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obesity

Classification: 1) body mass index (BMI) > 30; normal BMI: < 25 2) mild obesity: class 1 a) >20% over ideal body weight b) BMI: 30-35 3) moderate obesity: class 2 a) >40% over ideal body weight b) BMI: 35-40 4) morbid obesity: class 3 a) >100% over ideal body weight b) BMI: > 40 * body roundness index may be measure of obesity that predicts mortality better than BMI [125] Etiology: 1) increased energy intake in excess of energy expenditure over a prolonged period of time 2) idiopathic or essential obesity a) genetic factors* b) psychosocial factors c) cultural factors d) metabolic factors 3) secondary causes of obesity a) endocrine disorders 1] Cushing's disease 2] hypothyroidism 3] hypothalamic disease 4] polycystic ovary disease 5] insulinoma b) genetic disorders 1] Prader-Willi syndrome 2] Laurence-Moon-Biedl syndrome 3] Alstrom syndrome 4] MC4R gene mutation (melanocortin-4 receptor) c) pharmaceutical agents 1] glucocorticoids 2] tricyclic antidepressants 3] phenothiazines 4] cyproheptadine d) viral infection - adenovirus-36 4) other factors contributing to weight gain a) insulin therapy b) tricyclic antidepressant therapy c) smoking cessation d) sleep deprivation e) intestinal flora may play a role - proton pump inhibitors, H2-receptor antagonists & antibiotics in 1st 2 years of life increase risk [106] f) exposure to artificial light at night [108] g) maternal intake of ultraprocessed foods increases risk for pediatric obesity, but not specifically during pregnancy [115] 5) theories on the origins of obesity [126] a) energy balance model [126] - ability of the brain to control food intake is overwelmed by the environment of ubiquitous, calorie-dense, ultraprocessed foods - this results in increased energy intake despite internal signals from the body to the brain of energy sufficiency [126] b) carbohydrate-insulin model [126] - the ability of the brain to control food intake remains intact - food consumption increases & energy expenditure decreases in response to internal signals from the body to the brain of low energy availability [126] - example: post-prandial hypoglycemia * genetic factors may account for tendency for obesity despite high levels of exercise [124] Epidemiology: 1) nearly 40% of U.S. adults obese in 2015-2016 [97] a) 24-25% of American males [20] b) 27-33% of non-pregnant American females [20] c) prevalence highest in adults 40-59 years of age [97] d) nearly 50% of Americans will be obese by 2030 [109] - in Alabama, Arkansas, Mississippi, Oklahoma, & West Virginia prevalence of obesity will be 58% by 2030 - in no state will prevelance of obesity 2030 be below 35% [109] 2) obesity most common among Hispanic & black adults (47%), followed by whites (38%), Asians (13%) [97] - black women with highest obesity prevalence (55%) 3) 17% of children & adolescents [85]; 20% [97] - 13% of children in U.S. [95] - 29% of U.S. children in 1999-2000 overweight or obese [102] - 35% of U.S. children in 2015-2016 overweight or obese [102] - no increase in U.S. children between 2007-2008 & 2015-2016 [103] 4) > 50% of obesity begins after childhood - 8% of American children age 2-5 years classified as obese - 17% of American children age 2-19 years - 35% of adults >= 20 years of age [49] - most obese 35-year-olds were not obese as children [98] 5) prevalence is increasing [8]; - increase in obesity in U.S. adults between 2007-2008 & 2015-2016 [103] - 42% of Americans by 2030 [32] - 57% of children will be obese at age 35 years [98] - sugar-sweetened soft drinks may contribute significantly to childhood & adolescent obesity [36] 6) women may be less likely than men to suffer complications from the same degree of obesity 7) worldwide prevalence of overweight & obesity increased by 28% for adults & 47% for children from 1980-2013 - prevalence of adults with BMI of >=25 increased from 29% to 37% for men & 30% to 38% for women from 1980-2013 [53] - in 2015 12% of adults & 5% of children worldwide [95] 8) 36% of obese girls & 48% of obese boys do not admit or realize they are overweight [56] Pathology: 1) see proteins associated with obesity or lack of it 2) ALL obese individuals have elevated, NOT depressed metabolic rates [6] 3) Firmicutes (gut flora) may play role 4) fat is stored predominantly in white adipocytes derived from adipose vasculature [26] 5) health obesity is a myth [44] Genetics: - also see Etiology: genetic disorders (above) - MC4R gene mutation (most common) - leptin gene mutation (rare) - ob (leptin) receptor gene mutation (rare) - POMC deficiency - up-regulation of PID1 in fat of obese subjects - the FTO allele rs1421085 T-to-C single-nucleotide variant disrupts a conserved motif for the ARID5B repressor, leading to derepression of a preadipocyte enhancer & overexpression of IRX3 & IRX5 skewing development of adipocytes more toward white fat, which store energy as fat, & less toward brown fat, which burn energy via their mitochondria [70] - genetic factors can exacerbate effect of poor diet [50] - other implicated genes ARHGAP23, ADRB3, DRD2, PPARG, UCP2, UCP3, SLC27A4, POMC, SCG3 - intestinal Christensenellaceae under genetic control - Christensenellaceae appear to protect against obesity [59] - > 2000 specific bacteriophages infecting gut bacteria are associated human chronic diseases, particularly Parkinson disease & obesity [110] - many of the viral sequences are integrated into human chromosomal DNA or in circular episomes [110] Clinical manifestations: 1) shortness of breath 2) failure to lose weight 3) fatigue 4) daytime sleepiness 5) weakness 6) joint pain 7) waist-to-hip circumference a) >1 in men & >0.8 in women indicates upper body obesity b) increase risk of cardiovascular complications c) waist circumference >= 102 cm (40 inches) in men & >= 88 cm (35 inches) in women increases risk of type 2 diabetes, cardiovascular disease & mortality [3] 8) pedal edema 9) varicose veins 10) hypertension 11) body mass index > 30 kg/m2 12) signs of Cushing's disease 13) signs of hypothyroidism Laboratory: 1) none required for diagnosis 2) baseline testing prior to initiating dietary therapy a) complete blood count (CBC) b) blood glucose (all) [3], hemoglobin A1c c) serum electrolytes d) serum calcium e) serum magnesium f) serum uric acid g) liver function tests h) thyroid function tests i) testing for Cushing's syndrome if indicated 1] 24 hour urine cortisol 2] overnight dexamethasone suppression test j) fasting lipid profile (all) for assessment of metabolic syndrome [3] 3) urinalysis may show proteinuria due to glomerular hyperfiltration [118] 4) arterial blood gas for suspecte obesity hypoventilation syndrome Special laboratory: - electrocardiogram: check QT interval (QTc) - polysomnography for suspected sleep apnea Complications: (health risks of obesity) 1) cardiovascular a) hypertension - risk of hypertension in children going from overweight to obese (RR=2-3) [76] b) coronary artery disease (CAD) - fatty streaks occur in men age 15-34 [7] c) congestive heart failure (CHF) d) atrial fibrillation [3] e) stroke [3] f) increased cardiovascular risk indicators in overweight & obese children [37] g) increased cardiovascular risk in obese adolescents even in those that are fit, albeit less than those that are unfit [73] h) fit obese adolescents at higher cardiovascular risk than unfit normal weight adolescents [73] 2) pulmonary [13] a) restrictive pulmonary disease b) obstructive sleep apnea c) obesity hypoventilation syndrome 3) endocrine [13] a) diabetes mellitus type-2, insulin resistance syndrome - 4-fold risk for type 2 diabetes in obese children & adolecents [93] b) hyperlipidemia 4) gastrointestinal a) cholelithiasis b) fatty liver - non-alcoholic steatohepatitis (NASH) c) gastroesophageal reflux disease (GERD) 5) renal/urinary a) nephrolithiasis [14] b) focal & segmental glomerulonephropathy c) chronic renal failure d) increased risk for end-stage renal disease [38] e) increased risk of stress urinary incontinence [118] 6) malignancy [3,23,24,57] a) large increases - uterine cancer - gallbladder cancer - hepatocellular carcinoma - renal cell carcinoma b) smaller increases in - hematologic malignancies - leukemia - non-Hodgkin's lymphoma - multiple myeloma - colorectal carcinoma - obesity in adolescent males increases risk for colorectal cancer later in life [67] - cervical cancer - ovarian cancer - post-menopausal breast cancer - pancreatic cancer - thyroid cancer c) stomach cancer & esophageal cancer in never smokers d) lower risk of - prostate cancer - pre-menopausal breast cancer [57] e) increased risk of meningioma (RR=1.5) [71] f) see obesity-related cancer 7) increased risk for dermatologic conditions [74] - acanthosis nigricans, acrochordons, keratosis pilaris, hyperandrogenism & hirsutism (females), striae distensae, adiposis dolorosa, lymphedema, chronic venous insufficiency, plantar hyperkeratosis, cellulitis, hidradenitis suppurativa, psoriasis, intertrigo 8) other a) gout b) osteoarthritis c) varicose veins d) chronic venous insufficiency e) maternal obesity increases risk of preterm delivery [41] & birth defects [25] f) increased risk for cerebral palsy in offspring in women overweight or obese prior to pregnancy g) liver disease [3] 9) increased mortality [22] (RR=1.9 for men 50-71, BMI= 35-40) - no increase in mortality in the elderly [52,54] - prognosis in Management: section below - longevity diminished by ~6 years due to increased mortality from diabetes mellitus & cardiovascular disease [60] - higher adiposity associated with higher mortality after adjustment for BMI [77] - body roundness index may be measure of obesity that predicts mortality better than BMI [125] 10) children who are overweight or obese, then became nonobese as adults have similar risks as those who were never obese [31] 11) effect of increased incidence of obesity has not increased overall disability & mortality [95] - obesity & overweight implicated in 7% of deaths from any cause, mostly cardiovascular [95] 12) increased risk of mental health disorder [3] Management: 1) behavioral interventions first line (USPSTF) [101] a) for patients with a BMI of 30 or higher, clinicians should provide intensive, multicomponent behavioral interventions or refer patients to such a program [35] b) avoid activities associated with overeating, i.e. watching televison c) keeping a record of eating may be helpful d) meal planning is advisable e) require patient to get up & get food for himself/herself - don't bring food to (serve) the patient - keep food in another room - getting up to get food includes second helpings f) behavioral interventions focused on food intake & physical activity, with or without orlistat, are effective in slowing weight regain [55] g) structured behavioral interventions for obese children [66] h) a 30-second intervention with obese patients during primary care] visits proved effective in promoting weight loss [90] - advice on advantages of losing weight - enrollment in a behavioral support group i) total weight loss of 10% is a reasonable initial goal [3] 2) diet therapy a) primary mode of therapy b) begin with 1200 kcal/day - 1500-1800 kcal/day for men, 1200-1500 kcal/day for women [3] c) very low calorie diet - use commercial formulas - 800 kcal/day [105] - 60-90 g of protein/day - 100% of daily vitamins & minerals - need to see patient weekly - monitor - K+, Mg+2, uric acid - EKG: QT interval (QTc) - contraindications - cardiac arrhythmia - unstable angina - pregnancy - lactation - hepatic or renal insufficiency - type 1 diabetes mellitus - gout d) diet alone without restricted access to food is unlikely to produce sustained weight reduction e) most men lose weight on < 1300 kcal/day f) most women lose weight on < 1000 kcal/day g) a negative energy balance of 500 kCals/day is associated with weight reduction of 0.7 kg (1.1 pound) per week [2] h) limit dietary sugars to < 5% of total energy intake [64] - stop high-fructose corn syrup-containing carbonated beverages [12] - industry-funded research is 5x more likely to report no relation between sugar-sweetened beverages & obesity than industry-independent work [63] i) diet & excercise better than either alone [28] j) weight gain associated with potatoes, sugar-sweetened beverages & meat [29] k) weight reduction associated with vegetables, whole grains, fruits, nuts, yogurt [29] l) fruits & vegetables without reduction in calorie intake is not associated with weight reduction [39] m) no specific diet has proven superior to others in achieving long-term weight loss [3] n) isocaloric substitution of sucrose with starch leads to short-term (10-day) improvements in metabolic markers in obese children (serum glucose, mean arterial pressure, serum insulin, body mass index) [72] o) low fat weight loss diet may reduce premature all cause mortality [99] p) DASH diet decreases BMI in individuals at high genetic risk for obesity [100] 3) exercise a) regular exercise program is an important part of weight-reduction program - brisk walking (moderate-intensity aerobic exercise) >= 30 minutes 5 days/week (minimum recommended activity for older adults) [2,88] b) benefits of aerobic exercise - increases lean body mass - increases glucose tolerance - strenous* (>= 75% VO2max) but not moderate (50% VO2max) associated with improved glycemic control [64] - walking at a brisk pace can achieve 75% VO2max in obese patients - decreases blood pressure - decreases risk of cardiovascular disease - utilizes calories c) home exercise equipment may facilitate weight reduction [2] d) non-exercise activity thermogenesis more closely [15] associated with body weight than vigorous exercise e) exercise has health benefits independent of weight reduction [39] 4) evidence for benefit of diet plus exercise (but not diet alone) in the elderly [52] - calorie restriction associated with loss of muscle mass in obese elderly [52]; also loss of adipose tissue; outcomes not considered - weight loss plus combined aerobic exercise & resistance exercise is the most effective in improving functional status of obese older adults [95] 5) pharmaceutical agents (also see weight reduction) a) indications - adjunct to diet, exercise & behavioral management b) at least 5% weight loss should be achieved after 3 months, otherwise agent should be discontinued [61] c) American Gastroenterological Association (AGA) recommends - semaglutide, liraglutide [3,116] - drug of choice, despite no diabetes + irritable bowel syndrome IBS-D [120] - tirzepatide (Mounjaro) 15 mg SC once weekly [114] - reduces blood pressure & weight within 9 months [122] - phentermine/topiramate extended-release (Qsymia) - phentermine/topiramate (15 mg/92 mg) for 1 year lowers BMI 10% [113] - contraindications: hypertension, nephrolithiasis [120] - sustained-release naltrexone/bupropion ER [79,116] - insomnia is an adverse effect, thus relative contraindication [120] d) orlistat (Xenical) only FDA-approved agent for adolescents - not recommended for children [66] - not recommended for adults by AGA [116] e) others not receiving AGA endorsement for adults - sibutramine (Meridia) - rimonabant - metformin may contribute to weight reduction even in nondiabetic children, but clinical significance unknown [48] - incretin mimetic or glysouric agent should be considered as an adjunct to metformin [61] f) other agents not recommended due to dependence potential & high incidence of adverse effects - methamphetamine - diethylpropion - fenfluramine (fen-phen) - phentermine - dexfenfluramine (Redux) 6) bariatric surgery a) indications: [3] - BMI > 40 - BMI > 35 with serious obesity-related comorbidities b) gastric banding vs gastroplasty [11] - vertical-banded gastroplasty - adjustable laparoscopic gastric banding [5] - vertical-banded gastroplasty may be superior [11] c) Roux-en-Y gastric bypass [4] d) intestinal bypass is no longer performed due to high incidence of complications e) bariatric surgery produces best long-term results [21] - reduces blood pressure & weight [123] f) most effective strategy for adolescents [42] g) not recommended for children [66] h) avoid intragastric balloon system 7) vagal nerve blockade - benefit to risk ratio unfavorable [58] 8) follow-up a) majority of patients regain lost weight b) non-compliance with diet & exercise programs are common 9) prognosis a) obesity (BMI > 30 kg/m2) associated with diminished life-expectancy of 6-7 years [9,10] b) even a modest weight reduction (5-15%) may lead to significant improvement in medical problems in the elderly - no evidence that weight reduction will improve mortality [52,111] c) few obese adults will achieve a normal weight [69] d) failure of resting metabolic rate to rise with body weight, after weight reduction makes regaining weight easier & losing weight harder [84] - patients with weight loss after bariatric surgery do not appear to suffer this failure [84] 10) prevention - breast-feeding should be encouraged [68] - limit television & screen time [68] - limit to 2 hours a day in children >= 2years - none for infants & children < 2 years of age - televisions should be restricted from children's bedrooms & the kitchen [68] - children & adolescents whose mothers follow a healthy lifestyle are less likely to become obese [104] - structured behavioral interventions for prevention of obesity in children not indicated [66] - removal of sweet drinks & addition of easily accessible water in schools may help mitigate the obesity epidemic [75] - early bedtime for preschool children may reduce adolescent obesity [87] Notes: - ref [62] presents patient's perspective on obesity & weight reduction counseling Comparative biology: - nanoparticles containing either rosiglitazone or a PGE2 analogue adhere selectively to endothelium within white fat of obese mice, stimulate angiogenesis, transforming white fat into brown fat, inhibiting weight gain, & improving plasma cholesterol, plasma triglycerides, & plasma insulin [86]

Interactions

disease interactions

Related

bariatric surgery body mass index (BMI) fatpad ideal body weight (IBW) management of obesity: ACP clinical guidelines, 2005 obesity syndrome; disorders associated with obesity obesity-related cancer proteins associated with obesity or lack of it screening for obesity weight reduction; intentional weight loss; excess weight reduction

General

chronic metabolic disease overweight

Database Correlations

OMIM correlations

References

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