tokenCount": 48, + "pageStart": 35, + "pageEnd": 35, + "hash": "557f5afb55d4ffd2d8e82f31b5ab05e9e66098b9e2956c7c9b54a26b572c6348" + }, + { + "text": "However, near the end of the development of the guideline, it came to the attention of the Clinical Guidelines Committee Chair that he had 2 consulting entries in Open Payments with 2 companies that had potential relevance to the guideline, Boehringer Ingelheim and Pfizer.", + "tokenCount": 54, + "pageStart": 35, + "pageEnd": 35, + "hash": "16a402e1f66fb87d5724ad62a89ec7aa3a9d9cdd41493780a08edcfa5c302e43" + }, + { + "text": "Upon assess - ment of the relationships, the amounts were considered min - imal and to not need further mitigation. Nadia Khan, MD University of British Columbia Expertise: Adult hypertension Disclosures (2023-2025):", + "tokenCount": 47, + "pageStart": 35, + "pageEnd": 35, + "hash": "1e5e26711ca39229f093d952a1e84e66dab8c002fc620a89bbd2adfca35cdfe0" + }, + { + "text": "• Canadian Institutes for Health Research, co-investigator • Brain Canada, co-investigator • Heart and Stroke Foundation of Canada, co-investigator • International Society of Hypertension, Executive Board Member Open Payments Database:", + "tokenCount": 47, + "pageStart": 35, + "pageEnd": 35, + "hash": "09a78c289bd2710da34e599a6310b1fe8a70ddf28e6cbcef4ce295e051100408" + }, + { + "text": "n/a Assessment and Management: • No COI relevant to this CPG. • No management required. Gregory Kline, MD Alberta Health Services Expertise: Adult endocrinology Disclosures (2023-2025): • Primary Aldosteronism Foundation, Medical Advisory Board Member Open Payments Database: n/a Assessment and Management: • No COI relevant to this CPG. • No management required. Michael McGowan Primary Aldosteronism Foundation Expertise: Patient representative Disclosures (2023-2025):", + "tokenCount": 109, + "pageStart": 35, + "pageEnd": 35, + "hash": "e3a0150cec0debdc27f2b2cfba8023f679d70f92e9dd291f716ac11bcd6b5033" + }, + { + "text": "• Cemosoft, consultant • Brainiest AI Technology, VP and Architect • Primary Aldosteronism Foundation, various leadership roles Open Payments Database: n/a Assessment and Management: • No COI relevant to this CPG. • No management required. Paolo Mulatero, MD University of Torino Expertise: Adult hypertension Disclosures (2022-2025):", + "tokenCount": 79, + "pageStart": 35, + "pageEnd": 35, + "hash": "f6fc1e3d18a11a85edc0ea457ddb1f5faa2c00c44af612b5fc38b4c910565eb3" + }, + { + "text": "• Diasorin (Diasorin manufactures and markets Liaison ® Hypertension Diagnostic Solution, which includes aldos - terone and renin assays.), speaker Open Payments Database:", + "tokenCount": 42, + "pageStart": 35, + "pageEnd": 35, + "hash": "74e32d3dea25e228738c6ddc8bbb5535ce6830452cab51d47d99993662f934d1" + }, + { + "text": "n/a Assessment and Management: • Dr. Mulatero has an industry relationship relevant to this CPG. • Dr. Mulatero was allowed to participate on the GDP be - cause he is a renowned expert in the area of primary aldos - teronism, and since he was nominated by the European Society of Hypertension.", + "tokenCount": 71, + "pageStart": 35, + "pageEnd": 35, + "hash": "479c15b0ec2a8e7220d7d5993b5195a290cec60ad898b8261aa80045638213a8" + }, + { + "text": "• Divestment: None required. • COI management: Mulatero ’ s relationship with Diasorin was deemed potentially relevant to questions re - lated to diagnostic testing.", + "tokenCount": 39, + "pageStart": 35, + "pageEnd": 35, + "hash": "a2da807b68f77c696d26744117610334fbfa6e67ab0ceb8431a93f7fef0703d4" + }, + { + "text": "Mulatero was not involved in systematic reviews for PICO questions directly related to the above considerations. Mulatero did not vote The Journal of Clinical Endocrinology & Metabolism , 2025, Vol.", + "tokenCount": 43, + "pageStart": 35, + "pageEnd": 35, + "hash": "ca996079555ded887255f1cd1624d8c55dd606511c44a2cca289643b5b078f0a" + }, + { + "text": "110, No. 9 2487 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 46, + "pageStart": 35, + "pageEnd": 35, + "hash": "7bb8a4e764367bac6835d5c6daed5859bcf138c719b439ca3e68c03fe8016b8c" + }, + { + "text": "on matters directly related to the above considerations. Mulatero did not draft guideline sections directly re - lated to the above considerations. All GDP participants were made aware of Dr. Mulatero ’ s potentially relevant industry relationship. Rhian Touyz, MBBCh, MSc, PhD McGill University Expertise: Adult hypertension Disclosures (2022-2025):", + "tokenCount": 77, + "pageStart": 36, + "pageEnd": 36, + "hash": "585d8e95be804635963cfb09b2fddfa68ebd15ef116547737d668f8c79ba7996" + }, + { + "text": "• American Heart Association, Editor-in-Chief Hypertension journal, Council on Hypertension • European Society of Cardiology, Co-chair, 2024 ESC guidelines on elevated blood pressure and hypertension Open Payments Database:", + "tokenCount": 44, + "pageStart": 36, + "pageEnd": 36, + "hash": "df83ddbf5b2fd823545d84239573155e0e528f7f5cecfb7b74bf3271a5dbfa31" + }, + { + "text": "n/a Assessment and Management: • No COI relevant to this CPG. • No management required. Anand Vaidya, MD Brigham and Women ’ s Hospital Expertise: Adult endocrinology Disclosures (2021-2025):", + "tokenCount": 53, + "pageStart": 36, + "pageEnd": 36, + "hash": "004426b552757b8b83d6e2017871b6abd768f8f395788205e92d8c2592aff80f" + }, + { + "text": "• Mineralys Therapeutics (Mineralys Therapeutics is devel - oping lorundrostat, an aldosterone synthase inhibitor.), Advisory Board • HRA Pharma, Advisory Board • Corcept, Advisory Board, Consulting Open Payments Database:", + "tokenCount": 54, + "pageStart": 36, + "pageEnd": 36, + "hash": "b1391be302ecd20d4cb214c38a51c38977e87de15405217d26b02aa3536ca57d" + }, + { + "text": "n/a Assessment and Management: • Dr. Vaidya has an industry relationship relevant to this CPG. • Dr. Vaidya was allowed to participate on the GDP be - cause he is a renowned expert in the area of primary aldosteronism.", + "tokenCount": 55, + "pageStart": 36, + "pageEnd": 36, + "hash": "db55a6242ad92fa3f874e2c37ba1c132633d6da52244c38970bfc01ee68f597c" + }, + { + "text": "• Divestment: Vaidya divested from advisory board par - ticipation with relevant companies prior to initiation of the guideline. • COI management: Vaidya ’ s relationship with Mineralys Therapeutics was deemed potentially relevant to questions re - lated to medical treatment of primary aldosteronism.", + "tokenCount": 67, + "pageStart": 36, + "pageEnd": 36, + "hash": "651a8411ee9f84f5fa8b39602c793aa7f436f5b8f0010cb4687092c0340f48c0" + }, + { + "text": "Vaidya was not involved in systematic reviews for PICO questions directly related to the above considerations. Vaidya did not vote on matters directly related to the above considerations. Vaidya did not draft guideline sections directly related to the above considerations. All GDP partici - pants were made aware of Dr. Vaidya ’ s potentially relevant industry relationship. Tracy Williams, PhD Ludwig Maximilian University, Munich Expertise: Adult endocrinology Disclosures (2022-2025): • None Open Payments Database: n/a Assessment and Management: • No COI relevant to this CPG. • No management required. Jun Yang, MBBS, FRAC, PhD Hudson Institute of Medical Research Expertise: Adult endocrinology Disclosures (2023-2025):", + "tokenCount": 161, + "pageStart": 36, + "pageEnd": 36, + "hash": "525dbda72f7889028b7d46b503dfff742ee7c04854b1840f1a589f28255ae95b" + }, + { + "text": "• Primary Aldosteronism Foundation, Patient Engagement Officer • New Zealand Health and Disability Commission, Expert • Endocrine Society, Annual Meeting Steering Committee Member • National Hypertension Taskforce, Member Open Payments Database:", + "tokenCount": 45, + "pageStart": 36, + "pageEnd": 36, + "hash": "8363e3c9cfac2d621a67e570585e110ca2f9f8b556c3b7f8e673f3fc95d59dfe" + }, + { + "text": "n/a Assessment and Management: • No COI relevant to this CPG. • No management required. William Young, MD Mayo Clinic Expertise: Adult endocrinology Disclosures (2021-2025):", + "tokenCount": 45, + "pageStart": 36, + "pageEnd": 36, + "hash": "079e39755be1e1782f357aaa32af26833e5c9835fee6dd678ce4488fe544f8c4" + }, + { + "text": "• Bayer AG (Bayer manufactures and markets the anti- hypertensive agents Pritor ® (telmisartan), Adalt LA ® (nifedipine), Baycaron ® (mefruside), and Adempas ® (riociguat), and the mineralocorticoid receptor antagon - ist Kerendia ® (finerenone).), Consulting, Data Safety Monitoring Board • AstraZeneca (AstraZeneca manufactures and markets the anti-hypertensive agents Atacand ® (candesartan cilexetil), Plendil ® (felodipine), and Zestril ® (lisinopril) and is devel - oping Baxdrostat, an aldosterone synthetase inhibitor.), Consulting • Merck Sharp & Dohme (Merck Sharp & Dohme, manu - factures and markets the anti-hypertensive Inspra ® (epler - enone).), Consulting Open Payments Database:", + "tokenCount": 212, + "pageStart": 36, + "pageEnd": 36, + "hash": "46d889fa7a592981890ced65912ea80e86a63bd6bf96ef555400882e0631029e" + }, + { + "text": "https:/ /openpaymentsdata.cms.gov/ physician/1145085 Assessment and Management: • Dr. Young has an industry relationship relevant to this CPG. • Dr. Young was allowed to participate on the GDP because he is a renowned expert in the area of primary aldosteronism.", + "tokenCount": 63, + "pageStart": 36, + "pageEnd": 36, + "hash": "dd9fbaccf0418bed01fc859f588347bfb45b28433acfbb44ed4b2feab94b7576" + }, + { + "text": "• Divestment: None required. • COI management: Young ’ s relationships with Bayer AG and AstraZeneca were deemed potentially relevant to questions related to medical treatment of primary al - dosteronism.", + "tokenCount": 45, + "pageStart": 36, + "pageEnd": 36, + "hash": "c050343832140cc2604da17589057dd186f14e559149598d0b38114037903a59" + }, + { + "text": "Young was not involved in systematic reviews for PICO questions directly related to the above considerations. Young did not vote on matters dir - ectly related to the above considerations. Young did not draft guideline sections directly related to the above considerations. All GDP participants were made aware of Dr. Young ’ s potentially relevant industry relationships. 2488 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No.", + "tokenCount": 87, + "pageStart": 36, + "pageEnd": 36, + "hash": "37d1a302a782b6110e7966fd843d5e2ab67212e606ff836af583d26d3df0b63b" + }, + { + "text": "9 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 40, + "pageStart": 36, + "pageEnd": 36, + "hash": "86d3541f16c4cf3f3990fa58d424f397068a88b4c212a690d7cd989da5201309" + }, + { + "text": "Maria Christina Zennaro, MD, PhD Université Paris Cité, Inserm, PARCC Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique Expertise: Adult endocrinology Disclosures (2022-2025): • Springer Nature, Associate Editorial Board, 2022 • French Society of Endocrinology, Leadership • European Society of Endocrinology, Leadership (com - pleted 2024) • Endocrine Society, Annual Meeting Steering Committee Member (completed 2022) Open Payments Database: n/a Assessment and Management: • No COI relevant to this CPG. • No management required. M. Hassan Murad, MD, MPH Mayo Clinic Expertise: Epidemiology, guideline methodology Disclosures (2021-2025): • Society for Vascular Surgery, methodologist • American Society of Hematology, methodologist • CHEST, methodologist • World Health Organization, methodologist • Evidence Foundation, methodologist Open Payments Database: No entries. Assessment and Management: • No COI relevant to this CPG. • No management required. Juan P. Brito, MBBS Mayo Clinic Expertise: Adult endocrinology, guideline methodology Disclosures (2021-2025): • Gordon and Betty Moore Foundation • National Heart, Lung, and Blood Institute Open Payments Database: No entries. Assessment and Management: • No COI relevant to this CPG. • No management required. NOTES ON PRIOR PANEL MEMBERS: 1. An individual with no relevant conflicts of interest was appointed as co-chair at the outset of guideline develop - ment but stepped down from the panel in July 2023. This occurred after the development of the PICO ques - tions and prioritization of outcomes, but before the Evidence to Decision process and development of recom - mendations. 2. An individual with the following relevant relationships was appointed to the panel: (a) Daiichi Sankyo (Daiichi Sankyo manufactures and markets the anti-hypertensive agents Olmetec ® / Rezaltas ® /Sevikar ®", + "tokenCount": 447, + "pageStart": 37, + "pageEnd": 37, + "hash": "7ba4d262a2e1c732a2085c8c16f89106a4fcce0026619074385c7caae127d70d" + }, + { + "text": "(Olmesartan medoxomil), Nilemdo ® (bempedoic acid) and Nustendi ® (bempe - doic acid and ezetimibe), and is developing mineralo - corticoid receptor inhibitor esaxerenone.): Speaker (b) Pfizer manufactures and markets aldosterone antag - onist and Aldactone ® (spironolactone) and the anti- hypertensive agents Accupril ® (quinapril HCl), Accuretic ® (quinapril HCl/hydrochlorothiazide), Norvasc ® (amlodipine) and Minipress ® (prazosin hydrochloride). Speaker This individual ’ s participation on the panel ended in July 2023, after the development of the PICO questions and priori - tization of outcomes, but before the Evidence to Decision pro - cess and development of recommendations. 3. An individual with the following relevant relationships was appointed to the panel: (a) Mineralys Therapeutics (4Mineralys Therapeutics is developing lorundrostat, an aldosterone synthase in - hibitor.): Site Primary Investigator (b) Astra Zeneca (AstraZeneca manufactures and mar - kets the anti-hypertensive agents Atacand ® (cande - sartan cilexetil), Plendil ® (felodipine), and Zestril ® (lisinopril) and is developing Baxdrostat, an aldoster - one synthetase inhibitor.): North American Steering Committee Chair This individual ’ s participation on the panel ended in July 2023, after the development of the PICO questions and prioritization of outcomes, but before the Evidence to Decision process and development of recommendations. References 1. Monticone S, Sconfienza E, D ’ Ascenzo F, et al. Renal damage in primary aldosteronism: a systematic review and meta-analysis. J Hypertens . 2020;38(1):3-12. 2. Monticone S, D ’ Ascenzo F,", + "tokenCount": 450, + "pageStart": 37, + "pageEnd": 37, + "hash": "6b7ddfe7091ec92867117995124c93821d7315820f646c5bc4376d127cd47b9c" + }, + { + "text": "Moretti C, et al. Cardiovascular events and target organ damage in primary aldosteronism com - pared with essential hypertension: a systematic review and meta- analysis. Lancet Diabetes Endocrinol . 2018;6(1):41-50. 3. Tan YK, Kwan YH, Teo DCL, et al. Improvement in quality of life and psychological symptoms after treatment for primary aldoster - onism: Asian cohort study. Endocr Connect . 2021;10(8): 834-844. 4. Buffolo F, Cavaglià G, Burrello J, et al. Quality of life in primary aldosteronism: a prospective observational study. Eur J Clin Invest . 2021;51(3):e13419. 5. Ahmed AH, Gordon RD, Sukor N, Pimenta E, Stowasser M. Quality of life in patients with bilateral primary aldosteronism be - fore and during treatment with spironolactone and/or amiloride, including a comparison with our previously published results in those with unilateral disease treated surgically. J Clin Endocrinol Metab . 2011;96(9):2904-2911. 6. McEvoy JW, McCarthy CP, Bruno RM, et al. 2024 ESC Guidelines for the management of elevated blood pressure and hypertension: developed by the task force on the manage - ment of elevated blood pressure and hypertension of the European Society of Cardiology (ESC) and endorsed by the European Society of Endocrinology (ESE) and the European Stroke Organisation (ESO", + "tokenCount": 333, + "pageStart": 37, + "pageEnd": 37, + "hash": "14be73b3ddbbf89f8251f8d564e5a703b1604787e93b94d5aa1d9a9fbe79eaf4" + }, + { + "text": "Eur Heart J . 2024;45(38): 3912-4018. 7. Hundemer G, Curhan G, Yozamp N, Wang M, Vaidya A. Cardiometabolic outcomes and mortality in medically treated The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 2489 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 113, + "pageStart": 37, + "pageEnd": 37, + "hash": "14339f150a040133ad29ff1b72eb3d9856a04a0f442693e6cc73acd1c94fce62" + }, + { + "text": "primary aldosteronism: a retrospective cohort study. Lancet Diabetes Endocrinol . 2018;6(1):51-59. Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A.", + "tokenCount": 50, + "pageStart": 38, + "pageEnd": 38, + "hash": "d554a0dfe0d5d4539a6105e76ae80bef797df234b6fbc38b4acb7cd401e0981d" + }, + { + "text": "Renal outcomes in medically and surgically treated primary aldos - teronism. Hypertension . 2018;72(3):658-666. Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A.", + "tokenCount": 54, + "pageStart": 38, + "pageEnd": 38, + "hash": "8bf4dbe4636273dfdd458ccda419c248b58252da85a3d34dddbc585824c43b79" + }, + { + "text": "Incidence of atrial fibrillation and mineralocorticoid receptor ac - tivity in patients with medically and surgically treated primary al - dosteronism. JAMA Cardiol . 2018;3(8):768-774. McCartney CR, Corrigan MD, Drake MT, et al. Enhancing the trustworthiness of the Endocrine Society ’ s clinical practice guide - lines. J Clin Endocrinol Metab . 2022;107(8):2129-2138.", + "tokenCount": 102, + "pageStart": 38, + "pageEnd": 38, + "hash": "f69d6b372d8f3c032b785036a0c2370fed88eeca72c605fbaa6d8bc90eb0a5c4" + }, + { + "text": "Swiglo BA, Murad MH, Schünemann HJ, et al. A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in endocrinology using the grading of recommenda - tions, assessment, development, and evaluation system.", + "tokenCount": 63, + "pageStart": 38, + "pageEnd": 38, + "hash": "ddb855a31d53daf298c3d793eb9409d831c25f6a9d57af6fbc9ec0c4ad03a68e" + }, + { + "text": "J Clin Endocrinol Metab . 2008;93(3):666-673. Schünemann HJ, Broz ̇ ek J, Guyatt GH, Oxman AD.", + "tokenCount": 43, + "pageStart": 38, + "pageEnd": 38, + "hash": "43229e1442bea4f502554d8d642491b032fabcba3b3bf4306246f2e9c7af7cef" + }, + { + "text": "GRADE hand - book for grading quality of evidence and strength of recommenda - tions. https://gdt.gradepro.org/app/handbook/handbook.html 13.", + "tokenCount": 41, + "pageStart": 38, + "pageEnd": 38, + "hash": "e430d226c0ab22f9ae83c34e98e1cb77b37c2a15f203a48d82fc47121bf38671" + }, + { + "text": "Schünemann HJ, Cushman M, Burnett AE, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospital - ized medical patients. Blood Adv . 2018;2(22):3198-3225. Alonso-Coello P, Oxman AD, Moberg J, et al. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent ap - proach to making well informed healthcare choices. clinical practice guidelines. Gac Sanit . 2018;32(2):167.e1-167.e10. GRADEpro software: GRADEpro GDT: Guideline Development Tool [Software]. Prime MUaE, ed. 2024. https://www. gradepro.org/ . Piggott T, Baldeh T, Dietl B, et al.", + "tokenCount": 193, + "pageStart": 38, + "pageEnd": 38, + "hash": "479554616939cbd10906da2a80af229bedb29468baf459268865e8ce52bce59a" + }, + { + "text": "Standardized wording to im - prove efficiency and clarity of GRADE EtD frameworks in health guidelines. J Clin Epidemiol . 2022;146:106-122. Andrews JC, Schünemann HJ, Oxman AD, et al. GRADE guide - lines: Going from evidence to recommendation-determinants of a recommendation ’ s direction and strength. J Clin Epidemiol . 2013;66(7):726-735. Andrews J, Guyatt G, Oxman AD, et al. GRADE guidelines: Going from evidence to recommendations: the significance and presentation of recommendations. J Clin Epidemiol . 2013;66(7): 719-725. Williams B, MacDonald TM, Morant SV, et al.", + "tokenCount": 153, + "pageStart": 38, + "pageEnd": 38, + "hash": "3d181c00935fb7bbb228083a38b5b4d8ad8aec9ef9e4a6d6797c24cf325be632" + }, + { + "text": "Endocrine and haemodynamic changes in resistant hypertension, and blood pres - sure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies. Lancet Diabetes Endocrinol . 2018;6(6): 464-475. Williams B, MacDonald TM, Morant S, et al.", + "tokenCount": 69, + "pageStart": 38, + "pageEnd": 38, + "hash": "9339cebfdaef2b95e59bf7ed7e7046ac1c56fe3aac5efcf427f9a12639928406" + }, + { + "text": "Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treat - ment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet . 2015;386(10008):2059-2068. Carey RM, Douglas JG, Schweikert JR, Liddle GW. The syn - drome of essential hypertension and suppressed plasma renin ac - tivity. Normalization of blood pressure with spironolactone. Arch Intern Med . 1972;130(6):849-854. Weinberger MH, White WB, Ruilope LM, et al.", + "tokenCount": 140, + "pageStart": 38, + "pageEnd": 38, + "hash": "95a8d1f134ea323a981902187524833a2e225237a7d521a727637b2b9acddc7b" + }, + { + "text": "Effects of eplere - none versus losartan in patients with low-renin hypertension. Am Heart J . 2005;150(3):426-433. Brown JM, Siddiqui M, Calhoun DA, et al. The unrecognized prevalence of primary aldosteronism: a cross-sectional study. Ann Intern Med . 2020;173(1):10-20. Cornu E, Steichen O, Nogueira-Silva L, et al.", + "tokenCount": 100, + "pageStart": 38, + "pageEnd": 38, + "hash": "196b89130bc0a89f4cdcf31c0d6a0f99b7f43f6bc16c474ef67b711705d93681" + }, + { + "text": "Suppression of aldosterone secretion after recumbent saline infusion does not exclude lateralized primary aldosteronism. Hypertension . 2016; 68(4):989-994. Parksook WW, Brown JM, Omata K, et al. The spectrum of dys - regulated aldosterone production: an international human physi - ology study. J Clin Endocrinol Metab . 2024;109(9):2220-2232. Tsai CH, Brown JM, Parisien-La Salle S, et al. ACE inhibition to distinguish low-renin hypertension from primary aldosteronism. Hypertension . 2025;82(6):1046-1055. Leung AA, Padwal RS, Hundemer GL, et al. Confirmatory testing for primary aldosteronism: a study of diagnostic test accuracy. Ann Intern Med . Published online May 6, 2025. 10.7326/ ANNALS-24-03153 28. Brown JJ, Davies DL, Ferriss JB, et al.", + "tokenCount": 219, + "pageStart": 38, + "pageEnd": 38, + "hash": "f82fa300649c542e90cd7a290ac08ee7b0ecb8078d4ce87fa2e2a3d668c0467b" + }, + { + "text": "Comparison of surgery and prolonged spironolactone therapy in patients with hypertension, aldosterone excess, and low plasma renin. Br Med J . 1972; 2(5816):729-734. Fourkiotis V, Vonend O, Diederich S, et al.", + "tokenCount": 62, + "pageStart": 38, + "pageEnd": 38, + "hash": "f992b61a730301fd2a54f1682cfe5d19e3767b18c7a99704340fbe2ecc04b938" + }, + { + "text": "Effectiveness of epler - enone or spironolactone treatment in preserving renal function in primary aldosteronism. Eur J Endocrinol . 2013;168(1):75-81. Saiki A, Otsuki M, Tamada D, et al.", + "tokenCount": 59, + "pageStart": 38, + "pageEnd": 38, + "hash": "977341091cb159cbee649605faaecbb0f73bf3627066493502815a449ff570e9" + }, + { + "text": "Increased dosage of MRA im - proves BP and urinary albumin excretion in primary aldosteron - ism with suppressed plasma renin. J Endocr Soc . 2022;6(1): bvab174. Schneider H, Sarkis AL, Sturm L, et al.", + "tokenCount": 60, + "pageStart": 38, + "pageEnd": 38, + "hash": "b581dba11569cfdfa36f213bd87d1745342c045fc6dea06a84eac45825762f7b" + }, + { + "text": "Moderate dietary salt re - striction improves blood pressure and mental well-being in pa - tients with primary aldosteronism: the salt CONNtrol trial. J Intern Med . 2023;294(1):47-57. Katsuragawa S, Goto A, Shinoda S, et al.", + "tokenCount": 69, + "pageStart": 38, + "pageEnd": 38, + "hash": "6040faed7657159e36f3932518083fb625f4068c5c162406acf06ed5356624fe" + }, + { + "text": "Association of reversal of renin suppression with long-term renal outcome in medically treated primary aldosteronism. Hypertension . 2023;80(9):1909-1920. Nakano Y, Murakami M, Hara K, et al.", + "tokenCount": 56, + "pageStart": 38, + "pageEnd": 38, + "hash": "d288c0f9a079f5c859a648cee7230cb1d473f4680868597f20ed051fae9a91a5" + }, + { + "text": "Long-term effects of pri - mary aldosteronism treatment on patients with primary aldoster - onism and chronic kidney disease. Clin Endocrinol (Oxf) . 2023; 98(3):323-331. Monticone S, Burrello J, Tizzani D, et al. Prevalence and clinical manifestations of primary aldosteronism encountered in primary care practice. J Am Coll Cardiol . 2017;69(14):1811-1820. Xu Z, Yang J, Hu J, et al. 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Buffolo F, Monticone S, Burrello J, et al. Is primary aldosteronism still largely unrecognized? Horm Metab Res . 2017;49(12): 908-914. Calhoun DA. Hyperaldosteronism as a common cause of resistant hypertension. Annu Rev Med . 2013;64(1):233-247. Douma S, Petidis K, Doumas M, et al. Prevalence of primary hy - peraldosteronism in resistant hypertension: a retrospective obser - vational study. Lancet . 2008;371(9628):1921-1926.", + "tokenCount": 199, + "pageStart": 38, + "pageEnd": 38, + "hash": "8433395f301843d8f01626703edf1d42c73bd49c772990584e88066562cfb6ef" + }, + { + "text": "Parasiliti-Caprino M, Lopez C, Prencipe N, et al. Prevalence of primary aldosteronism and association with cardiovascular com - plications in patients with resistant and refractory hypertension.", + "tokenCount": 50, + "pageStart": 38, + "pageEnd": 38, + "hash": "4217386d07e2b61c0088e660b2bca8e783e7093743f3bea71c62d40a1698e6f9" + }, + { + "text": "J Hypertens . 2020;38(9):1841-1848. 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N Engl J Med . 2023;388(5):395-405. Kristensen M, Fenton RA, Poulsen SB.", + "tokenCount": 143, + "pageStart": 43, + "pageEnd": 43, + "hash": "13e4ecc0fb86097d44c714f38350d70e43958389fad7e710f32f84c4caf0b45d" + }, + { + "text": "Dissecting the effects of al - dosterone and hypokalemia on the epithelial Na(+) channel and the NaCl cotransporter. Front Physiol . 2022;13:800055. Jia G, Habibi J, Aroor AR, et al.", + "tokenCount": 59, + "pageStart": 43, + "pageEnd": 43, + "hash": "b2a31fdba2d96b05bc0d057ec99b1cebc887c627fdaecf78302599b910f6f392" + }, + { + "text": "Epithelial sodium channel in aldosterone-induced endothelium stiffness and aortic dysfunction. Hypertension . 2018;72(3):731-738. Muiesan ML, Salvetti M, Rizzoni D, et al. Resistant hypertension and target organ damage. Hypertens Res . 2013;36(6):485-491.", + "tokenCount": 78, + "pageStart": 43, + "pageEnd": 43, + "hash": "b72beea41b7ad05fb516603a1553f77e9cdec2b2e403a6908df05b16532b39b1" + }, + { + "text": "Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol . 2005;45(8): 1243-1248. Hill MA, Jaisser F, Sowers JR.", + "tokenCount": 75, + "pageStart": 43, + "pageEnd": 43, + "hash": "a9add9a8f287f4c18930a60a50faac36e781cbab1ff200969d20eaa1bad23e77" + }, + { + "text": "Role of the vascular endothelial sodium channel activation in the genesis of pathologically in - creased cardiovascular stiffness. Cardiovasc Res . 2022;118(1): 130-140. Hood SJ, Taylor KP, Ashby MJ, Brown MJ.", + "tokenCount": 50, + "pageStart": 43, + "pageEnd": 43, + "hash": "1841805c8e1096dba78746c1c2b7c4ecd0611f55ee55667547f4853000606d63" + }, + { + "text": "The spironolac - tone, amiloride, losartan, and thiazide (SALT) double-blind crossover trial in patients with low-renin hypertension and elevated aldosterone-renin ratio.", + "tokenCount": 48, + "pageStart": 43, + "pageEnd": 43, + "hash": "f3eaa8cfac1d4a02025e477c7202ccfde9b87e0a322b1994a08afc3078826719" + }, + { + "text": "Circulation . 2007;116(3): 268-275. Izzo JL, Jr., Hong M, Hussain T, Osmond PJ. Long-term BP control and vascular health in patients with hyperaldosteronism treated with low-dose, amiloride-based therapy.", + "tokenCount": 61, + "pageStart": 43, + "pageEnd": 43, + "hash": "1b12c0cc5edd09ace16872c1284627b67bf4900168cce34346dfa6e32795604b" + }, + { + "text": "J Clin Hypertens (Greenwich) . 2019;21(7):922-928. Griffing GT, Cole AG, Aurecchia SA, Sindler BH, Komanicky P, Melby JC.", + "tokenCount": 49, + "pageStart": 43, + "pageEnd": 43, + "hash": "82152169641e38b9ee8a931c8f58a2fbf8d255060a5fea4cdf26c0c71672d66b" + }, + { + "text": "Amiloride in primary hyperaldosteronism. Clin Pharmacol Ther . 1982;31(1):56-61. Oxlund CS, Buhl KB, Jacobsen IA, et al.", + "tokenCount": 43, + "pageStart": 43, + "pageEnd": 43, + "hash": "24681076cecaaaa79cff0ba9a7c2c4c87db407025206d0529b68a726307139e9" + }, + { + "text": "Amiloride lowers blood pressure and attenuates urine plasminogen activation in patients with treatment-resistant hypertension. J Am Soc Hypertens . 2014;8(12):872-881.", + "tokenCount": 43, + "pageStart": 43, + "pageEnd": 43, + "hash": "4771c809fd9c2606b2f64e8b55944b0a7c5e32691cc552459845397461076c32" + }, + { + "text": "Hoefnagels WH, Drayer JI, Smals AG, Kloppenborg PW. Spironolactone and amiloride in hypertensive patients with and without aldosterone excess.", + "tokenCount": 43, + "pageStart": 43, + "pageEnd": 43, + "hash": "389bfc321a5248e85dfbe085f7677e59ee5328cd97e6b1250f81bc87eb75eb61" + }, + { + "text": "Clin Pharmacol Ther . 1980; 27(3):317-323. Douglas JG, Hollifield JW, Liddle GW. Treatment of low-renin essential hypertension. Comparison of spironolactone and a hydrochlorothiazide-triamterene combination.", + "tokenCount": 61, + "pageStart": 43, + "pageEnd": 43, + "hash": "937667ff3afe803e841408d8a21e4886803851dff82862315f26dc6f6637d65a" + }, + { + "text": "JAMA . 1974;227(5):518-521. DeCarvalho JG, Emery AC Jr, Frohlich ED. Spironolactone and triamterene in volume-dependent essential hypertension. Clin Pharmacol Ther . 1980;27(1):53-56. Hill MA, Sowers JR.", + "tokenCount": 71, + "pageStart": 43, + "pageEnd": 43, + "hash": "0088a62cbc29ccb74b8726beaca1088487ca981e27303baaf180eb2a65f8d00a" + }, + { + "text": "Mineralocorticoid antagonists and ENaC in - hibitors in hyperaldosteronism. J Clin Hypertens (Greenwich) . 2019;21(7):929-931. Ho WY, Hsiao CC, Wu PH, et al. Comparison of different medical treatments for primary hyperaldosteronism: a systematic review and network meta-analysis. Ther Adv Chronic Dis . 2024;15: 20406223241239775. Baker EH, Duggal A, Dong Y, et al. Amiloride, a specific drug for hypertension in black people with T594M variant? Hypertension . 2002;40(1):13-17. The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No.", + "tokenCount": 167, + "pageStart": 43, + "pageEnd": 43, + "hash": "591e6e69807a5fc426607b7fdd0db7cd6311d0bacd8a5f722a70dcf3cbea0b53" + }, + { + "text": "9 2495 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026", + "tokenCount": 42, + "pageStart": 43, + "pageEnd": 43, + "hash": "269f575bf26f249851ceaeb2625d1c4ac078ad29c4508e6f642d8217db0c3b8f" + } +] \ No newline at end of file diff --git a/Adrenal Nodule information/Unveiling the Silent Threat_ Disparities in Adrenal Incidentaloma Management.pdf_semantic.json b/Adrenal Nodule information/Unveiling the Silent Threat_ Disparities in Adrenal Incidentaloma Management.pdf_semantic.json new file mode 100644 index 0000000000000000000000000000000000000000..96d82ce4ef02f5f5c0935d5e7c25e98304fa3b2c --- /dev/null +++ b/Adrenal Nodule information/Unveiling the Silent Threat_ Disparities in Adrenal Incidentaloma Management.pdf_semantic.json @@ -0,0 +1,415 @@ +[ + { + "text": "categorizing clinical notes using our established themes with the ability to create new classifications if necessary. Following completion, we again reviewed our results as a team to finalize our results. All statistical analyses were performed with SAS software.", + "tokenCount": 46, + "pageStart": 3, + "pageEnd": 3, + "hash": "87282e64930677b1e7a2b5efd8e894f66e783ee7bdd2901623a1fd52c45c1f85" + }, + { + "text": "A bivariate analysis was performed using chi-squared and Student’s t-test analysis. Multivariate logistic regression was performed to evaluate factors associated with biochemical workup. Results Study cohort During the study period, 9022 patients had a qualifying CT scan performed and 533 (5.9%) individuals with IAMs were identified.", + "tokenCount": 70, + "pageStart": 3, + "pageEnd": 3, + "hash": "48e6d284db8724a0d7cfccb4485df7f221e2fe8d996c7a2552615e5580283175" + }, + { + "text": "After applying exclusion criteria, 245 (46.0%) of 533 patients were included in our final analysis ( Fig. Demographics Overall, the final patient cohort was 58.8% female, 58.0% over 65 y of age, and 86.1% White ( Table 1 ).", + "tokenCount": 59, + "pageStart": 3, + "pageEnd": 3, + "hash": "b03d62fdae2ccbf0412688febb834c1f73df27df25d68e82297eaa561a979ac9" + }, + { + "text": "The patient population was generally healthy with 50.6% reporting a CCI of 0 or 1. Most patients were covered by Medicare (49.0%) or private insurance (43.3%). The most common ADI deciles were 4 or 5, making up 17.0% and 17.4% respectively.", + "tokenCount": 64, + "pageStart": 3, + "pageEnd": 3, + "hash": "89d0bc4bac06fee3b5115403a704fad91beeb33c047bd4dc42daa5ad2b49c191" + }, + { + "text": "A total of 135 pa- tients (56.0%) were from advantaged neighborhoods (lower 50th percentile ADI). Imaging and ordering provider characteristics The majority of the imaging which discovered the IAM was ordered by EM providers (50.6%), followed by subspecialists (36.7%), and PCPs (12.7%).", + "tokenCount": 69, + "pageStart": 3, + "pageEnd": 3, + "hash": "68983589e01dd4b39e5a331f39b9ad06449bf514a278445b2702216588c9f55b" + }, + { + "text": "A total of 77.1% of ordering providers were physicians, while the remainder were physician assis- tants or nurse practitioners. The vast majority of the CTs or- dered were with contrast (93.1%).", + "tokenCount": 46, + "pageStart": 3, + "pageEnd": 3, + "hash": "8ef0611ba8953f168dc4d9a7bbbb1629710833a13d0987370a8e9800c797699f" + }, + { + "text": "Rate of IAM workup Most (71%) IAM patients received no further workup, 18% had partialevaluation,and11%hadfullassessment( Fig. A chi-square test revealed statistically significant associations between sex, neighborhood disadvantage, and ordering provider with IAM workup.", + "tokenCount": 60, + "pageStart": 3, + "pageEnd": 3, + "hash": "56a4eb9a5bbb275acd29bea5cc289b11af6dfa503f2731fe4571cfa29bfd4735" + }, + { + "text": "More specifically, female (71.8% versus 28.2% males, P < 0.01) and advantaged (67.1% versus 32.9% disadvantaged, P ¼ 0.03) patients had a significantly higher rate of workup, while patients with imaging ordered by EM providers had a significantly lower rate of workup compared to those ordered by primary care (54.6% received no workup versus 7.5% from PCPs, P < 0.01).", + "tokenCount": 101, + "pageStart": 3, + "pageEnd": 3, + "hash": "f76d3e40b3b8342c4c9ab34af15d81bfc3daca9cb9a8620abf89fb78d65567a4" + }, + { + "text": "Among advan- taged patients, 54.8% had scans ordered by EM providers and 17.8% had scans ordered by PCPs ( Table 2 ). Of the disadvan- taged patients, scans ordered by EM providers and PCPs were 45.3% and 6.6%, respectively.", + "tokenCount": 63, + "pageStart": 3, + "pageEnd": 3, + "hash": "b47dc8e7d9ccfeaeffdbe1c334fafb69d3ac9e2c1780d1f955795c722b6edd2b" + }, + { + "text": "Comparison of patients who hadapartialorfullworkupispresentedin Supplementary Table 1 . Factors associated with biochemical evaluation Logistic regression demonstrated disadvantaged patients were less likely to undergo any workup compared to advan- taged patients (odds ratio [OR] 0.51, confidence interval [CI] 0.26-0.98) ( Table 3 ).", + "tokenCount": 75, + "pageStart": 3, + "pageEnd": 3, + "hash": "a2a4af65ecd0e5d610add9dd58bd99210f068280dbea18eabdb0b0b32d0dad58" + }, + { + "text": "Other factors significantly associated with receiving any workup included female sex (OR 2.26, CI 1.19- 4.31) and scans ordered by PCPs (OR 4.08, CI 1.69-9.81) compared to EM providers.", + "tokenCount": 53, + "pageStart": 3, + "pageEnd": 3, + "hash": "d2578c6d546e7b83817bd864b26c804375469f37392671e5c755ce58555cb93f" + }, + { + "text": "There was no statistically signifi- cant difference in workup based on age, race, ethnicity, in- surance status, or CCI. Secondary chart review Examination of physician notes and radiology reports from 30 disadvantaged patients without IAM workup revealed three main themes which may have contributed to the lack of evaluation ( Table 4 ).", + "tokenCount": 67, + "pageStart": 3, + "pageEnd": 3, + "hash": "b04bc93203096a200e5d4bb81f4d1352cacb00f4749b4b181c26f2d43f972c4c" + }, + { + "text": "The most common theme of missed evaluation related to radiology reports recom- mending no further workup. While this was likely meant to signal that the lesion needed no further radiographic workup to evaluate for malignant potential, this was often interpreted as no further workup was needed at all, including biochemical workup.", + "tokenCount": 66, + "pageStart": 3, + "pageEnd": 3, + "hash": "a1ed221655207909458d2b559e10c536eed4647238bcb29eba0fcf4274ca221d" + }, + { + "text": "For instance, a communi- cation from one PCP to a patient with an adrenal nodule noted that the scan demonstrated an adrenal lesion that was “benign,” and echoed the report that no further evaluation was needed, even though a functional workup was never performed.", + "tokenCount": 62, + "pageStart": 3, + "pageEnd": 3, + "hash": "d1d9d5619007b547a9be8caec5ef138050cb8ec28bacc693becc6ea42f8cd992" + }, + { + "text": "Second most common was PCPs not acknowledging the nodule nor ordering additional tests, suggesting these incidental findings were missed. Lastly, Fig. 1 e Included patients flowchart. o’connor et al \u0001 adrenal incidentaloma management 145", + "tokenCount": 49, + "pageStart": 3, + "pageEnd": 3, + "hash": "e9875e4bc8089394fd4c8bd2956175a8afa860b42fd75be18ee0f45d870cfe43" + }, + { + "text": "patients were frequently lost to follow-up after imaging and never completed biochemical testing when recommended. Discussion In our study, the rates of complete guideline-concordant biochemical workup or partial evaluations of adrenal inci- dentalomas were 11% and 18%, respectively.", + "tokenCount": 56, + "pageStart": 4, + "pageEnd": 4, + "hash": "d2359f4e3b7e9127bcdb50c0d6b8a9a4a2cb535982aa032e6055d4a5b8669b4a" + }, + { + "text": "These alarmingly low rates align with other publications, confirming absent or incomplete IAM evaluations are commonplace. 2 , 12 , 20 For instance, Ebbehoj et al . (2020) reported appropriate workup of IAMs was completed in only 15.2% of cases.", + "tokenCount": 57, + "pageStart": 4, + "pageEnd": 4, + "hash": "b2326c8ace3a63436b4e4d77ba350e221015f98eaaaf9d60d2f7aec813915314" + }, + { + "text": "2 These low rates of workup undoubtedly lead to poor patient outcomes, as untreated hormonally active adrenal incidentalomas have been tied to higher rates of cardiovascular events and even mortality. 10 , 11 , 21 Workup rates were particularly low for patients living in disadvantaged neighborhoods.", + "tokenCount": 55, + "pageStart": 4, + "pageEnd": 4, + "hash": "2a1d88d0c9f7d3feefc15da5a0da8e6f6ec866a57787bfbb023c33c7fc377f35" + }, + { + "text": "We found patients from these neighborhoods had roughly half the odds of obtaining any IAM workup compared to those from advantaged neighbor- hoods. Our findings are consistent with literature linking neighborhood-level disadvantage with poorer health out- comes and disease management.", + "tokenCount": 50, + "pageStart": 4, + "pageEnd": 4, + "hash": "9a17faa74be6a0e14e62813be1c1947ad8fba0de19a7dab7eff0c9fe10686bff" + }, + { + "text": "22 , 23 Similarly, Schut and Mortani Barbosa (2020) reported racial/ethnic disparities in incidental pulmonary nodule management. 24 Differences in care of IAMs may have downstream effects, potentially exacerbating preexistent disparities in comorbidities such as diabetes and hypertension.", + "tokenCount": 58, + "pageStart": 4, + "pageEnd": 4, + "hash": "c4ae76e15872f63c0215cbbba46417a7fc3d09eb7d0022ffffbca08cc2135db2" + }, + { + "text": "25 , 26 The relationship is likely multifactorial and involves patient access to PCPs, reliance on safety net programs or emergency departments (EDs), and more fragmented care. 23 , 27 Furthermore, our secondary chart analysis revealed lack of follow-up as a common theme among patients in disadvantaged neighborhoods, reinforcing that many of the issues revolve around the ability to access Table 1 e Demographics.", + "tokenCount": 79, + "pageStart": 4, + "pageEnd": 4, + "hash": "c64fe23550d27a7c76f02d8c95a2132c58139c75a1d9d4b1a0b4cb1d929c446b" + }, + { + "text": "No workup (n ¼ 174) % Any workup (n ¼ 71) % Total cohort (n ¼ 245) % P value Sex < 0.01 Female 53.5 71.8 58.8 Male 46.5 28.2 41.2 Age 0.10 < 65 54.6 66.2 58.0 > 65 45.4 33.8 42.0 Race/Ethnicity 0.68 White 86.2 85.9 86.1 Black 5.2 7.0 5.7 Hispanic 2.9 4.2 3.3 Asian 3.5 2.8 3.3 Other/Unknown 2.3 0.0 1.6 CCI 0.96 0 22.4 21.1 22.0 1 28.2 29.6 28.6 2 þ 49.4 49.3 49.4 ADI 0.03 Advantaged ( < 50 percentile) 51.5 67.1 56.0 Disadvantaged ( > 50 percentile) 48.5 32.9 44.0 Ordering provider < 0.001 EM 54.6 40.9 50.6 PCP 7.5 25.4 12.7 Specialist 37.9 33.8 36.7 Insurance 0.06 Private 38.5 54.9 43.3 Medicaid 1.7 4.2 2.5 Medicare 52.9 39.4 49.0 Uninsured 5.8 1.4 4.5 Tricare 1.2 0.0 0.8 146 journalofsurgicalresearch \u0001 july 2025 (311) 143 e 150", + "tokenCount": 329, + "pageStart": 4, + "pageEnd": 4, + "hash": "bdbd149442fdf3d626fe004b56613138dbbc3a273dfead4b93c5da97df35a5a8" + }, + { + "text": "primary care and navigate the health-care system. Addition- ally, clinics serving disadvantaged patients typically have limited resources, and as a result, prioritization of other ur- gent health matters may supersede evaluation of incidentalomas.", + "tokenCount": 46, + "pageStart": 5, + "pageEnd": 5, + "hash": "6f1df06392545fdad3b94c3ebe1346e78137d85e3c0cc9dbc027dfc75fd057da" + }, + { + "text": "28 While our study demonstrated poor IAM workup compli- ance across all medical/surgical fields, investigations were significantly lower when diagnoses were established during ED visits. Similarly, Feeney et al .", + "tokenCount": 43, + "pageStart": 5, + "pageEnd": 5, + "hash": "d5428d6cc76b6a5e12431054dfe08dd1f0acf77bc9dd5364a2fcabff5f6fd76a" + }, + { + "text": "(2020) reported a three-fold lower rate of follow-up imaging if the index study was per- formed while the individual was an inpatient or in the ED compared to outpatient. 29 Interestingly, several previous publications focused on poor IAM workup compliance in pri- mary care outpatient settings.", + "tokenCount": 61, + "pageStart": 5, + "pageEnd": 5, + "hash": "36f0192cd2014c8aedcc945149b72dcf3c1b4aa9bb4637b58ae5f62c73defb14" + }, + { + "text": "30 , 31 The authors suggested PCPs may lack time and/or knowledge of appropriate biochemical evaluations to adequately address IAMs. However, our study suggests the emergency room as a potentially larger source of missed IAM management.", + "tokenCount": 45, + "pageStart": 5, + "pageEnd": 5, + "hash": "c0604f6d4f4ee08e682967f27f9d3b9cf098d42493a7537e1a90402badbe5e35" + }, + { + "text": "Although disadvantaged patients had higher rates of detection by EM providers, ordering pro- vider remained a significant factor even when controlling for socioeconomic deprivation. Our chart review noted PCPs failing to acknowledge the nodule as a major reason for missed workup, and suggests that communication between EM and PCPs remains a challenge to properly addressing IAMs.", + "tokenCount": 68, + "pageStart": 5, + "pageEnd": 5, + "hash": "dee4876e1ac34eb478cf92cbeabebfc82fe4509dd0bd5824ef5e290534e8491d" + }, + { + "text": "One strategy to improve coordination of care is the develop- ment of an adrenal nodule identification system which uses artificial intelligence natural language processing to create automated messages for PCPs regarding the nodule and guidelines for next steps.", + "tokenCount": 44, + "pageStart": 5, + "pageEnd": 5, + "hash": "e1655261096c861a9dc037fd45f6c7e083686ebcae0472ca4617fd433c537fa1" + }, + { + "text": "A recent study utilized artificial in- telligence technology to flag patient electronic health records with adrenal nodules 32 and pairing similar technology with notifications to PCPs can be an effective way to reduce the amount of IAMs lost during the transition of care.", + "tokenCount": 52, + "pageStart": 5, + "pageEnd": 5, + "hash": "3b5c56a3d54b22857de0b2c7f46cf7dfe6d522aaee9b09b8548f8c8d2d22ea6b" + }, + { + "text": "Another problem contributing to incomplete IAM evalua- tion is radiologists recommending no further workup. Although radiologists rule out malignant potential and label the nodule as “benign”, biochemical workup is required to understand the functional potential.", + "tokenCount": 52, + "pageStart": 5, + "pageEnd": 5, + "hash": "5bf54f5147d8f6a0d713ef40f1c146b6da4ae587092b45e31b4e4134571a7e1d" + }, + { + "text": "To combat the issue, the use of radiology reporting templates which encourage addi- tional testing and provide specific follow-up recommenda- tions have led to increased rates of follow-up imaging and biochemical testing.", + "tokenCount": 45, + "pageStart": 5, + "pageEnd": 5, + "hash": "688dfcc7ef661fa8c7fba7a1901b3af9e11f3c7d23f4c3a5be7397fb24b4ceda" + }, + { + "text": "33-35 While modifications to radiology reporting language (e.g., low concern for malignancy, could consider a functional workup) are a step in the right direction, additional protocols and interdisciplinary teams are neces- sary to ensure even more patients are adequately evaluated.", + "tokenCount": 58, + "pageStart": 5, + "pageEnd": 5, + "hash": "76ad3eac6ce9aa5ed656ddcb4bfbbedb22c6ea2057efcde99c5859635b5fe2c0" + }, + { + "text": "Recently, a program combining standardized radiologic reporting, chart-based messages to PCPs, and easier referrals to a multispecialty adrenal clinic resulted in an approximate 4x increase in the number of biochemical testing orders placed by PCPs.", + "tokenCount": 50, + "pageStart": 5, + "pageEnd": 5, + "hash": "2aca21fbb15c723892ab0a12f86cc2f05720f25d8389eccf334cb9aab8efc455" + }, + { + "text": "36 Similarly, interdisciplinary collaboration between radiologists, EM physicians, nurse case managers, and PCPs resulted in 95% of ED patients with incidental radi- ology findings having follow-up plans for evaluation after discharge.", + "tokenCount": 45, + "pageStart": 5, + "pageEnd": 5, + "hash": "6bbc621091007e903eb2f1a8637435f22be8c261effd11d2fe98bfabc21d1c30" + }, + { + "text": "37 While these interventions highlight the promising out- comes for incidentaloma management using providers from multiple areas of health care, no studies to date have examined if these interventions have reduced disparities in Fig. 2 e IAM workup. DST [ dexamethasone suppression test; HTN [ hypertension. Table 2 e ADI and ordering provider.", + "tokenCount": 70, + "pageStart": 5, + "pageEnd": 5, + "hash": "90c20d724e007af6758810d808a00632b96a0fb05e4e0554be66631ca93b3a9e" + }, + { + "text": "Ordering provider ADI Advantaged ( < 50 percentile) Disadvantaged ( > 50 percentile) N% n % EM 74 54.8 48 45.3 PCP 24 17.8 7 6.6 Subspecialist 37 27.4 51 48.1 o’connor et al \u0001 adrenal incidentaloma management 147", + "tokenCount": 70, + "pageStart": 5, + "pageEnd": 5, + "hash": "ed16488249b30ed48d3df9910e0bbade93d5047b7fb3cd71b127b1b1443635c2" + }, + { + "text": "the workup of adrenal nodules. It is not hard to imagine positive resources directed to identify IAM patients may be unequally distributed and benefit well-resourced clinics. Thus, to further improve health outcomes and equity, in- terventions must consider the patient population and setting.", + "tokenCount": 60, + "pageStart": 6, + "pageEnd": 6, + "hash": "922c67a1822c68c0f770b48601b1db522d7cd268b51633cd16446e33e20a8931" + }, + { + "text": "One relevant model to help achieve these goals is the Health Disparities Framework, developed by the National Institute on Minority Health and Health Disparities. 38 The adaptation of the socioecological model evaluates five domains (biological, behavioral, physical/built environment, sociocul- tural environment, and health-care system) and drives research and interventions toward solutions which address the fundamental causes of disparities.", + "tokenCount": 83, + "pageStart": 6, + "pageEnd": 6, + "hash": "1477dddc437a046181532e14111af5c9f7a4ab2974cb30901deb58ca26d500bf" + }, + { + "text": "Building upon this and the findings of our study, we encourage researchers and doctors to consider patient and neighborhood-level dispar- ities when implementing subsequent interventions. We found a major obstacle for patients in disadvantaged com- munities is following up with PCPs after the identification of an IAM.", + "tokenCount": 58, + "pageStart": 6, + "pageEnd": 6, + "hash": "2db69ae42f1fb9ddbcd86928106d8c29a490c61e23e996b4b03cc990981e9712" + }, + { + "text": "Although we cannot determine the exact reason for each patient, one proposal could be the use of patient navi- gators who can help overcome environmental and neigh- borhood factors such as transportation, costs, and insurance coverage.", + "tokenCount": 46, + "pageStart": 6, + "pageEnd": 6, + "hash": "3609df69ef9f190b85302eb4939b0d8d884dbb9db910a8a30e4fb83d2fbbbdd3" + }, + { + "text": "This strategy has demonstrated success in improving cancer management and treatment. 39 , 40 For instance, one randomized control trial found patient navi- gation led to significantly greater compliance with follow-up among minority women with abnormal mammograms.", + "tokenCount": 46, + "pageStart": 6, + "pageEnd": 6, + "hash": "3ae624b88caac97be474c9dfb0c42e2d6152bf84bd98fc60b6d77b24b3a3b0df" + }, + { + "text": "41 As a result, navigators remain a promising method through which to eliminate disparities in care for IAMs, although obvious barriers such as costs and workflow burden require more in-depth investigation. Overall, the low rates of IAM follow-up, particularly among patients from disadvantaged neighborhoods, suggest the need for new protocols consid- ering health disparities to ensure more patients are adequately evaluated.", + "tokenCount": 79, + "pageStart": 6, + "pageEnd": 6, + "hash": "e0d04f6f384a1bdbd0e3ea7caf9a7c2abd2f38edfe432cb0e8b4853ba81c104d" + }, + { + "text": "Our study had a number of limitations. For one, retro- spective data and inherent inaccuracies in the electronic medical record may skew results. The data were only from a single institution and the population skewed more toward White and insured, making the results less generalizable.", + "tokenCount": 54, + "pageStart": 6, + "pageEnd": 6, + "hash": "d3f02d5533bb86e48563dbfee06da3b4c61dd2f90dfe6afed1887417af60e5e3" + }, + { + "text": "Including a greater percentage of non-White or Medicaid patients could allow for further elucidation of barriers to workup which specifically constrain these populations. In addition, due to the retrospective nature, we cannot deter- mine the direction of the relationship between neighbor- hood disadvantage and lower rates of biochemical workup.", + "tokenCount": 62, + "pageStart": 6, + "pageEnd": 6, + "hash": "c008bf90de17e0f37cd42dc9171ef722aa82f22d1dbcce31ece272c99a555cf3" + }, + { + "text": "We are also unable to determine any verbal or other communication provided to the patient regarding their identified nodule. Table 3 e Factors associated with workup. Variable OR (95% CI) Sex Male ref Female 2.26 (1.19-4.31) Age > 65 ref < 65 1.34 (0.54-3.32) CCI 0 ref 1 1.03 (0.43-2.48) 2+ 1.16 (0.49-2.73) Race/Ethnicity White ref Black 1.54 (0.40-5.97) Hispanic 1.96 (0.37-10.49) Asian 0.68 (0.12-3.88) Other * Ordering provider ED ref PCP 4.08 (1.69-9.81) Subspecialist 1.48 (0.73-3.01) ADI < 50 ref > 50 0.51 (0.26-0.98) Insurance Private ref Medicaid 2.10 (0.35-12.67) Medicare 0.63 (0.25-1.55) Uninsured 0.16 (0.02-1.48) Tricare * * Not enough patients for analysis.", + "tokenCount": 257, + "pageStart": 6, + "pageEnd": 6, + "hash": "2527e9f5df09ce885ae8323598329a5afaa72e825fdcae7492cbc2a1d83ddd61" + }, + { + "text": "Table 4 e Common themes for lack of workup among disadvantaged patients Radiologist recommended no workup PCP did not acknowledge nodule Patient lost to follow-up Number of patients 11 13 6 Selected quote from Electronic Health Record “Benign 1.6 cm left adrenal adenoma.", + "tokenCount": 59, + "pageStart": 6, + "pageEnd": 6, + "hash": "74624d5d0e7cdb17d311b4b6a587a2fb82be983c165a3ae32f1e4780ef494d64" + }, + { + "text": "No follow-up imaging is necessary” “Partially imaged, indeterminant 4.6 cm right adrenal mass, likely adenoma or adrenal myelolipoma, both benign.", + "tokenCount": 44, + "pageStart": 6, + "pageEnd": 6, + "hash": "148443087747107abc145b2d1a1f73b5c1c831a90c7a1298be40de680095076a" + }, + { + "text": "Consider nonurgent adrenal protocol CT or MR for further characterization.” “Incidental indeterminate 1.4 cm adrenal nodule. Consider follow-up in 12 mo if no history of malignancy versus nonurgent evaluation with adrenal protocol CT or MRI.” “Discussed the need to complete testing for evidence of hypercortisolism or pheochromocytoma.” MR ¼ magnetic resonance; MRI ¼ magnetic resonance imaging.", + "tokenCount": 102, + "pageStart": 6, + "pageEnd": 6, + "hash": "5de7efddedc2d1f9f8a53dbda4e9e1ddd830a1467010754a72d635c53eab364f" + }, + { + "text": "148 journalofsurgicalresearch \u0001 july 2025 (311) 143 e 150", + "tokenCount": 17, + "pageStart": 6, + "pageEnd": 6, + "hash": "f268f8628097f5cc57ec181b8c29963c5dc7e2cb077a88ac61f03e4f4116104c" + }, + { + "text": "Conclusions Overall, the rates of complete or partial guideline-based biochemical workup of adrenal incidentalomas in our study population were low at 11% and 18%, respectively. Patient neighborhood disadvantage and studies ordered by EM pro- viders were associated with lower rates of biochemical workup. Further investigation into barriers to IAM workup and focused interventions to improve the rate of IAM workup for patients in disadvantaged settings are needed. Supplementary Materials Supplementary data related to this article can be found at https://doi.org/10.1016/j.jss.2025.04.031 . Disclosure John P. O’Connor reports that financial support was provided by Herman and Gwendolyn Shapiro Foundation. Amy Kind reports financial support was provided by National Institute on Aging. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Funding None. CRediT authorship contribution statement John P. O’Connor: Writing e review & editing, Writing e original draft, Investigation, Formal analysis, Data curation. Alekya Poloju: Investigation, Formal analysis, Data curation. Samantha K. Pabich: Project administration, Methodology, Data curation. Betty Allen: Investigation, Data curation. Rebecca Sippel: Supervision, Project administration, Method- ology. Amy Kind: Supervision, Methodology. Alexander Chiu: Writing e review & editing, Validation, Supervision, Project administration, Methodology, Formal analysis, Data curation, Conceptualization. references 1. Sherlock M, Scarsbrook A, Abbas A, et al. Adrenal incidentaloma. Endocr Rev . 2020;41:775 e 820 . 2. Ebbehoj A, Li D, Kaur RJ, et al. Epidemiology of adrenal tumours in Olmsted County, Minnesota, USA: a population- based cohort study. Lancet Diabetes Endocrinol . 2020;8:894 e 902 . 3. Geelhoed GW, Druy EM. Management of the adrenal “incidentaloma.”. Surgery .", + "tokenCount": 447, + "pageStart": 7, + "pageEnd": 7, + "hash": "1e2d6ad6ee140d0e8c05c2fe8ddf178a55d7cd4f9418941c0de8172057aa403d" + }, + { + "text": "1982;92:866 e 874 . 4. Fassnacht M, Arlt W, Bancos I, et al. 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Making neighborhood- disadvantage metrics accessible d the neighborhood atlas. N Engl J Med . 2018;378:2456 e 2458 . 18. Hu J, Kind AJH, Nerenz D. Area deprivation index predicts readmission risk at an urban teaching hospital. Am J Med Qual . 2018;33:493 e 501 . 19. Shen J, Fuemmeler BF, Sheppard VB, et al. Neighborhood disadvantage and biological aging biomarkers among breast cancer patients. Sci Rep . 2022;12:11006 . 20. Maher DI, Williams E, Grodski S, Serpell JW, Lee JC. Adrenal", + "tokenCount": 450, + "pageStart": 7, + "pageEnd": 7, + "hash": "a3d7ccfb2b3ba79217917a98ec6050540a7b483852aaa17997cf866000b6e317" + }, + { + "text": "incidentaloma follow-up is influenced by patient, radiologic, and medical provider factors: a review of 804 cases. Surgery . 2018;164:1360 e 1365 . 21. Morelli V, Reimondo G, Giordano R, et al. Long-term follow-up in adrenal incidentalomas: an Italian multicenter study. J Clin Endocrinol Metab . 2014;99:827 e 834 . 22. Durfey SNM, Kind AJH, Buckingham WR, DuGoff EH, Trivedi AN. Neighborhood disadvantage and chronic disease management. Health Serv Res . 2019;54:206 e 216 . o’connor et al \u0001 adrenal incidentaloma management 149", + "tokenCount": 153, + "pageStart": 7, + "pageEnd": 7, + "hash": "e72e35c5ccdfdead343693a234bbca8d2b97815d88602b5f1930e5e05758b35a" + }, + { + "text": "Kirby JB, Kaneda T. Neighborhood socioeconomic disadvantage and access to health care. J Health Soc Behav . 2005;46:15 e 31 . Schut RA, Mortani Barbosa EJ. Racial/ethnic disparities in follow-up adherence for incidental pulmonary nodules: an application of a cascade-of-care Framework. 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Nwana N, Chan W, Langabeer J, Kash B, Krause TM. Does hospital location matter? Association of neighborhood socioeconomic disadvantage with hospital quality in US metropolitan settings. Health Place . 2022;78:102911 . Feeney T, Talutis S, Janeway M, et al. Evaluation of incidental adrenal masses at a tertiary referral and trauma center. Surgery . 2020;167:868 e 875 . Becker J, Woloszyn J, Bold R, Campbell MJ. The adrenal incidentaloma: an opportunity to improve patient care. J Gen Intern Med . 2018;33:256 e 257 . Talutis SD, Childs E, Goldman AL, et al. Strategies to optimize management of incidental radiographic findings in the primary care setting: a mixed methods study. Am J Surg . 2022;223:297 e 302 . Schumm M, Hu MY, Sant V, et al. Automated extraction of incidental adrenal nodules from electronic health records. Surgery . 2023;173:52 e 58 . Woods AP, Godley F, Feeney T, et al. A standardized radiology template improves incidental adrenal mass follow-up: a prospective effectiveness and implementation study. JAm Coll Radiol . 2023;20:87 e 97 . Hamilton AE, Green RL, Gao TP, et al. To report hounsfeld units or not: there is no question. Am J Surg . 2024;229:111 e 115 .", + "tokenCount": 449, + "pageStart": 8, + "pageEnd": 8, + "hash": "3c05cfbe4a4a644e7211f3c6da70762c7a11ff4713caf87f49d04f031f8b992b" + }, + { + "text": "Watari J, Vekaria S, Lin Y, et al. Radiology report language positively influences adrenal incidentaloma guideline adherence. Am J Surg . 2022;223:231 e 236 .", + "tokenCount": 41, + "pageStart": 8, + "pageEnd": 8, + "hash": "7c008bf656da3f0ce847fa4d634b585fbed16d17dac52a5441d8bc47d4c72800" + }, + { + "text": "Woods AP, Feeney T, Gupta A, Knapp PE, McAneny D, Drake FT. Prospective study of a system-wide adrenal incidentaloma quality improvement initiative. J Am Coll Surg . 2024;238:961 e 970 . Barrett TW, Garland NM, Freeman CL, et al. 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Patient navigation and case management following an abnormal mammogram: a randomized clinical trial. Prev Med . 2007;44:26 e 33 . 150 journalofsurgicalresearch \u0001 july 2025 (311) 143 e 150", + "tokenCount": 204, + "pageStart": 8, + "pageEnd": 8, + "hash": "f135acba110eda106ef5277fbdfc7e6d44678b7db405b111467e60dc37d00a26" + } +] \ No newline at end of file diff --git a/Adrenal Nodule information/primary-aldosteronism Family Medicine Clinical Guidelines.pdf_semantic.json b/Adrenal Nodule information/primary-aldosteronism Family Medicine Clinical Guidelines.pdf_semantic.json new file mode 100644 index 0000000000000000000000000000000000000000..f0f4baa3cbb94a84536393f1baadf03a9c8bfed3 --- /dev/null +++ b/Adrenal Nodule information/primary-aldosteronism Family Medicine Clinical Guidelines.pdf_semantic.json @@ -0,0 +1,170 @@ +[ + { + "text": "September 2023 ◆ Volume 108, Number 3 www.aafp.org/afp American Family Physician 275 ORAL SALT LOADING TEST For the oral salt loading test, a high-salt diet supplemented with sodium chloride tablets is consumed for three days with a goal sodium intake of 6 g per day. High salt intake should cause physiologic suppression of the RAAS and a marked decrease in aldosterone levels. A 24-hour urine col - lection is performed on the third day. Persistently elevated 24-hour urine aldosterone levels (more than 12 mcg in 24 hours) are consistent with nonphysiologic production of aldosterone and confirm the diagnosis of primary aldoste - ronism. The saline infusion test can also confirm pathologic aldosterone production if plasma aldosterone concentra - tion is greater than 10 ng per dL after an infusion of 2 L of normal saline. FLUDROCORTISONE TEST The fludrocortisone test involves administration of the syn - thetic mineralocorticoid fludrocortisone at a dosage of 0.1 mg every six hours for four days. Exogenous mineralocor - ticoid administration should suppress serum aldosterone levels. A plasma aldosterone concentration of greater than 6 ng per dL on day 4 confirms the diagnosis of primary aldosteronism. Subtyping Once primary aldosteronism has been diagnosed, the next step is to determine if aldosterone production is unilateral or bilateral. 13,18,19 Unilateral production is typically caused by an aldosterone-producing adenoma and should be treated surgically, whereas bilateral production is typically from idiopathic hyperplasia and is treated medically. This differentiation, termed subtyping, is accomplished with adrenal computed tomography (CT) and adrenal vein sampling. 13,18,19 Adrenal CT has three phases: an initial scan without contrast media, a scan at 60 to 75 seconds after con - trast media administration, and again at 15 minutes. By assessing baseline nodule density, as well as contrast media uptake and subsequent washout, benign", + "tokenCount": 450, + "pageStart": 3, + "pageEnd": 3, + "hash": "1be443893ec2274d4c7747022b364c7fb565c683b2e249cb05ec9e2fe4c5dd44" + }, + { + "text": "adenomas can be reliably distinguished from malignant masses. 20 CT has lim - ited sensitivity for the detection of sub-centimeter nodules. Additionally, CT is unable to distinguish nonfunctioning adenomas from functioning adenomas. A systematic review showed an almost 40% rate of discordance between CT and adrenal vein sampling in subtyping patients with primary aldosteronism. 21 Therefore, adrenal vein sampling is consid - ered the preferred method of subtyping. A systematic review and meta -analysis performed in 2022 found a statistically FIGURE 1 Suggested interpretation of initial case detection testing for primary aldosteronism. Note: An aldosterone-renin ratio > 30 is the most common cutoff during initial case detection when plasma aldosterone concentration and plasma renin activity are in conventional units (ng per dL and ng per mL per hour, respectively). Values above the threshold should not be viewed in isolation because the aldosterone-renin ratio may be exaggerated in cases of very low renin levels without significant elevation of aldosterone. Information from references 10, 13, and 15. Aldosterone-renin ratio Plasma renin activity > 1 ng per mL per hour Diagnosis unlikely Plasma renin activity 0.6 to 1 ng per mL per hour Perform confirmatory testing Plasma renin activity < 0.6 ng per mL per hour Plasma aldosterone concen - tration 20 to 29 ng per dL Plasma aldosterone con - centration ≥ 30 ng per dL Diagnosis confirmed Plasma aldosterone concen - tration 11 to 19 ng per dL Perform confirmatory testing Plasma aldosterone con - centration ≤ 10 ng per dL Diagnosis unlikely Potassium < 3.5 mEq per L Diagnosis confirmed Potassium ≥ 3.5 mEq per L Perform confirmatory testing > 30 Diagnosis unlikely ≤ 30", + "tokenCount": 389, + "pageStart": 3, + "pageEnd": 3, + "hash": "ecae8350f8b196ea37b6df11b07d157f3c0a8445ae9a71345cc702722aabb733" + }, + { + "text": "276 American Family Physician www.aafp.org/afp Volume 108, Number 3 ◆ September 2023 significant higher rate of complete biochemical success when adrenalectomy was guided by adrenal vein sampling com - pared with adrenalectomy guided by CT alone (odds ratio = 2.78; 95% CI, 1.88 to 4.12).", + "tokenCount": 76, + "pageStart": 4, + "pageEnd": 4, + "hash": "347dbb1840718490ef3d70bec45fc56888a1039700af3d70e4f697f5592d8ef9" + }, + { + "text": "18 Adrenal vein sampling is a nuanced procedure. Blood samples are taken from a peripheral vein and the right and left adrenal veins and tested for aldosterone and cortisol lev - els. 22 Success rates for adequate sampling range from 30.5% 23 to 99.2%.", + "tokenCount": 57, + "pageStart": 4, + "pageEnd": 4, + "hash": "f1c779379f984475984dd4694989ac594a6a9189af58ca1d15a7b28d7caab4a0" + }, + { + "text": "24 Operator experience at a center that performs at least 12 procedures per year has been shown to be associated with higher sampling adequacy. 25,26 An experienced and dedicated laboratory is necessary for a successful adrenal vein sampling program, 27 and the results should be interpreted based on expert consensus guidelines.", + "tokenCount": 58, + "pageStart": 4, + "pageEnd": 4, + "hash": "beba1cd76cc46bda5662f46d3d1d8f587bd08382096fa17d32cf3007c620892e" + }, + { + "text": "28,29 Treatment UNILATERAL ALDOSTERONE PRODUCTION Adrenalectomy is recommended in cases of uni - lateral aldosterone production. Although hyper - tension is cured in only approximately one-third of cases, biochemical cure is achieved in 94% of cases.", + "tokenCount": 57, + "pageStart": 4, + "pageEnd": 4, + "hash": "223ada36a173b2c8656a3e2d3aa0a9d73499a4387251d32acf9fbaa46cef8ac0" + }, + { + "text": "30 Compared with medical management, adrenalectomy reduces the rate of composite adverse cardiovascular outcomes by one-half 31 and is associated with superior quality of life. 32 BILATERAL ALDOSTERONE PRODUCTION When aldosterone production is bilateral, medi - cal therapy is necessary.", + "tokenCount": 58, + "pageStart": 4, + "pageEnd": 4, + "hash": "f43e1e1d72b9abc450d464448572c0f027849ccf01ba787b8b9511e889f7d7a7" + }, + { + "text": "Mineralocorticoid recep - tor antagonists are the cornerstone of therapy for patients with primary aldosteronism. They are often used concurrently with other antihyper - tensives. Dietary sodium restriction of less than 1,500 mg per day is recommended.", + "tokenCount": 54, + "pageStart": 4, + "pageEnd": 4, + "hash": "2e33e5ea301a3d7e78f2e84eeb89a46839aee461ffa52a0ae033263d998650f1" + }, + { + "text": "33 Spironolactone is a nonselective mineralocorti - coid receptor antagonist and is the initial medica - tion of choice. Typical starting dosages are 12.5 to 25 mg per day and are increased, as needed, to a maximum dosage of 400 mg per day.", + "tokenCount": 61, + "pageStart": 4, + "pageEnd": 4, + "hash": "94d064b375926110cfa95049a0efbbddc09d4343b9dc4aee6daedf8c2bc6a2bb" + }, + { + "text": "10 Its dose - dependent antiandrogenic properties can lead to adverse effects, such as gynecomastia (more than 10%), erectile dysfunction, decreased libido, and irregular menses (1% to 10%).", + "tokenCount": 46, + "pageStart": 4, + "pageEnd": 4, + "hash": "b44f649a226f191e3a8a3ad68ebd04cd5fafa60d939d43dd304d74eadf1e901a" + }, + { + "text": "34 If these adverse effects occur, eplerenone, a more selective but less potent and more expensive mineralocorticoid receptor blocker, may be used. 13,34 Recent observational studies have shown that titrating mineralocorticoid receptor antagonists based on plasma renin concentrations may lead to better outcomes.", + "tokenCount": 63, + "pageStart": 4, + "pageEnd": 4, + "hash": "5d97d6819cd9ddc69f83581c0ca6a6a03dc5c04c43c3a6c8fd0b2748416b6efa" + }, + { + "text": "35,36 Therefore, future guidelines may include interval measurements of renin as part of the mineralocorticoid receptor antagonist dosing strategy. 36 Data Sources: A PubMed search of clinical trials, meta-analyses, randomized controlled trials, and systematic reviews from 2000 to 2022 was completed using the key terms primary hyperaldo - steronism, primary aldosteronism, and hyperaldosteronism.", + "tokenCount": 84, + "pageStart": 4, + "pageEnd": 4, + "hash": "3dfaa0c17cf448821b4564c696d07ad6ad507b5aa6ee50967d18d0a64d083c9b" + }, + { + "text": "We also searched the Cochrane database, Agency for Healthcare Research and Quality (AHRQ), and Essential Evidence Plus using the same terms, but with limited results. If studies used race and/ or gender as a patient category but did not define how these TABLE 3 Medications to Hold Before Primary Aldosteronism Te s t in g* Medications Hold priority Duration of hold (weeks) Mineralocorticoid receptor antagonists † Mandatory 4 Angiotensin-converting enzyme inhib - itors, angiotensin receptor blockers, beta blockers, diuretics, dihydropyridine calcium channel blockers Optional 2 to 4 Alpha blockers, nondihydropyridine cal - cium channel blockers, vasodilators Continue — Note:", + "tokenCount": 154, + "pageStart": 4, + "pageEnd": 4, + "hash": "f6e7f6246c1f0fef0229810759083d084af125fbaa1aa1b8755322a0b406afc0" + }, + { + "text": "Because of interference with the renin -angiotensin-aldosterone system, certain antihypertensive medications may alter renin and angiotensin levels. *—Based on the 2016 Endocrine Society Guidelines.", + "tokenCount": 45, + "pageStart": 4, + "pageEnd": 4, + "hash": "0b64056d505839be2028280aa720ba2dd85cda50a6a266513c5fb9b0d76aaeea" + }, + { + "text": "† —Low-dose mineralocorticoid receptor antagonists may not need to be held before aldosterone-renin ratio testing, especially if renin levels are not suppressed. Information from reference 13.", + "tokenCount": 42, + "pageStart": 4, + "pageEnd": 4, + "hash": "9959f9eb299f3a001c415e590dbfaf46e3e4746849b7bcf79c6e5f74dfc6b75c" + }, + { + "text": "TABLE 2 Clinical Criteria for Patients Who Require Case Detection Testing for Primary Aldosteronism Controlled hypertension (any one of the following) Adrenal nodule Atrial fibrillation* Family history of early stroke (i.e., younger than 40 years) First-degree relative with primary aldosteronism Hypokalemia Obstructive sleep apnea Resistant hypertension † All patients Note:", + "tokenCount": 83, + "pageStart": 4, + "pageEnd": 4, + "hash": "8ceeafc5ddf24294c74c71623822c48c66f0fc937da5f7c3d7a7de568c7b0f7b" + }, + { + "text": "Criteria are based on the 2016 Endocrine Society Guidelines. *—The Endocrine Society does not distinctly list atrial fibrillation as criteria, but it acknowledges that some centers recommend testing given its association with primary aldosteronism.", + "tokenCount": 49, + "pageStart": 4, + "pageEnd": 4, + "hash": "acfe3ee680d2f2c502a10ae24f381503982eb9e809096defc5f944d30293c8e6" + }, + { + "text": "† —Resistant hypertension is hypertension that persists despite the concurrent use of three different classes of antihypertensive medications or the use of four antihypertensive medications to achieve adequate blood pressure control.", + "tokenCount": 40, + "pageStart": 4, + "pageEnd": 4, + "hash": "2777a5e9acbe0cd35674c77edfb9239b1696b6c0cd96c55ab6563b6ba7583c97" + }, + { + "text": "Information from reference 13. September 2023 ◆ Volume 108, Number 3 www.aafp.org/afp American Family Physician 277 PRIMARY ALDOSTERONISM categories were assigned, they were excluded. Studies may not represent all populations. Physicians may need to exercise caution in applying such guidelines to populations not included (e.g., patients of color, younger individuals). Search dates: Octo - ber 2, 2022, and May 19, 2023. The Authors KEITH B. QUENCER, MD, is an associate professor in the Department of Interventional Radiology at Oregon Health & Science University, Portland. J. B. (BRUIN) RUGGE, MD, is an associate professor in the Department of Family Medicine at Oregon Health & Science University. OLGA SENASHOVA, MD, is an assistant professor of otolar - yngology at Oregon Health & Science University. Address correspondence to Keith B. Quencer, MD, Oregon Health & Science University Hospital, 3181 SW Sam Jack - son Park Rd., Portland, OR 97239 (kbquencer@ gmail.com", + "tokenCount": 231, + "pageStart": 4, + "pageEnd": 5, + "hash": "72412e65735b94cb9b68e4b01765c8179279f3f44470916941db520417ad1d28" + }, + { + "text": "Reprints are not available from the authors. References 1. Conn JW, Louis LH. Primary aldosteronism, a new clinical entity. Ann Intern Med . 1956; 44(1): 1-15. 2. Monticone S, Burrello J, et al. Prevalence and clinical manifestations of primary aldosteronism encountered in primary care practice. J Am Coll Cardiol . 2017; 69(14): 1811-1820. 3. Brown JM, Siddiqui M, et al. The unrecognized prevalence of primary aldo - steronism: a cross-sectional study. Ann Intern Med . 2020; 173(1): 10-20. 4. Cohen JB, Cohen DL, et al. Testing for primary aldosteronism and min - eralocorticoid receptor antagonist use among U.S. veterans: a retro - spective cohort study. Ann Intern Med . 2021; 174(3): 289-297. 5. 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Monticone S, D’Ascenzo F, et al. Cardiovascular events and target organ damage in primary aldosteronism compared with essential hyperten - sion: a systematic review and meta-analysis. Lancet Diabetes Endocri - nol . 2018; 6(1): 41-50. 12. Monticone S, Sconfienza E, et al. Renal damage in primary aldosteronism: a systematic review and meta-analysis. J Hypertens . 2020; 38(1): 3-12 . 13. Funder JW, Carey RM, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab . 2016; 101(5): 1889-1916. 14. Rossi GP, Bernini G, et al.; PAPY Study Investigators. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol . 2006; 48(11): 2293-2300. 15. Kawashima J, Araki E, et al. Baseline plasma aldosterone level and renin activity allowing omission of confirmatory testing in primary aldostero - nism. 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Improved adrenal vein sampling from a dedi - cated programme: experience of a low-volume single centre in Singa - pore. Singapore Med J . 2022; 63(2): 111-116. 26. Jakobsson H, Farmaki K, et al. Adrenal venous sampling: the learning curve of a single interventionalist with 282 consecutive", + "tokenCount": 450, + "pageStart": 5, + "pageEnd": 5, + "hash": "4a7e0efb68233a2f9cc3d9c675777329f05caf4a44e59ecca9153cd061f2da89" + }, + { + "text": "procedures. Diagn Interv Radiol . 2018; 24(2): 89-93. 27. Kline G, Holmes DT. Adrenal venous sampling for primary aldosteronism: laboratory medicine best practice. J Clin Pathol . 2017; 70(11): 911-916. 28. Kline GA, Harvey A, et al. Adrenal vein sampling may not be a gold-stan - dard diagnostic test in primary aldosteronism: final diagnosis depends upon which interpretation rule is used. Variable interpretation of adre - nal vein sampling. Int Urol Nephrol . 2008; 40(4): 1035-1043. 29. Rossi GP, Auchus RJ, et al. An expert consensus statement on use of adrenal vein sampling for the subtyping of primary aldosteronism. Hypertension . 2014; 63(1): 151-160. 30. Williams TA, Lenders JWM, et al.; Primary Aldosteronism Surgery Out - come (PASO) Investigators. Outcomes after adrenalectomy for unilat - eral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. Lancet Diabetes Endocrinol . 2017; 5(9): 689-699. 31. Huang WC, Chen YY, et al. Composite cardiovascular outcomes in patients with primary aldosteronism undergoing medical versus surgi - cal treatment: a meta-analysis. Front Endocrinol (Lausanne) . 2021; 12: 644260. 32. Velema M, Dekkers T, et al.; SPARTACUS Investigators. Quality of life in primary aldosteronism: a comparative effectiveness study of adrenalec - tomy and medical treatment. J Clin Endocrinol Metab . 2018; 103(1): 16-24. 33. Vaidya A, Hundemer GL, et al. Primary aldosteronism: state-of-the-art review. Am J Hypertens . 2022; 35(12): 967-988. 34. Lainscak M, Pelliccia", + "tokenCount": 450, + "pageStart": 5, + "pageEnd": 5, + "hash": "1d40e3bb985f5ec9c89db05d54a0cab0db0635bd8efa3a2e3bd3f105babea788" + }, + { + "text": "F, et al. Safety profile of mineralocorticoid receptor antagonists: spironolactone and eplerenone. Int J Cardiol . 2015; 200: 25-29. 35. Köhler A, Sarkis AL, et al. Renin, a marker for left ventricular hypertrophy, in primary aldosteronism: a cohort study. Eur J Endocrinol . 2021; 185(5): 663-672. 36. Hundemer GL, Curhan GC, et al. Cardiometabolic outcomes and mor - tality in medically treated primary aldosteronism: a retrospective cohort study. Lancet Diabetes Endocrinol . 2018; 6(1): 51-59.", + "tokenCount": 151, + "pageStart": 5, + "pageEnd": 5, + "hash": "5af38d2eda7a3feef6ab2e58b00b4fbde5044bd6bf01ed50301dd2f9fff913ab" + } +] \ No newline at end of file