Nejm 2002;346:591; 1997;337:396

Cause:70% genetic including 5% of the morbidly obese w melanocortin-4 receptor gene (MC4R) (Nejm 2003;348:1085, 1096, 1160) mutations altering alpha MSHormone, and another significant % w leptin receptor gene mutations. Little environmental impact (twin studies—Nejm 1990;322:1477, 1483)

Pathophys:

Many theories:

• Brain appetite/satiety center imbalance, "adipostat" set higher (eg, by sedentary lifestyle) or lower (eg, by regular exercise) (Nejm 1995;332:621, 673, 679)
• Fat tissue regulatory failure, increased numbers of fat cells in utero leads to fat adults (Nejm 1976;295:349)
• Psychiatric
• Cellular sodium pump thermogenesis decreased (in rbc anyway—Nejm 1980;303:1017)
• Lower activity index (Nejm 1988;318:461, 467, 509)
• Insensitivity of brain to leptin, satiety regulator protein secreted by adipose cells? (Nejm 1996;334:292)
• Ghrelin hormone secretion by stomach/duodenum when dieting is inhibited by gastric bypass procedures (Nejm 2002;346:1623)
• Sleep deprivation decr leptin and incr ghrelin levels (Ann IM 2004;141:846)

Prevalence incr in US, ~18% in 1998 (Jama 1999;282:1519), and varies inversely w breastfeeding duration as infant (Jama 2001;285:2453, 2461, 2506)

Sx:Frequently pts falsely report more activity and less intake than actual amounts, and falsely ascribe inability to lose weight to genetic resistance (Nejm 1992;327:1893)

Si:Triceps skin fold >23 mm; BP elevated (increased renin and aldosterone—Nejm 1981;304:930); 30 kg/m², or 20+% over ideal body wgt (formula for IDBW: men = 106 lb + 6 lb/in over 5 ft; for women = 100 lb + 5 lbs/in over 5 ft)

Obesity in adolescence is associated w markedly decreased lifetime comparable to smoking (Ann IM 2003;138:24); also w lower education, incomes, and marriage rates, unlike other chronic disease states; is it genetics, discrimination, or both? (Nejm 1993;329:1008, 1076)

Fatty liver w hepatocellular enzyme elevation and low level of subsequent cirrhosis very prevalent. Higher in diabetics and those w full metabolic syndrome; prognosis correlates best w cardiovascular risk (Nejm 2010;363:1341).

Sleep apnea (Obstructive Sleep Apnea); osteoarthritis of knees (Ann IM 1988;109:18); gallstones with weight loss (Nejm 1988;319:1567); fatty liver (75%) (Ann IM 2000;132:112); ASHD, diabetes, CHF (incid incr 5%—[Framingham] Nejm 2002;347:305) hypertension, premature death (Jama 1999;282:1523, 1530; Ann IM 1985;103:977); incr in almost all Ca's by up to 50% in severely obese (Nejm 2002;348:1625) including cervical and breast cancers and less frequent screening for them (Ann IM 2000;132:697)

r/o night eating syndrome (Jama 1999;282:657, 689)

Rx:(Ann IM 2005;142:525)

Prevent gallstone formation w ursodeoxycholic acid 300 mg po bid or 600 mg qd, NNT = 4 (Ann IM 1995;122:899), cost $140/mo

Diet:

• 600-800 qd mixed calories and as effective as any other (Nejm 2009;360:859); low carbohydrate, high protein, Mediterannean dies most effective esp after wgt reduced by fat restriction (Nejm 2008;359:229; 2010;363:2102)

Exercise program, 45 min at 60-80% maximal pulse 3 ×/wk helps weight and HDL (Nejm 1991;326:461) no matter the genetic predisposition (Ann IM 1999;130:873)

Medications (ACP J Club 2008;148:50; Ann IM 2005;142:532): all of marginal benefit

• Appetite suppressants (Jama 1996;276:1907) like:
• SSRIs like fluoxetine (Prozac) 60 mg po qd, or sertraline (Zoloft); but both lose efficancy and wgt increases after 6 mo
• Sibutramine (Meridia) (Ann IM 2005;143:380; Jama 2003;289:1805; 2001;286:1331) 10-15 mg po qd × 1 mo, then cont'd × 1 yr if lose 2 kg in that 1st month for eventual 8 ± 1 kg avg loss, most effective when combined w intensive lifestyle modification counselling (Nejm 2005;353:2111); adv effects: incr CAD risk (Nejm 2010;363:905, 972), dry mouth, HA, insomnia, constipation, many drug interactions; $112/30 d
• Rimonabant (Nejm 2005;353:2121), a selective cannabinoid receptor blocker, 20 mg po qd w dietary counselling impacts both satiety and fat cell metabolism to reduce weight and lipids
• Ephedra (mahuang)-containing supplements, but many health risks (Nejm 2000;343:1833)
• Zonisamide (Zonegram) 4-500 mg po daily w dietrary counseling can lead to 1 lb/wk losses over 4 mo (Jama 2003;289:1821)
• Herbal Garcinia sp.(hydroxycitric acid) no help (Jama 1998;280:1596)
• Gut hormone fragment peptide (Ghrelin antagonists) eventually? (Nejm 2003;349:941; 2002;346:1623)
• NOT phentermine (Ionamin) + fenfluramine (Pondimin) or dexfenfluramine (Redux), withdrawn because of fatal primary pulmonary HT and cardiac valve abnormalities (Nejm 1998;339:713, 719)
• Pancreatic lipase inhibitor
• Orlistat (Xenical) (J Intern Med 2000;248:245; Med Let 1999;41:55; Jama 1999;281:243, 278) 120 mg po tid w meals; adv effects: fat soluble vitamin depletion, steatorrhea, possible incr breast Ca; $120/mo
• Other experimental meds: bupropion (Welbutrin) SR, topiramate (Topamax), metformin (Glucophage)

Surgical (Nejm 2007;356:2176) gastric Roux-en-Y bypass, adjustable banding or stapling or plication; 3 mo- and 1-yr mortalities = 2% and 6%, respectively, worse w older pts and less experienced surgeons (Jama 2005;294:1903, 1909, 1919, 1957, 1960) at 5 yr, 20% failure, 50% benefiting; if BMI >34 in men or >38 in women, survivals at 10+ yr significantly better (Sweden—Nejm 2007;357:741,753); adverse effects: bacterial overgrowth causing diarrhea and malabsorption, B₁₂ and iron commonly (Ann Int Med 1996;124:469); fatty liver, cirrhosis, gallstones (Nejm 1974;290:921); immune complex arthritis, rash (Ann IM 1980;93:557), and nephritis (Ann IM 1976;84:594); uric acid renal stones (20%) and hyperoxaluria; polyneuropathy, esp position sense, even in stapled patients (Ann IM 1982;96:453); metronidazole (Flagyl) 0.75-2 gm qd po helps all cmplc of blind loop; dumping syndrome w reactive hypoglycemia and islet cell hypertrophy/hyperreactivity (Nejm 2005;353:249)

Surgical liposuction, “tumescent” method w sc lidocaine + epinephrine has cmplc of sudden death (5 cases—Nejm 1999;340:1471)