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801 | discourages eating in the pres ence of distractions such as television, tablets, mobile devices, and other screens and eating in a car where an adult cannot adequately observe and assist the child. FEEDING SCHOOL AGED CHILDREN AND ADOLESCENTS MyPlate The U.S. Department of Agriculture (USDA) MyPlate (www.myplate.gov) is a basis for building an optimal diet for children and adults (Fig. 61.1). MyPlate is based on the 2020 Dietary Guidelines for Americans. MyPlate provides a visual representation of the different food groups and portion sizes designed for the general public. The website provides reci pes, weight management strategies, and tools to track calories and physi cal activity goals. A personalized eating plan based on these guidelines provides, on average over a few days, all the essential nutrients necessary for health and growth, while limiting nutrients associated with chronic disease development. MyPlate can also be used as an interactive tool for customized recommendations based on age, sex, physical activity, and for some populations, weight and height. Print materials from the USDA are also available for families without internet access. The MyPlate model emphasizes making half the plate vegetables and fruits, prioritizing whole grains, and eating protein from both animal and plant sources. A separate dairy section is included. Physical activity recom mendations to achieve a healthful energy balance are not visually displayed but are provided on the website. MyPlate has removed foods that have low nutritional value, such as sugar sweetened beverages and sweetened baked goods. In the United States, the vast majority of children and adolescents do not consume a diet that follows the recommendations of MyPlate. The intake of high calorielow nutrient density foods is much higher than recommended, with frequent consumption of sugar sweetened beverages (e.g., soda, juice drinks, iced tea, sport drinks), snack foods, Table 61.10 Recommended Daily Amounts for Children TODDLERS AGES 12 23 MO CHILDREN AGES 2 8 YR CHILDREN AGES 9 YR AND OLDER Calories per day 700 1,000 1,000 1,400 1,600 3,200 Vegetables 23 1 cup 1 1 cups 2 4 cups Fruits 1 cup 1 1 cups 1 2 cups Grains 1 3 ounces 3 5 ounces 5 10 ounces Dairy 123 2 cups 2 2 cups 3 cups Protein foods 2 ounces 2 4 ounces 5 7 ounces Oils 9 13 grams 15 17 grams 22 51 grams Calorie needs may be higher for children who are active far above typical levels for age. Additionally, calorie needs may change on a daily basis as children experience illness, growth spurts, and variations in activity. Adapted from the U.S. Department of Agriculture and U.S. Department of Health and Human Services. Dietary Guidelines for Americans, 2020 2025, 9th Edition. December 2020. Available at DietaryGuidelines.gov. Table 61.9 Suggested Language for Discussing Growth Charts with Families UNDERWEIGHT NORMAL WEIGHT OVERWEIGHT OR OBESE Looking at how your childs weight is matched for their height, only 2 of 100 children are at a weight that is lower at the same height. Your childs weight for their height is lower |
802 | than what is generally thought to be healthy. BMI looks at the way height and weight are balanced with each other. Currently your childs BMI is too low, which has a higher risk of developing health problems related to weight. Looking at how your childs weight is matched for their height, 75 of 100 children are at a weight that is lower at the same height. Your childs weight and height are matched for each other in a way that is generally thought to be healthy. If you were to line up 100 children of the same age by weight, your child would be right in the middle. Looking at how your childs weight is matched for their height, 99 of 100 children are at a weight that is lower at the same height. Your childs weight for their height is heavier than what is generally thought to be healthy. BMI looks at the way height and weight are balanced with each other. Currently your childs BMI is too high, which has a higher risk of developing health problems related to weight. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 416 Part V u Nutrition high fat meat (e.g., bacon, sausage), and high fat dairy products (e.g., cheese, ice cream). Intake of dark green and orange vegetables (vs fried white potatoes), whole fruits, reduced fat dairy products, and whole grains is typically lower than recommended (see Table 61.10 for rec ommendations). Other common unhealthful eating habits include consuming larger than recommended portion sizes; preparing foods with added fat, sugar, or salt; skipping breakfast andor lunch; graz ing; consuming packaged snack foods; and following fad diets. MyPlate offers a helpful and customer friendly tool to assist pediatricians coun seling families on optimal eating plans for short and long term health. Diet quality tends to decline with child age, and ensuring that chil dren and adolescents consume sufficient nutrient dense foods is a chal lenge for many parents. The vast majority of children and adolescents consume more than the recommended amounts of added sodium, sat urated fats, and added sugars, with 17 of calorie intake coming from highly processed packaged foods. Frequent snacking and consumption of sugar sweetened beverages are major contributors to this excess and are valuable targets for dietary counseling. Among adolescents, night eating may be an important source of lower quality food intake that may be missed during a standard diet recall. In the United States, nearly 85 of adolescents consume caffeinated beverages. Although moderate consumption (up to 2.5 mgkgday, equivalent to 6 ounces of coffee for a 30 kg child) is generally considered safe, higher levels of caffeine consumption are associated with impaired sleep and with negative physiologic, emotional, and behavioral outcomes. NUTRITION ISSUES OF IMPORTANCE ACROSS PEDIATRIC AGES Eating at Home At home, parents control much of what children and adolescents |
803 | eat because they typically shop for groceries and monitor which foods are available in the household. Home food availability is associated with child dietary intake: availability of foods such as fruits, vegetables, and dairy has been associated with intake of those foods, whereas availability of foods such as sugar sweetened beverages is associated with lower diet quality. Parents can help to influence childrens healthy food choices by model ing healthful eating behaviors themselves. Dietary counseling includes encouraging parents to make healthier food choices available and attrac tive at home and part of routine family meals. Improved diet quality for children is associated with regular family meals while sitting at a table (vs eating alone or watching a TV or other screen), perhaps because of increased opportunities for positive parenting during meals. Although there are many reasons families may be unable to provide an ideal meal setting (busy schedules, parents working multiple jobs, no kitchen table), family meals at predictable times are encouraged to the extent families are able. Another important aspect of food parenting is helping children learn to be mindful of and respond to internal cues of hunger and satiety. This can be a challenge for some families who have children with a propensity to overeat or to eat in response to nonhunger sig nals (such as eating as an emotional response). Parents can sup port their children to eat at a slower pace and to chew their food properly. Useful strategies when the child is still hungry after a meal include a 15 to 20 minute pause (to allow the child to engage in another activity) before providing a second serving or offering foods that are insufficiently consumed, such as vegetables, whole grains, or fruits. Eating in Childcare and School Settings Many U.S. toddlers and preschool children attend formal or infor mal childcare and receive meals and snacks in this setting. There is wide variation in the quality of food offered (if food is provided) and level of mealtime supervision. Parents are encouraged to assess the quality of the food and supervision by asking questions, visiting the center, and taking part in parent committees. Free or reduced price snacks and meals are provided in childcare centers for low and medium income communities through the USDA Child and Adult Care Food Program. Participating programs are required to provide meals and snacks that meet meal regulations set by the USDA, enabling a certain level of food quality. However, many cen ters and schools still struggle to provide high quality meals and snacks due to cost. The National School Lunch Program and the School Breakfast Pro gram provide low cost meals to millions of children. Guidelines for meals are taken from the Dietary Guidelines for Americans. Recommen dations include the use of age grade portion sizes and the amounts of vegetables and fruits, grains, and fats (Table 61.11). Among the necessary components of these programs are training and equipment for school food service staff, school community engagement, parent education, and food |
804 | industry involvement. Parents are encouraged to assist their child with food choices at school. If children bring their lunch from home, lunch should include, at a minimum, a fruit andor vegetable, a whole grain, and a protein source. Parents can be directed to www.myplate.gov for healthful lunch ideas. Additionally, parents are encouraged to be aware of school and classroom parties and work with teachers and other parents to ensure children have access to healthy choices. Fig. 61.1 MyPlate food guide. (From U.S. Department of Agriculture: http:www.myplate.gov.) Table 61.11 Revised National School Lunch Program and School Breakfast Program Recommendations 1. Portion sizes of food are to be based on age grade groups. 2. School lunches and breakfasts will have a minimum and maximum calorie level, maximum saturated fat content, and a maximum sodium content. 3. Foods must contain zero grams of trans fat per serving. 4. The inclusion of unsaturated vegetable oils is encouraged within calorie limits. 5. Vegetables and fruits are not interchangeable. 6. Vegetable offerings at lunch must include cup equivalent of the following: dark green vegetables, bright orange vegetables, and legumes. 7. No more than half of fruit servings may be in the form of juice. 8. At least one half of breadgrain offered must be whole grain. 9. Milk must be fat free if flavored and either fat free or 1 fat if plain. 10. Students must select a fruit option at breakfast with their meal and either a fruit or a vegetable at lunch for the meal to be reimbursable. Adapted from the National Academies of Engineering, Science and Medicine. School Meals: Building Blocks for Healthy Children. Washington, DC: National Academies Press; 2010. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 61 u Feeding Healthy Infants, Children, and Adolescents 417 Eating Outside the Home The number of meals eaten outside the home or brought home from takeout restaurants continues to increase among all age groups in the United States. The increased convenience of this meal pattern is under mined by the generally lower nutritional value of the meals compared with home cooked meals. Typically, meals from fast food or casual restaurants are of large portion size; are dense in calories; and con tain large amounts of saturated fat, salt, and sugar and low amounts of whole grains, fruits, and vegetables. Although an increasing number of restaurants offer healthier alternatives, the vast majority of what is consumed at restaurants does not fit MyPlate recommendations. Par ents are encouraged to evaluate menu labels when available, select the healthiest available options, and consider sharing meals to supplement childrens meals, which often comprise highly palatable options with low nutrient density. With increasing age, more meals and snacks are also consumed dur ing peer social gatherings at friends houses and parties. When a large part of a childs or adolescents diet is consumed on |
805 | these occasions, diet quality can suffer because food offerings are typically of low nutri tional value. Parents and pediatricians need to guide children and teens in navigating these occasions while maintaining a healthful diet and enjoying meaningful social interactions. These occasions may also be opportunities for teens to consume alcohol; consequently, adult super vision is important. Food Environment Environmental and social challenges can make it difficult for families to make healthful food choices. Although taste is the main determi nant of food choice, many other complex factors influence that choice, including cost, availability, accessibility, convenience, and marketing strategies, including shelf placement and special pricing. Recognizing the context of food and lifestyle choices can help providers understand lack of changes or poor adherence to dietary recommendations and can decrease the frustration often experienced by the pediatricians who might otherwise blame the victim for behavior that is not entirely under their control. Local and national efforts to improve access to fresh and unprocessed foods are ongoing but often struggle to address broader issues such as cost or time to prepare foods at home. Responsive Feeding and Contingent Feeding Practices Responsive feeding entails recognizing and responding to childrens hunger and satiety cues in an age appropriate and developmentally appropriate way across all stages of childhood and adolescence (Table 61.12). It also includes providing routines and structure with clear expectations (e.g., providing meals and snacks at scheduled intervals with a variety of healthy foods to choose from) and a warm emotional context that promotes positive interactions about food and eating. Responsive feeding strategies can include encouraging children to eat foods that are healthful, teaching them about various foods, and involving them in the selection and preparation of meals. Allowing children to select (within reason) how much to eat of each offered food encourages children to listen to internal cues of hunger and satiety. It is common for parents to use food as a reward or sometimes with draw preferred foods as punishment. Most parents use this practice occasionally, and some use it systematically, starting at young ages. The practice is also commonly used in other settings, such as in child care, school, or even athletics. Although it is a good idea to limit some unhealthful but desirable foods to special occasions, using food as a reward can be problematic. Making access to food contingent on an accomplishment increases the desirability of that food. Conversely, pressuring children to consume some healthful foods renders those foods less desirable. Therefore phrases such as, Finish your vegeta bles, and you will get ice cream for dessert can result in establishing unhealthful eating habits once the child has more autonomy in food choices. Parents are encouraged to choose items other than food as rewards, such as stickers, inexpensive toys or sporting equipment, additional time for a favorite activity, special family events, or collect ible items. Similar types of behavior are also seen in schools and extra curricular events, and parents are encouraged to work with teachers and coaches to |
806 | identify appropriate alternative rewards. Cultural Considerations in Nutrition and Feeding Food choices, food preparation, eating patterns, and infant feeding practices all have very deep cultural roots. Beliefs, attitudes, and prac tices related to food and eating are some of the most important com ponents of cultural identity (Fig. 61.2). In multicultural societies, high dietary variability can be observed. In a world where global marketing forces tend to reduce geographic differences in the types and brands of food that are available, most families are still influenced by their cultural background, especially during family meals at home. There fore pediatricians are encouraged to become familiar with the dietary characteristics of various cultures in their community, so that they can identify the potential nutritional benefits and concerns related to their patients diets and address concerns in a nonjudgmental way. Vegetarianism Vegetarianism is the practice of following a diet that excludes animal flesh foods, including beef, pork, poultry, fish, and shellfish. There are several variations on the vegetarian diet, some of which also exclude eggs andor some products produced from animal labor, such as dairy products and honey. Another expression used for different varieties of vegetarianism is plant based diets. It is important to ask parents or adolescents about their diets when they report following a vegetarian, vegan, or plant based diet, because these terms may mean different restrictions for different families. Veg etarian and vegan diets, with extensive knowledge and forethought, can be safely followed by children. Some people practice diets that are even more restrictive, such as those that exclude foods from the allium fam ily (e.g., onion, garlic, chives) or include only raw foods cooked below a certain temperature. The safety of these more restrictive diets, which can be very limited in macronutrients and micronutrients, has not been studied in children, and these more restrictive diets are not recom mended. Although being on a vegetarian or vegan diet does not appear to increase the risk of an eating disorder, some teenagers with disor dered eating may choose such diets to aid in limiting their caloric intake. Vegetarianism, or following a plant based diet, is considered a health ful and viable diet: both the U.S. Academy of Nutrition and Dietetics and the Dietitians of Canada have found that a properly planned and well balanced vegetarian diet can satisfy the nutritional goals for all stages of life. Recommendations for healthy vegetarian dietary patterns at all ages can be found in the 2020 Dietary Guidelines for Americans. Families may benefit from consultation with a registered dietitian to ensure all nutrient requirements are being met. Compared with meat based diets, vegetarian diets tend to have lower intakes of saturated fat, cholesterol, and animal protein and relatively higher levels of complex carbohydrates, fiber, magnesium, potassium, Table 61.12 Responsive Feeding Recommendations WAYS TO PROMOTE RESPONSIVE FEEDING WHAT TO AVOID Have set meal and snack times and a consistent place to eat. Select and provide healthful snack and meal options. Allow child to decide what to eat and |
807 | how much. Sit and eat with the child. Encourage child to try what is on the plate. Notice when child attempts to try a food: You tried your broccoli, or good job trying your broccoli. Allow child to graze or eat small bites throughout the day. Allow child to eat whatever they want. Make child eat all of the food on their plate. Leave child to eat by themselves. Offer the child a (food) reward for eating their food. Offer person praise to child: You are a good person for trying your broccoli. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 418 Part V u Nutrition folate, vitamins C and E, and phytochemicals. Vegetarians tend to have a lower body mass index, cholesterol level, and blood pressure and are at decreased risk for cancer and ischemic heart disease. Specific nutri ents of concern in vegetarian diets include the following: Iron (see Chapter 72): Vegetarian diets may have similar levels of iron intake as nonvegetarian diets, but iron from plant sources has lower bioavailability than iron from meat sources. Addition ally, iron absorption may be inhibited by other dietary constituents, such as phytate (found in leafy green vegetables and whole grains). Iron stores are lower in vegetarians and vegans than in nonvegetar ians, and iron deficiency is more common in vegetarian and vegan women and children. Plant based foods rich in iron include iron fortified cereals, black beans, cashews, kidney beans, lentils, oat meal, raisins, black eyed peas, soybeans, sunflower seeds, chickpeas, molasses, chocolate, and tempeh. Iron absorption from plants is increased when consumed with vitamin Ccontaining foods (e.g., bell peppers, citrus fruits, strawberries, tomatoes, broccoli). Periodic monitoring of iron stores may be valuable in vegan and vegetarian children and adolescents with low iron intake. Vitamin B12: Plants are not a good source of B12 (see Chapter 67.7). Vegetarians may consume vitamin B12 through dairy products and eggs; vegans need fortified foods or supplements. Breastfeeding by B12 unsupplemented vegan mothers can place an infant at risk for vitamin B12 deficiency. Only some infant liquid multivitamins con tain B12. Vegan children and adolescents may need assessment of vitamin B12 levels if supplementation is inconsistent. Fatty acids: Vegetarians and vegans may be at risk for insufficient eicosapentaenoic acid (EPA) and DHA. The inclusion of sources of linolenic acid (a precursor of EPA and DHA), such as walnuts, soy products, flaxseed oil, and canola oil, is recommended. Calcium and vitamin D: Without supplementation, vegan diets can be low in calcium and vitamin D, putting vegans at risk for im paired bone mineralization (see Chapter 69). Monitoring serum 25 hydroxyvitamin D levels can identify patients with deficiency (30 ngmL) and start supplementation. Calcium sources include leafy greens with low oxalate, such as broccoli, kale, and Chinese cabbage. Calcium and vitamin D are found in some fortified plant based milks |
808 | and yogurts and some brands of orange juice. Zinc: The bioavailability of zinc in plant sources tends to be low be cause of the presence of phytates and fiber that inhibit zinc absorp tion (see Chapter 72). Zinc is found in soy products, legumes, grains, cheese, and nuts. Iodine: Plant based diets can be low in iodine, and vegetarians and vegans who do not consume iodized salt or sea vegetables (which have variable iodine content) may be at risk of iodine deficiency. The exclusive use of noniodized salt such as Himalayan, sea, or kosher salts could further increase that risk. Iodized salt is not typically used in processed foods such as crackers, although some bread products are fortified with iodine. Families may also choose to restrict specific foods in the form of elimination diets to prevent allergies or to treat real or presumed gas trointestinal disorders. Figure 61.3 provides an approach to elimina tionrestrictive diets. Organic Food Organic food is defined as produce and ingredients grown without the use of synthetic pesticides, synthetic fertilizers, sewage sludge, geneti cally modified organisms, or ionizing radiation. Animals that produce organic meat, poultry, eggs, and dairy products are not given antibi otics or growth hormones. In the United States, certification must be obtained, and USDA regulations must be followed to market food as organic. Genetically modified organisms (GMOs) in themselves are not thought to be harmful to consume. However, GMOs are modified to be resistant to the effects of herbicides, including glyphosate and 2,4 dichlorophenoxyacetic acid (2,4 D), which give GMOs a selective growth advantage and facilitate use of these chemicals. Glyphosate and 2,4 D have been designated by the International Agency for Research on Cancer as probable and possible human carcinogens, respectively. Therefore higher concentrations of these chemicals in GMO foods are of concern. Parents may prefer organic foods to feed children secondary to concerns regarding chemical and hormonal content of animals and produce. Although nutritional differences between organic and con ventional foods have been reported (e.g., higher levels of PUFAs, tocopherol, and iron and lower levels of cadmium, selenium, and Fig. 61.2 A conceptual framework of the context of food and lifestyle choices. Child risk factors (shown in uppercase lettering) refer to child behaviors associated with the development of overweight. Characteristics of the child (shown in italic lettering) interact with child risk factors and contextual factors to influence the development of overweight (i.e., moderator variables). (From Davison KK, Birch LL. Childhood overweight: a con textual model and recommendations for future research. Obes Rev. 2001;2:159171. 2001 The International Association for the Study of Obesity.) Ethnicity Child feeding practices Types of foods available in the home Nutritional knowledge Parent dietary intake DIETARY INTAKE SEDENTARY BEHAVIOR PHYSICAL ACTIVITY Parent food preferences Parent weight status Parent encouragement of child activity Parent activity patterns Parent preference for activity Parent monitoring of child TV viewing Family TV viewing Peer and sibling interactions Gender Age Familial susceptibility to weight gain School lunch programs Work hours Leisure time Accessibility of |
809 | recreational facilities Family leisure time activity School physical education programs Crime rates and neighborhood safety Socioeconomic status Accessibility of convenience foods and restaurants Child weight status Child characteristics and child risk factors Parenting styles and family characteristics Community, demographic, and societal characteristics Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 61 u Feeding Healthy Infants, Children, and Adolescents 419 iodine), they may not be clinically relevant. Similarly, children con suming organic foods have lower levels of pesticides in their urine compared with those consuming nonorganic foods, but it remains unclear whether such a reduction is clinically meaningful. However, other chemicals in the environment, such as the endocrine disruptors bisphenol A and phthalates (found in plastics), are best avoided. A high frequency of organic food ingestion has been associated with a lower risk of cancer in adults. Nutritional Supplements The use of nutritional supplements as complementary or alterna tive medicine is increasing, despite limited data on safety and effi cacy, especially in children. Many parents assume that if a food or supplement is natural or organic, there is no potential for risk and some potential for benefit. However, adverse effects of some dietary supplements have been documented, and some supplements have been discovered to contain common allergens. In the United States, dietary supplements, including botanical and herbal products, are regulated differently from medications. Manufacturers do not have to prove safety or efficacy before marketing the supplement; the potential for adverse effects, inefficacy, unnecessary cost, and con tamination is therefore high. It can be difficult to compete against the aggressive marketing of food supplements. Medical professionals must also compete against advice from people without a scientific background and those with significant conflicts of interest, particu larly on the internet. Assess nutritional risk 05 years Indicators for followup: Weight for height or height for age 2 zscore Recent static weightgrowth faltering or downward crossing of 2 centiles or 1 zscore Feeding difficulties Exclusion of cows milk Food allergy and concomitant atopic eczema Multiple food elimination Family is vegetarian or vegan Other food restrictions due to religious or cultural factors Indicators for followup: Weight for heightBMI 2 zscore growth faltering or downward crossing of 2 centiles or 1 zscore Avoidant restrictive food intake disorder Multiple food elimination Family are vegetarian or vegan Other food restrictions due to religious or cultural factors Indicators for followup: BMI 18.5 Exclusion of milk or wheat or multiple foods 6 months Vegetarian or vegan Other food restrictions due to religious or cultural factors Presence of another chronic condition Other dietary restrictions, e.g., diabetes 617 years Review intake of key staple foods, amount and frequency, and advise on substitute foods Agedependent substitute milk Other cheese and yogurt substitutes, e.g., soy or coconut based Assess protein and energy intakes Calcium, iron, zinc, vitamins A and D supplements may be required Milk Avoidance Check need |
810 | to avoid barley and rye Advise alternative sources of grains, e.g., oats, rice, corn, quinoa, teff, and buckwheat Check if wheat substitute foods (glutenfree products) are being eaten B vitamin and iron supplements may be required Wheat Avoidance If vegetarian, ensure diet is enhanced with other highprotein foods including beans and lentils Egg Avoidance Omega 3 supplements may be required Fish Avoidance High nutritional risk if avoiding both wheat and milk Check individual requirement for vitamin D and follow countryspecific guidelines for ageappropriate vitamin D supplementation Vitamin D Legumes, e.g., beans and lentils, will often be tolerated, and can be substituted for peanuts or tree nuts Vegans may need iron, calcium, and B vitamin supplements Soy, peanut, tree nut, and seed avoidance 18 years or over Fig. 61.3 Approach to evaluate risk for adverse elimination diets. BMI, Body mass index. (Modified from Skypala IJ, McKenzie R. Nutritional issues in food allergy. Clin Rev Allergy Immunol. 2019;57:166178, Fig. 1, p. 172.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 420 Part V u Nutrition Pediatricians may be asked whether a child needs to receive a daily multivitamin. Many children do not follow all the guidelines of MyPlate, and parents and pediatricians may be tempted to use multivitamin supplements to fill gaps. The average U.S. diet pro vides more than a sufficient amount of most nutrients. Therefore multivitamins are recommended only where there is concern for dietary inadequacy, especially when intake of one of the major food groups is very limited or absent (fruits, vegetables, proteins, whole grains, dairy or equivalent). Using vitamin supplements as a sup port while working to expand dietary variety can help avoid micro nutrient deficiencies in cases of dietary restriction whether due to food selectivity or for health, cultural, or religious reasons. Food Safety Food safety issues are an important aspect of feeding infants, chil dren, and adolescents. In addition to choking hazards and food allergies, pediatricians and parents need to be aware of food safety issues related to infectious agents and environmental contaminants. Food poisoning with bacteria, viruses, or their toxins is most com mon with raw or undercooked food, such as meat, poultry, eggs, and seafood, or cooked foods that have not been handled or stored properly. Unwashed fruits and vegetables may also be contami nated. The specific bacteria and viruses involved in food poisoning are described in Chapter 259. Many chemical contaminants, such as heavy metals, pesticides, and organic compounds, are present in various foods, usually in small amounts. Because of concerns regarding their childs neurologic development and cancer risk, many questions arise from parents, especially after media coverage of isolated incidents. A recurring debate is the balance between the benefits of seafood for the growing brain and cardiovascular health and the risk of mercury contamination from consuming large, pred atory fish species. The Food Safety Modernization Act |
811 | provides the FDA with authority to have stricter control over food produc tion and distribution, including requirements that manufacturers develop food safety plans. A good source of information for patients and parents can be found at www.foodsafety.gov. Other reliable sources of information include the websites of the U.S. Environ mental Protection Agency (EPA), FDA, and CDC. Preventive Nutrition Counseling in Pediatric Primary Care An important part of the primary care well child visit focuses on nutrition and growth because most families turn to pediatric health care providers for guidance on child nutrition. Preventive nutrition is one of the cornerstones of preventive pediatrics and a critical aspect of anticipatory guidance. The first steps of nutrition counsel ing are nutritional status assessments, primarily achieved through growth monitoring and dietary intake assessment. Although dietary assessment is somewhat simple in infants who have a relatively monotonous diet, it is more challenging at older ages. The goals of dietary assessment in the primary care setting need to include an idea of the eating patterns (time, location, and environment) and usual diet. A basic assessment of the childs intake includes eval uating meal routine, dietary diversity (ensuring that a child eats foods from all food groups, namely vegetables, fruits, whole grains, sources of iron and protein, and low fat or nonfat dairy products), and consumption of sugar sweetened beverages, including 100 fruit juice. Pediatricians can encourage regularly scheduled meals and one or two healthy snacks (depending on the childs age) with avoidance of grazing, particularly on foods and beverages that are energy dense but of low nutritional value. For more ambitious goals of dietary assessment, referral to a registered dietitian with pediat ric experience is recommended. After understanding the childs usual diet, existing or anticipated nutritional problems can be addressed, such as diet quality, dietary habits, and portion size. Most nutritional issues, such as overeating or poor food choices, are not solely the result of lack of parents knowledge but can be the result of access, availability, and economic factors. Therefore nutrition education alone is insufficient in these situations, and pediatricians need to acquire training in behavior modification techniques such as motivational interviewing (see Chapter 18) or refer to specialists to assist their patients in engaging in healthful feeding and eating behaviors. The physical, cultural, and family environment in which the child lives must be considered so that nutrition counseling is relevant and changes feasible (see Fig. 61.2). The phone app ChangeTalk from the AAP provides free training on motivational interviewing for the prevention and treat ment of pediatric obesity. One important aspect of nutrition counseling is providing fami lies with sources of additional information and behavioral change tools. Although some handouts are available from government agencies, the AAP, and other professional organizations for families without internet access, an increasing number of families rely on the internet to find nutrition information. Therefore pediatricians need to become familiar with common websites so that they can point families to reliable and unbiased sources of information. Per haps the |
812 | most useful websites for children are the AAP and USDA MyPlate sites and those of the CDC, FDA, National Institutes of Health, The National Academies, and Food and Nutrition Board for government sources. Other professional resources include the American Heart Association and Academy of Nutrition and Dietet ics. Unfortunately, there are websites that provide biased or even dangerous information. Examples include dieting sites, sites that openly promote dietary supplements or other food products, and the sites of nonprofit organizations that are mainly sponsored by food companies or that have other social or political agendas. Food Security and U.S. Food Assistance Programs Food insecurity is defined as the state of being without reliable access to a sufficient quantity of affordable, nutritious food. In 2016, minoritized households were 1.5 to almost 2 times more likely to be food insecure than the national average of 12.3. Children in food insecure homes are more likely to have medical problems, includ ing asthma and depression, and are more likely to seek emergency medical care. Patients from all backgrounds can experience food insecurity, and selective screening risks reinforcing bias and miss ing children in need. Answering often true or sometimes true (versus never) to the following two question screen has a sensitiv ity of 97 and specificity of 83 for identifying food insecurity: For the last 12 months: (1) We worried whether our food would run out before we got money to buy more. (2) The food we bought just didnt last, and we didnt have money to get more. Several programs exist in the United States to help meet the needs of families experiencing food insecurity. One of the most utilized fed eral programs is the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). This program provides nutri tion supplements to a large proportion of pregnant and postpartum women and children up to their fifth birthday. One of its strengths is that families regularly visit a WIC nutritionist, who can be a useful resource for nutritional counseling. For older children, federal pro grams provide school lunches, breakfasts, and after school meals, as well as daycare and summer nutrition. Lower income families are also eligible for the Supplemental Nutrition Assistance Program (SNAP), formerly known as the Food Stamp Program. This program provides funds directly to families to purchase various food items in regular food stores. Food insecurity screening should be universal in clinical settings. Eligibility criteria for both WIC and SNAP can be found on the programs federal websites. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 62 u Nutrition, Food Security, and Health 421 MALNUTRITION AS THE INTERSECTION OF FOOD INSECURITY AND HEALTH INSECURITY Undernutrition is usually an outcome of three factors, often in com bination: household food supply insecurity, suboptimal childcare practices, and restricted access to or use |
813 | of health and watersanita tion services. In famine and emergency settings, food shortage is the foremost factor, but in many countries with widespread undernutri tion, food production or access to food might not be the most limiting factor. More important causes might be repeated childhood infections, especially diarrheal diseases associated with an unsanitary environ ment, poor infant and young child feeding practices, or various chal lenges that may prevent families from using quality maternal and child health services. Figure 62.1 shows some of the many causal factors on the pathway to undernutrition and how they extend from household and community levels to nationalinternational levels. Inequitable dis tribution of resources because of political, economic, and agricultural policies often denies families their right to adequate land, water, food, healthcare, education, and a safe environment, all of which can influ ence nutritional status. Families with few economic resources who know how to care for their children and are enabled to do so can often use available food and health services to produce well nourished children. If food resources and health services are not available in a community, not used, or not accessible to some families, children might become undernourished. Undernutrition is not confined to low income countries. It has been noted in chronically ill patients in neonatal and pediatric intensive care units in high income countries and among patients with burns, human immunodeficiency virus (HIV) infection, tuberculosis, cys tic fibrosis, chronic diarrhea syndromes, malignancies, bone marrow transplantation, and inborn errors of metabolism (see Chapter 64). Severe malnutrition has been reported in affluent communities in infants whose families believe in fad diets and in infants with food allergies fed nutritionally inadequate foods such as rice milk, which has a very low protein and micronutrient content (Figs. 62.2 and 62.3; also see Fig. 61.3). FOOD SECURITY Food security exists when all people, at all times, have access to suf ficient, safe, nutritious food to maintain a healthy and active life. Four main dimensions of food security can be identified: availability, access, utilization, and stability. Availability refers to the supply of food, reflecting the level of food production, food stocks, and net trade. Access is typically defined at the household level, reflecting purchasing power, household food production, and foodcash transfers received through social safety net programs. The utilization dimension recog nizes that even when a household has access to food, it is not necessar ily shared equitably within a household. Stability refers to being food secure at all times: Examples of situations that affect stability are the lean seasons before a harvest, natural disasters, political unrest, and rising food prices. To be food secure, all four dimensions must be met simultaneously. Measuring Food Insecurity The most commonly used measurement of food insecurity is under nourishment (chronic hunger), which is the proportion of the popu lation who are unable to meet daily energy requirements for light activities. It is an estimate calculated by the Food and Agriculture Organization (FAO) based on country level food balance sheets. It |
814 | does not take nutrient adequacy into account, but has the advantage of being available for almost all countries annually (although with a time lag) and assists in monitoring global trends. In addition, FAO measures food access by asking individuals about their experiences over the last 12 months, such as whether they ran out of food or skipped meals. The responses are graded from mild to severe food insecurity. This rela tively simple monitoring tool, the Food Insecurity Experience Scale, provides timely information to guide decision making at national and local levels. In 2020, the FAO estimated that between 720 and 811 million peo ple, or approximately 9.9 of the worlds population, were undernour ished. More than half of the worlds undernourished were found in Chapter 62 Nutrition, Food Security, and Health Jason M. Nagata and Christine M. McDonald Inadequate Education Poverty, womens disempowerment, closelyspaced births Inadequate Care for Mothers and Children Psychosocial deprivation Poor Growth Impaired immunity, frequent, more severe infections Undernutrition Health Insecurity Inadequate health services, unhealthy environment Food Insecurity Food unavailable, unaffordable Disease Anorexia, nutrient losses, increased requirements Inadequate Dietary Intake Poor feeding practices, maternal competence, cultural beliefs Conflict Population displacement, migration, disruption to agriculturefood supply Resources and Control Natural Disasters Drought, flood, hurricane, earthquake Political, Economic Weak social systems, corruption, low GDP, high foreign debt, poor infrastructure Fig. 62.1 Basic, underlying, and immediate causes of undernutrition. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 422 Part V u Nutrition Asia, and more than one third were found in Africa. The majority are rural poor people subsisting on small plots of land or hired as labor ers and urban poor people who lack the means to grow or buy food. Alongside the 768 million people who are underfed are 1.9 billion who are overweight or obese, reflecting global inequalities and the double burden of malnutrition in low and middle income countries. Nutrition, Food Security, and Poverty Household food security tracks income closely. With rising incomes, very poor households first increase their dietary energy intake to avert hunger. If incomes rise further, there is a shift to more expensive sta ple foods and then to a more varied diet with a greater proportion of energy from animal sources, fruitsvegetables, and fatssugars and less from cereals, roots, and tubers. National economic growth tends to be accompanied by reductions in stunting, but economic growth can pass by poor persons if they work in unaffected sectors or are unable to take advantage of new opportunities because of lack of education, access to credit, or transportation, or if governments do not channel resources accruing from economic growth to healthcare, education, social pro tection, and other public services and infrastructure. There is good evi dence that economic growth reduces poverty but does not necessarily reduce undernutrition. Food Security and Nutrition Targets The period of the Millennium Development Goals |
815 | (MDGs) ended in 2015. All developing regions except sub Saharan Africa achieved the tar get to halve the proportion of people living in extreme poverty, with the proportion falling from 47 in 1990 to 14 in 2015. Reductions in hun ger were broadly consistent with those of poverty reduction, and rates of undernourishment in developing regions fell from 23 in 1990 to 13 in 2015. The prevalence of underweight among children under 5 years (another MDG indicator of hunger) fell from 29 in 1990 to 15 in 2015 for the developing regions combined. Rural children are almost twice as likely to be underweight as urban children, and the poorest quintile is almost 3 times as likely to be underweight as the richest quintile. Eradicating poverty and hunger continue to be core targets of the Sustainable Development Goals, as agreed by 193 countries of the United Nations General Assembly in September 2015, and are to be achieved by 2030. In addition, in 2012 the World Health Assembly agreed to six global nutrition targets to be reached by 2025, measured against a 2010 baseline, and the United Nations Secretary General launched the Zero Hunger Challenge with five objectives that would boost economic growth, reduce poverty and safeguard the environ ment and would foster peace and stability (Table 62.1). Future Food Security Between now and 2050 the worlds population is expected to exceed 9 billion, and an increase in the food supply of 70100 will be needed to feed this larger, more urban, and more affluent populace. Over this same period, the worlds food supply is expected to diminish unless action is taken. Accelerating the decline in fertility rates and reduc ing overconsumption are basic but difficult actions to bridge the gap between increasing demand and diminishing supply. Equally chal lenging actions include limiting climate disruption, increasing the effi ciency of food production, reducing waste, and reducing the demand for meat and dairy foods. The COVID 19 pandemic significantly dis rupted food systems and exacerbated food insecurity globally. u Limit climate disruption. Drought, floods, and other extreme weather events are becoming more prevalent and destroy crops and livestock, often on a huge scale. Rising sea levels will lead to loss of productive land through inundation and salinization. Acidification of oceans will reduce marine harvests. Because curbing greenhouse gas emis sions is essential to minimize climate disruption, the goals are (1) to cut fossil fuel use by at least half of present levels by 2050 so as to reduce carbon dioxide (CO2) emissions and (2) change livestock husbandry and agronomic practices to reduce methane and nitrous oxide (N2O) emissions. u Increase efficiency of food production. Expanding the area of agricul tural land to any large extent (e.g., by deforestation) is not a sus tainable option because of adverse consequences on ecosystems and biodiversity, although some expansion of food production could be Fig. 62.2 A 14 month old girl with flaky paint dermatitis. (From Katz KA, Mahlberg MH, Honig PJ, et al. Rice nightmare: Kwashiorkor |
816 | in 2 Philadelphia area infants fed Rice Dream beverage. J Am Acad Derma tol. 2005;52:S69S72.) Fig. 62.3 Paired, transverse, homogeneous, and smooth bordered lines noted in all fingernails suggestive of Muehrcke lines in an infant fed diluted cows milk since birth. Muehrcke lines are an apparent leukonychia most often associated with hypoalbuminemia. (From Williams V, Jayashree M. Muehrcke lines in an infant. J Pediatr. 2017;189:234.) Table 62.1 Global Food Security and Nutrition Targets ZERO HUNGER CHALLENGE OBJECTIVES WORLD HEALTH ASSEMBLY GLOBAL NUTRITION TARGETS FOR 2025 1. Access to an adequate and stable food supply for all 2. Elimination of stunting in children 2 yr, and no malnutrition in pregnancy and early childhood 3. Sustainable food systems 4. Doubling of smallholder productivity and income, particularly for women 5. No loss or waste of food and responsible consumption 1. A 40 reduction in the number of stunted children 5 yr 2. A 50 reduction in anemia in women of reproductive age 3. A 30 reduction in low birthweight 4. No increase in childhood overweight 5. Increase exclusive breastfeeding rates to at least 50 in the first 6 mo 6. Reduce and maintain childhood wasting to 5 Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 62 u Nutrition, Food Security, and Health 423 achieved by switching good quality land away from first generation biofuels. For example, almost 40 of the U.S. corn harvest in 2016 2017 went to biofuels. Efforts to increase the intensity of production need to be environmentally sustainable. These include optimizing yields by soil and water conservation, removal of technical and fi nancial constraints faced by farmers, and breeding resource efficient crops and livestock that are also climate resilient and pestdisease resistant. u Reduce waste. Approximately 3040 of food is wasted, between harvesting and the market, during retail, at home, and in the food service industry. Better transport and storage facilities in develop ing countries, less stringent sell by dates, lower cosmetic standards for fruits and vegetables, and ending supersized portions would help reduce waste. u Change diets. As wealth increases, so does the demand for processed foods, meat, dairy products, and fish. About one third of global ce real production is fed to animals, so reducing consumption of meat from grain fed livestock and increasing the proportion derived from the most efficient sources (pigs and poultry) would allow more peo ple to be fed from the same amount of land. UNDERNUTRITION The greatest risk of undernutrition (underweight, stunting, wasting, and micronutrient deficiencies) occurs in the first 1,000 days, from conception to 24 months of age, and this early effect on growth and development can have adverse consequences on health, intellectual ability, school achievement, work productivity, and earnings in later life. Governments and agencies are therefore advised to focus interven tions on this critical window of opportunity. Measurement of Undernutrition The term malnutrition |
817 | encompasses both ends of the nutrition spec trum, undernutrition as well as overweight and obesity. Many poor nutritional outcomes begin in utero and are manifest as low birth weight (LBW, 2,500 g). Preterm birth and fetal growth restriction are the two main causes of LBW, with prematurity relatively more common in richer countries and fetal growth restriction relatively more com mon in lower income countries. Nutritional status is often assessed in terms of anthropometry (Table 62.2). International standards of normal child growth under optimum conditions from birth to 5 years have been established by the World Health Organization (WHO). To compile the standards, longitudinal data from birth to 24 months of healthy, breastfed, term infants were combined with cross sectional measurements of children ages 18 71 months. The standards allow normalization of anthropometric mea sures in terms of z scores (standard deviation SD scores). A z score is the childs height (weight) minus the median height (weight) for the childs age and sex divided by the relevant SD. The standards are applicable to all children everywhere, having been derived from a large, multicountry study reflecting diverse ethnic backgrounds and cultural settings. Height for age (or length for age for children 2 years) is a mea sure of linear growth, and a deficit represents the cumulative impact of adverse events, usually in the first 1,000 days from conception, that result in stunting, or chronic undernutrition. A low height for age typi cally reflects socioeconomic disadvantage. A low weight for height, or wasting, usually indicates acute malnutrition. Conversely, a high weight for height indicates overweight. Weight for age is the most commonly used index of nutritional status, although a low value has limited clinical significance because it does not differentiate between wasting and stunting. Weight for age has the advantage of being some what easier to measure than indices that require height measurements. In humanitarian emergencies and some community or outpatient set tings, mid upper arm circumference is used as a screening tool to identify wasted children (Fig. 62.4). Body mass index (BMI) is calculated by dividing weight in kilo grams by the square of height in meters. For children, BMI is age and gender specific. BMI for age can be used from birth to 20 years and is a screening tool for thinness (less than 2 SD), overweight (between 1 SD and 2 SD), and obesity (greater than 2 SD). To diagnose obesity, additional measures of adiposity are desirable because a high BMI can result from high muscularity and not only from excess sub cutaneous fat. Micronutrient deficiencies are another dimension of undernu trition. Those of particular public health significance are vitamin A, iodine, iron, and zinc deficiencies. Vitamin A deficiency is caused by a low intake of retinol (in animal foods) or its carotenoid precursors, mainly beta carotene (in orange colored fruits and vegetables and dark green leaves) (see Chapter 66). The prevalence of clinical deficiency is assessed from symptoms and signs of xerophthalmia (principally night blindness and Bitot spots). |
818 | Subclinical deficiency is defined as serum retinol concentration 0.70 molL. Vitamin A deficiency is the leading cause of preventable blind ness in children. It is also associated with a higher morbidity and mor tality among young children. Table 62.2 Classification of Undernutrition CLASSIFICATION INDEX GRADING Gomez (underweight) 9075 of median weight for age Grade 1 (mild) 7560 Grade 2 (moderate) 60 Grade 3 (severe) Waterlow (wasting) 9080 of median weight for height Mild 8070 70 Moderate Severe Waterlow (stunting) 9590 of median height for age Mild 9085 Moderate 85 Severe WHO (wasting) 2 to 3 SD weight for height Moderate 3 Severe WHO (stunting) 2 to 3 SD height for age Moderate 3 Severe WHO (wasting) (for age group 6 59 mo) 115 125 mm mid upper arm circumference Moderate 115 mm Severe SD, Standard deviation; WHO, World Health Organization. Fig. 62.4 Measuring mid upper arm circumference. (Courtesy Nyani QuarmynePanos Pictures.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 424 Part V u Nutrition Iodine deficiency is the worlds leading cause of preventable intellectual impairment (see Chapter 72). An enlarged thyroid (goi ter) is a sign of deficiency. Severe deficiency in pregnancy causes fetal loss and permanent damage to the brain and central nervous system in surviving offspring (cretinism). It can be prevented by iodine supplementation before conception or during the first tri mester of pregnancy. Postnatal iodine deficiency is associated with impaired mental function and growth stunting. The median urinary iodine concentration in children age 6 12 years is used to assess the prevalence of deficiency in the general population, and a median of 100 gL indicates insufficient iodine intake. Iron deficiency anemia is common in childhood either from low iron intakes or poor absorption, or as a result of illness or parasite infestation (see Chapter 72). Women also have relatively high rates of anemia as a result of menstrual blood loss, pregnancy, low iron intake, poor absorption, and illness. Hemoglobin cutoffs to define anemia are 110 gL for children 6 59 months, 115 gL for children 5 11 years, and 120 gL for children 12 14 years. Cutoffs to define anemia are 120 gL for nonpregnant women, 110 gL for pregnant women, and 130 gL for men. Zinc deficiency increases the risk of morbidity and mortality from diarrhea, pneumonia, and possibly other infectious diseases (see Chap ter 72). Zinc deficiency also has an adverse effect on linear growth. Deficiency at the population level is assessed from dietary zinc intakes or serum zinc concentrations. For children under 10 years of age, serum zinc cutoffs of 65 gdL and 57 gdL are used to define zinc deficiency according to whether the blood sample was obtained in the morning or afternoon, respectively. For females 10 years of age or older, cutoffs of 70 gdL, 66 gdL, and 59 gdL are used depending on whether the |
819 | blood sample was obtained in the morning in a fasted state, the morning in a nonfasted state, or in the afternoon in a non fasted state, respectively. Prevalence of Undernutrition It is estimated that approximately 14.6 of births worldwide in 2015 were LBW. Rates of LBW are highest (48) in southern Asia, which are twice those of sub Saharan Africa. Globally, in 2015, 14 of children 5 years of age were underweight (weight for age 2 SD). The global prevalence of stunting (height for age 2 SD) has declined from 33 in 2000 to 22 in 2017, with the greatest reduc tions occurring in Asia. Stunting prevalence is highest in the Afri can region (30). Wasting (weight for height 2 SD) affects 7 of children 5 years, with minimal change in prevalence over the past 2 decades. These figures represent 149 million stunted children and 50 million wasted children under 5 years of age. Asia carries most of the global burden of underweight children because of the com bination of large population size and high prevalence. In 2017, 55 of all stunted children and 69 of all wasted children lived in Asia. Africa carries most of the remaining global burden. Approximately 29 of children under 5 years of age in low and middle income countries (LMICs) suffer from vitamin A defi ciency. Nationally representative data on the zinc status of children are sparse, but an estimated 17 of the global population is believed to be at risk of inadequate zinc intake. The estimated prevalence of anemia in children and women of reproductive age in 2016 was 42 and 33, respectively. Iron deficiency is considered to be the primary cause of anemia in 2542 and 5060 of anemia cases among children and women, respectively. Universal salt iodiza tion has made great strides in reducing the global burden of iodine deficiency. However, mild to moderate iodine deficiency remains a public health concern in 25 countries. Consequences of Undernutrition The most profound consequence of undernutrition is premature death (Table 62.3). Fetal growth restriction together with suboptimal breast feeding in the first month of life contribute to 19 of all deaths in chil dren 5 years (1.3 million deathsyear). When the effects of stunting, wasting, and deficiencies of vitamin A and zinc are also considered, these six items jointly contribute to 45 of global child deaths (3.1 million deathsyear), and many more are disabled or stunted for life. Anemia contributes to over one quarter of maternal deaths. The risk of child death from infectious diseases increases even with mild undernutrition, and as the severity of undernutrition increases, the risk increases exponentially (Table 62.4). Undernu trition impairs immune function and other host defenses; conse quently, childhood infections are more severe and longer lasting and more likely to be fatal than the same illnesses in well nourished children. Infections can adversely affect nutritional status, and young children can quickly enter a cycle of repeated infections and ever worsening malnutrition. Even for the survivors, physical and cognitive |
820 | damage as a result of undernutrition can affect their future health and economic well being. For females, the cycle of undernutrition is passed on to the next generation when under nourished women give birth to LBW babies. Fetal growth restriction and early childhood undernutrition have con sequences for adult chronic illness. LBW is associated with an increased risk of hypertension, stroke, and type 2 diabetes in adults. This increased risk is thought to reflect fetal programming, a process by which fetal undernutrition leads to permanent changes in the structure and metab olism of organs and systems that manifest as disease in later life. The risk is exacerbated by low weight gain during the first 2 years of life. The increased risk of adult chronic disease from undernutrition early in life is a particular challenge to LMICs with rapid economic growth. Stunting before age 3 years is associated with poorer motor and cog nitive development and altered behavior in later years. The develop mental quotient (DQ; see Chapter 28) is reduced by 613 points. Iodine and iron deficiencies also lead to loss of cognitive potential. Indications are that children living in areas of chronic iodine deficiency have an average reduction in intelligence quotient (IQ) of 12 13.5 points com pared with children in iodine sufficient areas. Iron deficiency has a detrimental effect on the motor development of children 4 years and on cognition of school aged children. The estimated deficit is 1.73 IQ points for each 10 gL decrease in hemoglobin concentration. Undernutrition can have substantial economic consequences for survivors and their families. The consequences can be quantified in five categories: (1) increased costs of healthcare, either neonatal care for LBW babies or treatment of illness for infants and young children; (2) productivity losses (and thus reduced earnings) associated with smaller stature and muscle mass; (3) productivity losses from reduced cognitive ability and poorer school performance; (4) increased costs of chronic diseases associated with fetal and early child malnutrition; and Table 62.3 Global Deaths in Children 5 Years Attributed to Nutritional Conditions CONDITION ATTRIBUTABLE DEATHS OF TOTAL DEATHS 5 YR (a) Fetal growth restriction (1 mo) 817,000 11.8 (b) Stunting (1 59 mo) 1,017,000 14.7 (c) Wasting (1 59 mo) 875,000 12.6 (d) Zinc deficiency (12 59 mo) 116,000 1.7 (e) Vitamin A deficiency (6 59 mo) 157,000 2.3 (f) Suboptimal breastfeeding (0 23 mo) 804,000 11.6 Joint effects of (a) (f) 1,348,000 19.4 Joint effects of all 6 factors 3,097,000 44.7 From Black RE, Victora CG, Walker SP, et al. Maternal and child undernutrition and overweight in low and middle income countries. Lancet. 2013;382:427451. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 62 u Nutrition, Food Security, and Health 425 (5) consequences of maternal undernutrition on future generations. The impact of nutrition on earnings appears to be independent of the effects of childhood |
821 | deprivation. Interventions for Undernutrition Interventions to address child undernutrition can be divided into those that address immediate causes (nutrition specific interventions) and those that address underlying or indirect causes (nutrition sensitive interven tions) (Table 62.5). In the short term, nutrition specific interventions (e.g., salt iodization) can have substantial impact even in the absence of economic growth, and micronutrient interventions (supplementation and fortification) are consistently ranked as the most cost effective investment. However, there is increased attention to nutrition sensitive interventions as the best means of sustainably eliminating malnutrition and to multisec toral policies that harness the synergism between the two types of inter ventions (e.g., cross sectoral linkages among agriculture, nutrition, and health). To reduce the adverse consequences of undernutrition on mor tality, morbidity, and cognitive development, interventions must encompass both fetal and postnatal periods. Preventing LBW is essential, with emphasis on prevention of low maternal BMI and anemia, and in the longer term, prevention of low maternal stature. Maternal height is a strong predictor of birth outcomes, and approx imately 6.5 million small for gestational age (SGA) or preterm births are associated with maternal short stature each year. Other measures include smoking cessation, birth spacing, delaying preg nancy until after 18 years of age, and intermittent preventive treat ment of malaria in malaria endemic areas. In the postnatal period, promotion and support of exclusive breastfeeding is a high priority. Although the Baby Friendly Hospital Initiative has a marked benefit on rates of exclusive breastfeeding in hospitals, postnatal counsel ing from community workers or volunteers is needed to facilitate continuation of exclusive breastfeeding at home for 6 months (see Chapter 61). Most studies show a lower risk of HIV transmission with exclusive breastfeeding than with mixed breastfeeding. The risk of HIV transmission by breastfeeding is approximately 520 depending on duration, but can be reduced to 2 with antiretro viral drugs. Even without antiretroviral drugs, exclusively breastfed children of HIV infected mothers in low income countries have lower mortality than nonbreastfed children, because the latter are at increased risk of death from diarrhea and pneumonia. Interventions to improve infant feeding must be designed for the local setting and thus require careful formative research dur ing their development. Messages should be few, feasible, and Table 62.4 Hazard Ratios for All Cause and Cause Specific Deaths Associated with Stunting, Wasting, and Underweight in Children 5 Years STANDARD DEVIATION (SD) SCORE DEATHS ALL PNEUMONIA DIARRHEA MEASLES OTHER INFECTIONS HEIGHTLENGTH FOR AGE 3 5.5 6.4 6.3 6.0 3.0 3 to 2 2.3 2.2 2.4 2.8 1.9 2 to 1 1.5 1.6 1.7 1.3 0.9 1 1.0 1.0 1.0 1.0 1.0 WEIGHT FOR LENGTH 3 11.6 9.7 12.3 9.6 11.2 3 to 2 3.4 4.7 3.4 2.6 2.7 2 to 1 1.6 1.9 1.6 1.0 1.7 1 1.0 1.0 1.0 1.0 1.0 WEIGHT FOR AGE 3 9.4 10.1 11.6 7.7 8.3 3 to 2 2.6 3.1 2.9 3.1 1.6 2 to 1 1.5 1.9 1.7 1.0 1.5 1 1.0 1.0 1.0 1.0 1.0 From Black RE, |
822 | Victora CG, Walker SP, et al. Maternal and child undernutrition and overweight in low and middle income countries. Lancet. 2013;382:427451. Table 62.5 Examples of Nutrition Specific and Nutrition Sensitive Interventions NUTRITION SPECIFIC INTERVENTIONS NUTRITION SENSITIVE INTERVENTIONS Promotion and support for exclusive breastfeeding for 6 mo, and continued breastfeeding for at least 2 yr Promotion of adequate, timely, and safe complementary feeding from 6 mo Increased micronutrient intake through dietary diversity Micronutrient supplements for pregnant women (ironfolate) and young children (vitamin A, iron, zinc) in deficient areas Zinc supplements to children during and after diarrhea (10 20 mgday for 2 wk) Prevention and treatment of severe acute malnutrition Crop biofortification, food fortification, salt iodization Reduced heavy physical activity in pregnancy Increased access to affordable, nutritious food; smallholder agriculture; credit and microfinance Postharvest food processing and preservation Vaccination against neonatal and childhood illness; access to healthcare Improved watersanitation and hygiene (e.g., handwashing with soap) Education; womens empowerment; gender equality Social protection (e.g., cash transfers) Malaria prevention (vector controlbednets); intermittent preventive treatment during pregnancy and in children 3 59 mo Birth spacing; delaying pregnancy until after 18 yr of age Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 426 Part V u Nutrition culturally appropriate. For complementary feeding, the introduc tion of nutrient rich energy dense mixtures of foods at 6 months of age and responsive feeding are often emphasized. Where adequate complementary feeding is difficult to achieve and subclinical defi ciencies are common, high dose vitamin A supplementation every 6 months in children 6 59 months of age reduces all cause mortality and death caused by diarrhea by 12, and zinc supplementation can reduce 1 to 4 year mortality by 18, diarrhea incidence by 13, and pneumonia by 19. Monitoring of child growth provides an early alert to a nutrition or health problem but is only worthwhile if accompanied by good counseling and growth promotion activities. The impact of growth monitoring and promotion will depend on coverage, intensity of contact, health worker performance and com munication skills, adequacy of resources, and the motivation and ability of families to follow agreed actions. Other Nutritional Interventions Treatment of vitamin and mineral deficiencies is discussed in Chapters 66 72. Treatment of LBW and intrauterine growth restriction is dis cussed in Chapter 119. SEVERE ACUTE MALNUTRITION Severe acute malnutrition is defined as severe wasting andor bilateral edema. Severe wasting is extreme thinness diagnosed by a weight for length (or height) 3 SD of the WHO Child Growth Standards. In children ages 6 59 months, a mid upper arm cir cumference 115 mm also denotes severe acute malnutrition: a color banded tape (see Fig. 62.4) is a convenient way of screening children in need of treatment. Bilateral edema is diagnosed by grasping both feet, placing a thumb on top of each, and pressing gently but firmly for 10 seconds. A pit |
823 | (dent) remaining under each thumb indicates bilateral edema. This definition of severe acute malnutrition distinguishes wasted edematous children from those who are stunted because stunted children (although underweight) are not a priority for acute clinical care because their deficits in height and weight cannot be corrected in the short term. The previous name protein energy malnutrition is avoided because it oversimplifies the complex, multifactorial etiology. Other terms are marasmus (severe wasting), kwashiorkor (characterized by edema), and marasmic kwashiorkor (severe wast ing and edema). Children with severe acute malnutrition have had a diet insuffi cient in energy and nutrients relative to their needs. The magnitude of the deficits will differ depending on the duration of inadequacy, quantity and diversity of food consumed, presence of antinutrients (e.g., phytate), individual variation in requirements, and number and severity of coexisting infections and their duration. Infections can lead to profound nutrient deficits and imbalances: For exam ple, amino acids are diverted to form acute phase proteins, potas sium, magnesium, vitamin A, and zinc are lost through diarrhea, and losses of glycine and taurine are linked to small bowel bacterial overgrowth. Ingested microbes can cause villous atrophy and loss of nutrients from maldigestion and malabsorption, as well as dis ruption of gut barrier function leading to microbial translocation, chronic immune activation, and altered gut microbiome (environ mental enteric dysfunction). Deficits can also arise from increased nutrient utilization in response to toxins (e.g., cysteine and methio nine to detoxify dietary cyanogens). Children affected by severe acute malnutrition may have different clinical presentations and metabolic disturbances due to variations in the type and extent of deficits and imbalances in their bodies. This heterogeneity is a result of diverse pathways that lead to severe acute malnutrition. Children who develop edematous malnutrition are more likely than nonedematous children to have had exposures that generate oxidative stress andor to have greater deficits in free radicalscavenging antioxidants (glutathione; vitamins A, C, and E; and essential fatty acids) or cofactors (zinc, copper, selenium). Clinical Manifestations of Severe Acute Malnutrition (Table 62.6) Severe wasting is most visible on the thighs, buttocks, and upper arms and over the ribs and scapulae, where loss of fat and skeletal muscle is greatest (Fig. 62.5). Wasting is preceded by failure to gain weight and then by weight loss. The skin loses turgor and becomes loose as subcutaneous tissues are broken down to provide energy. The face may retain a relatively normal appearance, but eventually becomes wasted and wizened. The eyes may be sunken from loss of retroorbital fat, and lacrimal and salivary glands may atrophy, leading to lack of tears and a dry mouth. Weakened abdominal muscles and gas from bacterial over growth of the upper gut may lead to a distended abdomen. Severely wasted children are often fretful and irritable. In edematous malnutrition the edema is most likely to appear first in the feet and then in the lower legs. It can quickly develop into generalized edema affecting also the hands, arms, and face (Fig. 62.6). Skin |
824 | changes typically occur over the swollen limbs and include dark, crackled peeling patches (flaky paint dermatosis) with pale skin underneath that is easily infected (see Figs. 62.2 and 62.6). The hair is sparse, easily pulled out, and may lose its curl. In dark haired children, the hair may turn pale or reddish. The liver is often enlarged with fat. Children with edema are uncomfortable, irritable andor apathetic, and often refuse to eat. Table 62.6 Clinical Signs of Malnutrition SITE SIGNS Face Moon face (kwashiorkor), simian facies (marasmus) Eye Dry eyes, pale conjunctiva, Bitot spots (vitamin A), periorbital edema Mouth Angular stomatitis, cheilitis, glossitis, spongy bleeding gums (vitamin C), parotid enlargement Teeth Enamel mottling, delayed eruption Hair Dull, sparse, brittle hair; hypopigmentation; flag sign (alternating bands of light and normal color); broomstick eyelashes; alopecia Skin Loose and wrinkled (marasmus); shiny and edematous (kwashiorkor); dry, follicular hyperkeratosis; patchy hyperpigmentation and hypopigmentation (crazy paving or flaky paint dermatoses); erosions; poor wound healing Nails Koilonychia; thin and soft nail plates, fissures, or ridges Musculature Muscle wasting, particularly buttocks and thighs; Chvostek or Trousseau sign (hypocalcemia) Skeletal Deformities, usually as a result of calcium, vitamin D, or vitamin C deficiencies Abdomen Distended: hepatomegaly with fatty liver; ascites may be present Cardiovascular Bradycardia, hypotension, reduced cardiac output, small vessel vasculopathy Neurologic Global developmental delay, loss of knee and ankle reflexes, impaired memory Hematologic Pallor, petechiae, bleeding diathesis Behavior Lethargic, apathetic, irritable on handling Gastrointestinal tract Atrophy of small intestine mucosa, lactase deficiency common Modified from Grover Z, Ee LC. Protein energy malnutrition. Pediatr Clin North Am. 2009;56:10551068. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 62 u Nutrition, Food Security, and Health 427 Pathophysiology When a childs intake is insufficient to meet daily needs, physiologic and metabolic changes take place in an orderly progression to con serve energy and prolong life. This process is called reductive adap tation. Fat stores are mobilized to provide energy. Later, protein in muscle, skin, and the gastrointestinal tract is mobilized. Energy is conserved by reducing physical activity and growth, reducing basal metabolism and the functional reserve of organs, and reducing inflammatory and immune responses. These changes have impor tant consequences: u The liver makes glucose less readily, making the child more prone to hypoglycemia. It produces less albumin, transferrin, and other transport proteins. It is less able to cope with excess dietary protein and to excrete toxins. u Heat production is less, making the child more vulnerable to hypo thermia. u The kidneys are less able to excrete excess fluid and sodium, and fluid easily accumulates in the circulation, increasing the risk of fluid overload. u The heart is smaller and weaker and has a reduced output, and fluid overload readily leads to death from cardiac failure. u Sodium builds up inside cells because of leaky cell membranes and reduced activity of the |
825 | sodium potassium pump, leading to excess body sodium, fluid retention, and edema. u Potassium leaks out of cells and is excreted in urine, contributing to electrolyte imbalance, fluid retention, edema, and anorexia. u Loss of muscle protein is accompanied by loss of potassium, magne sium, zinc, and copper. u The gut produces less gastric acid and enzymes. Motility is reduced, and bacteria may colonize the stomach and small intestine, damag ing the mucosa and deconjugating bile salts. Digestion and absorp tion are impaired. u Cell replication and repair are reduced, increasing the risk of bacte rial translocation through the gut mucosa. u Immune function is impaired, especially cell mediated immunity. The usual responses to infection may be absent, even in severe ill ness, increasing the risk of undiagnosed infection. u Red blood cell mass is reduced, releasing iron, which requires glu cose and amino acids to be converted to ferritin, increasing the risk of hypoglycemia and amino acid imbalances. If conversion to fer ritin is incomplete, unbound iron promotes pathogen growth and formation of free radicals. u Micronutrient deficiencies limit the bodys ability to deactivate free radicals, which cause cell damage. Edema and hairskin changes are outward signs of cell damage. When prescribing treatment, it is essential to take these changes in function into account. Otherwise, organs and systems will be over whelmed, and death will rapidly ensue. Principles of Treatment Figure 62.7 shows the 10 steps of treatment, which are separated into two phases: stabilization and rehabilitation. These steps apply to all clinical forms and all geographic locations, including North America and Europe. The aim of the stabilization phase is to repair cellular function, correct fluid and electrolyte imbalance, restore homeostasis, and prevent death from the interlinked triad of hypo glycemia, hypothermia, and infection. The aim of the rehabilita tion phase is to restore wasted tissues (i.e., catch up growth). It is essential that treatment proceeds in an ordered progression and that the metabolic machinery is repaired before any attempt is made to promote weight gain. Pushing ahead too quickly risks inducing the potentially fatal refeeding syndrome (see Chapter 63). Caregivers bring children to health facilities because of illness, rarely because of their malnutrition. A common mistake among healthcare providers is to focus on the illness and treat as for a well nourished child. This approach ignores the deranged metabolism in malnourished children and can be fatal. Such children should be considered as severely malnourished with a complication, and Fig. 62.5 Child with severe wasting. Fig. 62.6 Child with generalized edema. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 428 Part V u Nutrition treatment should follow the 10 steps. Two other potentially fatal mis takes are to treat edema with a diuretic and to give a high protein diet in the early phase of treatment. Emergency Treatment Table 62.7 summarizes emergency treatment |
826 | for malnourished children with shock and other emergency conditions. Note that treatment of shock in these children is different (less rapid, smaller volume, different fluid) from treatment of shock in well nourished children. However, shock from dehydration and shock from sepsis often coexist and are difficult to differentiate on clinical grounds. Thus the physician must be guided by the response to treatment: children with dehydration respond to IV fluid, whereas those with septic shock will not respond. Because severely malnourished chil dren can quickly succumb to fluid overload, they must be moni tored closely. Stabilization Table 62.8 summarizes the therapeutic directives for stabilization steps 1 7 (see Fig. 62.7). Giving broad spectrum antibiotics (Table 62.9) and feeding frequent small amounts of F75 (a specially formulated low lactose milk with 75 kcal and 0.9 g protein per 100 mL to which potassium, magnesium, and micronutrients are added) will reestablish metabolic control, treat edema, and restore appetite. The parenteral route should be avoided; children who lack appetite should be fed by nasogastric tube, because nutrients delivered within the gut lumen help in its repair. Table 62.10 provides recipes for preparing the spe cial feeds and their nutrient composition. Of the two recipes for F75, one requires no cooking, and the other is cereal based and has a lower osmolality, which may benefit children with persistent diarrhea. F75 is also commercially available; maltodextrins replace some of the sugar, and potassium, magnesium, minerals, and vitamins are already added. Table 62.7 Emergency Treatment in Severe Malnutrition CONDITION IMMEDIATE ACTION Shock Lethargic or unconscious and Cold hands Plus either: Slow capillary refill (3 sec) or Weak fast pulse 1. Give oxygen. 2. Give sterile 10 glucose (5 mLkg) rapidly by IV injection. 3. Give IV fluid at 15 mLkg over 1 hr, using: Ringer lactate with 5 dextrose or Half normal saline with 5 dextrose or Half strength Darrow solution with 5 dextrose If all these are unavailable, Ringer lactate 4. Measure and record pulse and respirations at the start and every 10 min. If there are signs of improvement (pulse and respiration rates fall), repeat IV drip, 15 mLkg for 1 more hr. Then switch to oral or nasogastric rehydration with ReSoMal, 5 10 mLkg in alternate hr (see Table 62.8 step 3). If there are no signs of improvement, assume septic shock and: 1. Give maintenance fluid IV (4 mLkghr) while waiting for blood. 2. Order 10 mLkg fresh whole blood and transfuse slowly over 3 hr. If signs of heart failure, give 5 7 mLkg packed cells rather than whole blood. 3. Give furosemide, 1 mgkg IV at start of transfusion. Hypoglycemia Blood glucose 3 mmolL See Table 62.8 step 1 for treatment. Severe dehydration Do not give IV fluids except in shock. See Table 62.8 step 3 for treatment. Very severe anemia Hgb 4 gdL If very severe anemia (or Hgb 4 6 gdL and respiratory distress): 1. Give whole blood 10 mLkg slowly over 3 hr. If signs of heart failure, |
827 | give 5 7 mLkg packed cells rather than whole blood. 2. Give furosemide 1 mgkg IV at the start of the transfusion. Emergency eye care Corneal ulceration If corneal ulceration: 1. Give vitamin A immediately (age 6 mo: 50,000 IU; 6 12 mo: 100,000 IU; 12 mo: 200,000 IU) 2. Instill 1 drop atropine (1) into affected eye to relax the eye and prevent the lens from pushing out. Some would recommend 5 dextrose in normal saline. Hgb, Hemoglobin; IV, intravenous(ly). Stabilization Rehabilitation Day 12 Day 37 Week 26 1. Preventtreat hypoglycemia 2. Preventtreat hypothermia 3. Treatprevent dehydration 4. Correct imbalance of electrolytes 5. Treat infections 6. Correct deficiencies of micronutrients no iron with iron 7. Start cautious feeding 8. Rebuild wasted tissue (catchup growth) 9. Provide loving care and play 10. Prepare for followup Fig. 62.7 The 10 steps of treatment for severe acute malnutrition and their approximate time frames. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 62 u Nutrition, Food Security, and Health 429 Table 62.8 Therapeutic Directives for Stabilization of Malnourished Children STEP PREVENTION TREATMENT 1. Preventtreat hypoglycemia blood glucose 3 mmolL. Avoid long gaps without food and minimize need for glucose: 1. Feed immediately. 2. Feed every 3 hr day and night (2 hr if ill). 3. Feed on time. 4. Keep warm. 5. Treat infections (they compete for glucose). Note: Hypoglycemia and hypothermia often coexist and are signs of severe infection. If conscious: 1. Give 10 glucose (50 mL), or a feed (see step 7), or 1 tsp sugar under tongue, whichever is quickest. 2. Feed every 2 hr for at least first day. Initially give 14 of feed every 30 min. 3. Keep warm. 4. Start broad spectrum antibiotics. If unconscious: 1. Immediately give sterile 10 glucose (5 mLkg) rapidly by IV. 2. Feed every 2 hr for at least first day. Initially give 14 of feed every 30 min. Use nasogastric (NG) tube if unable to drink. 3. Keep warm. 4. Start broad spectrum antibiotics. 2. Preventtreat hypothermia axillary 35C (95F); rectal 35.5C (95.9F). Keep warm and dry and feed frequently. 1. Avoid exposure. 2. Dress warmly, including head, and cover with blanket. 3. Keep room hot; avoid drafts. 4. Change wet clothes and bedding. 5. Do not bathe if very ill. 6. Feed frequently day and night. 7. Treat infections. Actively rewarm. 1. Feed. 2. Skin to skin contact with caregiver (kangaroo technique) or dress in warmed clothes, cover head, wrap in warmed blanket, and provide indirect heat (e.g., heater; transwarmer mattress; incandescent lamp). 3. Monitor temperature hourly (or every 30 min if using heater). 4. Stop rewarming when rectal temperature is 36.5C (97.7F). 3. Preventtreat dehydration. Replace stool losses. 1. Give ReSoMal after each watery stool. ReSoMal (37.5 mmol NaL) is a low sodium rehydration solution for malnutrition. Do not give IV fluids |
828 | unless the child is in shock. 1. Give ReSoMal 5 mLkg every 30 min for first 2 hr orally or NG tube. 2. Then give 5 10 mLkg in alternate hours for up to 10 hr. Amount depends on stool loss and eagerness to drink. Feed in the other alternate hour. 3. Monitor hourly and stop if signs of overload develop (pulse rate increases by 25 beatsmin and respiratory rate by 5 breathsmin; increasing edema; engorged jugular veins). 4. Stop when rehydrated (3 signs of hydration: less thirsty, passing urine, skin pinch less slow, eyes less sunken, moist mouth, tears, less lethargic, improved pulse and respiratory rate). 4. Correct electrolyte imbalancedeficit of potassium and magnesium, excess sodium. 1. Give extra potassium (4 mmolkgday) and magnesium (0.6 mmolkgday) for at least 2 wk (see Table 62.12). Note: Potassium and magnesium are already added in Nutriset F75 and F100 packets. 5. Preventtreat infections. Minimize risk of cross infection. 1. Avoid overcrowding. 2. Wash hands. 3. Give measles vaccine to unimmunized children age 6 mo. Infections are often silent. Starting on first day, give broad spectrum antibiotics to all children. 1. For antibiotic choicesschedule, see Table 62.9. 2. Ensure all doses are given, and given on time. 3. Cover skin lesions so that they do not become infected. Note: Avoid steroids because they depress immune function. 6. Correct micronutrient deficiencies. Note: Folic acid, multivitamins, zinc, copper, and other trace minerals are already added in Nutriset F75 and F100 packets. Do not give iron in the stabilization phase. 1. Give vitamin A on day 1 (6 mo 50,000 units; 6 12 mo 100,000 units; 12 mo 200,000 units) if child has any eye signs of vitamin A deficiency or has had recent measles. Repeat this dose on days 2 and 14. 2. Give folic acid, 1 mg (5 mg on day 1). 3. Give zinc (2 mgkgday) and copper (0.3 mgkgday). These are in the electrolytemineral solution and Combined Mineral Vitamin mix (CMV) and can be added to feeds and ReSoMal. 4. Give multivitamin syrup or CMV. 7. Start cautious feeding. 1. Give 8 12 small feeds of F75 to provide 130 mLkgday, 100 kcalkgday, and 1 1.5 g proteinkgday. 2. If gross edema, reduce volume to 100 mLkgday. 3. Keep a 24 hr intake chart. Measure feeds carefully. Record leftovers. 4. If child has poor appetite, coax and encourage to finish the feed. If unfinished, reoffer later. Use NG tube if eating 80 of the amount offered. 5. If breastfed, encourage continued breastfeeding but also give F75. 6. Transfer to F100 when appetite returns (usually within 1 wk) and edema has been lost or is reduced. 7. Weigh daily and plot weight. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 430 Part V u Nutrition Dehydration status is easily misdiagnosed in severely wasted chil dren, because the |
829 | usual signs (e.g., slow skin pinch, sunken eyes) may be present even without dehydration. Rehydration must therefore be closely monitored for signs of fluid overload. Serum electrolyte levels can be misleading because of sodium leaking from the blood into cells and potassium leaking out of cells. Keeping the intake of electrolytes and nutrients constant (see Table 62.8) allows systems to stabilize more quickly than adjusting intake in response to laboratory results. Table 62.11 provides a recipe for the special rehydration solu tion used in severe malnutrition (ReSoMal). Therapeutic Combined Mineral Vitamin mix (CMV) contains electrolytes, minerals, and vita mins and is added to ReSoMal and feeds. If unavailable, potassium, magnesium, zinc, and copper can be added as an electrolytemineral stock solution (Table 62.12 provides a recipe), and a multivitamin sup plement can be given separately. Rehabilitation The signals for entry to the rehabilitation phase are reduced or minimal edema and return of appetite. A controlled transition over 3 days is recommended to prevent refeeding syndrome (see Chap ter 63). After the transition, unlimited amounts should be given of a high energy, high protein milk formula such as F100 (100 kcal and 3 g protein per 100 mL), or a ready to use therapeutic food Table 62.10 Recipes for Milk Formulas F75 and F100 F75B (STARTER) F75C (STARTER) (CEREAL BASED) F100D (CATCH UP) Dried skimmed milk (g) 25 25 80 Sugar (g) 100 70 50 Cereal flour (g) 35 Vegetable oil (g) 30 30 60 Electrolytemineral solution (mL)a 20 20 20 Water: make up to (mL) 1000 1000 1000 Content100 mL Energy (kcal) 75 75 100 Protein (g) 0.9 1.1 2.9 Lactose (g) 1.3 1.3 4.2 Potassium (mmol) 4.0 4.2 6.3 Sodium (mmol) 0.6 0.6 1.9 Magnesium (mmol) 0.43 0.46 0.73 Zinc (mg) 2.0 2.0 2.3 Copper (mg) 0.25 0.25 0.25 Energy from protein 5 6 12 Energy from fat 32 32 53 Osmolality (mOsmL) 413 334 419 Whisk at high speed to prevent oil from separating out. aSee Table 62.12 for recipe, or use commercially available therapeutic Combined Mineral Vitamin mix (CMV). bA comparable F75 can be made from 35 g dried whole milk, 100 g sugar, 20 g oil, 20 mL electrolytemineral solution, and water to 1,000 mL or from 300 mL full cream cows milk, 100 g sugar, 20 g oil, 20 mL electrolytemineral solution, and water to 1,000 mL. cThis lower osmolality formula may be helpful for children with dysentery or persistent diarrhea. Cook for 4 min. dA comparable F100 can be made from 110 g dried whole milk, 50 g sugar, 30 g oil, 20 mL electrolytemineral solution, and water to 1000 mL or from 880 mL full cream cows milk, 75 g sugar, 20 g oil, 20 mL electrolytemineral solution, and water to 1,000 mL. Table 62.9 Recommended Antibiotics for Malnourished Children GIVE If no complications Amoxicillin, 25 mgkg PO twice daily for 5 days If complications (shock, hypoglycemia, hypothermia, skin lesions, respiratory or urinary tract infections, or lethargysickly) Gentamicin, 7.5 mgkg IV or IM |
830 | once daily for 7 days and Ampicillin, 50 mgkg IV or IM every 6 hr for 2 days, then amoxicillin, 25 40 mgkg PO every 8 hr for 5 days If specific infections are identified, add appropriate antibiotics. For persistent diarrhea or small bowel overgrowth, add metronidazole, 7.5 mgkg PO every 8 hr for 7 days. Local resistance patterns may require these to be adjusted: Ensure that there is gram negative coverage. PO, Orally; IM, intramuscularly; IV, intravenously. Table 62.11 Recipe for Rehydration Solution for Malnutrition (ReSoMal) INGREDIENT AMOUNT Water 2 L WHO ORS One 1 L sachet Sucrose 50 g Electrolytemineral solution 40 mL ReSoMal contains 37.5 mmol sodium and 40 mmol potassiumL. Sachet contains 2.6 g sodium chloride, 2.9 g trisodium citrate dihydrate, 1.5 g potassium chloride, and 13.5 g glucose. See Table 62.12 for recipe, or use commercially available therapeutic Combined Mineral Vitamin mix (CMV). WHO ORS, World Health Organization Oral Rehydration Solution. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 63 u Refeeding Syndrome 431 (RUTF), or family foods modified to have comparable energy and protein contents. To make the transition, for 2 days replace F75 with an equal vol ume of F100, then increase each successive feed by 10 mL until some feed remains uneaten (usually at about 200 mLkgday). After this transition, give 150 220 kcalkgday and 4 6 g proteinkgday and continue to give potassium, magnesium, and micronutrients. Add iron (3 mgkgday). If breastfed, encourage continued breastfeed ing. Children with severe malnutrition have developmental delays, so loving care, structured play, and sensory stimulation during and after treatment are essential to aid recovery of brain function. Community Based Treatment Many children with severe acute malnutrition can be identified in their communities before medical complications arise. If these children have a good appetite and are clinically well, they can be rehabilitated at home through community based management of acute malnutrition, which has the added benefit of reducing their exposure to nosocomial infec tions and providing continuity of care after recovery. It also reduces the time caregivers spend away from home and their opportunity costs and can be cost effective for health services. Table 62.12 Recipe for Concentrated ElectrolyteMineral Solution INGREDIENT g mol20 mL Potassium chloride: KCl 224.0 24 mmol Tripotassium citrate 81.0 2 mmol Magnesium chloride: MgCl26H2O 76.0 3 mmol Zinc acetate: Zn acetate2H2O 8.2 300 mol Copper (cupric) sulfate: CuSO45H2O 1.4 45 mol Water: make up to 2500 mL Add 20 mL when preparing 1 L of feed or ReSoMal. Make fresh each month. Use cooled boiled water. Severe acute malnutrition Without complicationsWith complications Severe edema () MUAC ?115 mm AND any of the following: Anorexia Clinically unwell Not alert OR Inpatient care Edema () MUAC ?115 mm All of the following: Good appetite Clinically well Alert OR AND Outpatient therapeutic care Fig. 62.8 Flow diagram for |
831 | inpatient care (left) and outpatient care (right) in the child with severe acute malnutrition. MUAC, Mid upper arm circumference. Refeeding syndrome occurs in response to reintroduction of nutri tion in the malnourished patient. Rapid electrolyte and fluid shifts in response to the surge of insulin brought on by the presence of nutrients can lead to numerous medical complications shown in Table 63.1 and may progress to life threatening outcomes, includ ing coma, heart failure, and sudden death. Early accounts of the syndrome were among starved survivors of wartime sieges and con centration camps and among prisoners of war when given sudden access to unlimited food. Refeeding syndrome occurs as a result of oral, enteral, or parenteral (highest risk) feeding of malnour ished individuals, especially in the setting of aggressive refeed ing. Patient populations at risk for refeeding syndrome include those with anorexia nervosa and other restrictive eating disorders, chronic conditions causing malnutrition (cancer, congenital heart disease), malabsorptive syndromes (inflammatory bowel disease, cystic fibrosis), cerebral palsy, bariatric surgery, and bowel resec tions (Table 63.2). In malnourished patients with anorexia nervosa, cases of refeeding syndrome have been documented during refeeding. Risk is greatest within the first 7 days of the start of feeding and is primarily indi cated by serum hypophosphatemia (3.0 ngdL); hypokalemia (3.5 mmolL) and hypomagnesemia (1.8 mgdL) are also seen. Studies have identified low weight, but not the caloric load, as the primary risk factor for refeeding syndrome. An increase in the supply of energy (usually carbohydrates) is accompanied by an increase in sodium pump activity, and too sudden a supply risks causing a rapid release of accumulated sodium from cells, causing expansion of extracellular and plasma volumes. At the same time, there is increased cellular uptake of glucose, potassium, magnesium, and phosphate. Reactivation of metabolic pathways for adenosine triphosphate (ATP) production further depletes serum phosphorus. For decades, the key to preventing the syndrome was believed to be lower calorie refeeding with cautious advancement. Diets start ing at 1,000 1,200 calories per day were recommended by multiple organizations in the United States. Diets as low as 500 calories per day were recommended in Europe. These cautious approaches are still recommended for patients with extreme malnutrition (60 of median body mass index for age and sex) and children in developing Chapter 63 Refeeding Syndrome Jason M. Nagata and Andrea K. Garber Figure 62.8 shows the criteria for inpatient and outpatient care. To maximize coverage and compliance, community based therapeutic care has 4 main elements: community mobilization and sensitization, active case finding, therapeutic care, and follow up after discharge. Community based therapeutic care comprises steps 8 10 (see Fig. 62.7), plus a broad spectrum antibiotic (step 5). RUTF is usually pro vided, especially in times of food shortage. RUTF is specially designed for rehabilitating children with severe acute malnutrition at home. It is high in energy and protein and has electrolytes and micronutrients added. The most widely used RUTF is a thick paste that contains milk powder, peanuts, vegetable oil, and |
832 | sugar. Pathogens cannot grow in it because of its low moisture content. Hospitalized children who have completed steps 1 7 can be transferred to community based care for completion of their rehabilitation, thereby reducing their hospital stay to about 7 10 days. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 432 Part V u Nutrition Table 63.1 Clinical Signs and Symptoms of Refeeding Syndrome HYPOPHOSPHATEMIA HYPOKALEMIA HYPOMAGNESEMIA VITAMINTHIAMINE DEFICIENCY SODIUM RETENTION HYPERGLYCEMIA Cardiac Hypotension Decreased stroke volume Respiratory Impaired diaphragm contractility Dyspnea Respiratory failure Neurologic Paresthesia Weakness Confusion Disorientation Lethargy Areflexic paralysis Seizures Coma Hematologic Leukocyte dysfunction Hemolysis Thrombocytopenia Other Death Cardiac Arrhythmias Respiratory Failure Neurologic Weakness Paralysis Gastrointestinal Nausea Vomiting Constipation Muscular Rhabdomyolysis Muscle necrosis Other Death Cardiac Arrhythmias Neurologic Weakness Tremor Tetany Seizures Altered mental status Coma Gastrointestinal Nausea Vomiting Diarrhea Other Refractory hypokalemia and hypocalcemia Death Encephalopathy Lactic acidosis Death Fluid overload Pulmonary edema Cardiac compromise Cardiac Hypotension Respiratory Hypercapnia Failure Other Ketoacidosis Coma Dehydration Impaired immune function Data from Kraft MD, Btaiche IF, Sacks GS. Review of RFS. Nutr Clin Pract. 2005;20:625633. From Fuentebella J, Kerner JA. Refeeding syndrome. Pediatr Clin North Am. 2009;56:12011210. nations, where the World Health Organization (WHO) guidelines for the treatment of malnutrition are still in place (see Chapter 62). However, the majority of patients hospitalized in the United States are adolescents with acute, moderate malnutrition. In this patient population, studies have demonstrated the feasibility of higher calorie refeeding beginning 1,400 calories per day. A randomized clinical trial has demonstrated the efficacy and safety of starting with 2,000 calories per day in hospitalized adolescents with mod erate malnutrition secondary to anorexia nervosa. In the United States, meal based refeeding is most common, with food served on bedside trays, whereas higher calorie refeeding by nasogastric tube is reported in Australia. Electrolyte shifts are much lower than expected using these protocols; serum electrolyte levels can be monitored daily in hospital settings and decreased electrolyte levels may be corrected with supplementation. The following guidance is a suggestion for possible electrolyte repletion for refeeding syndrome in adolescents with eating disor ders. For hypophosphatemia: Phos Na K 1 packet (250 mg) tid for phosphorous 2.5 2.9 mgdL; Phos Na K 2 packets (500 mg) tid for phosphorous 2.0 2.4 mgdL; IV Na K Phos 0.24 mmolkg max 15 mmoldose, and consider intensive care consultation for phospho rous 2.0 mgdL. For hypokalemia: extended release KCl 20 mEq PO for potassium 3.1 3.4 mmolL (recheck in 8 12 hours); extended release KCl 40 mEq PO for potassium 2.5 3.0 mmolL (recheck in 8 12 hours); extended release KCl 40 mEq PO stat for potassium 2.2 2.4 mmolL; and IV KCl and consider intensive care consulta tion for potassium 2.2 mmolL. For hypomagnesemia: Mag oxide 1 tablet (133 200 mg elemental Mg each) bid for magnesium 1.3 |
833 | 1.7 mgdL; Mag oxide 2 tablets (133 200 mg elemental Mg each) bid for magnesium 1.0 1.2 mgdL; and IV Mg SO4 50 mgkg; max 2 g dose and consider intensive care consultation for magnesium 1.0 mgdL. Declining electrolytes but within the normal range gener ally do not need to be treated. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 63.2 Refeeding Syndrome: National Institutes for Clinical Excellence (NICE) Guidelines for Management of Refeeding Syndrome PATIENTS AT RISK FOR REFEEDING SYNDROME ONE OR MORE OF THE FOLLOWING TWO OR MORE OF THE FOLLOWING BMI 16 kgm2 BMI 18.5 kgm2 Unintentional weight loss of 15 in the previous 3 6 mo Unintentional weight loss of 10 in the previous 3 6 mo Little or no nutritional intake for 10 days Little or no nutritional intake for 5 days Low levels of potassium, phosphorus, or magnesium before refeeding History of alcohol or drug use, including insulin, chemotherapy, antacids, or diuretics From Sachs K, Andersen D, Sommer J, Winkelman A, Mehler PS. Avoiding medical complications during the refeeding of patients with anorexia nervosa. Eat Disord. 2015;23(5):411421, Table 1, p. 414. OR Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 64 u Malnutrition in High Resource Settings 433 See Chapter 62 for malnutrition in low and middle income coun tries. Malnutrition refers to undernutrition and is defined as an imbalance between nutrient requirements and intake or delivery that then results in deficitsof energy, protein, or micronutrients that negatively affect growth and development. Malnutrition may be illness related or nonillness related, or both. Illness related malnu trition may be caused by one or more diseases, infections, or con genital anomalies and by injury or surgery. Nonillness related causes include environmental, psychosocial, or behavioral factors. Often, one cause may be primary and exacerbated by another. Patients with malnutrition may present with growth deceleration, or actual weight loss, as measured by anthropometric parameters, including weight, lengthheight, skinfolds, and mid upper arm circumference (see Chapter 62). Wasting is defined as being too thin for height (weight for length or body mass index BMI z score less than 2). Stunting is defined as being too short for age (height or length z score less than 2). U.S. data suggest 10 of children seen by primary care physicians are diagnosed with growth faltering. Malnutrition is a primary diagno sis in 15 of all hospital admissions. The prevalence of malnutrition in hospitalized patients is 25; malnutrition in children can contrib ute to poor outcomes, especially in intensive care units. Although failure to thrive (FTT) has classically been the term used to describe children who are not meeting weight gain targets based on growth curves, the term malnutrition more accurately describes this cohort of children and removes perceived accusations or blame from the diagnosis. CLINICAL MANIFESTATIONS The degree of malnutrition can be assessed by inadequate |
834 | weight for corrected age, failure to gain adequate weight over time (weight gain velocity), height velocity, weight for length or BMI depend ing on age, and developmental outcomes (see Chapter 62). These growth and anthropometric parameters are measured longitudi nally and plotted on growth charts appropriate for the childs sex, age (corrected if premature), and, if known, genetic disorders, such as trisomy 21 or Turner syndrome. The American Academy of Pediatrics (AAP) and the U.S. Centers for Disease Control and Pre vention (CDC) recommend the 2006 World Health Organization (WHO) standards for infants up to 2 years of age who are measured supine for length. The CDC 2000 growth references are recom mended for children and adolescents (age 2 20 years) when mea sured with a standing height. The severity of malnutrition (mild, moderate, or severe) may be determined by plotting the z score (standard deviation SD from the mean) for each of these anthro pometric values on the age and sex appropriate growth chart (Table 64.1). Most electronic health records are able to calculate and plot the z scores for measured anthropometrics. Z scores can also be obtained by entering measurements in electronic applications such as peditools.org. In infants less than 6 months old, a slow or slowing weight gain velocity can indicate malnutrition even if weightlength is preserved. The presence of bilateral pitting edema and low albu min triggers concern for edematous malnutrition (kwashiorkor) in the absence of an alternative explanation (such as heart, liver, or renal disease). Edema in the setting of malnutrition automatically classifies as severe malnutrition (see Table 64.1). ETIOLOGY AND DIAGNOSIS The most common mechanisms of pediatric malnutrition are nonillness related and are secondary to insufficient calorie intake, whether the result of low maternal breast milk supply, psychosocial factors such as food insecurity, or feeding difficulties. Picky eat ing, although common in young children, can occasionally be so restrictive as to result in malnutrition andor micronutrient defi ciencies. Avoidant restrictive food intake disorder is one risk fac tor and is often seen in children with autism, food aversions, or those on elimination diets for fear of food allergies or gluten sen sitivity (Fig. 61.3) (Table 64.2). The most important illness related Chapter 64 Malnutrition in High Resource Settings Liliane K. Diab, Stephanie P. Gilley, and Nancy F. Krebs Table 64.1 Comprehensive Malnutrition Indicators INDICATORS SEVERE MALNUTRITION MODERATE MALNUTRITION MILD MALNUTRITION Weight for length z score 3 2.0 to 2.99 1.0 to 1.99 BMI for age z score 3 2.0 to 2.99 1.0 to 1.99 Length z score 3 No data No data Mid upper arm circumference 3 2.0 to 2.99 1.0 to 1.99 Weight gain velocity (2 years of age) 75 of the norm for expected weight gain 50 of the norm for expected weight gain 25 of the norm for expected weight gain Weight loss (2 20 yr of age) 10 of UBW 7.5 UBW 5 UBW Deceleration in weight for lengthheight or BMI for age Deceleration across 3 z score lines Deceleration |
835 | across 2 z score lines Deceleration across 1 z score line Inadequate nutrient intake 25 of estimated energyprotein need 2650 of estimated energy protein need 5175 of estimated energy protein need Edema Present Absent Absent Use clinical judgment when applying these diagnostic criteria. It is recommended that when a child meets more than one malnutrition acuity level, the highest acuity level is used for diagnosis to ensure that appropriate evaluation, monitoring, and treatment are provided. The presence of bilateral pitting edema and low albumin is diagnostic for kwashiorkor, which is severe malnutrition regardless of any other indicator(s). Needs additional positive diagnostic criteria to make a malnutrition diagnosis. BMI, Body mass index; UBW, usual body weight. Adapted with modifications from Becker PJ, Nieman Carney L, Corkins MR, et al. Consensus statement of the Academy of Nutrition and DieteticsAmerican Society for Parenteral and Enteral Nutrition: indicators recommended for the identification and documentation of pediatric malnutrition (undernutrition). J Acad Nutr Diet. 2014;114(12):1988 2000. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 434 Part V u Nutrition cause of insufficient growth is inability to consume sufficient calo ries or starvation. The differential diagnosis in this case is broad and includes many health conditions such as cardiac and neuro logic diseases. Oral aversion can sometimes be a manifestation of eosinophilic esophagitis or dysphagia. Other causes of malnutrition are (1) increased nutrient losses (e.g., protein losing enteropathy, chronic diarrhea); (2) increased metabolic demands, as seen in extensive burn injuries, congenital heart disease, and thyroid disor ders; (3) altered nutrient digestion, absorption, or utilization (e.g., cystic fibrosis, short bowel syndrome, celiac disease); and (4) some chromosome abnormalities that can be associated with poor growth such as Russel Silver syndrome. More than one mechanism can exist simultaneously (Fig. 64.1). Chronic malnutrition is defined as mal nutrition having a duration of 3 months (see Chapter 62). A complete history includes information regarding the onset of the growth faltering, a detailed review of systems, past medical his tory, and family history including parents heights and growth pat terns. The perinatal history is also important to identify children who are born small for gestational age (SGA). SGA infants who are asymmetric (birthweight is disproportionally more depressed than length or head circumference) have a better prognosis for catch up growth than do infants who have symmetric intrauterine growth restriction. A detailed nutritional history should include unusual nutritional beliefs and the quantity, quality, and frequency of meals. A comprehensive physical examination can help elucidate possible underlying etiologies and manifestations of micronutrient deficien cies to guide laboratory or imaging evaluation if indicated (Table 64.3 and see Table 62.6). Tanner staging cannot be used as a marker for nutritional status, but it is influenced and often delayed by mal nourishment. Puberty will usually resume progression when the malnourished state improves. A reasonable initial screen should include a complete blood |
836 | count, a comprehensive metabolic panel (CMP), and urinalysis. Additional measurements that are useful for classifying the severity of malnutrition and following the progress of the acutely malnourished child are mid upper arm circumference (MUAC) and triceps skin folds (TSF). MUAC can be used as an indepen dent anthropometric tool to screen for and diagnose malnutrition (depletion of subcutaneous fat stores) when obtaining an accurate length or height is difficult. The MUAC is used as a predictor of malnutrition related mortality by the WHO (increased risk of death from malnutrition if less than 11.5 cm in infants and children 6 64 Table 64.2 DSM 5 Diagnosis of AvoidantRestrictive Food Intake Disorder A. An eating or feeding disturbance (e.g., apparent lack of interest in eating or food; avoidance based on the sensory characteristics of food; concern about aversive consequences of eating) as manifested by persistent failure to meet appropriate nutritional andor energy needs associated with one (or more) of the following: 1. Significant weight loss (or failure to achieve expected weight gain or faltering growth in children). 2. Significant nutritional deficiency. 3. Dependence on enteral feeding or oral nutritional supplements. 4. Marked interference with psychosocial functioning. B. The disturbance is not better explained by lack of available food or by associated culturally sanctioned practice. C. The eating disturbance does not occur exclusively during the course of anorexia nervosa or bulimia nervosa, and there is no evidence of a disturbance in the way in which ones body weight or shape is experienced. D. The eating disturbance is not attributable to a concurrent medical condition or not better explained by another mental disorder. When the eating disturbance occurs in the context of another condition or disorder, the severity of the eating disturbance exceeds that routinely associated with the condition or disorder and warrants additional clinical attention. From the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. p. 947. Copyright 2013. American Psychiatric Association. ANTHROPOMETRY ETIOLOGY CHRONICITY MECHANISM IMBALANCE OF NUTRIENTS OUTCOMES MALNUTRITION IN TA K E N U T R IE N T R E Q U IR E M E N T STARVATION Anorexia, socio economic, iatrogenic feeding interruptions, or intolerance NONILLNESS RELATED Behavioral, socioeconomic or environmental ACUTE (3 months) e.g. : Infection, trauma, burns CHRONIC (3 months) e.g. : Cystic fibrosis, chronic lung disease, cancer ILLNESS RELATED INFLAMMATION OR MALABSORPTION NUTRIENT LOSS Altered utilization of nutrients INTAKE REQUIREMENT ENERGY PROTEIN IMBALANCE MICRONUTRIENT DEFICIENCIES Parameters Statistic Zscores Weight, height or length, skin folds, mid upper arm circumference. Reference charts WHO MGRS (02 yr) CDC 2000 (220 yr) LOSS OF LEAN BODY MASS MUSCLE WEAKNESS INFECTIONS IMMUNE DYSFUNCTION DELAYED WOUND HEALING PROLONGED HOSPITAL STAY DEVELOPMENTAL OR INTELLECTUAL DELAY HYPERMETABOLISM Energy expenditure Fig. 64.1 Defining malnutrition in hospitalized children (ASPEN). CDC, Centers for Disease Control and Prevention; MGRS, Multicenter Growth Reference Study; WHO, World Health Organization. (From Mehta NM, Corkins MR, Lyman B, et al. Defining pediatric malnutrition: A paradigm shift toward etiology related definitions. J Parenter Enteral Nutr. 2013;374:460 481.) Downloaded for mohamed |
837 | ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 64 u Malnutrition in High Resource Settings 435 months of age). TSF is a measure of subcutaneous fat and is a sen sitive indicator of total body fat. Both MUAC and TSF are espe cially useful tools for nutrition status assessment in children with altered body composition such as low muscle mass due to cerebral palsy. However, TSF needs to be done by experienced providers to minimize errors. MUAC and TSF charts are available on the WHO website. TREATMENT While an illness related etiology of malnutrition is being investi gated, caloric supplementation can occur simultaneously. Both the medical workup and the initiation of supplemental oral feeds can occur in the outpatient setting with close follow up. Con sider including a speech or occupational therapist for a suck and swallow evaluation if the history suggests difficulty with oral feeds. Hospitalization may be indicated for cases of severe malnutrition because of the potential for refeeding syndrome (see Chapter 63), or if a child with mild to moderate malnutrition has not responded after 2 3 months of outpatient management. Hospitalization may include initiation of nasogastric tube feeds, further diagnostic and laboratory evaluation, assessment and observed implementation of adequate nutrition, and evaluation of the parent child feeding interaction. The type of caloric supplementation is based on the age of the child, the severity of malnutrition, and the underlying medi cal condition. Every effort to maximize the breastfeeding relation ship in breastfed infants should be made, ideally involving lactation support, expressing breast milk to increase supply if low, and forti fication of maternal milk if indicated. Feeding style is equally important to caloric intake. Parents should be encouraged to respond to the childs cues of hunger and satiety and to have a structured schedule for meals and snacks (every 2 3 hours). A responsive feeding style that respects the tod dlers autonomy but retains parental control over food choices helps establish healthy feeding habits (see Chapter 61). Grazing behaviors with frequent small snacks interfere with eating at mealtimes. Com monly used spill proof and squeezable packaging foster eating on the go and has been associated with poor self regulation of energy intake. Use of liquid oral nutritional supplements resulted in significantly better catch up growth in children with moderate to severe mal nutrition (Tables 64.4 and 64.5). Oral nutritional supplements are most helpful when monitored and balanced with food intake. Start with 30 40 kcal per kg per day and serve them in small amounts simultaneously with meals to allow intake of age appropriate food. However, children with oral motor difficulties may need to con sume a larger proportion of calories in a liquid form. Table 64.3 Approach to Malnutrition Based on Review of Systems CAUSE HISTORY AND PHYSICAL EXAMINATION DIAGNOSTIC CONSIDERATION WORKUP Psychosocial Lack of structure, poor sleep, permissive or intrusive feeding, |
838 | feeding difficulties and food refusal starting in infancy Low caloric intake secondary to home feeding environment; in extreme cases need to consider child neglect or abuse Avoidant restrictive food intake disorder (ARFID) May need blood tests to check for certain micronutrient deficiencies based on diet history CNS Developmental delay, poor feeding, vomiting, large head circumference, abnormal neurologic exam Brain tumor, intracranial bleeding (consider child abuse) Referral to developmental pediatrics or neurology, MRI, EEG, specific test for neuromuscular function Gastrointestinal Chronic vomiting or diarrhea, fatty stool, crying with feedings, nocturnal cough, snoring, history of travel tofrom developing countries Malabsorption, intestinal parasites, milk protein intolerance, pancreatic insufficiency, cystic fibrosis, celiac disease, immunodeficiency, inflammatory bowel disease, small bowel bacterial overgrowth May need referral to gastroenterology; stool studies (reducing substance, occult blood, fat stain), upper GI with small bowel follow through; may need endoscopic evaluation Cardiac Slow feeding, dyspnea, diaphoresis with feeding, restless sleep, heat murmur Congenital heart disease, heart failure Referral to cardiology, ECG, echocardiogram Genetic May have a positive family history of developmental delay; often facies typical of a syndrome, skeletal abnormalities, heart murmur; consider in symmetric IUGR. Noonan syndrome, William syndrome, Turner syndrome, Russel Silver syndrome Specific genetic testing Pulmonary Dyspnea, tachypnea, recurrent wheezing, pulmonary infections Asthma, aspiration, food allergies, cystic fibrosis, immunodeficiency, neuroendocrine hyperplasia of infancy Chest x ray, sweat chloride test; specialty referral Renal History of recurrent UTI, abnormal urinalysis, elevated BUN and creatinine UTI, renal tubular acidosis General chemistry with BUN and creatinine, urinalysis, urine and serum osmolality Endocrine Hypothyroidism is associated with decreased activity level; diabetes is associated with polyuria and polydipsia; growth hormone deficiency is associated with decreased linear growth velocity Hypothyroidism, type 1 diabetes, growth hormone deficiency Thyroid function tests, blood glucose and urinalysis, pituitary function tests BUN, Blood urea nitrogen; CNS, central nervous system; CT, computed tomography; ECG, electrocardiogram; EEG, electroencephalogram; IUGR, intrauterine growth restriction; UTI, urinary tract infection. Adapted from Carrasco MM, Wolford JE. Child abuse and neglect. In Zitelli BJ, McIntire SC, Nowalk AJ, eds. Atlas of Pediatric Physical Diagnosis, 7th ed. Philadelphia: Elsevier; 2018, Table 6.6. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 436 Part V u Nutrition Table 64.4 Nutritional Supplements CATEGORY BRAND EXAMPLES FEATURES AND COMMENTS ORAL SUPPLEMENTS Standard, cows milk protein Boost Kid Essentials 1.0 or 1.5 (with or without fiber) PediaSure 1.0 or 1.5 (with or without fiber) Nutren Jr 1.0 (with or without fiber) Kate Farms Pediatric Standard 1.2 EnfaGrow Nido Scandishake May or may not contain lactose. Semi elemental Kate Farms Pediatric Peptide 1.5 PediaSure Peptide 1.0 or 1.5 Peptamen Jr Used for malabsorption. Contains MCT. Elemental EleCare Junior Neocate Splash Neocate Jr Puramino Peptamen Jr Used for malabsorption or severe protein allergy. Contains MCT. Soy protein Bright Beginnings Soy Pediasmart Soy Cow milk protein free. Clear liquid Boost Breeze Ensure Clear Clear liquid, fruit flavored, fat free; |
839 | cows milk protein source. For supplemental nutrition only; none are a complete nutrition supplement. Wound healing supplement Juven Arginaid Arginaid: l Arginine only. Juven: Arginine glutamine, and betahydroxy betamethylbutyrate. TUBE FEEDING Standard, cows milk protein Boost Kid Essentials 1.0, 1.5 Nutren Junior PediaSure 1.0 Isotonic, most available with or without additional fiber. High calorie Boost Kid Essentials 1.5 (1.5 kcalmL) PediaSure 1.5 (1.5 kcalmL) Kate Farms Pediatric Peptide 1.5 (1.5 kcalmL) For increased caloric needs or fluid restriction. Food based formulas Compleat Pediatric (1.0 kcalmL) Compleat Pediatric Reduced Calorie (0.6 kcalmL) Compleat Pediatric Organic Blends (1.2 kcalmL) PediaSure Harvest (1.0 kcalmL) Kate Farms Pediatric Standard (1.2 kcalmL) Nourish (1.13 kcalmL) List of products is not exhaustive and does not imply endorsement. Pediatric formulas are appropriate for children ages 1 11 years and are not appropriate for use in infants. After 11 years, adult formulations (not listed) may be used. Does not provide complete sole source of nutrition. Adapted from Pediatric Nutrition Handbookinternal guide at Childrens Hospital Colorado. The response to feeding depends on the specific diagnosis, medi cal treatment, and severity of malnutrition. The same anthropomet ric measures used to diagnose malnutrition can be used to measure progress and recovery from the malnourished state. Target recovery growth is 150 of the normal rate of weight gain for age (Table 64.6). Many children with malnutrition require empiric micronu trient supplementation with zinc (and thiamine, if concerns about refeeding). Iron deficiency is also common in young children, but supplementation is most effective if initiated after resolution of any acute inflammatory processes (such as infection) and is typically not initiated until after 1 2 weeks of successful weight restoration. Additional supplementation for other micronutrients such as vita min D and vitamin A can be considered based on symptoms and laboratory evaluation. Interventions for contributing psychosocial factors are ideally tar geted to the underlying issue, such as maternal depression or insuf ficient funds for food. Some children who develop feeding aversion behaviors will require treatment by a specialized feeding team. If abuse or purposeful neglect is a concern, the family should be referred to the child protective services team. Kwashiorkor has a specific set of treatment guidelines from the WHO, including empiric antibiotics and avoidance of intravenous fluids and rapid repletion, as this can precipitate heart failure. Treat ment of kwashiorkor in a low resource setting is discussed in more detail in Chapter 62. In a high resource setting, treatment may involve continuous feeds of a semi elemental formula through a nasogastric tube to stabilize blood sugars in conjunction with close monitoring of electrolytes. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 64 u Malnutrition in High Resource Settings 437 Table 64.5 Calorie Boosters for Oral and Enteral Feeding Kcalg KcalTbsp FEATURES AND COMMENTS CARBOHYDRATE (CHO) Cornstarch 3.8 33 Can add to formula or water to treat |
840 | hypoglycemia in glycogen storage disease or other disorders; dose per weight, age, and glucose levels; suggested starting dose of 0.5 g per kg per feed. Infant rice cereal 15 Thickens formula, not human milk; start with 1 teaspoon rice cerealoz formula (adds 5 kcaloz, dilutes other nutrients). Not recommended to administer through feeding tube. FAT MCT oil 8.3 116 7.7 kcalmL; does not mix well, can administer as small bolus. Heavy whipping cream 50 3.3 kcalmL can be added to milk or nutritional supplements. Butter 100 Easy to mix and use in a variety of foods. PROTEIN Beneprotein 3.6 16.7 100 whey protein; 1 packet 1 scoop 7 g weight, 6 g protein, 25 kcal; can add to formula, human milk, food, or beverages. COMBINATION Duocal 4.9 42 Hydrolyzed corn starch and fat (35 MCT); can add to formula, human milk, food, or beverages. MCT Procal 6.6 1 packet (16 g) 105 kcal, 10 g MCT, 2 g protein. For altered fat absorption or metabolism. Contains MCT and milk protein; can add to formula, food, and beverages. Carnation Instant Breakfast 1 packet (36 g) 140 kcal Table 64.6 Weight Gain Velocity (0 2 Years of Age, gday) AGE (MONTHS) EXPECTED GROWTH (gDAY) CATCH UP GROWTH (gDAY) Preterm infant 30 40 0 3 20 30 30 45 3 6 15 20 20 30 6 9 10 15 15 20 9 12 10 15 12 24 6 10 PROGNOSIS Malnutrition, regardless of cause, can potentially have a detrimental effect on physical and intellectual growth and development, especially in infants younger than 2 years old. Early diagnosis and treatment of acute malnutrition may avoid long term consequences. Multiple stud ies point to a negative impact of chronic malnutrition and stunting on intelligence quotient (IQ) later in life. Pediatric medical providers are encouraged to approach nutritional status in children as a controllable factor that can have a profound influence on brain function throughout life. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 438 Part V u Nutrition EPIDEMIOLOGY Obesity is an important pediatric public health problem associated with risk of complications in childhood and increased morbidity and mortality throughout adult life. Obesity is linked to more deaths than underweight. In 2016, according to the World Health Organization (WHO), 39 of adults aged 18 years and older were overweight and 13 were obese. In the United States, child and adolescent obesity prevalence has increased by 300 over the past 40 years. In 20172018, the U.S. prevalence of pediatric obesity was 19.3, affecting about 14.4 mil lion children and adolescents. Obesity prevalence increases by age group, with 13.4 of 2 to 5 year olds, 20.3 of 6 to 11 year olds, and 21.2 of 12 to 19 year olds affected. Some U.S. populations have higher rates of childhood obesity than others do. Prevalence |
841 | of obesity in children was 25.6 among Hispanic children, 24.2 among non Hispanic Black children, 16.1 in non Hispanic White children, and 8.7 in non Hispanic Asian children. Higher mater nal education confers protection against childhood obesity across all ethnic groups. The first 1,000 days, the period from conception to age 2 years, are a modifiable period related to risk for childhood obesity. Recommen dations for the first 1,000 days include (1) a healthy and nutritious diet during pregnancy; (2) good care for all mothers during preg nancy; (3) exclusive breastfeeding for 6 months; (4) nurturing and responsive care for infants and toddlers; (5) the right foods intro duced to babies at the right time; (6) water and other healthy bever ages with no added sugars for toddlers; (7) a healthy and nutritious diet for babies and toddlers; (8) the right knowledge and skills for parents and caregivers to properly nourish young children; (9) con sistent access to enough nutritious food for families of young chil dren; and (10) societal investments in the well being of every baby and toddler (for further information see https:thousanddays.orgre sourcenourishing americas future). Parental obesity correlates with a higher risk for obesity in the children. Prenatal factors, including high preconceptual weight, ges tational weight gain, high birthweight, and maternal smoking, are asso ciated with increased risk for later obesity. Paradoxically, intrauterine growth restriction with early infant catch up growth is associated with the development of central adiposity and adult onset cardiovascu lar (CV) risk. Breastfeeding is modestly protective for obesity based on dose and duration. Infants with high levels of negative reactivity (temperament) are more at risk for obesity than those with better self regulation. The incidence of obesity in children was noted to increase during the COVID 19 pandemic. BODY MASS INDEX Obesity, or increased adiposity, is defined using the body mass index (BMI), an excellent proxy for more direct measurement of body fat. BMI weight in kg(height in meters)2. Adults with a BMI 30 meet the criterion for obesity, and those with a BMI 25 30 fall in the over weight range. During childhood, levels of body fat change begin ning with high adiposity during infancy. Body fat levels decrease for approximately 5.5 years until the period called adiposity rebound, when body fat is typically at the lowest level. Adiposity then increases until early adulthood (Fig. 65.1). Consequently, obesity and overweight are defined using BMI percentiles for children 2 years old and weight length percentiles for infants 2 years old. The criterion for obesity is BMI 95th percentile, and for overweight is BMI between 85th and 95th percentiles. ETIOLOGY Humans have the capacity to store energy in adipose tissue, allowing improved survival in times of famine. Simplistically, obesity results from an imbalance of caloric intake and energy expenditure. Even incremental but sustained caloric excess results in excess adiposity. Individual adiposity is the result of a complex interplay among geneti cally determined body habitus, appetite, nutritional intake, physical activity (PA), and energy expenditure. Environmental |
842 | factors deter mine levels of available food, preferences for types of foods, levels of PA, and preferences for types of activities. Food preferences play a role in the consumption of energy dense foods. Humans innately prefer sweet and salty foods and tend initially to reject bitter flavors, common to many vegetables. Repeated exposure to healthy foods promotes their acceptance and liking, especially in early life. This human characteristic to adapt to novel foods can be used to promote healthy food selection. Environmental Changes Over more than 4 decades, the food environment changed dramati cally related to urbanization and the food industry as fewer families routinely prepare meals. Foods prepared by a food industry have higher levels of calories, simple carbohydrates, and fat. The price of many foods has declined relative to the family budget. These changes, in combination with marketing pressure, have resulted in larger por tion sizes and increased snacking between meals. The increased con sumption of high carbohydrate beverages, including sodas, sport drinks, fruit punch, and juice, adds to these factors. According to the National Center for Health Statistics, fast food is consumed by 36.3 of 2 to 19 year old U.S. children each day and by two thirds of children every week. A typical fast food meal can con tain 2,000 kcal and 84 g of fat. Many children consume four servings of high carbohydrate beverages per day, resulting in an additional 560 kcal of low nutritional value. Sweetened beverages have been linked to increased risk for obesity. The dramatic increase in the use of high fructose corn syrup to sweeten beverages and prepared foods is another important environmental change, leading to availability of inexpensive calories. Since World War II, levels of PA in children and adults have declined. According to the 2017 National Health and Nutrition Examination Survey (NHANES) survey, 26.1 of adolescents met PA guidelines of 60 minutes of PA per day. Only 20 met guidelines for aerobic PA and muscle strengthening. The persistence of low levels of PA is related to many factors, including changes in the built environment, more reli ance on cars, lower levels of active transportation, safety issues, and increasingly sedentary lifestyles. Many sectors of society do not engage in PA during leisure time. For children, budgetary constraints and pressure for academic performance have led to less time devoted to physical education in schools. Perception of poor neighborhood safety also leads to lower levels of PA. Furthermore, screens (televisions, tab lets, smartphones, computers) offer compelling sedentary activities that do not burn calories. Sleep plays a role in the risk for obesity. Over the past 4 decades, children and adults have decreased the amount of time spent sleep ing. Reasons for these changes may relate to increased time at work, increased time watching television, and a generally faster pace of life. Chronic partial sleep loss can increase risk for weight gain and obesity, with the impact possibly greater in children than in adults. In stud ies of young, healthy, lean men, short |
843 | sleep duration was associated with decreased leptin levels and increased ghrelin levels, along with increased hunger and appetite. Sleep debt also results in decreased glu cose tolerance and insulin sensitivity related to alterations in gluco corticoids and sympathetic activity. Some effects of sleep debt might relate to orexins, peptides synthesized in the lateral hypothalamus that can increase feeding, arousal, sympathetic activity, and neuropeptide Y activity. Genetics Genetic determinants also have a role in individual susceptibility to obesity (Table 65.1). Findings from genome wide association studies explain a very small portion of interindividual variability in obesity. Chapter 65 Overweight and Obesity Sheila Gahagan Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 65 u Overweight and Obesity 439 2 543 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 24 22 20 18 16 14 12 kgm2 28 26 24 22 20 18 16 14 12 kgm2 30 32 34 BMI BMI AGE (YEARS) 13 15 17 19 21 23 25 27 13 15 17 19 21 23 25 27 29 31 33 35 95 90 75 50 25 10 5 85 2 to 20 years: Boys Body mass indexforage percentiles NAME RECORD SOURCE: Developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). http:www.cdc.govgrowthcharts Date Age Weight Stature BMI Comments Published May 30, 2000 (modified 101600). A Fig. 65.1 A, Body mass index (BMI) for age profiles for boys and men. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 440 Part V u Nutrition 2 to 20 years: Girls Body mass indexforage percentiles NAME RECORD SOURCE: Developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). http:www.cdc.govgrowthcharts 2 543 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 24 22 20 18 16 14 12 kgm2 28 26 24 22 20 18 16 14 12 kgm2 30 32 34 BMI BMI AGE (YEARS) 13 15 17 19 21 23 25 27 13 15 17 19 21 23 25 27 29 31 33 35 Date Age Weight Stature BMI Comments 95 90 85 75 50 10 25 5 Published May 30, 2000 (modified 101600). B Fig. 65.1, contd B, BMI for age profiles for girls and women. Developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion, 2000. See www.cdc.govgrowthcharts. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier |
844 | Inc. All rights reserved. Chapter 65 u Overweight and Obesity 441Table 65.1 Endocrine and Genetic Causes of Obesity DISEASE SYMPTOMS LABORATORY ENDOCRINE Cushing syndrome Central obesity, hirsutism, moon face, hypertension Dexamethasone suppression test GH deficiency Short stature, slow linear growth Evoked GH response, IGF 1 Hyperinsulinism Nesidioblastosis, pancreatic adenoma, hypoglycemia, Mauriac syndrome Insulin level Hypothyroidism Short stature, weight gain, fatigue, constipation, cold intolerance, myxedema TSH, FT4 Pseudohypoparathyroidism Short metacarpals, subcutaneous calcifications, dysmorphic facies, intellectual disability, short stature, hypocalcemia, hyperphosphatemia Urine cAMP after synthetic PTH infusion GENETICSYNDROMIC Albright hereditary osteodystrophy Short stature, skeletal defects, PTH resistance GNAS gene, in syndromic but also in isolated nonsyndromic obesity Alstrm syndrome Cognitive impairment, retinitis pigmentosa, insulin resistant diabetes mellitus, hearing loss, hypogonadism, cardiomyopathy ALMS1 gene Bardet Biedl syndrome Retinitis pigmentosa, renal abnormalities, polydactyly, syndactyly, hypogonadism 21 different genes BDNFTrkB deficiency Hyperactivity, impaired concentration, limited attention span, impaired short term memory and pain sensation BDNFTrkB gene Biemond syndrome Cognitive impairment, iris coloboma, hypogonadism, polydactyly Carpenter syndrome Polydactyly, syndactyly, cranial synostosis, intellectual disability RAB23 gene, located on chromosome 6 in humans Cohen syndrome Mid childhood onset obesity, short stature, prominent maxillary incisors, hypotonia, intellectual disability, microcephaly, decreased visual activity, neutropenia, joint laxity VPS13B gene (often called COH1) at locus 8q22 Deletion 9q34 Early onset obesity, intellectual disability, brachycephaly, synophrys, prognathism, behavior and sleep disturbances Deletion 9q34 Down syndrome Short stature, dysmorphic facies, intellectual disability Trisomy 21 ENPP1 gene Insulin resistance, childhood obesity Gene on chromosome 6q Fragile X Long facies, large, prominent ears, macroorchidism, autism FMR1; CGG repeat expansion 200 Frhlich syndrome Hypothalamic tumor FTO gene polymorphism, plus upstream regulatory and downstream activation genes Dysregulation of orexigenic hormone acyl ghrelin, poor postprandial appetite suppression Homozygous for FTO AA allele Kabuki syndrome Characteristic facies, intellectual disability, visceral and skeletal malformations KMT2D, MLL2, ALR, KABUK1 Kleefstra syndrome Intellectual disability, autism like behavior, hypotonia, cardiac defects EHMT1 KSR2 deficiency Mild hyperphagia and reduced basal metabolic rate, insulin resistance often with acanthosis nigricans, irregular menses, early development of type 2 diabetes mellitus KSR2 gene Leptin or leptin receptor gene deficiency Leptin variant (antagonistic) Early onset severe obesity, infertility (hypogonadotropic hypogonadism), hyperphagia, infections Hyperphagia, obesity; treatment with high dose recombinant leptin Leptin High leptin levels Melanocortin 4 receptor gene mutation Early onset severe obesity, increased linear growth, hyperphagia, hyperinsulinemia; most common known genetic cause of obesity; homozygous worse than heterozygous MC4R variant MEHMO Intellectual disability, epilepsy, hypogonadism, microcephaly, obesity Xp22.13 p21.1 MORM Intellectual disability, obesity, retinal dystrophy, micropenis INPP5E PCSK1 deficiency Small bowel enteropathy, hypoglycemia, hypothyroidism, ACTH deficiency, diabetes insipidus PCSK1 gene Prader Willi syndrome Neonatal hypotonia, slow infant growth, small hands and feet, intellectual disability, hypogonadism, hyperphagia leading to severe obesity, paradoxically elevated ghrelin Partial deletion of chromosome 15 or loss of paternally expressed genes: MKRN3, ZNF127, MAGEL2, SNRPN Proopiomelanocortin (POMC) deficiency Obesity, red hair, pale skin, adrenal insufficiency due to ACTH deficiency, hyperproinsulinemia, hyperphagia, cholestatic jaundice Loss of function of POMC gene Rapid onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD); ROHHADNET (with neuroendocrine tumor) Often confused |
845 | with congenital central hypoventilation syndrome (CCHS); presentation 1.5 yr with weight gain, hyperphagia, hypoventilation, cardiac arrest, central diabetes insipidus, hypothyroidism, GH deficiency, pain insensitivity, hypothermia, precocious puberty, and neural crest tumors Unknown genes May be a paraneoplastic disorder Rubinstein Taylor syndrome Short stature, visual impairment, scoliosis, dysmorphic facies CREBBP, EP300 SH2B1 deficiency Hyperphagia, disproportionate hyperinsulinemia, early speech and language delay that often resolves, behavioral problems including aggression SH2B1 gene SIM1 deficiency (Prader Willilike) Hyperphagia with autonomic dysfunction (characterized by low systolic blood pressure), speech and language delay, neurobehavioral abnormalities including autistic type behaviors SIM1gene Smith Magenis syndrome Intellectual disability, delayed speech, facial dysmorphology RAI1 TUB deficiency Retinal dystrophy, deafness TUB gene Turner syndrome Ovarian dysgenesis, lymphedema, web neck, short stature, cognitive impairment XO chromosome WAGRO Wilms tumor, aniridia, genitourinary anomalies, mental retardation, obesity BDNF ACTH, Adrenocorticotropic hormone; cAMP, cyclic adenosine monophosphate; FT4, free thyroxine; GH, growth hormone; IGF, insulin like growth factor; PTH, parathyroid hormone; TSH, thyroid stimulating hormone. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 442 Part V u Nutrition One important example, the FTO gene at 16q12, is associated with adi posity in childhood, probably explained by increased energy intake. Monogenic forms of obesity have also been identified, including mel anocortin 4 receptor (MC4R) deficiency, associated with early onset obesity and food seeking behavior. Pathogenic variants in MC4R are a common cause of monogenetic obesity but a rare (0.1) cause of obesity in general. Deficient activation of MC4R is also seen in patients with proopiomelanocortin (POMC) deficiency, a prohormone pre cursor of adrenocorticotropic hormone (ACTH) and melanocyte stimulating hormone (MSH), resulting in adrenal insufficiency, light skin, red hair, hyperphagia, and obesity. Leptin releases MSH, which can then activate MC4R, affecting appetite. In addition, evidence suggests that appetitive traits are moderately heritable. Some genes associated with appetite also relate to weight, and vice versa. In addition, there are genetic conditions associated with obesity, such as Prader Willi syndrome, which results from absence of paternally expressed imprinted genes in the 15q11.2 q13 region. Prader Willi syndrome is characterized by insatiable appetite and food seeking. In the era of genomic medicine, it will be increasingly pos sible to identify risks according to specific genes and consider gene environment interactions. Epigenetic environmental modification of genes may have a role in the development of obesity, especially during fetal and early life. Endocrine and Neural Physiology Monitoring of stored fuels and short term control of food intake (appetite and satiety) occurs through neuroendocrine feedback loops linking adipose tissue, the GI tract, and the CNS (Figs. 65.2 and 65.3). GI hormones, including cholecystokinin, glucagon like peptide 1, pep tide YY (PYY), and vagal neuronal feedback, promote satiety. Ghrelin stimulates appetite. Adipose tissue provides feedback regarding energy storage levels to the brain through hormonal release of adiponectin and leptin. These hormones act on the arcuate nucleus in the hypothalamus |
846 | and on the solitary tract nucleus in the brainstem and in turn activate distinct neuronal networks. Adipocytes secrete adiponectin into the blood, with reduced levels in response to obesity and increased levels in response to fasting. Reduced adiponectin levels are associated with lower insulin sensitivity and adverse CV outcomes. Leptin is directly involved in satiety; low leptin levels stimulate food intake, and high leptin levels inhibit hunger in animal models and in healthy human volunteers. However, the negative feedback loop from leptin to appetite may be more adapted to preventing starvation than excess intake. Numerous neuropeptides in the brain, including PYY agouti related peptide, and orexin, appear to affect appetite stimulation, whereas melanocortins and melanocortinstimulating hormone are involved in satiety (see Fig. 65.3). The neuroendocrine control of appetite and weight involves a negative feedback system, balanced between short term control of appetite and long term control of adiposity (including leptin). PYY reduces food intake via the vagal brainstem hypothalamic pathway. Developmental changes in PYY are evident, as infants have higher PYY levels than school aged children and adults. Obese chil dren have lower fasting levels of PYY than adults. Weight loss may restore PYY levels in children, even though this does not happen in adults. In addition, patients homozygous for the FTO obesity risk allele demonstrate poor regulation of the orexigenic hormone acyl ghrelin and have poor postprandial appetite suppression. COMORBIDITIES Complications of pediatric obesity occur during childhood and adoles cence and persist into adulthood. An important reason to prevent and treat pediatric obesity is the increased risk for morbidity and mortality later in life. Males who are overweight during adolescence are twice as likely to die from CV disease as those who have normal weight. More immediate comorbidities include type 2 diabetes, hypertension, hyper lipidemia, and nonalcoholic fatty liver disease (NAFLD) (Table 65.2). Insulin resistance increases with increasing adiposity and indepen dently affects lipid metabolism and CV health. Metabolic syndrome (central obesity, hypertension, glucose intolerance, and hyperlipid emia) increases the risk for CV morbidity and mortality. NAFLD has been reported in 34 of patients treated in a pediatric obesity clinic. NAFLD is the most common chronic liver disease in U.S. children and adolescents. It can present with advanced fibrosis or nonalcoholic ste atohepatitis and may result in cirrhosis and hepatocellular carcinoma. Insulin resistance is often associated. NAFLD is also independently associated with increased risk of CV disease. Obesity may also be associated with chronic inflammation. Adipo nectin, a peptide with antiinflammatory properties, occurs in reduced levels in obese patients compared with insulin sensitive, lean persons. Low adiponectin levels correlate with elevated levels of free fatty acids and plasma triglycerides in addition to a high BMI, and high adiponec tin levels correlate with peripheral insulin sensitivity. Adipocytes secrete peptides and cytokines into the circulation, and proinflammatory pep tides such interleukin (IL) 6 and tumor necrosis factor (TNF) occur in higher levels in obese patients. Specifically, IL 6 stimulates production of CRP in the liver. CRP is a marker of inflammation |
847 | and might link obesity, coronary disease, and subclinical inflammation. Some complications of obesity are mechanical, including obstructive sleep apnea and orthopedic complications. Orthopedic complications include Blount disease and slipped femoral capital epiphysis (see Chap ters 718 and 719.4). Mental health problems can coexist with obesity, with the possibil ity of bidirectional effects. These associations are modified by gender, ethnicity, and socioeconomic status. Self esteem may be lower in obese adolescent females than in nonobese peers. Some studies have found an association between obesity and adolescent depression. There is considerable interest in the co occurrence of eating disorders and obe sity. Obese youth are also at risk for bullying. IDENTIFICATION Overweight and obese children are often identified as part of routine medical care. The child and family may be unaware that the child has increased adiposity. They may be unhappy with the medical provider for raising this issue and may respond with denial or apparent lack of concern. It is often necessary to begin by helping the family understand the importance of healthy weight for current and future health. Forging a good therapeutic relationship is important because obesity interven tion requires a chronic disease management approach. Intervention and successful resolution of this problem require considerable effort by the family and the child over an extended period in order to change eating and activity behaviors. EVALUATION The evaluation of the overweight or obese child begins with exami nation of the growth chart for weight, height, and BMI trajectories; consideration of possible medical causes of obesity; and detailed explo ration of family eating, nutritional, and activity patterns. A complete pediatric history is used to uncover comorbid disorders. The family history focuses on the adiposity of other family members and the fam ily history of obesity associated disorders. The physical examination adds data that can lead to important diagnoses. Laboratory testing is guided by the need to identify comorbidities. Examination of the growth chart reveals the severity, duration, and timing of obesity onset. Children who are overweight (BMI in 85th 95th percentile) are less likely to have developed comorbid conditions than those who are obese (BMI 95th percentile). Those with a BMI 99th percentile are most likely to have coexisting medical problems. Once obesity severity is determined, the BMI trajectory is examined to elucidate when the child became obese. Several periods during child hood are considered sensitive periods, or times of increased risk for developing obesity, including infancy, adiposity rebound (when body fat is lowest at approximately age 5.5 years), and adolescence. An abrupt change in BMI might signal the onset of a medical problem or a period of family or personal stress for the child. Examination of the weight trajectory can further reveal how the problem developed. A young child might exhibit high weight and high height because lin ear growth can increase early in childhood if a child consumes excess energy. At some point the weight percentile exceeds the height percen tile, and the childs BMI climbs into the obese range. Another |
848 | example Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 65 u Overweight and Obesity 443 Fig. 65.2 Regulation of energy homeo stasis by the brain gut adipose axis. CCK, Cholecystokinin; GLP 1, glucagon like peptide 1; PYY, peptide YY. (From Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinol ogy, 13th ed. Philadelphia: Elsevier; 2016, p. 1610.) Behavioral Outputs Autonomic Outputs Pituitary Fat Brainstem Liver Stomach Hypothalamus Metabolic Regulation Pancreas Muscle, Other Tissues Nutrients Autonomic Outputs Autonomic Outputs Autonomic Outputs Insulin Ghrelin PYY CCK GLP1 Bombesin Nutrients Endocrine Outputs Autonomic Afferents Leptin is a child whose weight rapidly increases when they reduce their activ ity level and consume more meals away from home. Examination of the height trajectory can reveal endocrine problems, which often occur with slowing of linear growth. Consideration of possible medical causes of obesity is essential, even though endocrine, syndromic, and monogenetic causes are rare (see Table 65.1). Growth hormone deficiency, hypothyroidism, and Cushing syndrome are examples of endocrine disorders that can lead to obesity. In general, these disorders manifest with slow linear growth. Because children who consume excessive amounts of calories tend to experi ence accelerated linear growth, short stature warrants further evalua tion. Genetic disorders associated with obesity may manifest extreme hyperphagia, or they can have coexisting dysmorphic features, cognitive impairment, vision and hearing abnormalities, or short stature. In some children with congenital disorders such as myelodysplasia or muscular dystrophy, lower levels of PA can lead to secondary obesity. Some medi cations, such as atypical antipsychotics, can cause excessive appetite and hyperphagia, resulting in obesity (Table 65.3). Rapid weight gain in a child or adolescent taking one of these medications might require its dis continuation. Poor linear growth and rapid changes in weight gain are indications for evaluation of possible medical causes. Exploration of family eating, nutritional, and activity patterns begins with a description of regular meal and snack times and family hab its for walking, bicycle riding, active recreation, and screen time (TV, computer, video games). It is useful to request a 24 hour dietary recall with special attention to intake of fruits, vegetables, and water, as well as high calorie foods and high carbohydrate beverages. When pos sible, evaluation by a nutritionist is extremely helpful. This information will form the basis for incremental changes in eating behavior, caloric intake, and PA during the intervention. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 444 Part V u Nutrition Satiety signals CCK Adiposity signals Leptin POMCAGRP POMCNTS AP DMV ARC ME PVNCEA LPB CNS RET BST LH Vagal afferent Fig. 65.3 Brain structures involved in energy homeostasis. Receipt of long term adipostatic signals and acute satiety signals by |
849 | neurons in arcu ate nucleus and brainstem, respectively. Pale blue boxes indicate nuclei containing proopiomelanocortin (POMC) neurons; tan boxes indicate nuclei containing melanocortin 4 receptor (MC4R) neurons that may serve to integrate adipostatic and satiety signals; and darker blue boxes show some circumventricular organs involved in energy homeostasis. Magenta arrows designate a subset of projections of POMC neurons; blue arrows show a subset of projections of agouti related peptide (AGRP) neurons. AP, Area postrema; ARC, arcuate nucleus; BST, bed nucleus of stria terminalis; CCK, cholecystokinin; CEA, central nucleus of amygdala; CNS, central nervous system; DMV, dorsal motor nucleus of vagus; LH, lateral hypothalamic area; LPB, lateral parabrachial nucleus; ME, median eminence; NTS, nucleus tractus solitarius; PVN, paraventricular nucleus of hypothalamus; RET, reticular formation. (Modified from Fan W, Ellacott KL, Halatchev IG, Takahashi K, Yu P, Cone RD. Cholecystokinin mediated suppression of feeding involves the brainstem melanocortin system. Nat Neurosci. 2004;74:335336.) Table 65.2 Obesity Associated Comorbidities DISEASE POSSIBLE SYMPTOMS LABORATORY CRITERIA CARDIOVASCULAR Dyslipidemia HDL 40, LDL 130, total cholesterol 200 mgdL Fasting total cholesterol, HDL, LDL, triglycerides Hypertension SBP 95 for sex, age, height Serial testing, urinalysis, electrolytes, blood urea nitrogen, creatinine ENDOCRINE Type 2 diabetes mellitus Acanthosis nigricans, polyuria, polydipsia Fasting blood glucose 110, hemoglobin A1c, insulin level, C peptide, oral glucose tolerance test Metabolic syndrome Central adiposity, insulin resistance, dyslipidemia, hypertension, glucose intolerance Fasting glucose, LDL and HDL cholesterol Polycystic ovary syndrome Irregular menses, hirsutism, acne, insulin resistance, hyperandrogenemia Pelvic ultrasound, free testosterone, LH, FSH GASTROINTESTINAL Gallbladder disease Abdominal pain, vomiting, jaundice Ultrasound Nonalcoholic fatty liver disease (NAFLD) Hepatomegaly, abdominal pain, dependent edema, transaminases Can progress to fibrosis, cirrhosis AST, ALT, ultrasound, CT, or MRI NEUROLOGIC Pseudotumor cerebri Headaches, vision changes, papilledema Cerebrospinal fluid opening pressure, CT, MRI Migraines Hemicrania, headaches None ORTHOPEDIC Blount disease (tibia vara) Severe bowing of tibia, knee pain, limp Knee radiographs Musculoskeletal problems Back pain, joint pain, frequent strains or sprains, limp, hip pain, groin pain, leg bowing Radiographs Slipped capital femoral epiphysis Hip pain, knee pain, limp, decreased mobility of hip Hip radiographs PSYCHOLOGIC Behavioral complications Anxiety, depression, low self esteem, disordered eating, signs of depression, worsening school performance, social isolation, problems with bullying or being bullied Child Behavior Checklist, Childrens Depression Inventory, Peds QL, Eating Disorder Inventory 2, subjective ratings of stress and depression, Behavior Assessment System for Children, Pediatric Symptom Checklist PULMONARY Asthma Shortness of breath, wheezing, coughing, exercise intolerance Pulmonary function tests, peak flow Obstructive sleep apnea Snoring, apnea, restless sleep, behavioral problems Polysomnography, hypoxia, electrolytes (respiratory acidosis with metabolic alkalosis) ALT, Alanine transaminase; AST, aspartate transaminase; CT, computed tomography; FSH, follicle stimulating hormone; HDL, high density lipoprotein; LDL, low density lipoprotein; LH, luteinizing hormone; MRI, magnetic resonance imaging; Peds QL, Pediatric Quality of Life Inventory; SBP, systolic blood pressure. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 65 u Overweight and Obesity |
850 | 445 Initial assessment of the overweight or obese child includes a com plete review of bodily systems, focusing on the possibility of comorbid conditions (see Table 65.2). Developmental delay and visual and hear ing impairment can be associated with genetic disorders. Difficulty sleeping, snoring, or daytime sleepiness suggests sleep apnea. Abdomi nal pain might suggest NAFLD. Symptoms of polyuria, nocturia, or polydipsia may be the result of type 2 diabetes. Hip or knee pain can be caused by secondary orthopedic problems, including Blount disease and slipped capital femoral epiphysis. Irregular menses may be associ ated with polycystic ovary syndrome. Acanthosis nigricans can suggest insulin resistance and type 2 diabetes (Fig. 65.4). The family history begins with identifying other obese family members. Parental obesity is an important risk for child obesity. If all family members are obese, focusing the intervention on the entire family is reasonable. The child may be at increased risk for develop ing type 2 diabetes if a family history exists. Identification of a family history of hypertension, CV disease, or metabolic syndrome indicates increased risk for developing these obesity associated conditions. If the clinician helps the family to understand that childhood obesity increases the risk for developing these chronic diseases, this educa tional intervention might serve as motivation to improve their nutri tion and PA. Physical examination should be thorough, focusing on possible comorbidities (see Table 65.2). Careful screening for hypertension using an appropriately sized blood pressure cuff is important. Sys tematic examination of the skin can reveal acanthosis nigricans, suggesting insulin resistance, or hirsutism, suggesting polycystic ovary syndrome. Tanner staging can reveal premature adrenarche secondary to advanced sexual maturation in overweight and obese females. Laboratory testing for fasting plasma glucose, triglycerides, low density lipoprotein and high density lipoprotein cholesterol, and liver function tests are recommended as part of the initial evaluation for newly identified pediatric obesity (Table 65.4). Overweight children (BMI 85th 95th percentile) who have a family history of diabetes mel litus or signs of insulin resistance should also be evaluated with a fast ing plasma glucose test. Other laboratory testing should be guided by history or physical examination findings. Figure 65.5 provides a rec ommended approach to categorization, evaluation, and treatment. INTERVENTION Evidence shows that some interventions result in modest but significant and sustained improvement in body mass. Based on behavior change theories (see Chapter 18), treatment includes specifying target behaviors, self monitoring, goal setting, stimulus control, and promotion of self efficacy and self management skills. Behavior changes associated with improving BMI include drinking lower quantities of sugar sweetened beverages, consuming higher quality diets, increasing exercise, decreas ing screen time, and self weighing. Most successful interventions have been family based and consider the childs developmental age. Parent only treatment may be as effective as parentchild treatment. Because obesity is multifactorial, not all children and adolescents will respond to the same approach. For example, loss of control eating, associated with weight gain and obesity, predicts poor outcome in response to family based treatment. Furthermore, clinical |
851 | treatment programs are expen sive and not widely available. Therefore interest has grown in novel approaches such as internet based treatments and guided self help. It is important to begin with clear recommendations about appro priate caloric intake for the obese child (Table 65.5). Working with a dietitian is essential. Meals should be based on fruits, vegetables, whole grains, lean meat, fish, and poultry. Prepared foods should be chosen for their nutritional value, with attention to calories and fat. Foods that provide excessive calories and low nutritional value should be reserved for infrequent treats. The World Health Organization recommends avoiding artificial sweeteners (aspartame, sucralose, stevia). Weight reduction diets in adults generally do not lead to sustained weight loss. Therefore the focus should be on changes that can be main tained for life. Attention to eating patterns is helpful. Families should be encouraged to plan family meals, including breakfast. It is almost impossible for a child to make changes in nutritional intake and eat ing patterns if other family members do not make the same changes. Table 65.3 Medications Associated with Obesity Prednisone and other glucocorticoids Thioridazine Olanzapine Clozapine Quetiapine Risperidone Lithium Amitriptyline and other tricyclic antidepressants Paroxetine Valproate Carbamazepine Gabapentin Cyproheptadine Propranolol and other blockers Fig. 65.4 Acanthosis nigricans. From Gahagan S. Child and adoles cent obesity. Curr Probl Pediatr Adolesc Health Care. 2004;34:643. Table 65.4 Normal Laboratory Values for Recommended Tests LABORATORY TEST NORMAL VALUE Glucose 110 mgdL Insulin 15 mUL Hemoglobin A1c 5.7 AST (age 2 8 yr) 58 UL AST (age 9 15 yr) 46 UL AST (age 15 18 yr) 35 UL ALT 35 UL Total cholesterol 170 mgdL LDL 110 mgdL HDL 45 mgdL Triglycerides (age 0 9 yr) 75 mgdL Triglycerides (age 10 19 yr) 90 mgdL AST, Aspartate transaminase; ALT, alanine transaminase; LDL, low density lipoprotein; HDL, high density lipoprotein. From Childrens Hospital of Wisconsin. The NEW (nutrition, exercise and weight management) kids program. http:www.chw.orgdisplaydisplayFile.asp?docid33672 filenameGroupsNEWKidsNewKidsReferral.PDF. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 446 Part V u Nutrition Dietary needs also change developmentally; adolescents require greatly increased calories during their growth spurts, and adults who lead inactive lives need fewer calories than active, growing children. Psychologic strategies are helpful. The traffic light diet groups foods into those that can be consumed without any limitations (green), in moderation (yellow), or reserved for infrequent treats (red) (Table 65.6). The concrete categories are very helpful to chil dren and families. This approach can be adapted to any ethnic group or regional cuisine. Motivational interviewing begins with assessing how ready the patient is to make important behavioral changes. The professional then engages the patient in developing a strategy to take the next step toward the ultimate goal of healthy nutritional intake. BMI 85th Percentile History and physical examination Abnormal Additional evaluations based on findings Attenuated growth velocity Endocrine evaluation Genetic |
852 | evaluation Hypothalamic obesity Is there developmental delay? Karyotype: DNA methylation studies Measure leptin, insulin, and proinsulin Yes Negative NegativeNegativePositive NegativePositive Positive Reevaluate pituitary function andor hormone therapy PraderWilli syndrome BardetBiedl syndrome Alstrom syndrome TUB deficiency Albright hereditary osteodystrophy BDNF, TrkB, SIM1 deficiency Leptinleptin receptor deficiency POMC deficiency MC4R deficiency SH2B1 deficiency KSR2 deficiency Is there evidence of retinal dystrophy, photophobia, or nystagmus? Congenital leptin deficiency PCSK1 deficiency Molecular genetic studies Data supporting use of these interventions are limited to pubertal individuals Consider pharmacotherapy andor surgery Maintain support for lifestyle changes and comorbidity treatment Continued weight gain Neuro developmental abnormalities or severe hyperphagia Reevaluate drug therapy choice Continued weight gain 6 months Weight loss stabilization Initiate lifestyle changes and specific treatment of comorbidity Initiate lifestyle changes CNS injury Antipsychotic drug use Evaluate for obesity comorbidities (Table 65.2) Normal Present Absent Fig. 65.5 Diagnostic and treatment algorithm for the evaluation of the overweight or obese child. Measure insulin and proinsulin in patients with clinical features of PCSK1 deficiency. BMI, Body mass index; CNS, central nervous system. (From Farooqi SOR, ORahilly S. Genetic obesity syndromes. In Grant S, ed. The Genetics of Obesity. New York: Springer; 2014, pp. 2332; originally adapted from August GP, Caprio S, Fennoy I, et al. Prevention and treatment of pediatric obesity: An Endocrine Society clinical practice guideline based on expert opinion. J Clin Endocrinol Metab. 2008;93:45764599.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 65 u Overweight and Obesity 447 This method allows the professional to take the role of a coach, helping the child and family reach their goals. Other behavioral approaches include family rules about where food may be consumed (e.g., not in the bedroom). Increasing PA without decreasing caloric intake is unlikely to result in weight loss. However, aerobic exercise training improves metabolic profiles in obese children and adolescents. Furthermore, it can increase aerobic fitness and decrease percent body fat even with out weight loss. Therefore increasing PA can decrease risk for CV disease, improve well being, and contribute to weight loss. Increased PA can be accomplished by walking to school, engaging in PA dur ing leisure time with family and friends, or enrolling in organized sports. Children are more likely to be active if their parents are active; family PA is recommended. When adults lose significant weight, they may regain that weight despite eating fewer calories. The body may adapt to weight loss by reducing the basal metabolic rate (BMR), thus requiring fewer calories. One approach to this phenomenon is to increase PA. Active pursuits can replace more sedentary activities. The American Academy of Pediatrics recommends that screen time be restricted to no more than 2 hoursday for children 2 years old and that children 2 years old not watch television. Screen time in general, and TV watching in particular, is often associated with eating and poorer |
853 | quality diets, as many highly caloric food products are marketed directly to children during child oriented television programs. Pediatric healthcare providers should assist families to develop goals to change nutritional intake and PA. They can also provide the child and family with needed information. The family should not expect immediate lowering of BMI percentile related to behavioral changes, but can instead count on a gradual decrease in the rate of BMI percen tile increase until it stabilizes, followed by a gradual decrease. Refer ral to multidisciplinary, comprehensive pediatric weight management programs is ideal for obese children whenever possible. Pharmacotherapy for weight loss in the pediatric population is understudied. Randomized controlled trials (RCTs) have evaluated many medications, including metformin, orlistat, sibutramine, and exenatide (Table 65.7). Available medications result in modest weight loss or BMI improvement, even when combined with behav ioral interventions. Various classes of drugs are of interest, includ ing those that decrease energy intake or act centrally as anorexiants, those that affect the availability of nutrients through intestinal or renal tubular reabsorption, and those that affect metabolism. One U.S. Food and Drug Administration (FDA)approved medication for obesity in children 16 years old is orlistat, which decreases absorption of fat, resulting in modest weight loss. Complications include flatulence, oily stools, and spotting. This agent offers little benefit to severely obese adolescents. Saxenda (liraglutide) and semaglutide are also FDA approved for chronic weight management among pediatric patients aged 12 and older who are obese. Both drugs are glucagonlike peptide1 recep tor agonists, are approved for children 12 years old, and have been effective in reducing weight. In addition, semaglutide improves adverse cardiometabolic features associated with obesity. Adverse reactions include headache, abdominal pain, emesis, and diarrhea. Longterm therapy may increase the risk of medullary thyroid car cinoma and pancreatitis. This class of medication has produced the most significant weight loss of drugtreated obesity. Because multiple redundant neural mechanisms act to protect body weight, promoting weight loss is extremely difficult. Thus there is considerable interest in combining therapies that simulta neously target multiple weight regulating pathways. One promising example is the combination of amylin analogs (decreases food intake and slows gastric emptying) with leptin, which has no anorexigenic effects when given alone. This combination requires injection and is in clinical trials in adults. Another FDA approved drug for adults is lorcaserin, a selective serotonin 2 receptor agonist. Some medica tions approved for the treatment of type 2 diabetes, such as other glucagon like peptide 1 (GLP 1) agonists and sodium glucose con transporter 2 (SGLT 2) inhibitors, are being evaluated for treatment of obesity in adults. Establishing long term safety and tolerability Table 65.5 Recommended Caloric Intake Designated by Age and Gender LIFE STAGE GROUP AGE (YR) RELATIVELY SEDENTARY LEVEL OF ACTIVITY (KCAL) MODERATE LEVEL OF ACTIVITY (KCAL) ACTIVE (KCAL) Child 2 3 1,000 1,000 1,400 1,000 1,400 Female 4 8 1,200 1,400 1,600 1,400 1,800 9 13 1,600 1,600 2,000 1,800 2,200 14 18 1,800 2,000 2,400 Male 4 8 1,400 1,400 |
854 | 1,600 1,600 2,000 9 13 1,800 1,800 2,200 2,000 2,600 14 18 2,200 2,400 2,800 2,800 3,200 Adapted from U.S. Department of Agriculture. Dietary guidelines for Americans, 2005. http:www.health.govDIETARYGUIDELINESdga2005documenthtmlchapter2.htm. Table 65.6 Traffic Light Diet Plan FEATURE GREEN LIGHT FOODS YELLOW LIGHT FOODS RED LIGHT FOODS Quality Low calorie, high fiber, low fat, nutrient dense Nutrient dense, but higher in calories and fat High in calories, sugar, and fat Types of food Fruits, vegetables Lean meats, dairy, starches, grains Fatty meats, sugar, sugar sweetened beverages, fried foods Quantity Unlimited Limited Infrequent or avoided Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 448 Part V u Nutrition Table 65.7 Medications for Weight Management with Mechanism of Action, Availability, and Dosing MEDICATION MECHANISM OF ACTION AVAILABLE FOR CHRONIC USE MEAN PERCENTAGE WEIGHT LOSS ADVANTAGES DISADVANTAGESUSA EU PLACEBO DRUG Phentermine, 15 30 mg PO Sympathomimetic For short term use No Not stated in label Not stated in label Inexpensive Side effect profile; no long term data Orlistat, 120 mg PO tid before meals Pancreatic lipase inhibitor Yes Yes 2.6 6.1 Not absorbed; long term data Modest weight loss; side effect profile Lorcaserin, 10 mg PO bid 5 HT2c serotonin agonist with little affinity for other serotonergic receptors Yes No 2.5 5.8 Mild side effects; long term data Expensive; modest weight loss Phentermine topiramate ER, 7.5 mg46 mg or 15 mg92 mg PO indicated as rescue (requires titration) Sympathomimetic anticonvulsant (GABA receptor modulation, carbonic anhydrase inhibition, glutamate antagonism) Yes No 1.2 7.8 (mid dose) 9.8 (full dose) Robust weight loss; long term data Expensive; teratogen Naltrexone SR bupropion SR, 32 mg360 mg PO (requires titration) Opioid receptor antagonist; dopamine and noradrenaline reuptake inhibitor Yes Yes 1.3 5.4 Reduces food craving; long term data Moderately expensive; side effect profile Liraglutide, 3.0 mg injection (requires titration) GLP 1 receptor agonist Yes Yes 3 7.4 (full dose) Side effect profile; long term data Expensive; injectable Semaglutide, 2.4 mg once weekly injection GLP1 receptor agonist Yes Yes 1 10 to 15 As above As above Information is from US product labels, except where noted. The data supporting these tables are derived from the prescribing information labeling approved by the US Food and Drug Administration. Data from randomized controlled trials lasting 52 wk. Assuming the average patient in the orlistat and placebo groups weighed 100 kg at baseline. ER, Extended release; GLP 1, glucagon like peptide 1; SR, sustained release; PO, orally; bid, twice daily; tid, 3 times daily. Adapted from Bray GA, Frhbeck G, Ryan DH, Wilding JPH. Management of obesity. Lancet. 2016;387:19471965, p. 1950. in children is a challenge because medications of interest have CNS effects or interfere with absorption of nutrients. Teratologic effects must be considered for use in adolescent females. Setmelanotide, which binds to and activates MC4R, is approved to treat proopi omelanocortin deficiency, leptic receptor deficiency, and proprotein subtilisinkexin |
855 | type 1 disorder. Hormone replacement therapy is available for patients with leptin deficiency and may become avail able for patients with POMC deficiency. In some cases, it is reasonable to refer adolescents for bariatric sur gery evaluation. The American Pediatric Surgical Association guidelines recommend that surgery be considered only in children with complete or near complete skeletal maturity, a BMI 40, and a medical complica tion resulting from obesity, after they have failed 6 months of a multidis ciplinary weight management program. Surgical approaches include the Roux en Y and the adjustable gastric band (Fig. 65.6). Endoscopically placed space occupying fluid or air filled gastric balloons(s) is approved for adults and may be a nonsurgical intervention. In obese adults, bar iatric surgery reduces the risk of developing type 2 diabetes mellitus. In obese adult patients with existing type 2 diabetes, bariatric surgery improves diabetic control. Nutritional complications of bariatric surgery include malabsorption and vitamin (A, B1, B2, B6, B12, D, E, K) and min eral (copper, iron) deficiencies that require supplementation. PREVENTION Prevention of child and adolescent obesity is essential for public health in the United States and most other countries (Tables 65.8 and 65.9). Efforts by pediatric providers can supplement national and community public health programs. The National Institutes of Health (NIH) and U.S. Centers for Disease Control and Prevention (CDC) recommend a variety of initiatives to combat the current obesogenic environment, including promotion of breastfeeding, access to fruits and vegetables, walkable communities, and 60 minutesday of activity for children. The U.S. Department of Agriculture (USDA) sponsors programs promot ing 5.5 cups of fruits and vegetables per day. Incentives for the food industry to promote consumption of healthier foods should be consid ered. Marketing of unhealthy foods to children is now being regulated. Changes in federal food programs are expected, including commod ity foods, the Women, Infant, and Children Supplemental Food Pro gram (WIC), and school lunch programs, to meet the needs of todays children. Pediatric prevention efforts begin with careful monitoring of weight and BMI percentiles at healthcare maintenance visits. Attention to changes in BMI percentiles can alert the pediatric provider to increas ing adiposity before the child becomes overweight or obese. All families should be counseled about healthy nutrition for their children, because the current prevalence of overweight and obesity in adults is 65. There fore approximately two thirds of all children can be considered at risk for becoming overweight or obese at some time in their lives. Those who have an obese parent are at increased risk. Prevention efforts begin with promotion of exclusive breastfeeding for 6 months and total breastfeeding for 12 months. Introduction of infant foods at 6 months should focus on cereals, fruits, and vegetables. Lean meats, poultry, and fish may be intro duced later in the first year of life. Parents should be specifically coun seled to avoid introducing highly sugared beverages and foods in the first Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on |
856 | April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 65 u Overweight and Obesity 449 year of life. Instead, they should expose their infants and young children to a rich variety of fruits, vegetables, grains, lean meats, poultry, and fish to facilitate acceptance of a diverse and healthy diet. Parenting matters, and authoritative parents are more likely to have children with a healthy weight than those who are authoritarian or permissive. Families who eat regularly scheduled meals together are less likely to have overweight or obese children. Child health professionals can address a childs nutri tional status and provide expertise in child growth and development. Child health professionals can also promote PA during regular healthcare maintenance visits. Parents who spend some of their lei sure time in PA promote healthy weight in their children. Beginning in infancy, parents should be cognizant of their childs developmental capability and need for PA. Because TV, computer, and video game time can replace health promoting PA, physicians should coun sel parents to limit screen time for their children. Snacking during TV watching should be discouraged. Parents can help their children to understand that television commercials intend to sell a product. Children can learn that their parents will help them by responsibly choosing healthy foods. Because obesity is determined by complex multifactorial condi tions, prevention will take efforts at multiple levels of social organi zation. Successful programs include EPODE (Ensemble Prvenons lObsit Des Enfants), a multilevel prevention strategy that began in France and has been adopted by more than 500 communities in 6 countries. Shape Up Somerville is a citywide campaign to increase daily PA and healthy eating in Somerville, Massachusetts, since 2002. The Lets Move campaign was championed by former First Lady Michelle Obama. Because community and environmental factors are related to pediatric obesity risk, changes in local environments, daycare centers, schools, and recreational settings can have a public health impact. Programs can empower families to adopt practices that promote healthy lifestyles for children and adolescents. The most successful programs are comprehensive and rely on four strat egies: political commitment to change, resources to support social RouxenY Gastric Bypass Vertical Banded Gastroplasty Biliopancreatic Diversion Laparoscopic Adjustable Gastric Banding Biliopancreatic Diversion with Duodenal Switch Vertical Sleeve Gastrectomy Ileal Interposition with Sleeve Gastrectomy Santoro III Fig. 65.6 Bariatric surgical procedures, including laparoscopic adjustable gastric banding, Roux en Y gastric bypass, and vertical sleeve gastrec tomy techniques. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 450 Part V u Nutrition Table 65.9 Anticipatory Guidance: Establishing Healthy Eating Habits in Children Do not punish a child during mealtimes with regard to eating. The emotional atmosphere of a meal is very important. Interactions during meals should be pleasant and happy. Do not use foods as rewards. Parents, siblings, and peers should model |
857 | healthy eating, tasting new foods, and eating a well balanced meal. Children should be exposed to a wide range of foods, tastes, and textures. New foods should be offered multiple times. Repeated exposure leads to acceptance and liking. Forcing a child to eat a certain food will decrease the childs preference for that food. Childrens wariness of new foods is normal and should be expected. Offering a variety of foods with low energy density helps children balance energy intake. Parents should control what foods are in the home. Restricting access to foods in the home will increase rather than decrease a childs desire for that food. Children tend to be more aware of satiety than adults, so allow children to respond to satiety and stop eating. Do not force children to clean their plate. Adapted from Benton D. Role of parents in the determination of food preferences of children and the development of obesity. Int J Obes Relat Metab Disord. 2004;28:858869. marketing and changes, support services, and evidence based prac tices. Community wide programs are important because neighbor hood environmental factors (e.g., poverty) have been associated with obesity in its residents. There is considerable interest in focusing these efforts early in the life cycle. Beginning obesity prevention during pregnancy and engaging health systems, early childhood programs, and community systems to support healthier life cycles is an approach with great promise. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 65.8 Proposed Suggestions for Preventing Obesity PREGNANCY Normalize body mass index (BMI) before pregnancy. Do not smoke. Maintain moderate exercise as tolerated. In women with gestational diabetes, provide meticulous glucose control. Monitor gestational weight gain within Institute of Medicine (IOM) recommendations. POSTPARTUM AND INFANCY Breastfeeding: exclusive for 4 6 mo; continue with other foods for 12 mo. Postpone introduction of baby foods to 4 6 mo and juices to 12 mo. FAMILIES Eat meals as a family in a fixed place and time. Do not skip meals, especially breakfast. Do not allow television during meals. Use small plates and keep serving dishes away from the table. Avoid unnecessary sweet or fatty foods and sugar sweetened drinks. Remove televisions from childrens bedrooms; restrict times for TV viewing and video games. Do not use food as a reward. SCHOOLS Eliminate candy and cookie sales as fundraisers. Review the contents of vending machines and replace with healthier choices; eliminate sodas. Avoid financial support for sports teams from beverage and food industries. Install water fountains and hydration stations. Educate teachers, especially physical education and science faculty, about basic nutrition and the benefits of physical activity (PA). Educate children from preschool through high school on appropriate diet and lifestyle. Mandate minimum standards for physical education, including 60 min of strenuous exercise 5 times weekly. Encourage the walking school bus: groups of children walking to school with adult supervision. COMMUNITIES Increase family friendly exercise and safe play facilities for children of all ages. Develop more mixed residential commercial developments for walkable and bicyclable communities. Discourage the use of |
858 | elevators and moving walkways. Provide information on how to shop and prepare healthier versions of culture specific foods. HEALTHCARE PROVIDERS Explain the biologic and genetic contributions to obesity. Give age appropriate expectations for body weight in children. Work toward classifying obesity as a disease to promote recognition, reimbursement for care, and willingness and ability to provide treatment. INDUSTRY Mandate age appropriate nutrition labeling for products aimed at children (e.g., red lightgreen light foods, with portion sizes). Encourage marketing of interactive video games in which children must exercise to play. Use celebrity advertising directed at children for healthful foods to promote breakfast and regular meals. Reduce portion size (drinks and meals). GOVERNMENT AND REGULATORY AGENCIES Classify childhood obesity as a legitimate disease. Find novel ways to fund healthy lifestyle programs (e.g., with revenues from food and drink taxes). Subsidize government sponsored programs to promote the consumption of fresh fruits and vegetables. Provide financial incentives to the industry to develop more healthful products and to educate the consumer on product content. Provide financial incentives to schools that initiate innovative PA and nutrition programs. Allow tax deductions for the cost of weight loss and exercise programs. Provide urban planners with funding to establish bicycle, jogging, and walking paths. Ban advertising of fast foods, non nutritious foods, and sugar sweetened beverages directed at preschool children, and restrict advertising to school aged children. Ban toys as gifts to children for purchasing fast foods. Adapted from Speiser PW, Rudolf MCJ, Anhalt H, et al. Consensus statement: Childhood obesity. J Clin Endocrinol Metab. 2005;90:18711887. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 66 u Vitamin A Deficiencies and Excess 451 OVERVIEW OF VITAMIN A Vitamin A is a fat soluble micronutrient that cannot be synthesized de novo by mammals; thus it is an obligatory dietary factor. The term vitamin A is generally used to refer to a group of compounds that possess the biologic activity of all trans retinol (Fig. 66.1). Vita min A is recognized as being essential for all vertebrates for normal vision, reproduction, cell and tissue differentiation, and immune system functions. Vitamin A plays critical roles in neonatal devel opment. It is required for normal embryonic development, hemato poiesis, and growth and differentiation of many types of cells. Vitamin A can be obtained from the diet from preformed vitamin A (retinyl esters, such as retinyl palmitate) primarily in foods of animal origin. Organ meats (especially liver and kidney) are very rich in vitamin A, whereas other meats, milk, and cheese contain moderate levels. Other sources of vitamin A include several provi tamin A carotenoids, which are found naturally in many fruits and vegetables, especially yellow orange vegetables (pumpkin, squash, sweet potato) and leafy green vegetables (chard, spinach, broccoli). One of the most abundant carotenoids is carotene. Several culti vars, or biofortified forms, of sweet potatoes have been |
859 | introduced to elevate carotene intake in areas of the world where vitamin A deficiency still is prevalent. carotene and oxygenated carotenoids, such as cryptoxanthin, found in oranges, also possess vitamin A activity, but at a lower bioactivity. In the body, these precursors are used for the synthesis of two essential metabolites of vitamin A. All trans retinoic acid is the form required for cell differentiation and regulation of gene transcription and is the most bioactive form of vitamin A; 11 cis retinal is the form required for vision as the light absorbing chromophore of the visual pigments rhodopsin and iodopsin. METABOLISM OF VITAMIN A Vitamin A compounds in foods must first be released through nor mal digestive processes. Retinyl esters must first be hydrolyzed in the intestinal lumen to liberate unesterified retinol for absorption across the mucosal barrier. Once in the enterocyte, most of the reti nol is reesterified, forming new retinyl esters for inclusion in chy lomicrons. Approximately 7090 of dietary preformed vitamin A is absorbed provided there is approximately 10 g of fat in the meal; otherwise, the absorption efficiency is lower. Chronic intestinal dis orders or lipid malabsorption can result in vitamin A deficiency. Provitamin A carotenoids are transported from the intestinal lumen into the enterocytes by specific transporters and then either incorporated intact into chylomicrons or cleaved to form retinal, a precursor for retinol; carotene becomes retinol through this process. The estimated efficiency of absorption of carotenoids is 2050, lower than for preformed vitamin A. Moreover, the effi ciency is reduced when the bodys vitamin A status is high, and because vitamin A status may vary, there is significant interindi vidual variability in absorption efficiency. The carotene cleavage enzyme carotene monooxygenase, present in the enterocyte and in other tissues at lower levels, exhibits certain single nucleotide polymorphisms (SNPs) that, at least in vitro, reduce the efficiency of conversion of carotene to retinol. Clinical studies suggest a similar effect in vivo. Once retinol is esterified in the enterocyte, retinyl ester is then packaged into nascent chylomicrons, which are secreted into the lymphatic vessels, enter the systemic circulation, and are then transported to and taken up by various tissues. When vitamin A status is adequate, in most mammals, including humans, the liver Chapter 66 Vitamin A Deficiencies and Excess Libo Tan and A. Catharine Ross A Retinol R CH2OH, retinol R CH2Ofatty acyl group, retinyl ester R COOH, retinoic acid Dietary forms: Preformed vitamin A Retinol Intestinal hydrolysis Intestinal cleavage Esterification and storage chylomicron transport, storage in liver, eyes (RPE), kidneys, testes, etc. Hydrolysis, mobilization Reduction Oxidation Oxidation Conjugation reactions Retinal RA Deactivation products Excretion RE Oxidized metabolites ?carotene and provitamin A carotenoids Absorption: Intracellular metabolism: R ?Carotene B Fig. 66.1 A, Vitamin A structures. B, Overview of vitamin A metabolism. RA, All trans retinoic acid; RE, retinyl ester; RPE, retinal pigment epithelium. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses |
860 | without permission. Copyright 2024. Elsevier Inc. All rights reserved. 452 Part V u Nutrition is the major site of chylomicron vitamin A uptake and storage, with potentially high levels of retinyl esters within hepatic stellate cells (HSCs). As vitamin A status deteriorates into the deficient range, vitamin A stores are mobilized from the HSCs, such that the released retinol can be taken up and used by extrahepatic tissues. Circulat ing retinol is bound to a specific transport protein, retinol binding protein (RBP), which in turn binds to the thyroid hormone trans port protein, transthyretin (TTR); this complex delivers plasma retinol (and the thyroid hormone) to a large number of vitamin A target tissues. The major physiologic mediator of retinol uptake by cells in many tissues is Stra6, a widely expressed multitransmem brane domain protein that functions as a cell surface receptor for retinol bound to RBP. Stra6 is not significantly expressed in the liver, but a homologous receptor may perform the similar function. Within target tissues, retinol is either esterified into retinyl esters for storage or oxidized into retinoic acid for function. In the eye, 11 cis retinal is formed and bound to the protein rhodopsin (rods) or iodopsin (cones), where it functions as a light sensing receptor. Inflammation Causing Low Plasma Retinol Inflammation is a cause of reduced levels of plasma retinol as a result of reduced synthesis of RBP and TTR. This condition may mimic a lack of vitamin A, but will not be corrected by supplemen tation. In U.S. adults, those with moderately elevated levels of CRP, indicative of mild inflammation, had lower average plasma retinol levels. The extent to which inflammation is a factor in low plasma retinol in children is uncertain but likely significant in acute infec tious diseases such as measles, and possibly in chronic inflamma tory conditions such as cystic fibrosis. FUNCTIONS OF VITAMIN A AND MECHANISMS OF ACTION Except for its role in vision, the pleiotropic actions of this micronu trient are mediated by all trans retinoic acid (RA), which is a ligand for specific nuclear transcription factors, retinoic acid receptor (RAR) and retinoid X receptor (RXR), that regulate the expres sion of several hundred genes. When an RAR is activated by RA, an RAR RXR complex is formed, which binds to and activates spe cific DNA sequences present in retinoid responsive genes, RAREs and RXREs. Genes can be either induced or repressed, depending on additional co activators or co repressors recruited to the RAR RXR complex. Retinoid regulated genes are involved in several fun damental biologic activities, including regulation of cell division, death, and differentiation. The term retinoids is now applied to both natural and synthetic compounds with vitamin A activity, although it is most often used in the context of vitamin A and RA acting at the gene level. Numerous synthetic retinoids have gained clinical acceptance in the treatment of skin disorders and certain cancers. During embryonic development, RA is among the most important signaling molecules that determine body patterning |
861 | (morphogenesis). Many physiologic processes are sensitive to a deficiency or excess of vitamin A or RA, including reproduction, growth, bone development, and the functions of the respiratory, gastrointestinal, hematopoietic, and immune systems. Vitamin A supplementation may be particu larly important in developing countries, where it reduces morbidity and mortality, presumably by enhancing immune function and host defense, from various infectious diseases, including measles (see Chap ter 293). Vitamin A plays a critical role in vision, mediated by 11 cis reti nal. The human retina contains two distinct photoreceptor systems: the rods, in which rhodopsin senses light of low intensity, and the cones, in which iodopsins detect different colors; 11 cis retinal is the prosthetic group on both these visual proteins. The mechanism of vitamin A action is similar for rods and cones, based on pho toisomerization of 11 cis to all trans retinal (change shape when exposed to light), which initiates signal transduction via the optic nerve to the brain, resulting in visual sensation. After isomeriza tion (also known as photobleaching), a series of reactions serves to regenerate the 11 cis retinal for resynthesis of rhodopsin and iodop sin, as is necessary for an efficient visual process. Accessory cells, including retinal pigment epithelium (RPE) cells and Mller cells, are involved in this recycling process. VITAMIN A DEFICIENCY If the growing child has a well balanced diet and obtains vitamin A from foods rich in vitamin A or provitamin A (Table 66.1), the risk of vitamin A deficiency is small. However, even subclinical vitamin A deficiency can have serious consequences. Deficiency states in developed countries are rare, except in some impoverished populations (see Chapter 62) or after mistakes in food preparation or with fad diets or restrictiveelimination diets, but are common in many developing countries and often associ ated with global malnutrition. In the clinical setting, vitamin defi ciencies can also occur as complications in children with various chronic disorders or diseases. Information obtained in the medi cal history related to dietary habits can be important in identifying the risk of such nutritional problems. Except for vitamin A, toxicity from excess intake of vitamins is rare. Table 66.1 summarizes the food sources, functions, and deficiency and excess symptoms of the vitamin. Vitamin A Status in Neonates Neonates begin life with low levels of vitamin A in plasma, liver, and extrahepatic tissues compared with those in adults. Normal plasma levels of retinol are 20 50 gdL in infants and increase gradually as children become older. Median serum retinol values are 1.19 molL in both males and females ages 4 8 years; 1.4 and 1.33 molL in males and females, respectively, ages 9 13; and 1.71 and 1.57 molL in males and females, ages 14 18 (for conversion, 1 molL 28.6 gdL). Values of 1.96 and 1.85 molL are found in 19 to 30 year old adult men and women, respectively. Figure 66.2 shows the distribution of serum retinol concentrations in U.S. chil dren. Few healthy children are severely vitamin A deficient, but |
862 | the 5th percentile of children 4 8 years and 9 13 years of age, respec tively, in the National Health and Examination Survey (NHANES) fell below 1.05 molL, which is interpreted as mild vitamin A deficiency. Retinol levels are even lower in neonates in developing countries, where vitamin A intakes may be low and vitamin A deficiency is a common nutritional problem. Lower vitamin A stores and plasma retinol concentrations are also seen in low birthweight infants and in preterm newborns, and poor vitamin A status (plasma retinol concentrations 0.35 molL) may contribute to the development of chronic lung disease, such as bronchopulmonary dysplasia (BPD; see Chapter 127). Clinical Manifestations of Vitamin A Deficiency The most obvious symptoms of vitamin A deficiency are associated with changes in epithelial cell morphology and functions. In the intestines, mucus secreting goblet cells are affected, and loss of an effective barrier against pathogens can cause diarrhea or impair ment of epithelial barrier function. Similarly, mucus secretion by the epithelium is essential in the respiratory tract for the disposal of inhaled pathogens and toxicants. Characteristic epithelial changes result from vitamin A deficiency, including proliferation of basal cells, hyperkeratosis, and formation of stratified cornified squa mous epithelium. Squamous metaplasia of the renal pelvis, ure ters, vaginal epithelium, and the pancreatic and salivary ducts can lead to increased infections in these areas. In the urinary bladder, Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 66 u Vitamin A Deficiencies and Excess 453 loss of epithelial integrity can result in pyuria and hematuria. In the skin, vitamin A deficiency manifests as dry, scaly, hyperkera totic patches, typically on the arms, legs, shoulders, and buttocks. The combination of defective epithelial barriers to infection, low immune response, and lowered response to inflammatory stress, all from insufficient vitamin A, can cause poor growth and serious health problems in children. The most characteristic and specific signs of vitamin A deficiency are eye lesions, but these may manifest rather late in the progression of vitamin A deficiency, develop insidiously, and rarely occur before age 2 years. An earlier symptom of vitamin A deficiency is delayed dark adaptation as a result of reduced resynthesis of rhodopsin; this may progress to night blindness. Photophobia is a common symptom. The RPE, one of the structural elements of the retina, undergoes keratinization. When the RPE degenerates, the rods and cones have no support and eventually break down, resulting in blindness. As vitamin A deficiency progresses, the corneal and conjunctival epithelial tissues of the eye become severely altered because of a lack of sufficient RA for normal epithelial cell differentiation. The cor nea protects the eye from the environment and is also important in light refraction. Stages in vitamin A deficiency include corneal kera tinization and opacity, susceptibility to infection, and formation of dry, scaly layers of cells (xerophthalmia) (Figs. 66.3 |
863 | and 66.4). The conjunctival membrane undergoes keratinization and may develop foamy appearing plaques (Bitt spots; Fig. 66.5). When lympho cytes infiltrate the cornea in later stages of infection, it degenerates irreversibly (keratomalacia and corneal ulceration), resulting in irreversible blindness. These eye lesions are primarily diseases of 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 S er um r et in ol , m ic ro m ol e lit er Age and sex groups 48 y M Male, 5th Male, 50th Male, 95th Female, 5th Female, 50th Female, 95th F 913 y 1418 y 1930 y 3150 y 5170 y 71 y M F M F M F M F M F M F Fig. 66.2 Distribution of serum retinol concentrations in U.S. children and adults by age and sex in the National Health and Nutrition Exami nation Survey (NHANES). Fig. 66.3 Advanced xerophthalmia with an opaque, dull cornea and some damage to the iris in a 1yrold boy. (From Oomen HAPC. Vitamin A deficiency, xerophthalmia and blindness. Nutr Rev. 1974;6:161166.) Table 66.1 Vitamin A Characteristics NAMES AND SYNONYMS CHARACTERISTICS BIOCHEMICAL ACTION EFFECTS OF DEFICIENCY EFFECTS OF EXCESS SOURCES Retinol (vitamin A1); 1 g retinol 3.3 IU vitamin A 1 RAE Provitamins A: the plant pigments , , and carotenes and cryptoxanthin have partial retinol activity: 12 g carotene, or 24 g other provitamin A carotenoids 1 g retinol Fat soluble; heat stable; destroyed by oxidation, drying Bile necessary for absorption Stored in liver Protected by vitamin E In vision, as retinal, for synthesis of the visual pigments rhodopsin and iodopsin In growth, reproduction, embryonic and fetal development, bone growth, immune and epithelial functions, via retinoic acid as a ligand for specific nuclear transcription factors, regulating genes involved in many fundamental cellular processes Nyctalopia Photophobia, xerophthalmia, Bitt spots, conjunctivitis, keratomalacia leading to blindness Faulty epiphyseal bone formation Defective tooth enamel Keratinization of mucous membranes and skin Stunted growth Impaired resistance to infection, anemia, reproductive failure, fetal abnormalities Anorexia, slow growth, drying and cracking of skin, enlargement of liver and spleen, swelling and pain of long bones, bone fragility, increased intracranial pressure, alopecia, carotenemia Fetal abnormalities Liver, fish liver oils Dairy products, except skim milk Egg yolk, fortified margarine, fortified skim milk Carotenoids from plants: green vegetables, yellow fruits, and vegetables RAE, Retinol activity equivalent. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 454 Part V u Nutrition the young and are a major cause of blindness in developing coun tries. Although rates of xerophthalmia have fallen, the number of affected children is still too high. Treatment with vitamin A, up to the stage of keratomalacia, is effective in rapidly repleting the indi vidual and saving vision. Other clinical signs of vitamin A deficiency include poor overall growth, diarrhea, susceptibility to infections, anemia, apathy, intellec tual impairment, and increased intracranial pressure, with wide sepa ration |
864 | of the cranial bones at the sutures. There may be vision problems as a consequence of bone overgrowth causing pressure on the optic nerve. Malnutrition, particularly protein deficiency, can cause vitamin A deficiency through impaired synthesis of retinol transport protein. In developing countries, subclinical or clinical zinc deficiency can increase the risk of vitamin A deficiency. There is also some evidence of marginal zinc intakes in U.S. children. Diagnosis Dark adaptation tests can be used to assess early stage vitamin A deficiency. Although Bitt spots develop relatively early, those related to active vitamin A deficiency are usually confined to preschool age children. Xerophthalmia is a very characteristic lesion of vitamin A deficiency. For detection of less severe defi ciency (marginal vitamin A status), methods include conjunctival impression cytology, relative dose response, and modified relative dose response tests. A diet history is useful in suggesting or ruling out low intake as a cause of symptoms. Marginal vitamin A sta tus is relatively prevalent among pregnant and lactating women in low resource (and therefore poor dietary intake) areas of the world. Although plasma retinol level is not a completely accurate indica tor of vitamin A status, various guidelines have been proposed for categorizing vitamin A status based on serum retinol. In children, plasma retinol 0.35 molL is considered very deficient, 0.35 0.7 molL deficient, 0.7 1.05 molL marginal, and 1.05 molL ade quate. It has long been thought that a liver vitamin A concentra tion 20 gg is needed to support a normal rate of secretion of retinol RBP into plasma, and therefore normal delivery of retinol to peripheral tissues. Epidemiology and Public Health Issues Vitamin A deficiency and xerophthalmia still occur through out much of the developing, income poor world and are linked to undernourishment and complicated by illness. Various public health programs to provide large doses of vitamin A periodically have been instituted. Vitamin A supplementation is considered part of the strategy of the World Health Organization (WHO) Millen nium Development Goals to reduce 5 year mortality. Neonatal supplementation may be most effective in populations with a high incidence of maternal vitamin A deficiency. Other strategies being tested include improving the content of carotene in staple foods through plant breeding (biofortification). Dietary Reference Intakes for the Healthy Population Table 66.2 summarizes the dietary reference intakes for infants and children. Dietary reference intake values include the estimated aver age requirement (EAR), which is the mean biologic requirement for the nutrient for the agesex group of interest; the recommended dietary allowance (RDA), which is set to cover the physiologic needs of 97 of the population (thus the needs of many people are more than met by consuming the RDA); and the upper level Table 66.2 Dietary Reference Intakes for Vitamin A in Children AGE RANGE RECOMMENDED DIETARY ALLOWANCE (RDA) UPPER LEVEL (UL) COMMENTS 0 6 mo 400 600 The recommended intake for infants is an adequate intake, based on the amount of vitamin A normally present in breast milk.7 12 mo 500 |
865 | 600 1 3 yr 300 600 The UL applies only to preformed vitamin A (retinol). 4 8 yr 400 900 9 13 yr 600 1,700 14 18 yr 900, male; 700, female 2,800 g retinol equivalents per day. Fig. 66.5 Bitt spots with hyperpigmentation seen in a 10moold Indonesian boy. (From Oomen HAPC. Vitamin A deficiency, xerophthal mia and blindness. Nutr Rev 1974;6:161166.) Fig. 66.4 Recovery from xerophthalmia, showing a permanent eye le sion. (From Bloch CE. Blindness and other disease arising from deficient nutrition lack of fat soluble A factor. Am J Dis Child. 1924;27:139.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 66 u Vitamin A Deficiencies and Excess 455 of normal (UL), an intake level above which risk of adverse effects may increase; the UL pertains only to chronic consumption of preformed vitamin A. The RDA is expressed as retinol activ ity equivalents (RAEs; 1 RAE 1 g all trans retinol; equivalents for provitamin A in foods 12 g carotene, 24 g carotene, or 24 g cryptoxanthin). From infancy to age 18 years, the RDA increases as a result of increased body size, becoming higher for males than for females during adolescence. During pregnancy the RDA is 750 770 g, and during lactation it increases to 1,200 1,300 g to ensure sufficient vitamin A content during breastfeeding. It is noteworthy that, especially for young children, the UL is only about two times higher than the RDA. This suggests that for children whose diet is good, care should be taken not to overuse dietary supple ments (vitamin mineral supplements) containing preformed vitamin A andor to avoid excessive consumption of foods that are very rich in vitamin A, such as liver. Vitamin A for Treatment of Deficiency A daily supplement of 1,500 g of vitamin A is sufficient for treat ing latent vitamin A deficiency, after which intake at the RDA level should be the goal. In children without overt signs of vitamin A deficiency but suspected low reserves of vitamin A, rates of morbid ity and mortality, as from viral infections such as measles, have been reduced by a weekly dose of vitamin A at the RDA level. More often, higher doses of 30 60 mg of retinol (100,000 200,000 IUchild) are given once or twice, under careful monitoring to avoid toxicity associated with excess vitamin A. Xerophthalmia is treated by giv ing 1,500 gkg body weight orally for 5 days, followed by intramus cular injection of 7,500 g of vitamin A in oil, until recovery. HYPERVITAMINOSIS A Chronic hypervitaminosis A results from excessive ingestion of preformed vitamin A (retinol or retinyl ester), generally for sev eral weeks or months. Hypervitaminosis A is most often caused by vitamin Acontaining supplements or food faddism, including high intakes of organ meats. Chronic daily intakes of 15,000 g and 6,000 g can be toxic |
866 | in adults and children, respectively. Because there is no antidote for hypervitaminosis A, and vitamin A is readily stored in liver and other tissues, it is most important to prevent tox icity. Symptoms may subside rapidly on withdrawal of the vitamin, but the rate of improvement depends on the amount of vitamin A stored in tissues. Extreme hypervitaminosis A is fatal. Signs of subacute or chronic toxicity can include headache; vomiting (early signs); anorexia; dry, itchy, desquamating skin; and seborrheic cuta neous lesions. With chronic hypervitaminosis A, one may observe fissuring at the corners of the mouth; alopecia and coarsening of the hair; bone abnormalities, including swelling and resorption; enlargement of the liver and spleen; diplopia; increased intracranial pressure; dryness of the mucous membranes; and desquamation of the palms and the soles of the feet. Radiographs may show hyper ostosis affecting several long bones, especially in the middle of the shafts (Fig. 66.6). Manifestations of hypervitaminosis A may also include nonspecific changes in affect, including severe headache, irritability, stupor, and limited motion. Serum levels of vitamin A are elevated, mostly in the form of retinyl esters carried in lipo proteins, which may result in tissue damage and release of liver enzymes into plasma. Hypercalcemia andor liver cirrhosis may be present. Hypervitaminosis A is distinct from cortical hyperostosis (see Chapter 741). In young children, signs of vitamin A toxicity include vomiting and bulging fontanels, neither of which is specific. Combined with anorexia, pruritus, and a lack of weight gain, vitamin A toxicity should be considered. Less common symptoms include diplopia, papilledema, A B Fig. 66.6 Hyperostosis of the ulna and tibia in 21 mo old infant, re sulting from vitamin A positioning. A, Long, wavy cortical hyperostosis of the ulna (arrow). B, Long, wavy cortical hyperostosis of the right tibia (arrow), with a striking absence of metaphyseal changes. (From Caffey J. Pediatric X Ray Diagnosis, 5th ed. Chicago: Year Book;1967: 994.) cranial nerve palsies, and other symptoms suggesting pseudotumor cerebri. If high levels of vitamin A or synthetic retinoids are taken early in pregnancy, severe congenital malformations may occur in the fetus. Teratogenicity has been associated with therapeutic doses (0.5 1.5 mgkg) of oral 13 cis retinoic acid (e.g., Accutane), gen erally taken for the treatment of acne or cancer, during the first trimester of pregnancy. A high incidence (20) of spontaneous abortions and birth defects, including characteristic craniofacial abnormalities, has prompted the U.S. Food and Drug Administra tion (FDA) to enact more stringent prescription regulations for such drugs in women of childbearing age to attempt to reduce these birth defects. Carotenoids, even in high doses, are not associated with toxic ity but can cause yellowing of the skin (carotenodermia), includ ing palms of the hands, and high levels in serum (carotenemia); this relatively benign state disappears slowly when carotene intake is reduced. Children with liver disease, diabetes mellitus, or hypo thyroidism are more susceptible. Food faddism, such as excessive consumption of carotene rich foods and juices, may be a cause |
867 | of carotenodermia. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 456 Part V u Nutrition Table 67.1 Water Soluble Vitamins NAMES AND SYNONYMS BIOCHEMICAL ACTION EFFECTS OF DEFICIENCY TREATMENT OF DEFICIENCY CAUSES OF DEFICIENCY DIETARY SOURCES DIETARY REFERENCE INTAKES BY AGE RDA EAR Thiamine (vitamin B1) Coenzyme in carbohydrate metabolism Nucleic acid synthesis Neurotransmitter synthesis Neurologic (dry beriberi): irritability, peripheral neuritis, muscle tenderness, ataxia Cardiac (wet beriberi): tachycardia, edema, cardiomegaly, cardiac failure 3 5 mg day PO thiamine for 6 wk Polished rice based diets Malabsorptive states Severe malnutrition Malignancies Alcoholism Meat, especially pork; fish; liver Rice (unmilled), wheat germ; enriched cereals; legumes 0 6 mo: 0.2 mgday 7 12 mo: 0.3 mg day 1 3 yr: 0.5 mgday 4 8 yr: 0.6 mgday 9 13 yr: 0.9 mgday 14 18 yr: Females: 1.0 mg day Males: 1.2 mgday 1 3 yr: 0.4 mgday 4 8 yr: 0.5 mgday 9 13 yr: 0.7 mgday 14 18 yr: Females: 0.9 mgday Males: 1.0 mgday Riboflavin (vitamin B2) Constituent of flavoprotein enzymes important in redox reactions: amino acid, fatty acid, and carbohydrate metabolism and cellular respiration Glossitis, photophobia, lacrimation, corneal vascularization, poor growth, cheilosis 3 10 mg day PO riboflavin Severe malnutrition Malabsorptive states Prolonged treatment with phenothiazines, probenecid, or OCPs Milk, milk products, eggs, fortified cereals, green vegetables 0 6 mo: 0.3 mgday 7 12 mo: 0.4 mg day 1 3 yr: 0.5 mgday 4 8 yr: 0.6 mgday 9 13 yr: 0.9 mgday 14 18 yr: Females: 1.0 mg day Males: 1.3 mgday 1 3 yr: 0.4 mgday 4 8 yr: 0.5 mgday 9 13 yr: 0.8 mgday 14 18 yr: Females: 0.9 mgday Males: 1.1 mgday Niacin (vitamin B3) Constituent of NAD and NADP, important in respiratory chain, fatty acid synthesis, cell differentiation, and DNA processing Pellagra manifesting as diarrhea, symmetric scaly dermatitis in sun exposed areas, and neurologic symptoms of disorientation and delirium 50 300 mg day PO niacin Predominantly maize based diets Anorexia nervosa Carcinoid syndrome Meat, fish, poultry Cereals, legumes, green vegetables 0 6 mo: 2 mgday 7 12 mo: 4 mgday 1 3 yr: 6 mgday 4 8 yr: 8 mgday 9 13 yr: 12 mgday 14 18 yr: Females: 14 mg day Males: 16 mgday 1 3 yr: 5 mg day 4 8 yr: 6 mg day 9 13 yr: 9 mgday 14 18 yr: Females: 11 mgday Males: 12 mgday Pyridoxine (vitamin B6) Constituent of coenzymes for amino acid and glycogen metabolism, heme synthesis, steroid action, neurotransmitter synthesis Irritability, convulsions, hypochromic anemia Failure to thrive Oxaluria 5 25 mg day PO for deficiency states 100 mg IM or IV for pyridoxine dependent seizures Prolonged treatment with INH, penicillamine, OCPs Fortified ready to eat cereals, meat, fish, poultry, liver, bananas, rice, potatoes 0 6 mo: 0.1 mgday 7 12 mo: 0.3 |
868 | mg day 1 3 yr: 0.5 mgday 4 8 yr: 0.6 mgday 9 13 yr: 1.0 mgday 14 18 yr: Females: 1.2 mg day Males: 1.3 mgday 1 3 yr: 0.4 mgday 4 8 yr: 0.5 mgday 9 13 yr: 0.8 mgday 14 18 yr: Females: 1.0 mgday Males: 1.1 mgday Vitamin B complex includes a number of water soluble nutrients, including thiamine (vitamin B1), riboflavin (B2), niacin (B3), pyridox ine (B6), folate (B9), cobalamin (B12), biotin (B7), and pantothenic acid (B5). Choline and inositol are also considered parts of the B com plex and are important for normal body functions, but specific defi ciency syndromes have not been attributed to a lack of these factors in the diet (Table 67.1). B complex vitamins serve as coenzymes in many metabolic path ways that are functionally closely related. Consequently, a lack of one of the vitamins has the potential to interrupt a chain of chemi cal processes, including reactions that are dependent on other vita mins, and ultimately can produce diverse clinical manifestations. Because diets deficient in any one of the B complex vitamins are often poor sources of other B vitamins, manifestations of several vitamin B deficiencies usually can be observed in the same person. It is therefore a general practice in a patient who has evidence of defi ciency of a specific B vitamin to treat with the entire B complex group of vitamins. Chapter 67 Vitamin B Complex Deficiencies and Excess H.P.S. Sachdev and Dheeraj Shah Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 67 u Vitamin B Complex Deficiencies and Excess 457 Table 67.1 Water Soluble Vitaminscontd NAMES AND SYNONYMS BIOCHEMICAL ACTION EFFECTS OF DEFICIENCY TREATMENT OF DEFICIENCY CAUSES OF DEFICIENCY DIETARY SOURCES DIETARY REFERENCE INTAKES BY AGE RDA EAR Biotin (vitamin B7) Cofactor for carboxylases, important in gluconeogenesis, fatty acid and amino acid metabolism Scaly periorificial dermatitis, conjunctivitis, alopecia, lethargy, hypotonia, and withdrawn behavior 1 10 mgday PO biotin Consumption of raw eggs for prolonged periods Parenteral nutrition with infusates lacking biotin Valproate therapy Liver, organ meats, fruits 0 6 mo: 5 gday 7 12 mo: 6 gday 1 3 yr: 8 gday 4 8 yr: 12 gday 9 13 yr: 20 gday 14 18 yr: 25 gday Not established Pantothenic acid (vitamin B5) Component of coenzyme A and acyl carrier protein involved in fatty acid metabolism Experimentally produced deficiency in humans: irritability, fatigue, numbness, paresthesias (burning feet syndrome), muscle cramps Isolated deficiency extremely rare in humans Beef, organ meats, poultry, seafood, egg yolk Yeast, soybeans, mushrooms 0 6 mo: 1.7 mgday 7 12 mo: 1.8 mg day 1 3 yr: 2 mgday 4 8 yr: 3 mgday 9 13 yr: 4 mgday 14 18 yr: 5 mgday Not established Folic acid (vitamin B9) Coenzymes in amino acid and nucleotide metabolism as an acceptor and donor of 1 carbon |
869 | units Megaloblastic anemia Growth stunting, glossitis Neural tube defects in progeny 0.5 1 mgday PO folic acid Malnutrition Malabsorptive states Malignancies Hemolytic anemias Anticonvulsant therapy Enriched cereals, beans, leafy vegetables, citrus fruits, papaya 0 6 mo: 65 gday 7 12 mo: 80 gday 1 3 yr: 150 gday 4 8 yr: 200 gday 9 13 yr: 300 gday 14 18 yr: 400 g day 1 3 yr: 120 gday 4 8 yr: 160 gday 9 13 yr: 250 gday 14 18 yr: 330 gday Cobalamin (vitamin B12) As deoxyadenosylcobalamin, acts as cofactor for lipid and carbohydrate metabolism As methylcobalamin, important for conversion of homocysteine to methionine and folic acid metabolism Megaloblastic anemia, irritability, developmental delay, developmental regression, involuntary movements, hyperpigmentation 500 1,000 g IM or oral vitamin B12 Vegan diets Malabsorptive states Crohn disease Intrinsic factor deficiency (pernicious anemia) Organ meats, seafood, poultry, egg yolk, milk, fortified ready to eat cereals 0 6 mo: 0.4 gday 7 12 mo: 0.5 g day 1 3 yr: 0.9 gday 4 8 yr: 1.2 gday 9 13 yr: 1.8 gday 14 18 yr: 2.4 g day 1 3 yr: 0.7 g day 4 8 yr: 1.0 gday 9 13 yr: 1.5 gday 14 18 yr: 2.0 gday Ascorbic acid (vitamin C) Important for collagen synthesis, metabolism of cholesterol and neurotransmitters Antioxidant functions and nonheme iron absorption Scurvy manifesting as irritability, tenderness and swelling of legs, bleeding gums, petechiae, ecchymoses, follicular hyperkeratosis, and poor wound healing 100 200 mg day PO ascorbic acid for up to 3 mo Predominantly milk based (nonhuman milk) diets Severe malnutrition Citrus fruits and fruit juices, peppers, berries, melons, tomatoes, cauliflower, leafy green vegetables 0 6 mo: 40 mgday 7 12 mo: 50 mg day 1 3 yr: 15 mgday 4 8 yr: 25 mgday 9 13 yr: 45 mgday 14 18 yr: Females: 65 mg day Males: 75 mgday 1 3 yr: 13 mg day 4 8 yr: 22 mgday 9 13 yr: 39 mgday 14 18 yr: Females: 56 mgday Males: 63 mgday For healthy breastfed infants, the values represent adequate intakes (AI), that is, the mean intake of apparently normal infants. For biotin and pantothenic acid also, the values represent AI, as the RDA has not been established. Values have not been established for infants (0 12 mo). PO, Orally; IM, intramuscularly; IV, intravenously; INH, isoniazid; NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; OCP, oral contraceptive pill; RDA, recommended dietary allowance (average daily nutrient intake level estimated to meet the requirements of nearly all the healthy individuals); EAR, estimated average requirement (average daily nutrient intake level estimated to meet the requirements of 50 of the healthy individuals). From The National Academies Press. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (https:www .nap.educatalog6015dietary reference intakes for thiamin riboflavin niacin vitamin b6 folate vitamin b12 pantothenic acid biotin and choline) and Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (https:www.nap.educatalog9810dietary reference intakes for vitamin |
870 | c vitamin e selenium and carotenoids) 67.1 Thiamine (Vitamin B1) H.P.S. Sachdev and Dheeraj Shah Thiamine diphosphate, the active form of thiamine, serves as a cofac tor for several enzymes involved in carbohydrate catabolism such as pyruvate dehydrogenase, transketolase, and ketoglutarate. These enzymes also play a role in the hexose monophosphate shunt that generates nicotinamide adenine dinucleotide phosphate (NADP) and pentose for nucleic acid synthesis. Thiamine is also required for the synthesis of acetylcholine (ACh) and aminobutyric acid (GABA), which have important roles in nerve conduction. Thia mine is absorbed efficiently in the gastrointestinal (GI) tract and Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 458 Part V u Nutrition may be deficient in persons with GI or liver disease. The require ment of thiamine is increased when carbohydrates are taken in large amounts and during periods of increased metabolism, such as fever, muscular activity, hyperthyroidism, pregnancy, and lactation. Alco hol affects various aspects of thiamine transport and uptake, con tributing to the deficiency in alcoholics. Pork (especially lean), fish, and poultry are good dietary sources of thiamine. Main sources of thiamine for vegetarians are rice, oat, wheat, and legumes. Most ready to eat breakfast cereals are enriched with thiamine. Thiamine is water soluble and heat labile; most of the vitamin is lost when the rice is repeatedly washed and the cooking water is discarded. The breast milk of a well nourished mother provides adequate thiamine; breastfed infants of thiamine deficient mothers are at risk for deficiency. Thiamine antagonists (coffee, tea, carbonated caffeinated beverages) and thiaminases (fermented fish) may contribute to thiamine deficiency. Most infants and older children consuming a balanced diet obtain an adequate intake of thiamine from food and do not require supplements. THIAMINE DEFICIENCY Deficiency of thiamine is associated with severely malnourished states, including malignancy and after surgery. The disorder (or spectrum of disorders) is classically associated with a diet consisting largely of polished rice (oriental beriberi); it can also arise if highly refined wheat flour forms a major part of the diet, in persons with alcoholic use disorder, and in food faddists (occidental beriberi). Thi amine deficiency has often been reported from inhabitants of refugee camps consuming the polished ricebased monotonous diets and in breastfed infants of mothers on a predominantly polished ricebased diet. Low thiamine concentrations are also noted during critical illnesses. Thiamine responsive megaloblastic anemia (TRMA) syn drome is a rare autosomal recessive disorder characterized by megaloblastic anemia, diabetes mellitus, and sensorineural hear ing loss, responding in varying degrees to thiamine treatment. The syndrome occurs because of pathologic variants of the SLC19A2 gene, encoding a thiamine transporter protein, leading to abnor mal thiamine transportation and cellular vitamin deficiency (Table 67.2). Another dependency state, biotin thiamineresponsive basal ganglia disease (BTBGD), results from pathologic variants of the SLC19A3 gene (see Table 67.2). It classically presents in chil dren with recurrent |
871 | episodes of subacute encephalopathy mani festing as lethargy, dystonia, rigidity, dysphagia, and convulsions and responds to combined treatment with biotin (5 10 mgkgday) and thiamine (up to 40 mgkgday). An infantile form manifesting with acidosis, lethargy, poor feeding, and infantile spasms is also described. Other genetic disorders are noted in Table 67.2. Thia mine and related vitamins may improve the outcome in children with Leigh encephalomyelopathy. Table 67.2 Genetic Pathogenic Variants Affecting Thiamine Metabolism DISEASE VARIANT PROTEIN AGE AT ONSET CLINICAL SYMPTOMS MANAGEMENT (DOSE) TRMARogers syndrome SLC19A2 THTR1 Birth to adolescence Megaloblastic anemia, diabetes mellitus, sensorineural deafness, optic atrophy, congenital heart defects, short stature Thiamine (50 200 mg day) Biotinthiamine responsive basal ganglia disease SLC19A3 THTR2 Birth to adolescence Episodic encephalopathy associated with febrile illness, seizures, external ophthalmoplegia, dysphagia, gait ataxia, bilateral lesions of the basal ganglia Biotin (5 10 mgkgday), thiamine (up to 40 mg kgday) Amish lethal microcephaly THMD3 SLC25A19 Mitochondrial TPP carrier Birth Episodic encephalopathy associated with lactic acidosis and alpha ketoglutaric aciduria, microcephaly, delayed psychomotor development, seizures, increased urinary lactate Phenobarbital (for seizures) and physical therapy High fat diet Thiamine metabolism dysfunction syndrome 4THMD4 (progressive polyneuropathy type) SLC25A19 MTPC Adolescence Episodic encephalopathy associated with febrile illness, transient neurologic dysfunction, residual weakness, progressive axonal polyneuropathy, bilateral striatal degeneration High dose (600 mgday) thiamine may prevent acute episodes Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type) THMD5 TPK1 Thiamine phosphokinase 1 Early childhood Episodic encephalopathy (Leigh like) associated with high serum and CSF lactate with progressive neurologic and motor dysfunctions (gait disturbances, ataxia, dystonia, and spasticity, which, in some cases, may result in loss of ability to walk) triggered by infections Cognitive function usually preserved; some developmental delay; some patients may recover from some neurologic deficits; in others, the outcome is fatal. Oral thiamine (100 200 mgday) Modified from Dhir S, Tarasenko M, Napoli E, Giulivi C. Neurological, psychiatric, and biochemical aspects of thiamine deficiency in children and adults. Front Psychiatry. 2019;10:207, Table 1. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 67 u Vitamin B Complex Deficiencies and Excess 459 Table 67.3 Suggested Criteria for the Diagnosis of Inherited Thiamine Defects with Prominent Neurologic Involvement REQUIRED 1. Clinical criteria a. SLCI9A3: Acute or recurrent episodes of encephalopathy (decreased consciousness, irritability) with two or more of the following: (a) dystonia, (b) hypotonia, (c) bulbar dysfunction, (d) ataxia, and (e) seizures. Of note, 16 of patients may have an insidious onset of symptoms (psychomotor regression, clumsy or abnormal gait, and stiff limbs). b. SLC25AI9: Acute or recurrent episodes of encephalopathy with (a) progressive peripheral neuropathy or (b) severe congenital microcephaly with brain malformations. c. TPK1: Acute or recurrent episodes of encephalopathy, with two or more of the following: (a) dystonia, (b) hypotonia, (c) ataxia, (d) seizures, and (e) developmental delay. Of note, some patients may have a nonepisodic early onset global developmental |
872 | delay. 2. Biochemical criteria a. Normal total thiamine blood levels b. Low free thiamine in CSF andor fibroblasts (SLC19A3) c. Low TPP in blood, muscle, andor fibroblasts (TPK1) d. High excretion of alpha ketoglutaric acid in urine (common in TPK1 and SLC25A19, rare in SLC19A3) 3. Radiologic criteria a. MRI pattern compatible with Leigh syndrome (SLC19A3, SLC25A19, TPK1) or Wernicke encephalopathy (SLC19A3) i. SLC19A3: Symmetric T2W hyperintensity of caudate, putamen, corticosubcortical areas, andor ventromedial thalamus. No involvement of mammillary bodies. Diffuse T2W hyperintensity of brain white matter (single adult patient reported). ii. SLC25A19: Symmetric T2W hyperintensity in the caudate and putamen. iii. TPK1: Symmetric T2W hyperintensity in basal ganglia and cerebellum (dentate nuclei). 4. Therapeutic criteria a. Clinical improvement after thiamine supplementation SUPPORTIVE 1. Consanguinity 2. Trigger event (e.g., infection, vaccination, trauma, intense physical activity) 3. Absence of predisposing factors of beriberi or Wernicke encephalopathy 4. Absence of systemic features of mitochondrial disease (cardiomyopathy, arrhythmiaconduction defects, renal tubulopathy, or dysmorphic features) 5. Increased lactate in blood andor CSF or presence of a lactate peak on MRS 6. Normal OXPHOS and PDHc activity in muscle and fibroblast CSF, Cerebrospinal fluid; MRI, magnetic resonance imaging; OXPHOS, oxidative phosphorylation: PDHc, pyruvate dehydrogenase complex; MRS, magnetic resonance spectroscopy; TPP, thiamine pyrophosphate; T2W, T2 weighted. From Marc Grau A, Mart Snchez L, Baide Mairena H, Ortigoza Escobar JD, Prez Dueas B. Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies. J Inherit Metab Dis. 2019;42(4):581597, Table 3, p. 586. Clinical Manifestations Thiamine deficiency can develop within 2 3 months of a deficient intake. Early symptoms of thiamine deficiency are nonspecific, such as fatigue, apathy, irritability, depression, drowsiness, poor mental concentration, anorexia, nausea, and abdominal discomfort. As the condition progresses, more specific manifestations of beriberi develop, such as peripheral neuritis (manifesting as tingling, burn ing, and paresthesias of the toes and feet), decreased deep tendon reflexes, loss of vibration sense, tenderness and cramping of the leg muscles, heart failure, and psychologic disturbances. Patients can have ptosis of the eyelids and atrophy of the optic nerve. Hoarseness or aphonia caused by paralysis of the laryngeal nerve is a character istic sign. Muscle atrophy and tenderness of the nerve trunks are followed by ataxia, loss of coordination, and loss of deep sensation. Later signs include increased intracranial pressure, meningismus, and coma. The clinical picture of nutritional thiamine deficiency is usually divided into a dry (neuritic) type and a wet (cardiac) type. The disease is wet or dry depending on the amount of fluid that accumulates in the body because of cardiac and renal dysfunc tion, even though the exact cause for this edema is unknown. Many cases of thiamine deficiency show a mixture of both features and are more properly termed thiamine deficiency with cardiopathy and peripheral neuropathy. A fulminant form of beriberi (Shoshin beriberi) manifesting acutely with severe metabolic acidosis, hypo tension, and cardiogenic shock has also been described. The classic clinical triad of Wernicke encephalopathymen tal status changes, ocular |
873 | signs, and ataxiais rarely reported in infants and young children with severe deficiency secondary to malignancies or feeding of defective formula. An epidemic of life threatening thiamine deficiency was seen in infants fed a defective soy based formula that had undetectable thiamine levels. Manifes tations included emesis, lethargy, restlessness, ophthalmoplegia, abdominal distention, developmental delay, failure to thrive (mal nutrition), lactic acidosis, nystagmus, diarrhea, apnea, seizures, and auditory neuropathy. An acute presentation with tachycardia, aphoniahoarse cry, pulmonary hypertension, and severe metabolic acidosis responding to parenteral thiamine has been reported in infants of mothers consuming polished and frequently washed rice. Death from nutritional thiamine deficiency usually is secondary to cardiac involvement. The initial signs are cyanosis and dyspnea, but tachycardia, enlargement of the liver, loss of consciousness, and convulsions can develop rapidly. The heart, especially the right side, is enlarged. The electrocardiogram (ECG) shows an increased QT interval, inverted T waves, and low voltage. These changes, as well as the cardiomegaly, rapidly revert to normal with treatment, but without prompt treatment, cardiac failure can develop rapidly and result in death. In fatal cases of beriberi, lesions are principally located in the heart, peripheral nerves, subcutaneous tissue, and serous cavities. The heart is dilated, and fatty degeneration of the myocardium is common. Generalized edema or edema of the legs, serous effusions, and venous engorgement are often present. Degen eration of myelin and axon cylinders of the peripheral nerves, with Wallerian degeneration beginning in the distal locations, is also common, particularly in the lower extremities. Lesions in the brain include vascular dilation and hemorrhage. Diagnosis The diagnosis is often suspected based on clinical setting and com patible symptoms. A high index of suspicion in children present ing with unexplained cardiac failure may sometimes be lifesaving. Objective biochemical tests of thiamine status include measure ment of erythrocyte transketolase activity and the thiamine pyro phosphate effect. The biochemical diagnostic criteria of thiamine deficiency consist of low erythrocyte transketolase activity and high thiamine pyrophosphate effect (normal range: 014). Urinary excretion of thiamine or its metabolites (thiazole or pyrimidine) after an oral loading dose of thiamine may also be measured to help identify the deficiency state. A diagnostic approach to genetic thia mine deficiencies is noted in Table 67.3. MRI changes of nutritional and genetic thiamine deficiency in infants are characterized by bilateral symmetric hyperintensities of the basal ganglia and frontal lobe, in addition to the lesions in the mammillary bodies, periaque ductal region, and thalami described in adults (Fig. 67.1). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 460 Part V u Nutrition Prevention A maternal diet containing sufficient amounts of thiamine prevents thiamine deficiency in breastfed infants, and infant formulas mar keted in all developed countries provide recommended levels of intake. During complementary feeding, adequate thiamine intake can be achieved with a varied diet that includes meat and enriched or |
874 | whole grain cereals. When the staple cereal is polished rice, special efforts need to be made to include legumes andor nuts in the ration. Thiamine and other vitamins can be retained in rice by parboiling, a process of steaming the rice in the husk before mill ing. Improvement in cooking techniques, such as not discarding the water used for cooking, minimal washing of grains, and reduction of cooking time, helps to minimize the thiamine losses during the preparation of food. Thiamine supplementation should be ensured during total parenteral nutrition (TPN). Treatment In the absence of GI disturbances, oral administration of thiamine is effective. Children with cardiac failure, convulsions, or coma should be given 1050 mg of thiamine intramuscularly (IM) or intravenously (IV) daily for the first week. This treatment should then be followed by 3 5 mgday of thiamine orally (PO) for at least 6 weeks. The response is dramatic in infants and in those having predominantly cardiovascu lar manifestations, whereas the neurologic response is slow and often incomplete. Epilepsy, mental disability, and language and auditory problems of varying degrees have been reported in survivors of severe infantile thiamine deficiency. Patients with beriberi often have other B complex vitamin defi ciencies; therefore all other B complex vitamins should also be administered. Treatment of TRMA syndrome and other genetic pathogenic variants of thiamine metabolism require higher dos ages (Table 67.2). The anemia responds well to thiamine admin istration, and insulin for associated diabetes mellitus can also be discontinued in many patients with TRMA syndrome. Patients with BTBGD need lifelong supplementation. THIAMINE TOXICITY There are no reports of adverse effects from consumption of excess thiamine by ingestion of food or supplements. A few isolated cases of pruritus and anaphylaxis have been reported in patients after paren teral administration of vitamin B1. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 67.2 Riboflavin (Vitamin B2) H.P.S. Sachdev and Dheeraj Shah Riboflavin is part of the structure of the coenzymes flavin adenine dinu cleotide (FAD) and flavin mononucleotide, which participate in oxidation reduction (redox) reactions in numerous metabolic pathways and in energy production via the mitochondrial respiratory chain. Specific trans porter proteins direct riboflavin intracellularly for these functions. Ribo flavin is stable to heat but is destroyed by light. Milk and dairy products, eggs, organ meats, legumes, and mushrooms are rich dietary sources of riboflavin. Most commercial cereals, flours, and breads are enriched with riboflavin. Fig. 67.1 MRI patterns in pa tients with inherited thiamine de fects. SLC19A3, Axial and coronal T2 weighted images show bilat eral symmetric involvement of the putamen and thalamus along with patchy cortical and subcortical hy perintensities. SLC25A19, Axial T2 weighted and T1 weighted im ages show cystic necrosis of the caudate and putamen. TPK1, Axial and coronal T2 weighted spin echo images show involvement of the posterior putamen and dentate nuclei (gray arrow). (Modified from Ortigoza Escobar JD, Alfadhel M, Molero Luis M, et al. Thiamine deficiency in childhood with atten tion to genetic causes: Survival and outcome predictors. Ann |
875 | Neurol. 2017;823:317 330, Fig. 3, p. 322.) SLC19A3 SLC25A19 TPK1 Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 67 u Vitamin B Complex Deficiencies and Excess 461 RIBOFLAVIN DEFICIENCY The causes of riboflavin deficiency (ariboflavinosis) are mainly related to malnourished and malabsorptive states, including GI infections. Treatment with some drugs, such as probenecid, phenothiazine, doxo rubicin, or oral contraceptives (OCs), can also cause the deficiency. Phototherapy for hyperbilirubinemia can contribute to deficiency as the side chain of the vitamin is photochemically destroyed because it is involved in the photosensitized oxidation of bilirubin to more polar excretable compounds. Brown Vialetto Van Laere syndrome (BVVLS) and Fazio Londe syndrome are clinically overlapping conditions related to riboflavin transporter deficiency (RTD). Pathologic variants (autosomal reces sive) of the SLC52A1 (type 1), SLC52A2 (type 2), and SLC52A3 (type 3) genes, which encode intestinal human riboflavin transporter proteins, have been demonstrated in these disorders characterized by progressive neurologic deterioration, peripheral neuropathy, hypotonia, ataxia, sensorineural hearing loss (usually the first symptom), optic atrophy, pontobulbar palsy, and respiratory insufficiency. Age of onset is vari able; the later the onset, the milder the symptoms. Treatment with high doses (10 80 mgkgday) of riboflavin lead to clinical improvement in the majority of cases, especially if treated early in the disease course. Prophylaxis with riboflavin has been demonstrated to be effective in the reduction of frequency of headache in adult migraine; the evidence is insufficient in children and adolescents. Clinical Manifestations Clinical features of nutritional riboflavin deficiency include cheilosis, glos sitis, keratitis, conjunctivitis, photophobia, lacrimation, corneal vascu larization, and seborrheic dermatitis. Cheilosis begins with pallor at the angles of the mouth and progresses to thinning and maceration of the epi thelium, leading to fissures extending radially into the skin (Fig. 67.2). In glossitis the tongue becomes smooth, with loss of papillary structure (Fig. 67.3). Normochromic, normocytic anemia may also be seen because of the impaired erythropoiesis. A low riboflavin content of the maternal diet has been linked to congenital heart defects, but the evidence is weak. Diagnosis Most often, the diagnosis is based on the clinical features of angular cheilosis in a malnourished child, who responds promptly to riboflavin supplementa tion. A functional test of riboflavin status is done by measuring the activity of erythrocyte glutathione reductase (EGR), with and without the addition of FAD. An EGR activity coefficient (ratio of EGR activity with added FAD to EGR activity without FAD) of 1.4 is used as an indicator of deficiency. Urinary excretion of riboflavin 30 g24 hr also suggests low intake. Riboflavin transporter deficiency may be detected by genetic testing. Prevention Table 67.1 lists the recommended daily allowance of riboflavin for infants, children, and adolescents. Adequate consumption of milk, milk products, and eggs prevents riboflavin deficiency. Fortification of cereal products is helpful for those who follow vegan diets or who are consuming inadequate amounts |
876 | of milk products for other reasons. Treatment Treatment includes oral administration of 3 10 mgday of ribofla vin, often as an ingredient of a vitamin Bcomplex mix. The child should also be given a well balanced diet, including milk and milk products. RIBOFLAVIN TOXICITY No adverse effects associated with riboflavin intake from food or sup plements have been reported, and the upper safe limit for consumption has not been established. Although the photosensitizing property of vitamin B2 suggests some potential risks, limited absorption in high intake situations precludes such concerns. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 67.3 Niacin (Vitamin B3) H.P.S. Sachdev and Dheeraj Shah Niacin (nicotinamide or nicotinic acid) forms part of two cofactors, nico tinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleo tide phosphate (NADP), which are important in several biologic reactions, including the respiratory chain, fatty acid and steroid synthesis, cell differen tiation, and DNA processing. Niacin is rapidly absorbed from the stomach and the intestines and can also be synthesized from tryptophan in the diet. Major dietary sources of niacin are meat, fish, and poultry for nonvegetar ians and cereals, legumes, and green leafy vegetables for vegetarians. Enriched and fortified cereal products and legumes also are major contributors to niacin intake. Milk and eggs contain little niacin but are good sources of tryptophan, which can be converted to NAD (60 mg tryptophan 1 mg niacin). NIACIN DEFICIENCY Pellagra, the classic niacin deficiency disease, occurs chiefly in popula tions where corn (maize), a poor source of tryptophan, is the major food stuff. A severe dietary imbalance, such as in anorexia nervosa and in war or famine conditions, also can cause pellagra. Pellagra is rare outside the African subcontinent; however, consumption of a highly restrictive diet, such as in autism, has led to some resurgence in high income countries. Pellagra can also develop in conditions associated with disturbed tryp tophan metabolism, such as carcinoid syndrome and Hartnup disease. Fig. 67.3 Papillary atrophy, inflammation, and ulceration of the tongue as seen in riboflavin deficiency. (From Zappe HA, Nuss S, Becker K, et al. Riboflavin deficiency in Baltistan. http:www.rzuser.uni heidelb erg.de7Ecn6baltistaribofle.htm.) Fig. 67.2 Clinical photograph of a child showing angular cheilosis with ulceration and crusting in riboflavin deficiency. (Courtesy National Insti tute of Nutrition, Indian Council of Medical Research, Hyderabad, India.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 462 Part V u Nutrition Clinical Manifestations The early symptoms of pellagra are vague: anorexia, lassitude, weak ness, burning sensation, numbness, and dizziness. After a long period of deficiency, the classic triad of dermatitis, diarrhea, and dementia appears. Dermatitis, the most characteristic manifestation of pellagra, can develop suddenly or insidiously and may be initiated by irritants, including intense sunlight. The lesions first appear as symmetric areas of erythema on exposed surfaces, resembling sunburn, and might go unrecognized. The lesions are usually sharply demarcated from |
877 | the surrounding healthy skin, and their distribution can change frequently. The lesions on the hands and feet often have the appearance of a glove or stocking (Fig. 67.4A). Similar demarcations can also occur around the neck (Casal necklace) (see Fig. 67.4B). In some cases, vesicles and bullae develop (wet type). In others there may be suppuration beneath the scaly, crusted epidermis; in still others the swelling can disappear after a short time, followed by desquamation (Fig. 67.5). The healed parts of the skin might remain pigmented. The cutaneous lesions may be preceded by or accompanied by stomatitis, glossitis, vomiting, and diarrhea. Swelling and redness of the tip of the tongue and its lateral margins is often followed by intense redness, even ulceration, of the entire tongue and the papillae. Central nervous system symptoms include depression, disorientation, insomnia, and delirium. The classic symptoms of pellagra usually are not well developed in infants and young children, but anorexia, irritability, anxiety, and apathy are common. Young patients might also have sore tongues and lips and usually have dry scaly skin. Diarrhea and constipation can alternate, and anemia can occur. Children who have pellagra often have evidence of other nutritional deficiency diseases. Diagnosis Because of lack of a good functional test to evaluate niacin status, the diagnosis of deficiency is usually made from the physical signs of glossi tis, GI symptoms, and a symmetric dermatitis. Rapid clinical response to niacin is an important confirmatory test. A decrease in the concentration andor a change in the proportion of the niacin metabolites N1 methyl nicotinamide and 2 pyridone in the urine provide biochemical evidence of deficiency and can be seen before the appearance of overt signs of defi ciency. Histopathologic changes from the affected skin include dilated blood vessels without significant inflammatory infiltrates, ballooning of the keratinocytes, hyperkeratosis, and epidermal necrosis. Prevention Adequate intake of niacin is easily met by consumption of a diet that con sists of a variety of foods and includes meat, eggs, milk, and enriched or fortified cereal products. The dietary reference intake (DRI) is expressed in milligram niacin equivalents (NE) in which 1 mg NE 1 mg niacin or 60 mg tryptophan. The DRI is summarized in Table 67.1. A B Fig. 67.5 Clinical manifestations of niacin deficiency before (A) and after (B) therapy. (From Weinsier RL, Morgan SL. Fundamentals of Clini cal Nutrition. St Louis: Mosby; 1993:99.) Fig. 67.4 A, Symmetric, well demarcated, erythematous, eroded plaques with desquamation over hands and forearms. B, Brownish plaques with desquamation in the distribution of neck collar (Casal neck lace) because of pellagra in a child with autism on highly restrictive diet. (From Zaenglein A, Martin A, Carlson L, Williams KE. Pellagra secondary to selective eating in a child with autism. Pediatr Dermatol. 2020;37:698700.) A B Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 67 u Vitamin |
878 | B Complex Deficiencies and Excess 463 Treatment Children usually respond rapidly to treatment. A liberal and varied diet should be supplemented with 50 300 mgday of niacin; in severe cases or in patients with poor intestinal absorption, 100 mg may be given IV. The diet should also be supplemented with other vitamins, especially other B complex vitamins. Sun exposure should be avoided during the active phase of pellagra, and the skin lesions may be covered with soothing applications. Other coexisting nutrient deficiencies such as iron deficiency anemia should be treated. Even after successful treat ment, the diet should continue to be monitored to prevent recurrence. NIACIN TOXICITY No toxic effects are associated with the intake of naturally occurring nia cin in foods. Shortly after the ingestion of large doses of nicotinic acid taken as a supplement or a pharmacologic agent, a person often experi ences a burning, tingling, and itching sensation, as well as flushing on the face, arms, and chest. Large doses of niacin also can have nonspecific GI effects and can cause cholestatic jaundice or hepatotoxicity. Tolerable upper intake levels for children are 10 mgday for 1 3 years, 15 mgday for 4 8 years, 20 mgday for 9 13 years, and 30 mgday for 14 18 years. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 67.4 Vitamin B6 (Pyridoxine) H.P.S. Sachdev and Dheeraj Shah Vitamin B6 includes a group of closely related compounds: pyri doxine, pyridoxal, pyridoxamine, and their phosphorylated derivatives. Pyridoxal 5 phosphate (PLP) and, to a lesser extent, pyridoxamine phosphate function as coenzymes for many enzymes involved in amino acid metabolism, neurotransmitter synthesis, glycogen metabolism, and steroid action. If vitamin B6 is lacking, glycine metabolism can lead to oxaluria. The major excretory prod uct in the urine is 4 pyridoxic acid. The vitamin B6 content of human milk and infant formulas is ade quate. Good food sources of the vitamin include fortified ready to eat cereals, meat, fish, poultry, liver, bananas, rice, and certain vegetables. Large losses of the vitamin can occur during high temperature pro cessing of foods or milling of cereals, whereas parboiling of rice pre vents its loss. VITAMIN B6 DEFICIENCY Because of the importance of vitamin B6 in amino acid metabo lism, high protein intake can increase the requirement for the vita min; the recommended daily allowances are sufficient to cover the expected range of protein intake in the population. The risk of deficiency is increased in persons taking medications that inhibit the activity of vitamin B6 (e.g., isoniazid, penicillamine, cortico steroids, phenytoin, carbamazepine), in young women taking oral progesterone estrogen contraceptives, and in patients receiving maintenance dialysis. Clinical Manifestations The vitamin B6 deficiency symptoms seen in infants are listlessness, irritability, seizures, vomiting, and failure to thrive. Peripheral neu ritis is a feature of deficiency in adults but is not usually seen in chil dren. EEG abnormalities have been reported in infants and in young adults in controlled depletion studies. Skin lesions include cheilo sis, glossitis, and seborrheic dermatitis around the eyes, |
879 | nose, and mouth. Microcytic anemia can occur in infants but is not common. Oxaluria, oxalic acid bladder stones, hyperglycinemia, lymphopenia, decreased antibody formation, and infections also are associated with vitamin B6 deficiency. Several types of vitamin B6 dependence syndromes, presum ably resulting from errors in metabolism or transport of PLP or pyridoxine, respond to large doses of pyridoxine. These syndromes include pyridoxine dependent epilepsy, a vitamin B6responsive anemia, xanthurenic aciduria, cystathioninuria, and homocys tinuria. Pyridoxine dependent epilepsy involves pathologic vari ants in the ALDH7A1 gene causing deficiency of antiquitin, an enzyme involved in dehydrogenation of aminoadipic semialde hyde. Pathologic variants of the genes PROSC, which encodes a PLP binding protein, and PNPO encoding for the pyridoxamine 5 phosphate oxidase enzyme also cause epilepsy responsive to PLP or high doses of pyridoxine. Neonatal epileptic encephalopa thy and hypophosphatasia are associated with impaired import of PLP into the neuronal cells, and seizures occurring in these condi tions also respond to pyridoxine therapy. Diagnosis The activity of aspartate (glutamic oxaloacetic) transaminase (AST) and alanine (glutamic pyruvic) transaminase (ALT) is low in vitamin B6 deficiency; tests measuring the activity of these enzymes before and after the addition of PLP may be useful as indicators of vitamin B6 status. Abnormally high xanthurenic acid excretion after tryptophan ingestion also provides evidence of deficiency. Plasma PLP assays are being used more often, but factors such as inflammation, renal func tion, and hypoalbuminemia can influence the results. Ratios between substrate product pairs (e.g., PAr index, 3 hydroxykynureninexanth urenic acid ratio, oxoglutarateglutamate ratio) may attenuate such influence. Quantification of a large number of metabolites, using mass spectrometrybased metabolomics, are being evaluated as functional biomarkers of pyridoxine status. Vitamin B6 deficiency or dependence should be suspected in all infants with seizures. If more common causes of infantile seizures have been eliminated, 100 mg of pyridoxine can be injected, with EEG mon itoring if possible. If the seizure stops, vitamin B6 deficiency should be suspected. In older children, 100 mg of pyridoxine may be injected IM while the EEG is being recorded; a favorable response of the EEG sug gests pyridoxine deficiency. Prevention Deficiency is unlikely in children consuming diets that meet their energy needs and contain a variety of foods. Parboiling of rice pre vents the loss of vitamin B6 from the grains. The dietary reference intake for vitamin B6 is shown in Table 67.1. Infants whose moth ers have received large doses of pyridoxine during pregnancy are at increased risk for seizures from pyridoxine dependence, and supple ments during the first few weeks of life should be considered. Any child receiving a pyridoxine antagonist, such as isoniazid, should be carefully observed for neurologic manifestations; if these develop, vitamin B6 should be administered or the dose of the antagonist should be decreased. Treatment Intramuscular or intravenous administration of 100 mg of pyridoxine is used to treat convulsions caused by vitamin B6 deficiency. One dose should be sufficient if adequate dietary intake follows. For pyridoxine dependent children, daily doses of 2 |
880 | 10 mg IM or 10 100 mg PO may be necessary. VITAMIN B6 TOXICITY Adverse effects have not been associated with high intakes of vita min B6 from food sources. However, ataxia and sensory neuropathy have been reported with dosages above 200 mgday in adults taking vitamin B6 supplements for several months. Tolerable upper intake levels for children are 30 mgday for 1 3 years, 40 mgday for 4 8 years, 60 mgday for 9 13 years, and 80 mgday for 14 18 years. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 464 Part V u Nutrition 67.5 Biotin H.P.S. Sachdev and Dheeraj Shah Biotin (vitamin B7 or vitamin H) functions as a cofactor for enzymes involved in carboxylation reactions within and outside mitochon dria. These biotin dependent carboxylases catalyze key reactions in gluconeogenesis, fatty acid metabolism, and amino acid catabolism. There is limited information on the biotin content of foods; biotin is believed to be widely distributed, making a deficiency unlikely. Avidin found in raw egg whites acts as a biotin antagonist. Signs of biotin deficiency have been demonstrated in persons who con sume large amounts of raw egg whites over long periods. Deficiency also has been described in infants and children receiving enteral and parenteral nutrition formula that lacks biotin. Treatment with valproic acid may result in a low biotinidase activity andor biotin deficiency. The clinical findings of biotin deficiency include scaly periorifi cial dermatitis, conjunctivitis, thinning of hair, and alopecia (Fig. 67.6). Central nervous system (CNS) abnormalities seen with biotin deficiency are lethargy, hypotonia, seizures, ataxia, and withdrawn behavior. Biotin deficiency can be successfully treated using 1 10 mg of biotin orally daily. The dietary reference intake for biotin is shown in Table 67.1. No toxic effects have been reported with very high doses. Biotin responsive basal ganglia disease or biotin and thiamine responsive basal ganglia disease is a rare childhood neurologic dis order characterized by encephalopathy, seizures, extrapyramidal manifestations, altered signals in basal ganglia (bilateral involvement of caudate nuclei and putamen with sparing of globus pallidus) on MRI, and homozygous pathologic variation in the SLC19A3 gene (see Table 67.2). Chapter 105 describes conditions involving deficiencies in the enzymes holocarboxylase synthetase and biotinidase that respond to treatment with biotin. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 67.6 Folate H.P.S. Sachdev and Dheeraj Shah Folate exists in different chemical forms (Fig. 67.7). Folic acid (pteroyl glutamic acid) is the synthetic form used in fortified foods and supple ments. Naturally occurring folates in foods retain the core chemical structure of pteroylglutamic acid but vary in their state of reduction, the single carbon moiety they bear, or the length of the glutamate chain. These polyglutamates are broken down and reduced in the small intestine to dihydrofolates and tetrahydrofolates, which are involved as coenzymes in amino acid and |
881 | nucleotide metabolism as acceptors and donors of 1 carbon units. Folate is important for CNS development during embryogenesis. Rice and cereals are rich dietary sources of folate, especially if enriched. Beans, leafy vegetables, and fruits such as oranges and papaya are good sources as well. The vitamin is readily absorbed from the small intestine and is broken down to monoglutamate derivatives by mucosal polyglutamate hydrolases. A high affinity proton coupled folate transporter (PCFT) seems to be essential for absorption of folate in the intestine and in various cell types at low pH. The vitamin is also synthesized by colonic bacteria, and its half life is prolonged by enterohepatic recirculation. FOLATE DEFICIENCY Because of folates role in protein, DNA, and RNA synthesis, the risk of deficiency is increased during periods of rapid growth or increased cellular metabolism. Folate deficiency can result from poor nutrient content in the diet, inadequate absorption (celiac dis ease, inflammatory bowel disease), increased requirement (sickle cell anemia, psoriasis, malignancies, periods of rapid growth as in infancy and adolescence), or inadequate use (long term treatment with high dose nonsteroidal antiinflammatory drugs; anticonvul sants such as phenytoin and phenobarbital; methotrexate). Rare causes of deficiency are hereditary folate malabsorption, inborn errors of folate metabolism (methylene tetrahydrofolate reductase, methionine synthase reductase, and glutamate formiminotransfer ase deficiencies), and cerebral folate deficiency. A loss of function pathologic variant in the gene coding for PCFT is the molecular basis for hereditary folate malabsorption. A high affinity blocking autoantibody against the membrane bound folate receptor in the choroid plexus preventing its transport across the blood brain bar rier is the likely cause of infantile cerebral folate deficiency. Clinical Manifestations Folic acid deficiency results in megaloblastic anemia and hyperseg mentation of neutrophils. Nonhematologic manifestations include glossitis, listlessness, and growth retardation not related to anemia. An association exists between low maternal folic acid status and neu ral tube defects, primarily spina bifida and anencephaly, and the role of periconceptional folic acid in their prevention is well established (see Chapter 503.1). Hereditary folate malabsorption manifests at 1 3 months of age with recurrent or chronic diarrhea, failure to thrive (malnutrition), oral ulcerations, neurologic deterioration, megaloblastic anemia, and oppor tunistic infections. Cerebral folate deficiency manifests at 4 6 months of age with irritability, microcephaly, developmental delay, cerebellar ataxia, pyramidal tract signs, choreoathetosis, ballismus, seizures, and blindness as a result of optic atrophy. 5 Methyltetrahydrofolate levels are normal in serum and red blood cells (RBCs) but greatly depressed in the cerebrospinal fluid (CSF). Diagnosis The diagnosis of folic acid deficiency anemia is made in the pres ence of macrocytosis along with low folate levels in serum or RBCs. Normal serum folic acid levels are 5 20 ngmL; with deficiency, levels are 3 ngmL. Levels of RBC folate are a better indicator of chronic deficiency. The normal RBC folate level is 150 600 ngmL of packed cells. The bone marrow is hypercellular because of erythroid hyper plasia, and megaloblastic changes are prominent. Large, abnormal neutrophilic forms (giant metamyelocytes) with cytoplasmic vacu |
882 | olation also are seen. Cerebral folate deficiency is associated with low levels of 5 methyltetrahydrofolate in CSF and normal folate levels in the plasma A B Fig. 67.6 A, Scalp rash in an infant with biotin deficiency before treat ment with biotin. B, After 3 weeks of biotin treatment. (From Ito T, Ni shie W, Fujita Y, et al. Infantile eczema caused by formula milk. Lancet. 2013;381:1958.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 67 u Vitamin B Complex Deficiencies and Excess 465 and RBCs. Pathologic variants of the PCFT gene are demonstrated in hereditary folate malabsorption. Prevention Breastfed infants have better folate nutrition than nonbreastfed infants throughout infancy. Consumption of folate rich foods and food fortification programs are important to ensure adequate intake in children and in women of childbearing age. The dietary refer ence intakes (DRIs) for folate are 65 g of dietary folate equiva lents (DFE) for infants 0 6 months of age and 80 g of DFE for infants 6 12 months. (1 DFE 1 g food folate 0.6 g of folate from fortified food or as a supplement consumed with food 0.5 g of a supplement taken on an empty stomach.) For the DRIs in older children, see Table 67.1. All women desirous of becoming pregnant should consume 400 800 g folic acid daily; the dose is 4 mgday in those having delivered a child with a neural tube defect. To be effec tive, supplementation should be started at least 1 month before con ception and continued through the first 2 3 months of pregnancy. The benefit of periconceptional folate supplementation in preven tion of congenital heart defects, orofacial clefts, childhood cancers, and autism spectrum disorders are unclear. Preconceptional folate supplementation continued throughout pregnancy may marginally reduce the risk of delivering a preterm or small for gestational age infant. Providing iron and folic acid tablets for prevention of ane mia in children and pregnant women is a routine strategy in at risk populations. Mandatory fortification of cereal flours with folic acid coupled with health education programs has been associated with a substantial reduction in incidence of neural tube defects in many countries. Treatment When the diagnosis of folate deficiency is established, folic acid may be administered orally or parenterally at 0.5 1.0 mgday. Folic acid therapy should be continued for 3 4 weeks or until a definite hemato logic response has occurred. Maintenance therapy with 0.2 mgday of folate is adequate. Prolonged treatment with oral or parenteral folinic acid is required in cerebral folate deficiency, and the response may be incomplete. High dose intravenous folinic acid may help in refractory cases. Treatment of hereditary folate malabsorption may be possible with intramuscular folinic acid; some patients may respond to high dose oral folinic acid therapy. FOLATE TOXICITY No adverse effects have been associated with consumption of the amounts |
883 | of folate normally found in fortified foods. Tolerable upper intake levels for children are 300 gday for 1 3 years, 400 g day for 4 8 years, 600 gday for 9 13 years, and 800 gday for 14 18 years. Excessive intake of folate supplements might obscure and potentially delay the diagnosis of vitamin B12 deficiency. Massive doses given by injection have the potential to cause neurotoxicity. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Folic acid Folinic acid 5,10 MYTHF 10F THF Purine biosynthesis 5MTHF Homocystene methionine cycle DHFR DHF THF Thymidine synthesis Methylation reactions (SAM) (pyrimidine) 5,10 METHF DHFR SHMT MTHFR MTHFD MTHFD Serine Glycine Food folates MTFS Fig. 67.7 Simplified scheme of folate metabolism; 5 MTHF is the predominant form in which dietary folate enters the circulation. Synthetic folic acid first has to be metabolized in two steps to the biologically active form THF, whereas the biologically derived folinic acid is already reduced and easily converted to 5,10 methenyl THF. Serine is an important one carbon donor and allows entry of THF into the active one carbon pool of intermediates by way of 5,10 methylene THF, which functions as a cofactor for the synthesis of thymidine. 5,10 Methylene THF can be metabolized to 5 MTHF for the remethylation of homocysteine to methionine, or it can be converted to 10 formyl THF for use in purine synthe sis.1 DHF, dihydrofolate; DHFR, dihydrofolate reductase; THF, tetrahydrofolate; 5 MTHF, 5 methyltetrahydrofolate; SAM, S adenosylmethionine; 5,10 ME THF, 5,10 methylene THF; 5,10 MYTHF, 5,10 methenyl THF; 10 F THF, 10 formyl THF; MTFS, 5,10 methenyltetrahydrofolate synthetase. (From Lubout CMA, Goorden SMI, van den Hurk K, et al. Successful treatment of hereditary folate malabsorption with intramuscular folinic acid. Pediatr Neurol. 2020;102:62 66, Fig. 2, p. 64.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 466 Part V u Nutrition 67.7 Vitamin B12 (Cobalamin) H.P.S. Sachdev and Dheeraj Shah Vitamin B12, in the form of deoxyadenosylcobalamin, functions as a cofactor for isomerization of methylmalonyl CoA to succinyl CoA, an essential reaction in lipid and carbohydrate metabolism. Methyl cobalamin is another circulating form of vitamin B12 and is essential for methyl group transfer during the conversion of homocysteine to methionine. This reaction also requires a folic acid cofactor and is important for protein and nucleic acid biosynthesis. Vitamin B12 is important for hematopoiesis, CNS myelination, and mental and psy chomotor development (Fig. 67.8). Dietary sources of vitamin B12 are almost exclusively from animal foods. Organ meats, muscle meats, seafood (mollusks, oysters, fish), poultry, and egg yolk are rich sources. Fortified ready to eat cereals and milk and their products are the important sources of the vitamin for vegetarians. Human milk is an adequate source for breastfeeding infants if the maternal serum B12 levels are adequate. Vitamin B12 is absorbed from ileum at alkaline pH after binding with intrinsic factor. |
884 | Enterohepatic circulation, direct absorption, and synthesis by intesti nal bacteria are additional mechanisms helping to maintain the vita min B12 nutriture. VITAMIN B12 DEFICIENCY Deficiency of vitamin B12 caused by inadequate dietary intake occurs primarily in persons consuming strict vegetarian or vegan diets. Prevalence of vitamin B12 deficiency is high in predomi nantly vegetarian or lactovegetarian populations. Breastfeeding infants of B12 deficient mothers are also at risk for significant defi ciency. Malabsorption of B12 occurs in celiac disease, ileal resec tions, Crohn disease, Helicobacter pylori infection, and autoimmune atrophic gastritis (pernicious anemia). Obesity, type 1 diabetes, and use of metformin and proton pump inhibitors histamine (H2) receptor antagonists and misuse of nitrous oxideusually in the form of inhaling aerosol whipped cream (whippits)may increase the risk of deficiency. Hereditary intrinsic factor deficiency and Imerslund Grsbeck disease are inborn errors of metabolism leading to vitamin B12 malabsorption. Pathologic variants of the hereditary intrinsic factor gene cause hereditary intrinsic factor deficiency, whereas pathologic variation in any of the two sub units (cubilin and amnionless) of the intrinsic factor receptor cause Imerslund Grsbeck disease. Maternal vitamin B12 deficiency may produce neonatal B12 deficiency, which may be detected by ele vated levels of homocysteine and methylmalonic acid on the new born screen. Homocysteine cbIG cbIX cbIC cbIF cbIJ cbIE cbIDv1 cbIDv2 cbID Methionine Cbl Cbl TC Cbl TC TCbIR MSMeCbl MScob(II)alamin MMACHC cob(II)alamin cob(II)alamin MethylmalonylCoA SuccinylCoA AdoCbl MSR MMADHC MMAA MCMAdoCbl ATR HCFC1 LMBD1 ABCD4 cbIB cbIA mut Fig. 67.8 Scheme of cobalamin (Cbl) metabolism. The sites affected by methylmalonyl CoA mutase deficiency (mut) and inborn errors of cobala min metabolism (cblA cblG, cblJ, and cblX) are shown in red. The cblA disorder is caused by defects in the MMAA protein; the cblB disorder by defects in the cob(I)alamin adenosyltransferase (MMAB) protein; the cblC disorder by defects in the MMACHC protein; the cblD, cblD variant 1 (cblDv1), and cblD variant 2 (cblDv2) disorders are caused by defects in the MMADHC protein; cblE disorder is caused by defects in the methionine synthase reductase (MSR) protein; cblG disorder by defects in the methionine synthase (MS) protein; cblJ disorder by pathologic variants in the ABCD4 protein; cblX disorder by pathologic variation in the HCFC1 protein, and the mut disorder by defects in methylmalonyl CoA mutase (MCM). The protein affected in the cblF disorder is unknown. MCM AdoCbl, Holomethylmalonyl CoA mutase (mutase with bound adenosylcobalamin); MS cob(II)alamin, methionine synthase with bound cob(II)alamin; MS MeCbl, holomethionine synthase (synthase with bound methylcobalamin); TC, transcobalamin. (From Orkin SH, Fisher DE, Ginsburg D, et al., eds. Nathan and Oskis Hematology and Oncology of Infancy and Childhood, 8th ed. Philadelphia: Elsevier; 2015:318.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 67 u Vitamin B Complex Deficiencies and Excess 467 Clinical Manifestations The hematologic manifestations of vitamin B12 deficiency are similar to manifestations of folate deficiency and are |
885 | discussed in Chapter 503.2. Irritability, hypotonia, developmental delay, devel opmental regression, and involuntary movements (predominantly coarse tremors) are the common neurologic symptoms in infants. Older children with vitamin B12 deficiency may show poor growth and poor school performance, whereas sensory deficits, paresthe sias, peripheral neuritis, and psychosis are seen in adolescents and adults (Fig. 67.9). Hyperpigmentation of the knuckles, palms, and soles is another common observation with B12 deficiency in chil dren and adolescents (Fig. 67.10). Diagnosis See Chapter 503.2. Vitamin B12 deficiency may be present with vitamin B12 levels in the normal or low normal range and without macrocytosis. Ancillary testing of methylmalonic acid and homocysteine levels may enhance the diagnosis. Treatment The hematologic symptoms respond promptly to parenteral admin istration of 250 1,000 g vitamin B12. Children with severe defi ciency and those with neurologic symptoms need repeated doses, daily or on alternate days in the first week, followed by weekly for the first 1 2 months and then monthly. Children with only hema tologic presentation recover fully within 2 3 months, whereas those with neurologic disease need at least 6 months of therapy. Children with a continuing malabsorptive state and those with inborn errors of vitamin B12 malabsorption need lifelong treatment. Daily treat ment with high dose (500 1,000 g) oral vitamin B12 preparations has also been shown to be equally effective in correcting biochemi cal vitamin B12 deficiency in a few trials in children, but data are inadequate to support use of the oral route in children with neuro logic manifestations and severe anemia. The sublingual route has recently been explored in infants and children and has been found to be effective in normalizing serum vitamin B12 levels. Fig. 67.9 MRI of the cervical spine illustrating a long segment of T2 hyperintensity involving the dorsal column of virtually the entire cervi cal spinal cord consistent with a diagnosis of subacute combined de generation from vitamin B12 deficiency. (From Stockton L, Simonsen C, Seago S. Nitrous oxide induced vitamin B12 deficiency. Proc Bayl Univ Med Cent. 2017;302:171172.) A B Fig. 67.10 Hyperpigmentation of (A) knuckles and (B) soles in an ado lescent female with severe anemia and vitamin B12 deficiency. Prevention Vitamin B12 dietary reference intakes (DRIs) are shown in Table 67.1. In pregnancy the DRI is 2.6 gday and in lactation 2.8 g day. Pregnant and breastfeeding women should ensure an adequate consumption of animal products to prevent cobalamin deficiency in infants. Strict vegetarians, especially vegans, should ensure regu lar consumption of vitamin B12. Food fortification with the vitamin helps to prevent deficiency in predominantly vegetarian popula tions. Though metabolic derangements suggestive of vitamin B12 deficiency are present in a high proportion of infants and children from low income country settings, routine supplementation with vitamin B12 does not seem to significantly improve their growth, development, or hemoglobin status. Toxicity Administration of therapeutic doses, both in oral and parenteral forms, is usually safe. Transient erythroderma and chromatu ria have been reported with administration of adult equivalent doses |
886 | of intravenous hydroxycobalamin in a child. Acneiform eruptions, palpitations, headache, and insomnia have been occa sionally reported in young adults receiving repeated high parenteral doses. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 468 Part V u Nutrition Vitamin C is important for synthesis of collagen at the level of hydroxyl ation of lysine and proline in precollagen. It is also involved in neurotrans mitter metabolism (conversion of dopamine to norepinephrine and tryptophan to serotonin), cholesterol metabolism (conversion of choles terol to steroid hormones and bile acids), and the biosynthesis of carnitine. Vitamin C functions to maintain the iron and copper atoms, cofactors of the metalloenzymes, in a reduced (active) state. Vitamin C is an important antioxidant (electron donor) in the aqueous milieu of the body. Vitamin C enhances nonheme iron absorption, the transfer of iron from transferrin to ferritin, and the formation of tetrahydrofolic acid and thus can affect the cellular and immunologic functions of the hematopoietic system. Though vitamin C has antiinflammatory and immunomodulating effects, there is no evidence of clinical benefit of vitamin C supplementation in pediatric critical illnesses and respiratory tract infections, including COVID 19. DIETARY NEEDS AND SOURCES OF VITAMIN C Humans depend on dietary sources for vitamin C. An adequate intake is 40 mg for ages 0 6 months and 50 mg for 6 12 months. For older children, the recommended dietary allowance is 15 mg for ages 1 3 years, 25 mg for 4 8 years, 45 mg for 9 13 years, and 65 75 mg for 14 18 years. The recommended dietary allowances during preg nancy and lactation are 85 mgday and 120 mgday, respectively. The requirement for vitamin C is increased during infectious and diarrheal diseases. Children exposed to smoking or environmental tobacco smoke also require increased amounts of foods rich in vita min C. The best food sources of vitamin C are citrus fruits and fruit juices, peppers, berries, melons, guava, kiwifruit, tomatoes, cauli flower, and green leafy vegetables. Vitamin C is easily destroyed by prolonged storage, overcooking, and processing of foods. Absorption of vitamin C occurs in the upper small intestine by an active process or by simple diffusion when large amounts are ingested. Vitamin C is not stored in the body but is taken up by all tissues; the highest levels are found in the pituitary and adrenal glands. The brain ascorbate con tent in the fetus and neonate is markedly higher than the content in the adult brain, a finding probably related to its function in neurotransmitter synthesis. When a mothers intake of vitamin C during pregnancy and lactation is adequate, the newborn will have adequate tissue lev els of vitamin C related to active placental transfer, subsequently maintained by the vitamin C in breast milk or commercial infant formulas. Breast milk contains sufficient |
887 | vitamin C to prevent deficiency throughout infancy. Infants consuming pasteurized or boiled animal milk are at significant risk of developing deficiency if the other sources of vitamin C are also lacking in the diet. Neo nates whose feeding has been delayed because of a clinical condi tion can also have ascorbic acid deficiency. For patients receiving total parenteral nutrition (TPN), 80 mgday is recommended for full term infants and 25 mgkgday for preterm infants. Parents and children who choose a limited (selective) diet or those on fad diets are at risk for vitamin C deficiency. VITAMIN C DEFICIENCY A deficiency of vitamin C results in the clinical presentation of scurvy. Children fed predominantly heat treated (ultrahigh temperature or pasteurized) milk or unfortified formulas and not receiving fruits and fruit juices are at significant risk for symptomatic disease. In the last decade, most cases of scurvy from North Amer ica and Europe have been reported in children with developmental and behavioral disorders, especially autism spectrum disorders, on highly restrictive diets. Such dietary patterns occur mainly due to severe self imposed dietary restrictions due to child preference or parental belief in unsubstantiated claims of benefit of such restric tions in autism and other developmental disorders. In scurvy, there is defective formation of connective tissues and collagen in skin, cartilage, dentine, bone, and blood vessels, leading to their fragility. In the long bones, osteoid is not deposited by osteoblasts, the cortex is thin, and the trabeculae become brittle and fracture easily. Clinical Features The early manifestations of vitamin C deficiency are irritability, loss of appetite, low grade fever, musculoskeletal pain, and tenderness in the legs. These signs and symptoms are followed by leg swellingmost marked at the knees and the anklesand pseudoparalysis. The infant might lie with the hips and knees semiflexed and the feet rotated out ward. Subperiosteal hemorrhages in the lower limb bones sometimes acutely increase the swelling and pain, and the condition might mimic acute osteomyelitis or arthritis. A rosary at the costochondral junc tions and depression of the sternum are other typical features (Fig. 68.1). The angulation of scorbutic beads is usually sharper than that of a rachitic rosary. Gum changes are seen in older children after teeth have erupted, manifested as bluish purple, spongy swellings of the mucous membrane, especially over the upper incisors (Fig. 68.2). Anemia, a common finding in infants and young children with scurvy, is related to impaired iron absorption and coexistent hematopoietic nutrient deficiencies, including iron, vitamin B12, and folate. Hemorrhagic manifestations of scurvy include petechiae, purpura, and ecchymo ses at pressure points; epistaxis; gum bleeding; and the characteristic perifollicular hemorrhages (Fig. 68.3). Other manifestations are poor wound and fracture healing, hyperkeratosis of hair follicles, arthralgia, and muscle weakness. Laboratory Findings and Diagnosis The diagnosis of vitamin C deficiency is usually based on the char acteristic clinical picture, the radiographic appearance of the long bones, and a history of poor vitamin C intake. A high index of suspicion is required in children on restrictive |
888 | diets, particularly those with autism and other developmental disorders, and they should be evaluated for scurvy whenever they present with diffi culty in walking or bone pains. The typical radiographic changes occur at the distal ends of the long bones and are particularly com mon at the knees. The shafts of the long bones have a ground glass appearance because of trabecular atrophy. The cortex is thin and dense, giving the appearance of pencil outlining of the diaphysis and epiphysis. The white line of Frnkel, an irregular but thickened white line at the metaphysis, represents the zone of well calcified cartilage. The epiphyseal centers of ossification also have a ground glass appearance and are surrounded by a sclerotic ring (Fig. 68.4). The more specific but late radiologic feature of scurvy is a zone of rarefaction under the white line at the metaphysis. This zone of rarefaction (Trmmerfeld zone), a linear break in the bone that is proximal and parallel to the white line, represents an area of debris of broken down bone trabeculae and connective tissue. A Pelkan spur is a lateral prolongation of the white line and may be present at the cortical ends. Epiphyseal separation can occur along the line of destruction, with either linear displacement or compression of the epiphysis against the shaft (Fig. 68.5). Subperiosteal hemorrhages are not visible using plain radiographs during the active phase of scurvy. However, during healing, the elevated periosteum becomes calcified and radiopaque (see Fig. 68.5), sometimes giving a dumb bell or club shape to the affected bone. MRI can demonstrate both acute and healing subperiosteal hematomas along with periostitis, metaphyseal changes (Fig. 68.4), and heterogeneous bone marrow signal intensity, even in the absence of changes in plain radiographs. Gelatinous transformation of bone marrow on aspiration has been reported in children with suspected malignancy. Chapter 68 Vitamin C (Ascorbic Acid) Deficiency and Excess Dheeraj Shah and H.P.S. Sachdev Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 68 u Vitamin C (Ascorbic Acid) Deficiency and Excess 469 Fig. 68.1 Sharp angulation of beading at costochondral junction (scorbutic rosary) in scurvy. (Courtesy Dr. J.D. MacLean, McGill Centre for Tropical Diseases, Montreal.) Fig. 68.2 Clinical photograph showing inflamed marginal gingiva in scurvy. (From Agarwal A, Shaharyar A, Kumar A, Bhat MS, Mishra M. Scurvy in pediatric age group: a disease often forgotten? J Clin Orthop Trauma. 2015;6:101107, Fig. 1, p. 103.) A B Fig. 68.3 Scurvy. A, Perifollicular hemorrhages. B, Corkscrew hairs with perifollicular hyperkeratotic papules. (Modified from Lipner S. A classic case of scurvy. Lancet. 2018;39210145:431.) A B Fig. 68.4 A, Radiograph of the knee in scurvy demonstrates a radi odense band at the chondroosseous junction (Frnkel line; long arrows) and a translucent band in the metaphysis (Trmmerfeld zone; short ar rows) of the distal femora and the proximal tibiae. B, Magnetic reso nance imaging (coronal |
889 | fat saturation T2 weighted imaging) of the knee demonstrates ill defined T2 hyperintensities in the metaphyses and jux taosseous soft tissue. The diaphysis was spared. (From Seya M, Handa A, Hasegawa D, et al. Scurvy: from a selective diet in children with developmental delay. J Pediatr. 2016;177:331, Fig. A and B, p. 331.) Biochemical tests are not very useful in the diagnosis of scurvy, because they do not reflect the tissue status. A plasma ascorbate concentration of 0.2 mgdL usually is considered deficient. Leu kocyte concentration of vitamin C is a better indicator of body stores, but this measurement is technically more difficult to per form. Leukocyte concentrations of 10 g108 white blood cells are considered deficient and indicate latent scurvy, even in the absence of clinical signs of deficiency. Saturation of the tissues with vitamin C can be estimated from the urinary excretion of the vitamin after a test dose of ascorbic acid. In healthy children, 80 of the test dose appears in the urine within 3 5 hours after parenteral administra tion. Generalized nonspecific aminoaciduria is common in scurvy, whereas plasma amino acid levels remain normal. Differential Diagnosis Scurvy is often misdiagnosed as infectious or juvenile idiopathic arthritis, osteomyelitis, nonaccidental trauma (child abuse), malig nancy, or acrodynia. The early irritability and bone pain are sometimes attributed to nonspecific pains or other nutritional deficiencies. Cop per deficiency results in a radiographic picture similar to that of scurvy. Henoch Schnlein purpura, (IgA vasculitis) thrombocytopenic pur pura, or leukemia is sometimes suspected in children presenting with hemorrhagic manifestations. Treatment Vitamin C supplements of 100 200 mgday orally or parenterally ensure rapid and complete cure. The clinical improvement is seen within 1 week in most cases, but the treatment should be continued for up to 3 months for complete recovery. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 470 Part V u Nutrition Prevention Breastfeeding protects against vitamin C deficiency throughout infancy. In children consuming milk formula, fortification with vitamin C must be ensured. Children consuming heat treated milk or plant based beverages (e.g., almond milk, soy milk) should consume adequate vitamin Crich foods in infancy. Dietary or medicinal supplements are required in children on restrictive diets deficient in vitamin C, severely malnourished children, and those with chronic debilitating conditions (e.g., malignancies, neurologic disorders). Providing antenatal supplements of vitamin C to smok ing mothers may mitigate some of the harmful effects of smoking on fetal and infant lung development and function. VITAMIN C TOXICITY Daily intake of 2 g of vitamin C is generally without adverse effects in adults. Larger doses can cause gastrointestinal problems, such as abdominal pain and osmotic diarrhea. Hemolysis has rarely been reported after high doses of ascorbic acid. Megadoses of vitamin C should be avoided in patients with a history of urolithiasis or condi tions related to excessive iron accumulation, such |
890 | as thalassemia and hemochromatosis. Data are sparse regarding vitamin C toxicity in children. The following values for tolerable upper intake levels are extrapolated from data for adults based on body weight differ ences: ages 1 3 years, 400 mg; 4 8 years, 650 mg; 9 13 years, 1,200 mg; and 14 18 years, 1,800 mg. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. CAL SH LD CE Fig. 68.5 Large subperiosteal hematoma (SH) with areas of calcifica tion (CAL) is seen along the shaft of the right femur of a child with ad vanced scurvy. Epiphyseal separation is seen in both knees, with linear displacement (LD) in the left knee and compression (CE) against the shaft in the right knee. RICKETS Bone consists of a protein matrix called osteoid and a mineral phase, principally composed of calcium and phosphate, mostly in the form of hydroxyapatite. Osteomalacia occurs with inadequate mineral ization of bone osteoid in children and adults. Rickets is a disease of growing bone caused by unmineralized matrix at the growth plates in children only before fusion of the epiphyses. Because growth plate cartilage and osteoid continue to expand but mineralization is inadequate, the growth plate thickens. Circumference of the growth plate and metaphysis is also greater, increasing bone width at the growth plates and causing classic clinical manifestations, such as widening of the wrists and ankles. The general softening of the bones causes them to bend easily when subject to forces such as weight bearing or muscle pull. This softening leads to a variety of bone deformities. Rickets is principally caused by vitamin D deficiency. Although largely corrected through public health measures that provided chil dren with adequate vitamin D, rickets remains a persistent problem in developed countries, especially in children with restrictive diets (autism) or elimination diets (fear of allergies). It remains a significant problem in developing countries and may be secondary to nutritional vitamin D deficiency and inadequate intake of calcium (Table 69.1). Etiology There are many causes of rickets, including vitamin D disorders, cal cium deficiency, phosphorus deficiency, and distal renal tubular aci dosis (Table 69.2). Clinical Manifestations Most manifestations of rickets are a result of skeletal changes (Table 69.3). Craniotabes is a softening of the cranial bones and can be detected by applying pressure at the occiput or over the parietal bones. The sensation is similar to the feel of pressing into a Ping Pong ball and then releasing. Craniotabes may also be secondary to osteogenesis imperfecta, hydrocephalus, and syphilis. It is a normal finding in many newborns, especially near the suture lines, but typically disappears within a few months of birth. Widening of the costochondral junctions results in a rachitic rosary, which feels like the beads of a rosary as the examiners fingers move along the costochondral junctions from rib to rib (Fig. 69.1). Growth plate widening is also responsible for the enlargement at the wrists and ankles (Fig. 69.2). The horizontal depres sion along the lower anterior chest known as the Harrison groove |
891 | occurs from pulling of the softened ribs by the diaphragm during inspi ration. Softening of the ribs also impairs air movement and predisposes patients to atelectasis and pneumonia. Valgus or varus deformities of the legs are common; windswept deformity occurs when one leg is in extreme valgus and the other is in extreme varus (Fig. 69.3). The clinical presentation of rickets may vary based on the etiology. Changes in the lower extremities tend to be the dominant feature in X linked hypophosphatemic rickets. Symptoms secondary to hypocalce mia occur only in those forms of rickets associated with decreased serum calcium. Chapter 69 Vitamin D Deficiency (Rickets) and Excess Larry A. Greenbaum Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Table 69.3 Clinical Features of Rickets GENERAL Failure to thrive (malnutrition) Listlessness Protruding abdomen Muscle weakness (especially proximal) Hypocalcemic dilated cardiomyopathy Fractures (pathologic, minimal trauma) Increased intracranial pressure HEAD Craniotabes Frontal bossing Delayed fontanel closure (usually closed by 2 yr) Delayed dentition No incisors by age 10 mo No molars by age 18 mo Caries Craniosynostosis CHEST Rachitic rosary Harrison groove Respiratory infections and atelectasis BACK Scoliosis Kyphosis Lordosis EXTREMITIES Enlargement of wrists and ankles Valgus or varus deformities Windswept deformity (valgus deformity of one leg with varus deformity of other leg) Anterior bowing of tibia and femur Coxa vara Leg pain HYPOCALCEMIC SYMPTOMS Tetany Seizures Stridor caused by laryngeal spasm These features are most frequently associated with the vitamin D deficiency disorders. These symptoms develop only in children with disorders that produce hypocalcemia (see Table 69.4). Table 69.1 Physical and Metabolic Properties and Food Sources of Vitamins D, E, and K NAMES AND SYNONYMS CHARACTERISTICS BIOCHEMICAL ACTION EFFECTS OF DEFICIENCY EFFECTS OF EXCESS SOURCES VITAMIN D Vitamin D3 (3 cholecalciferol), which is synthesized in the skin, and vitamin D2 (from plants or yeast) are biologically equivalent; 1 g 40 IU vitamin D Fat soluble, stable to heat, acid, alkali, and oxidation; bile necessary for absorption; hydroxylation in the liver and kidney necessary for biologic activity Necessary for GI absorption of calcium; also increases absorption of phosphate; direct actions on bone, including mediating resorption Rickets in growing children; osteomalacia; hypocalcemia can cause tetany and seizures Hypercalcemia, which can cause emesis, anorexia, pancreatitis, hypertension, arrhythmias, CNS effects, polyuria, neph rolithiasis, renal failure Exposure to sunlight (UV light); fish oils, fatty fish, egg yolks, and vitamin Dfortified formula, milk, cereals, bread VITAMIN E Group of related compounds with similar biologic activities; tocopherol is the most potent and most common form Fat soluble; readily oxidized by oxygen, iron, rancid fats; bile acids necessary for absorption Antioxidant; protection of cell membranes from lipid peroxidation and formation of free radicals Red cell hemolysis in premature infants; posterior column and cerebellar dysfunction; pigmentary retinopathy Unknown Vegetable oils, seeds, nuts, green leafy vegetables, margarine VITAMIN K Group of naphthoquinones with similar biologic |
892 | activities; K1 (phylloquinone) from diet; K2 (menaquinones) from intestinal bacteria Natural compounds are fat soluble; stable to heat and reducing agents; labile to oxidizing agent, strong acids, alkali, light; bile salts necessary for intestinal absorption Vitamin Kdependent proteins include coagulation factors II, VII, IX, and X; proteins C, S, Z; matrix Gla protein, osteocalcin Hemorrhagic manifestations; long term bone and vascular health Not established; analogs (no longer used) caused hemolytic anemia, jaundice, kernicterus, death Green leafy vegetables, liver, certain legumes and plant oils; widely distributed CNS, Central nervous system; GI, gastrointestinal; UV, ultraviolet. Table 69.2 Causes of Rickets VITAMIN D DISORDERS Nutritional vitamin D deficiency Congenital vitamin D deficiency Secondary vitamin D deficiency Malabsorption Increased degradation Decreased liver 25 hydroxylase Vitamin Ddependent rickets types 1A and 1B Vitamin Ddependent rickets types 2A and 2B Chronic kidney disease CALCIUM DEFICIENCY Low intake Diet Premature infants (rickets of prematurity) Malabsorption Primary disease Dietary inhibitors of calcium absorption PHOSPHORUS DEFICIENCY Inadequate intake Premature infants (rickets of prematurity) Aluminum containing antacids RENAL LOSSES X linked hypophosphatemic rickets Autosomal dominant hypophosphatemic rickets Autosomal recessive hypophosphatemic rickets types 1, 2, and 3 Hereditary hypophosphatemic rickets with hypercalciuria Hypophosphatemic rickets with nephrolithiasis and osteoporosis types 1 and 2 Overproduction of fibroblast growth factor 23 Tumor induced rickets McCune Albright syndrome Epidermal nevus syndrome (cutaneous skeletal hypophosphatemia syndrome) Neurofibromatosis Fanconi syndrome Dent disease Distal renal tubular acidosis Disorders secondary to excess fibroblast growth factor 23. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 472 Part V u Nutrition The chief complaint in a child with rickets is quite variable. Many children present because of skeletal deformities, whereas others have difficulty walking owing to a combination of deformity and weakness. Other common presenting complaints include failure to thrive (malnutrition) and symptomatic hypocalcemia (see Chapters 610612). Radiology Rachitic changes are most easily visualized on posteroanterior radio graphs of the wrist, although characteristic rachitic changes can be seen at other growth plates (Figs. 69.4 and 69.5). Decreased calcifica tion leads to thickening of the growth plate. The edge of the metaphysis loses its sharp border, which is described as fraying. The edge of the metaphysis changes from a convex or flat surface to a more concave surface. This change to a concave surface is termed cupping and is most easily seen at the distal ends of the radius, ulna, and fibula. There is widening of the distal end of the metaphysis, corresponding to the clin ical observation of thickened wrists and ankles, as well as the rachitic rosary. Other radiologic features include coarse trabeculation of the diaphysis and generalized rarefaction. Diagnosis The diagnosis of rickets is based on the presence of classic radio graphic abnormalities. It is supported by physical examination find ings, history, and laboratory results consistent with a specific etiology (Table 69.4). Clinical Evaluation Because the majority of children with rickets have a |
893 | nutritional defi ciency, the initial evaluation should focus on a dietary history, emphasizing intake of both vitamin D and calcium. Most children in industrialized nations receive vitamin D from formula, fortified milk, or vitamin supplements. Along with the amount, the exact composi tion of the formula or milk is pertinent, because rickets has occurred in children given products that are called milk (e.g., soy milk) but are deficient in vitamin D and minerals. Cutaneous synthesis mediated by sunlight exposure is an important source of vitamin D. It is important to ask about time spent outside, sunscreen use, and clothing, especially if there may be a cultural reason for increased covering of the skin. Because winter sunlight is ineffective at stimulating cutaneous synthesis of vitamin D, the season is an addi tional consideration. Children with increased skin pigmentation are at increased risk for vitamin D deficiency because of decreased cutaneous synthesis. The presence of maternal risk factors for nutritional vitamin D deficiency, including diet and sun exposure, is an important consider ation when a neonate or young infant has rachitic findings, especially if the infant is breastfed (Table 69.5). Determining a childs intake of dairy products, the main dietary source of calcium, provides a general sense of calcium intake. High dietary fiber can interfere with calcium absorption. The childs medication use is relevant, because certain medica tions, such as the anticonvulsants phenobarbital and phenytoin, increase degradation of vitamin D, and phosphate binders or aluminum containing antacids interfere with the absorption of phosphate. Malabsorption of vitamin D is suggested by a history of liver or intestinal disease. Undiagnosed liver or intestinal disease should be suspected if the child has gastrointestinal (GI) symptoms, although occasionally rickets is the presenting complaint. Fat malabsorption is often associated with diarrhea or oily stools, and there may be signs or symptoms suggesting deficiencies of other fat soluble vitamins (A, E, and K; see Chapters 66, 70, and 71). Fig. 69.1 Rachitic rosary in a child with rickets. (Courtesy Dr. Thom as D. Thacher, Rochester, MN.) Fig. 69.2 Hands and forearms of a young child with rickets show prominence above the wrist, resulting from flaring and poor mineraliza tion of lower end of the radius and ulna. (From Bullough PG. Orthopae dic Pathology, 5th ed. St Louis: Mosby: 2010: Fig 8 31.) Fig. 69.3 Windswept deformity of the legs in an older child with rick ets. (From Rickets and osteomalacia. In Hochberg MC, Silman AJ, Smo len JS, et al., eds. Rheumatology, 4th ed. London: Mosby; 2008: Fig 192 6.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 69 u Vitamin D Deficiency (Rickets) and Excess 473 A B Fig. 69.4 Radiographs of the wrist in normal child (A) and child with rickets (B), who has metaphyseal fraying and cupping of the distal ra dius and ulna. Table 69.4 Laboratory Findings |
894 | in Various Disorders Causing Rickets DISORDER Ca Pi PTH 25 (OH)D 1,25 (OH)2D ALP URINE Ca URINE Pi Vitamin D deficiency N, , N, VDDR, type 1A N, N VDDR, type 1B N, N VDDR, type 2A N, N VDDR, type 2B N, N Chronic kidney disease N, N N, Dietary Pi deficiency N N, N XLH N N, N RD ADHR N N N RD HHRH N N, N ARHR, type 1 or type 2 N N N RD Tumor induced rickets N N N RD Fanconi syndrome N N N RD or or Dents disease N N N N Dietary Ca deficiency N, N Elevated fibroblast growth factor 23 (FGF 23). FGF 23 elevated in some patients. ADHR, Autosomal dominant hypophosphatemic rickets; ALP, alkaline phosphatase; ARHR, autosomal recessive hypophosphatemic rickets; Ca, calcium; HHRH, hereditary hypophosphatemic rickets with hypercalciuria; N, normal; Pi, inorganic phosphorus; PTH, parathyroid hormone; RD, relatively decreased (because it should be increased given the concurrent hypophosphatemia); VDDR, vitamin Ddependent rickets; XLH, X linked hypophosphatemic rickets; 1,25 (OH)2D, 1,25 dihydroxyvitamin D; 25 OHD, 25 hydroxyvitamin D; , decreased; , increased; , extremely increased. Fig. 69.5 Radiographs of the knees in 7 year old female with distal re nal tubular acidosis and rickets. A, At initial presentation, there is widen ing of the growth plate and metaphyseal fraying. B, Dramatic improve ment after 4 months of therapy with alkali. A B A history of renal disease (proteinuria, hematuria, urinary tract infections) is an additional significant consideration, given the impor tance of chronic kidney disease as a cause of rickets. Polyuria can occur in children with chronic kidney disease or Fanconi syndrome. Children with rickets might have a history of dental caries, poor growth, delayed walking, waddling gait, pneumonia, and hypocalce mic symptoms. The family history is critical, given the large number of genetic causes of rickets, although most of these causes are rare. Along with bone disease, it is important to inquire about leg deformities, Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 474 Part V u Nutrition difficulties with walking, or unexplained short stature, because some parents may be unaware of their diagnosis. Undiagnosed dis ease in the mother is not unusual in X linked hypophosphatemia. A history of an unexplained sibling death during infancy may be pres ent in the child with cystinosis, the most common cause of Fanconi syndrome in children. The physical examination focuses on detecting manifestations of rickets (see Table 69.3). It is important to observe the childs gait, auscultate the lungs to detect atelectasis or pneumonia, and plot the patients growth. Alopecia suggests vitamin Ddependent rick ets type 2. The initial laboratory tests in a child with rickets should include serum calcium, phosphorus, alkaline phosphatase (ALP), parathy roid hormone (PTH), 25 hydroxyvitamin D, 1,25 dihydroxyvitamin D (1,25 D), creatinine, and electrolytes (see Table 69.4 for interpre |
895 | tation). Urinalysis is useful for detecting the glycosuria seen with Fanconi syndrome. Evaluation of urinary excretion of calcium (24 hour collection for calcium or calcium:creatinine ratio) is helpful if hereditary hypophosphatemic rickets with hypercalciuria or Dent disease is suspected. Direct measurement of other fat soluble vita mins (A, E, and K) or indirect assessment of deficiency (prothrom bin time for vitamin K deficiency) is appropriate if malabsorption is a consideration. VITAMIN D DISORDERS Vitamin D Physiology Vitamin D can be synthesized in skin epithelial cells and therefore technically is not a vitamin. Cutaneous synthesis is normally the most important source of vitamin D and depends on the conversion of 7 dehydrocholesterol to vitamin D3 (3 cholecalciferol) by ultravio let B (UVB) radiation from the sun. The efficiency of this process is decreased by melanin; therefore more sun exposure is necessary for vitamin D synthesis in people with increased skin pigmentation. Mea sures to decrease sun exposure, such as covering the skin with cloth ing or applying sunscreen, also decrease vitamin D synthesis. Children who spend less time outside have reduced vitamin D synthesis. The winter sun away from the equator is ineffective at stimulating vitamin D synthesis. There are few natural dietary sources of vitamin D. Fish liver oils have a high vitamin D content. Other good dietary sources include fatty fish and egg yolks. Most children in industrialized countries receive vitamin D via fortified foods, especially formula and milk (both of which contain 400 IUL) and some breakfast cereals and breads. Supplemental vitamin D may be vitamin D2 (which comes from plants or yeast) or vitamin D3. Breast milk has a low vitamin D content, approximately 12 60 IUL. Vitamin D is transported bound to vitamin Dbinding pro tein to the liver, where 25 hydroxlase converts vitamin D into 25 hydroxyvitamin D (25 D), the most abundant circulating form of vitamin D. Because there is little regulation of this liver hydrox ylation step, measurement of 25 D is the standard method for determining a patients vitamin D status. The final step in activa tion occurs in the kidney, where the enzyme 1 hydroxylase adds a second hydroxyl group, resulting in 1,25 D. The 1 hydroxylase is upregulated by PTH and hypophosphatemia and inhibited by hyperphosphatemia and 1,25 D. Most 1,25 D circulates bound to vitamin Dbinding protein. 1,25 Dihydroxyvitamin D acts by binding to an intracellular receptor, and the complex affects gene expression by interact ing with vitamin D response elements. In the intestine, this bind ing results in a marked increase in calcium absorption, which is highly dependent on 1,25 D. There is also an increase in phos phorus absorption, but this effect is less significant because most dietary phosphorus absorption is vitamin D independent. 1,25 D also has direct effects on bone, including mediating resorption. 1,25 D directly suppresses PTH secretion by the parathyroid gland, thus completing a negative feedback loop. PTH secretion is also suppressed by the increase in serum calcium mediated by 1,25 D. 1,25 |
896 | D inhibits its own synthesis in the kidney and increases the synthesis of inactive metabolites. Nutritional Vitamin D Deficiency Vitamin D deficiency remains the most common cause of rickets glob ally and even occurs in industrialized countries. Because vitamin D can be obtained from dietary sources or from cutaneous synthesis, most patients in industrialized countries have a combination of risk factors that lead to vitamin D deficiency. Etiology Vitamin D deficiency most frequently occurs in infancy because of a combination of poor intake and inadequate cutaneous synthesis. Transplacental transport of vitamin D, mostly 25 D, typically pro vides enough vitamin D for the first or second months of life unless there is severe maternal vitamin D deficiency. Infants who receive formula receive adequate vitamin D, even without cutaneous syn thesis. Because of the low vitamin D content of breast milk, breast fed infants rely on cutaneous synthesis or vitamin supplements. Cutaneous synthesis can be limited because of the ineffectiveness of the winter sun in stimulating vitamin D synthesis; avoidance of sunlight because of concerns about cancer, neighborhood safety, or cultural practices; and decreased cutaneous synthesis because of increased skin pigmentation. The effect of skin pigmentation explains why most cases of nutri tional rickets in the United States and Northern Europe occur in breastfed children of African descent or other dark pigmented populations. The additional impact of the winter sun is supported by such infants more often presenting in the late winter or spring. In some groups, complete covering of infants or the practice of not taking infants outside has a significant role, explaining the occur rence of rickets in infants living in areas of abundant sunshine, such as the Middle East. Because the mothers of some infants can Table 69.5 Risk Factors for Nutritional Rickets and Osteomalacia and Their Prevention MATERNAL FACTORS Vitamin D deficiency Dark skin pigmentation Full body clothing cover High latitude during winterspring season Other causes of restricted sun (UVB) exposure (e.g., predominant indoor living, disability, pollution, cloud cover) Lowvitamin D diet Low calcium diet Poverty, malnutrition, special diets INFANTCHILDHOOD FACTORS Neonatal vitamin D deficiency secondary to maternal deficiency vitamin D deficiency Lack of infant supplementation with vitamin D Prolonged breastfeeding without appropriate complementary feeding from 6 mo High latitude during winterspring season Dark skin pigmentation andor restricted sun (UVB) exposure (e.g., predominant indoor living, disability, pollution, cloud cover) Avoidant restrictive food intake disorder Lowvitamin D diet Low calcium diet Poverty, malnutrition, special diets PREVENTIVE MEASURES Sun exposure (UVB content of sunlight depends on latitude and season) Vitamin D supplementation Strategic fortification of the habitual food supply Normal calcium intake Adapted from Munns CF, Shaw N, Kiely M, et al. Global consensus recommendations on prevention and management of nutritional rickets. J Clin Endocrinol Metab. 2016;101:394415, p. 401. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 69 u Vitamin D Deficiency |
897 | (Rickets) and Excess 475 have the same risk factors, decreased maternal vitamin D can also contribute, both by leading to reduced vitamin D content in breast milk and by lessening transplacental delivery of vitamin D. Rickets caused by vitamin D deficiency can also be secondary to dietary practices, such as vegan diets that use unfortified soy milk or rice milk. Children with restrictive food habits (autism) or food elimination diets (fear of allergies) may be at risk for vitamin D deficiency. Clinical Manifestations The clinical features are typical of rickets (see Table 69.3), with a significant minority presenting with symptoms of hypocalcemia. Prolonged laryngospasm is occasionally fatal. These children have an increased risk of pneumonia and muscle weakness leading to a delay in motor development. Laboratory Findings Table 69.4 summarizes the principal laboratory findings. Hypocalce mia is a variable finding because the elevated PTH acts to increase the serum calcium concentration. The hypophosphatemia is caused by PTH induced renal losses of phosphate, combined with a decrease in intestinal absorption. The wide variation in 1,25 D levels (low, normal, or high) is secondary to the upregulation of renal 1 hydroxylase caused by concomitant hypophosphatemia and hyperparathyroidism. Because serum levels of 1,25 D are much lower than the levels of 25 D, even with low levels of 25 D, there is often enough 25 D still present to act as a precursor for 1,25 D synthesis in the presence of upregu lated 1 hydroxylase. The level of 1,25 D is only low when there is severe vitamin D deficiency. Some patients have a metabolic acidosis secondary to PTH induced renal bicarbonate wasting. There may also be generalized aminoaciduria. Diagnosis and Differential Diagnosis The diagnosis of nutritional vitamin D deficiency is based on the combination of a history of poor vitamin D intake and risk factors for decreased cutaneous synthesis, radiographic changes consistent with rickets, and typical laboratory findings (see Table 69.4). A normal PTH level almost never occurs with vitamin D deficiency and suggests a pri mary phosphate disorder. Treatment Children with nutritional vitamin D deficiency should receive vita min D and adequate nutritional intake of calcium and phospho rus. There are two strategies for administration of vitamin D. With stoss therapy, vitamin D (300,000 600,000 IU) is administered orally (preferred) or intramuscularly as 2 4 doses over 1 day (vita min D3 is preferred to D2 because of the longer half life of D3). Because the doses are observed, stoss therapy is ideal in patients in whom adherence to therapy is questionable. The alternative strat egy is daily vitamin D with a minimum dose of 2,000 IUday for a minimum of 3 months. Either strategy should be followed by daily vitamin D intake of 400 IUday if 1 year old or 600 IUday if 1 year old. It is important to ensure that children receive adequate dietary calcium (minimum of 500 mgday) and phosphorus; this dietary intake is usually provided by milk, formula, and other dairy products, although calcium supplements may |
898 | be needed in some patients. Children who have symptomatic hypocalcemia might need intra venous (IV) calcium acutely, followed by oral calcium supplements, which typically can be tapered over 2 6 weeks in children who receive adequate dietary calcium. Transient use of IV or oral 1,25 D (calcitriol) is often helpful in reversing hypocalcemia in the acute phase by providing active vitamin D during the delay, as supple mental vitamin D is converted to active vitamin D. Calcitriol doses are typically 0.05 gkgday. IV calcium is initially given as an acute bolus for symptomatic hypocalcemia (20 mgkg calcium chloride or 100 mgkg calcium gluconate). Some patients require a continu ous IV calcium drip, titrated to maintain the desired serum calcium level. These patients should transition to enteral calcium, and most infants require approximately 1,000 mg of elemental calcium. Prognosis Most children with nutritional vitamin D deficiency have an excel lent response to treatment, with radiologic healing occurring within a few months. Laboratory test results should also normal ize rapidly. Many of the bone malformations improve dramatically, but children with severe disease can have permanent deformities and short stature. Rarely, patients benefit from orthopedic interven tion for leg deformities, although this is generally not done until the metabolic bone disease has healed, there is clear evidence that the deformity will not self resolve, and the deformity is causing func tional problems. Prevention Most cases of nutritional rickets can be prevented by universal admin istration of 400 IU of vitamin D to infants 1 year old. Older children with risk factors for inadequate intake should receive 600 IUday. Vita min D may be administered as a component of a multivitamin or as a vitamin D supplement. Congenital Vitamin D Deficiency Congenital rickets is quite rare in industrialized countries and occurs when there is severe maternal vitamin D deficiency dur ing pregnancy. Maternal risk factors include poor dietary intake of vitamin D, lack of adequate sun exposure, and closely spaced pregnancies. These newborns can have symptomatic hypocalcemia, intrauterine growth restriction, and decreased bone ossification, along with classic rachitic changes (craniotabes, large fontanelle, fractures). In addition, neonates with congenital rickets may have bone pain, weakness, elevated PTH and ALP levels, and hypocalce mia with low serum 25 hydroxyvitamin D levels. Subtler maternal vitamin D deficiency can have an adverse effect on neonatal bone density and birthweight, cause a defect in dental enamel, and pre dispose infants to neonatal hypocalcemic tetany. Treatment of con genital rickets includes vitamin D supplementation and adequate intake of calcium and phosphorus. Use of prenatal vitamins con taining vitamin D (600 IU) prevents this entity. Secondary Vitamin D Deficiency Etiology Along with inadequate intake, vitamin D deficiency can result from inadequate absorption, decreased hydroxylation in the liver, and increased degradation. Because vitamin D is fat soluble, its absorp tion may be decreased in patients with a variety of liver and GI diseases, including cholestatic liver disease, defects in bile acid metabolism, cystic fibrosis and other causes of pancreatic dysfunc tion, celiac |
899 | disease, and Crohn disease. Malabsorption of vitamin D can also occur with intestinal lymphangiectasia and after intestinal resection. Severe liver disease, which usually is also associated with mal absorption, can cause a decrease in 25 D formation as a result of insufficient enzyme activity. Because of the large reserve of 25 hydroxlase activity in the liver, vitamin D deficiency caused by liver disease usually requires a loss of 90 of liver function. A variety of medications increase the degradation of vitamin D by inducing the cytochrome P450 (CYP) system. Rickets from vita min D deficiency can develop in children receiving anticonvulsants (e.g., phenobarbital, phenytoin) or antituberculosis medications (e.g., isoniazid, rifampin). Treatment Treatment of vitamin D deficiency attributable to malabsorption requires high doses of vitamin D. Because of its better absorption, 25 D (25 50 gday or 5 7 gkgday) is superior to vitamin D3. The dose is adjusted based on monitoring of serum levels of 25 D. Alternatively, Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 476 Part V u Nutrition patients may be treated with 1,25 D, which also is better absorbed in the presence of fat malabsorption, or with parenteral vitamin D. Chil dren with rickets as a result of increased degradation of vitamin D by the CYP system require the same acute therapy as indicated for nutri tional deficiency (discussed earlier), followed by long term adminis tration of high doses of vitamin D (e.g., 1,000 IUday), with dosing titrated based on serum levels of 25 D. Some patients require as much as 4,000 IUday. Vitamin DDependent Rickets, Type 1 Children with vitamin Ddependent rickets type 1A, an autoso mal recessive disorder, have pathologic gene variants in CYP27B, which encodes the renal 1 hydroxylase, preventing conversion of 25 D into 1,25 D. These patients normally present during the first 2 years of life and can have any of the classic features of rick ets (see Table 69.3), including symptomatic hypocalcemia. They have normal levels of 25 D but low levels of 1,25 D (see Table 69.4). Occasionally, 1,25 D levels are at the lower limit of normal, inappropriately low given the high PTH and low serum phospho rus levels, both of which should increase the activity of renal 1 hydroxylase and cause elevated levels of 1,25 D. As in nutritional vitamin D deficiency, renal tubular dysfunction can cause a meta bolic acidosis and generalized aminoaciduria. Vitamin Ddependent rickets type 1B is secondary to pathologic variants in the gene (CYP2R1) for the principal 25hydroxylase. Patients have low levels of 25 D but normal levels of 1,25 D (see Table 69.4). Treatment Vitamin Ddependent rickets type 1A responds to long term treat ment with 1,25 D (calcitriol). Initial doses are 0.25 2 gday, and lower doses are used once the rickets has healed. Especially during initial therapy, it is important to ensure adequate intake |
900 | of calcium. The dose of calcitriol is adjusted to maintain a low normal serum calcium level, a normal serum phosphorus level, and a high normal serum PTH level. Targeting a low normal calcium concentration and a high normal PTH level avoids excessive dosing of calcitriol, which can cause hypercalciuria and nephrocalcinosis. Therefore patient monitor ing includes periodic assessment of urinary calcium excretion, with a target of 4 mgkgday. Vitamin Ddependent rickets type 1B may respond to pharma cologic doses of vitamin D2 (3,000 Uday) as a result of alternative enzymes with 25 hydroxylase activity or residual activity of the abnor mal protein. Vitamin DDependent Rickets, Type 2 Patients with vitamin Ddependent rickets type 2A have pathologic variants in VDR, the gene encoding the vitamin D receptor, pre venting a normal physiologic response to 1,25 D. Levels of 1,25 D are extremely elevated in this autosomal recessive disorder (see Table 69.4). Most patients present during infancy, although rick ets in less severely affected patients might not be diagnosed until adulthood. Less severe disease is associated with a partially func tional vitamin D receptor. Approximately 5070 of children have alopecia, which tends to be associated with a more severe form of the disease and can range from alopecia areata to alopecia totalis. Epidermal cysts are a less common manifestation. Vitamin Ddependent rickets type 2B appears to result from over expression of a hormone response elementbinding protein that inter feres with the actions of 1,25 D. Alopecia may be present. Treatment Some patients respond to extremely high doses of vitamin D2 (25 D or 1,25 D), especially patients without alopecia. This response is caused by a partially functional vitamin D receptor in patients with vitamin Ddependent rickets type 2A, but may also occur in vitamin Ddepen dent rickets type 2B. All patients should be given a 3 to 6 month trial of high dose vitamin D and oral calcium. The initial dose of 1,25 D should be 2 gday, but some patients require doses as high as 50 60 gday. Calcium doses are 1,000 3,000 mgday. Patients who do not respond to high dose vitamin D may be treated with long term IV calcium, with possible transition to very high dose oral calcium sup plements. Treatment of patients who do not respond to vitamin D is difficult. Chronic Kidney Disease With chronic kidney disease, there is decreased activity of 1 hydroxylase in the kidney, leading to diminished production of 1,25 D. In chronic kidney disease, unlike the other causes of vitamin D defi ciency, patients have hyperphosphatemia as a result of decreased renal excretion (see Table 69.4 and Chapter 572.2). Treatment Therapy requires the use of a form of vitamin D that can act without 1 hydroxylation by the kidney (calcitriol), which both permits ade quate absorption of calcium and directly suppresses the parathyroid gland. Because hyperphosphatemia is a stimulus for PTH secretion, normalization of the serum phosphorus level through a combination of dietary phosphorus restriction and use of oral phosphate binders is |
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