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GASTROENTEROLOGY 2002;123:882–932 AGA Technical Review on Obesity This literature review and the recommendations therein were prepared for the American Gastroenterological Association Clinical Practice Committee. The paper was approved by the Committee on March 3, 2002, and by the AGA Governing Board on May 19, 2002. besity is a chronic and stigmatizing disease that has become a major health problem in most industrialized countries because of its high prevalence, causal relationship with serious medical illnesses, and economic impact. In the United States, it is estimated that obesity is responsible for approximately 300,000 deaths per year,1 and that the direct (medical expenses) and indirect (value of lost productivity) costs of obesity exceed $100 billion per year.2 Obesity has particular relevance for gastroenterologists because (1) obesity causes gastrointestinal diseases, including cholelithiasis, pancreatitis, and liver disease; (2) patients who have had obesity surgery may need a gastroenterologist to evaluate and treat postoperative intestinal complications; and (3) the gastrointestinal tract is a viable target for current and future obesity therapies that affect nutrient absorption or gut hormones involved in appetite regulation. This review provides gastroenterologists with a comprehensive evaluation of the important clinical issues in adult obesity, including prevalence, etiology, physiology, pathophysiology, medical complications, metabolic and medical effects of weight loss, treatment options, and treatment guidelines. The information reviewed by the authors was identified by a literature search of Index Medicus between 1966 (volume 1) and January 2002, a hand search of individual journals that focus on obesity, and identifying papers from the reference lists of research and review articles. O Definition of Obesity Body Fat and Body Mass Index Obesity can be defined as an excessive amount of body fat, which increases the risk of medical illness and premature death. Accurate assessment of body fat mass requires the use of sophisticated and expensive technologies that are not readily available to most physicians. Moreover, the determination of healthy and unhealthy amounts of fat mass is complicated because the amount of body fat that causes medical complications depends on sex, age, fat distribution, weight (fat) gain since early adulthood, level of fitness, genetic factors, and concomitant disease risk factors. Recently, the World Health Organization,3 the National Institutes of Health (NIH),4 Healthy People 2010,5 and the 2000 Dietary Guidelines for Americans6 proposed guidelines for classifying weight status by body mass index (BMI) (Table 1). BMI represents the relationship between weight and height and is calculated as weight (in kg) divided by height (in m2) or as weight (in pounds) times 704 divided by height (in inches2). Although, BMI usually is correlated closely with percent body fat mass in a curvilinear fashion,7 some persons with an “obese” BMI may have a normal amount of body fat and a large muscle mass, while others with a “normal” BMI may have excess adiposity and reduced muscle mass. BMI and Mortality The BMI classification scheme for weight status is based on data obtained from large epidemiological studies that evaluated the relationship between BMI and mortality8 –10 and provides a mechanism for identifying patients who are at increased risk for having or developing adiposity-related complications. Both men and women who have a BMI ⱖ30 kg/m2 are considered obese and are generally at higher risk for adverse health events than are those who are considered overweight (BMI between 25.0 and 29.9 kg/m2) (Figure 1). It could be argued that these cutoff values, which are based on BMI-mortality relationships, are too high because the prevalence of obesity-related diseases, such as diabetes, Abbreviations used in this paper: BDD, balanced-deficit diet; BMI, body mass index; CHD, coronary heart disease; FFM, fat-free mass; GBP, gastric bypass procedure; GERD, gastroesophageal reflux disease; HDL, high-density lipoprotein; IIH, idiopathic intracranial hypertension; JIB, jejunoileal bypass; LASGB, laparoscopically inserted adjustable silicone gastric band; LCDs, low-calorie diets; LDL, low-density lipoprotein; LES, lower esophageal sphincter; NASH, nonalcoholic steatohepatitis; NAFLD, nonalcoholic fatty liver disease; NHLBI, National Heart, Lung and Blood Institute; PAI-1, plasminogen activator inhibitor 1; REE, resting energy expenditure; SF-36, Study Short-Form Health Survey; SOS, Swedish Obese Subjects; TEE, total energy expenditure; TOHP II, Trials of Hypertension Prevention Phase II; UGI, upper gastrointestinal radiographic; USFDA, United States Food and Drug Administration; VBG, vertical-banded gastroplasty; VLCDs, very-low-calorie diets. © 2002 by the American Gastroenterological Association 0016-5085/02/$35.00 doi:10.1053/gast.2002.35514 September 2002 AMERICAN GASTROENTEROLOGICAL ASSOCIATION Table 1. BMI-associated Disease Risk Underweight Normal Overweight Obesity Extreme obesity Obesity class BMI (kg/m2) Risk I II III ⬍18.5 18.5–24.9 25.0–29.9 30.0–34.9 35.0–39.9 ⱖ40.0 Increased Normal Increased High Very high Extremely high Additional risks: (1) waist circumference ⬎40 inches in men and ⬎35 inches in women; (2) weight gain of ⱖ5 kg since age 18 –20 years; (3) poor aerobic fitness; and (4) Southeast Asian descent. Data from National Institutes of Health, National Heart, Lung, and Blood Institute. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults—The Evidence Report. Obes Res 1998;6(Suppl 2):51S–209S.4 hypertension, and coronary artery disease, begins to increase at BMI values below 25 kg/m2. Furthermore, the relationship between adiposity and health risk is a continuum. Classification by BMI imposes cutoff values for risk within this continuum; this is similar to the way in which the definition of hypertension imposes cutoff values within the continuous relationship between blood pressure and cardiovascular disease risk. Therefore, BMI values should be considered as one component of an assessment of adiposity-related disease risk and not the absolute criterion for determining clinical care. In adults, the relative risk of death associated with increasing BMI decreases with increasing age.11 These data have been misinterpreted as demonstrating that obesity is less harmful in the elderly than in young and middle-aged adults.12 However, the absolute mortality risk associated with an increased BMI actually increases with age, up to the age of 75 years, because of the marked increase in mortality with advancing age. Therefore, from a clinical perspective, the health complications associated with obesity increase linearly with increasing BMI until the age of 75 years. In elderly persons, BMI has less of an impact on mortality but possibly a greater effect on quality of life. 883 (abdominal subcutaneous and visceral fat) phenotype are at increased risk for diabetes, hypertension, dyslipidemia, and ischemic heart disease. Measurement of abdominal fat content requires the use of expensive radiological imaging techniques, so waist circumference is often used as a surrogate marker because it has been shown to correlate closely with abdominal fat mass.15 The Expert Panel on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, convened by the National Institutes of Health, proposed that men with a waist circumference greater than 102 cm (40 inches) and women with a waist circumference greater than 88 cm (35 inches) are at increased risk for metabolic diseases.4 Although this recommendation is based on sound epidemiological and metabolic studies, it imposes cutoff values on the continuous relationship between waist circumference and metabolic disease risk. Weight gain. Weight gain during adulthood is an additional risk factor for medical complications. Data obtained from epidemiological studies suggest that a gain of 5 kg or more in body weight since the age of 18 to 20 years increases the risk of developing cholelithiasis, diabetes, hypertension, and coronary heart disease (CHD) in both men and women.16 –21 Moreover, greater weight gain is associated with a greater risk of disease. Even lean adults (BMI 18.5 to 24.9 kg/m2) have an increased risk of these medical illnesses if they have gained more than 5 kg since young adulthood. Fitness. Aerobic fitness can modify the risk of developing diabetes or cardiovascular disease associated with obesity. In large, prospective, epidemiological studies, Blair et al.22 found that, across a range of body adiposity, those who were fit, defined by their maximal BMI–Related Risk Modification In general, the higher the BMI, the greater the risk of adiposity-related diseases and premature mortality. However, other factors, such as fat distribution, weight gain since young adulthood, level of fitness, and ethnic background modify BMI-related risk (Table 1). Fat distribution. The importance of fat distribution on health was first realized about 50 years ago,13 but was not fully appreciated until the early 1980s.14 Compared with obese persons who have predominantly increased lower body fat (gluteal and femoral fat) phenotype, obese persons with excess upper body fat Figure 1. Relationship between BMI and cardiovascular mortality in 302,233 adult men and women in the United States who never smoked and had no preexisting illness. Vertical lines indicate overweight (BMI 25.0 –29.9 kg/m2) and obese (BMI ⱖ30 kg/m2) cutoff values. (Data from Calle et al.9) 884 AMERICAN GASTROENTEROLOGICAL ASSOCIATION GASTROENTEROLOGY Vol. 123, No. 3 ability to consume oxygen during exercise, had a lower incidence of diabetes22 and cardiovascular mortality23 than those who were unfit. Ethnicity. The cut-off values for BMI-associated risk vary by ethnic group.24,25 For example, at the same BMI values, Southeast Asian populations have a higher risk of diabetes and cardiovascular disease than white patients. In contrast, Polynesians usually have more muscle mass and less body fat than white patients at the same BMI level. Prevalence In the last 20 years, the prevalence of obesity has increased markedly in industrialized and nonindustrialized countries, and it is estimated that there are now more than 500 million overweight and 250 million obese adults in the world.26 Moreover, the prevalence is likely to continue to increase. In the United States, approximately 61% (110 million) of adults (age 20 to 74 years) are overweight or obese.27 Data from national population surveys obtained since 1960 (1960 –1962 National Health Examination Survey I [NHES I], 1971–1974 National Health and Nutrition Examination Survey I [NHANES I], 1976 – 1980 NHANES II, 1988 –1994 NHANES III, and preliminary 1999 NHANES data) have demonstrated that the prevalence of overweight increased slightly, from 30.5% to 34.0%, whereas the prevalence of obesity (BMI ⱖ30 kg/m2) has more than doubled, from 12.8% to 27%27,28 (Figure 2). Most of the increase in body weight has occurred since 1980. The prevalence of obesity in the United States increases progressively from 20 to 50 years of age, but begins to decline after age 60 to 70. The prevalence of obesity is particularly high in many ethnic minority women, such as African American, Mexican American, Native American, Pacific Islander American, Puerto Rican, and Cuban American women. In the United Kingdom and Europe, approximately 15% of men and 20% of women are obese.29 Obesity also has increased in Southeast Asia, Japan, and China; it is now more prevalent than undernutrition in Malaysia and occurs in more than 60% of men and 75% of women in urban Samoa.25,29 Obesity also has increased in children and adolescents. Data from NHANES III (1988 –1994) showed that 10% to 15% of children and adolescents (age 6 to 17 years) in the United States are overweight, defined as a BMI ⱖ95th percentile for age and gender from the revised National Center for Health Statistics growth charts.30 These values represent a doubling of the prevalence rates of overweight reported for children and adolescents ob- Figure 2. Age-adjusted prevalence of overweight (BMI 25.0 –29.9 kg/m2) and obesity (BMI ⱖ30 kg/m2) in adults (age 20 –74 years) in the United States since 1960. Data obtained from 1960 –1962 NHES I, 1971–1974 National Health and Nutrition Examination Survey I (NHANES I), 1976 –1980 NHANES II, 1988 –1994 NHANES III, and preliminary data from NHANES 1999. The prevalence of overweight or obesity increased (from 43% to 61%) between NHES I (1960 –1962) and NHANES 1999 caused by a small increase in overweight (from 30.5% to 34%) and to more than a doubling in the prevalence of obesity (from 12.8% to 27%). (Data obtained from Flegal et al.28) and National Center for Health Statistics, Centers for Disease Control and Prevention web site www.cdc.gov/nchs/products/pubs/pubd/ hestats/obese/obse99.htm (accessed December 14, 2001).27 served in earlier surveys. Obesity-related diseases that typically are seen in adults, such as type 2 diabetes mellitus, hyperlipidemia, hypertension, orthopedic complications, sleep apnea, gallbladder disease, and nonalcoholic steatohepatitis (NASH), are now being seen with increasing frequency in children.31 In addition, earlyonset obesity is associated with an increased chance of being an obese adult and an increased risk of obesityrelated diseases.32–33 Pathogenesis Energy Balance In all persons, obesity is caused by ingesting more energy than is expended over a long period of time. Very small but chronic differences between energy intake and energy expenditure can lead to large increases in body fat. For example, ingestion of only 5% more calories than expended could result in the accumulation of ⬃5 kg of adipose tissue in 1 year. Ingestion of only 8 kcal per day more than expended over 30 years could lead to an increase in 10 kg in body weight, which is the average amount of weight gained by American adults during the 30-year period from 25 to 55 years of age.34 Genetics and Environment Both genetic and environmental factors contribute to body size. It has been estimated that genetic September 2002 background can explain 40% or more of the variance in body mass in humans.35 The genetic component of human obesity is complex and likely to involve the interaction between multiple genes. More than 250 genes, markers, and chromosomal regions have been linked with human obesity,35a but the clinical importance of each association is not yet known. Several monogenic causes of obesity have been described in humans, and include mutations in genes for leptin,36 –38 leptin receptor,39 prohormone convertase 1,40 pro-opiomelanocortin,41 melanocortin-4 receptor,42 and SIM1.43 Although rare, these cases have increased our understanding of the molecular mechanisms that regulate energy balance in humans. The marked increase in the prevalence of obesity in the last 20 years cannot be attributed to genetic changes and must be a result of alterations in environmental influences. It is likely that both an increase in energy intake44 and a decline in physical activity45– 47 are responsible for the recent epidemic of obesity. Energy consumption has increased presumably because more meals are eaten outside the home, serving sizes are larger, there is greater availability of convenience and snack foods, and there is an increase in food variety and palatability. Advances in technology have led to decreased daily physical activity because of energy-conserving devices, sedentary work and social activities, and motorized transportation. Environmental impact in high-risk populations. Persons with certain genetic backgrounds are particularly predisposed to weight gain and obesity-related diseases when they are exposed to a modern lifestyle. Striking examples of the influence of environment on body weight have been reported globally. Pima Indians living in Arizona have experienced a dramatic change in their lifestyle, which has led to an epidemic of obesity and diabetes in the last 50 years.48 These Pimas now eat a high-fat diet (50% of energy as fat) provided by government surplus commodities rather than their traditional low-fat (15% of energy as fat) diet, and are much more sedentary than when they lived as farmers. In contrast, Pima Indians who live in the Sierra Madre Mountains of Northern Mexico have been isolated from Western influences, eat a traditional Pima diet, and are physically active as farmers and sawmill workers. The Pimas of Mexico have a much lower incidence of obesity and diabetes than their genetic kindred who live in Arizona. Another example is the Aborigine population of northern Australia. Urbanized Aborigines have a high prevalence of type 2 diabetes mellitus and hypertriglyceridemia, and are heavier than their typically very lean (BMI ⬍20 kg/m2) relatives who live a traditional hunter-gatherer AMERICAN GASTROENTEROLOGICAL ASSOCIATION 885 lifestyle.49 In urbanized Aborigines with type 2 diabetes and hypertriglyceridemia, short-term (7-week) reversion to a traditional hunter-gatherer lifestyle, which entailed a low-fat, low-energy diet of wild game, fish, and plants and increased physical activity, produced weight loss and marked improvement or normalization of fasting blood glucose, insulin, and triglyceride concentrations and glucose tolerance.50 In Papua New Guinea, the prevalence of obesity in the rural Highlands is approximately 3%, whereas 38% of the population in urban Wanigelas is obese.25 Early environmental factors. Environmental factors in very early life may influence subsequent body weight and the development of metabolic abnormalities. A series of studies have found that adult men and women who were small for gestational age at birth, defined by a low birthweight, low ponderal index (birthweight/ length3), or small head circumference, were more likely to have a higher BMI, a higher waist-to-hip circumference ratio, the metabolic syndrome, and coronary artery disease than men and women who were normal-sized at birth.51–54 The mechanism for this observation is not known, but it has been hypothesized that fetal undernutrition and impaired fetal development may have longterm effects on organ function.55 Nutritional factors during infancy also may be involved in subsequent body size. A cross-sectional survey of 13,345 children in Bavaria, Germany, found that breast-feeding during the first year of life decreased the risk of overweight and obesity at ages 5 and 6 years.56,57 Moreover, the protective effect of childhood breast-feeding followed a doseresponse relationship and could not be explained by social class or lifestyle. Influence of childhood and parental obesity. Both childhood and parental obesity affect the risk of obesity in adulthood. Data obtained from long-term members of a health maintenance organization in the state of Washington showed that the risk of being an obese young adult (21 to 29 years of age) ranged from 8% for obese 1- and 2-year-olds without obese parents to 79% for obese 10- to 14-year-olds with at least one obese parent.58 The probability of being an obese adult increased with increasing age and severity of obesity in childhood. An obese child at 1 or 2 years of age who had lean parents did not have an increased risk of obesity in adulthood, whereas being obese after 6 years of age was associated with more than a 50% chance of being an obese adult. In addition, the presence of obesity in one or both parents increased the risk of obesity in adulthood. For example, lean children with at least one obese parent 886 AMERICAN GASTROENTEROLOGICAL ASSOCIATION GASTROENTEROLOGY Vol. 123, No. 3 had a 3-fold greater risk of obesity in adulthood than did lean children with lean parents. Energy Metabolism Daily total energy expenditure (TEE) is comprised of (1) resting energy expenditure (REE) (i.e., energy expended for normal cellular and organ function during postabsorptive resting conditions; approximately 70% of TEE); (2) thermic effect of food (i.e., the increase in energy expenditure associated with digestion, absorption, and increased sympathetic nervous system activity after eating a meal; approximately 10% of TEE); and (3) energy expended in physical activity (i.e., energy cost of volitional mechanical work, such as exercise and daily activities, and nonvolitional activity, such as fidgeting, spontaneous muscle contractions, and maintaining posture; approximately 20% of TEE). The resting energy requirements of specific tissues differ dramatically (Table 2). Organs that function continuously, such as the liver, gut, brain, kidney, and heart, have the highest energy requirements per gram of tissue. In a lean adult, these organs account for approximately 75% of the resting metabolic rate, although they constitute only 10% of total body weight. In contrast, resting skeletal muscle consumes approximately 20% of resting metabolic rate but represents approximately 40% of body weight, and adipose tissue consumes less than 5% of resting metabolic rate but usually accounts for more than 20% of body weight. The possibility that defects in energy metabolism are associated with obesity has been carefully evaluated in cross-sectional studies. REE is typically greater in obese than in lean individuals who are the same height because of increased lean, as well as adipose, tissue cell masses in Table 2. Resting Energy Requirements of a Man Weighing 70 kg Tissue mass Liver Brain Kidneys Heart Gut Skeletal muscle Adipose tissue Daily energy consumption g % body weight kcal/g tissue kcal % REE 1550 1400 300 300 2000 28,000 15,000 2.2 2.0 0.4 0.4 3.0 40.0 21.0 0.28 0.30 1.27 0.80 0.15 0.014 0.005 445 420 360 235 300 400 80 19 18 15 10 13 18 4 Data from Klein S, Jeejeebhoy K. The malnourished patient: nutritional assessment and management. In: Feldman M, Friedman LS, Sleisenger MH, eds. Gastrointestinal and Liver disease. Philadelphia, Saunders, 2002:266. obese persons.59 Studies in obese and lean volunteers matched for either lean body mass or fat mass suggest that increased adiposity in obese subjects is associated with a small (⬃75 kcal per day) but possibly important reduction in the thermic effect of food,60 which may be related to insulin resistance and blunted sympathetic nervous system activity associated with obesity.61 Obese persons require the same amount of energy as lean persons to perform the same amount of work when body weight is supported.62 Moreover, obese persons expend more energy than lean persons during weight-bearing activities because of the increased work involved in carrying more weight. However, it is not known whether obese adults expend less total energy on daily physical activity because they are less active than lean persons. Two comprehensive studies performed in children found that sleeping metabolic rate, REE, energy expenditure of physical activity, and daily TEE were the same in lean and obese children after adjusting for differences in body composition.63,64 In summary, the results from a large number of studies suggest that obese persons do not have obvious abnormalities in any of the components of energy metabolism. In fact, defects in REE or TEE have not even been found in “diet-resistant” patients who fail to lose weight despite claiming strict adherence to a lowcalorie diet.65,66 These patients unknowingly underestimate their food intake and may consume twice as many calories as recorded in daily food records. Although significant abnormalities in energy metabolism have not been found in adults or children who are already obese, it is still possible that inherent alterations in energy expenditure contribute to the pathogenesis of human obesity. However, establishing a causal relationship between energy expenditure and subsequent obesity is difficult because measurement of energy metabolism represents a brief “snapshot” in time, which may not capture abnormalities that occur during specific stages of life. In addition, the ability to detect small, but possibly clinically important, chronic defects in metabolic rate is limited by currently available research technology. Nonetheless, most, but not all, studies do not support the notion that a defect in metabolic rate predisposes to obesity. One longitudinal study in children found that daily TEE at 3 months of age was 21% lower in infants who later became overweight67 than in those who remained normal weight, but this finding was not confirmed in larger subsequent studies.68,69 A longitudinal study of 126 Pima Indians revealed that those in the lowest REE tertile at baseline had the highest cumulative incidence of a 10-kg weight gain 1 to 4 years later.70 In contrast, the Baltimore Longitudinal Study did not find September 2002 a relationship between initial REE and weight change during a 10-year average follow-up of 775 men.71 Although weight gain always occurs when energy intake exceeds energy expenditure, the amount of weight that is gained after overfeeding may be genetically determined and certain individuals may be more resistant to weight gain than others. Bouchard et al.72 found that chronic overfeeding of 1000 kcal per day caused a variable increase in body weight among a group of 12 monozygotic twin pairs. However, the weight gained by one twin was very similar to the weight gained by the other. The differences in weight gained between twin pairs may have been caused by differences in their thermogenic response to overfeeding. A recent study indicated that body fat gain in response to 8 weeks of overfeeding was inversely related to changes in nonvolitional energy expenditure (e.g., fidgeting).73 Therefore, nonvolitional energy expenditure during overfeeding may be genetically determined and can prevent or limit excessive weight gain in some individuals by considerable dissipation of excess ingested energy. Diet-induced weight loss decreases REE, which contributes to weight regain. This phenomenon has led to the “set-point theory,” which proposes that body weight is predetermined so that weight loss (or weight gain) will decrease (or increase) metabolic rate, to return body weight to a preset value.74 Hypocaloric feeding in either lean or obese persons causes a 15% to 30% decline in REE, which cannot be explained completely by the concomitant decrease in body size or lean body mass and is part of the normal metabolic adaptation to energy restriction.75 However, the decline in REE below predicted values is a transient phenomenon that occurs during negative energy balance but does not persist during weight maintenance. Many studies have demonstrated that long-term maintenance of lost weight does not cause an abnormal decrease in REE or TEE when adjusted for changes in body composition.76,77 A meta-analysis of 15 studies found that REE was similar in formerly obese and never obese subjects.78 Therefore, the decline in absolute REE and TEE that occurs after weight loss is likely to contribute to recidivism; the decrease in energy metabolism appears to be largely appropriate for the changes in body composition. Adipose Tissue Triglycerides present within adipose tissue are the body’s major fuel reserve (Table 3). A lean adult has about 35 billion adipocytes and each adipocyte contains about 0.4 to 0.6 g of triglyceride; an extremely obese adult can have 4 times as many adipocytes (125 billion), AMERICAN GASTROENTEROLOGICAL ASSOCIATION 887 Table 3. Endogenous Fuel Stores in a Man Weighing 70 kg Mass Tissue Fuel source Adipose tissue Liver Triglyceride Glycogen Proteina Triglyceride Proteina Glycogen Triglyceride Glucose Triglyceride Free fatty acids Muscle Blood aNot g 13,000 100 300 50 6000 500 300 3 4 0.5 kcal 120,000 400 1200 450 24,000 2000 2700 12 35 5 normally considered a fuel source. each containing twice as much lipid (0.8 to 1.2 g of triglyceride).79 The high energy density and hydrophobic nature of triglycerides make it a 5-fold better fuel per unit mass than glycogen. Triglycerides liberate 9.3 kcal/g when oxidized and are stored compactly as an oil inside the fat cell, accounting for 85% of adipocyte weight. By comparison, glycogen produces only 4.1 kcal/g when oxidized and is stored intracellularly as a gel containing approximately 2 g of water for every gram of glycogen. Therefore, adipose tissue represents an effective mechanism for storing transportable fuel and permits mobility and survival during periods of food deprivation. In fact, the duration of survival during starvation depends on the amount of body fat mass. In lean men, death occurs after approximately 2 months of starvation when more than 35% (⬃25 kg) of body weight is lost.80 In contrast, obese persons have undergone therapeutic fasts for more than a year without adverse consequences. The longest reported fast was that of a 207-kg man who ingested acaloric fluids, vitamins, and minerals for 382 days and lost 61% (126 kg) of his initial weight.81 The cornerstone of obesity therapy is to eat fewer calories than are expended to consume endogenous fat stores as fuel. Approximately 75% to 85% of weight that is lost by dieting is composed of fat and 15% to 25% is fat-free mass (FFM).82 Therefore, although an energy deficit of approximately 3500 kcal is needed to oxidize 1 pound of adipose tissue, a 3500-kcal energy deficit will cause more than a 1-pound loss in body weight because of the oxidation of lean tissue and associated water losses. In addition, there is regional heterogeneity in the distribution of fat loss, with greater relative losses of intraabdominal fat than total body fat mass, particularly in men and women with increased initial intra-abdominal fat mass.83,84 Most, if not all, of the loss of fat is caused by a decrease in the size (lipid content) of existing fat cells.85 There is also evidence in humans that large, 888 AMERICAN GASTROENTEROLOGICAL ASSOCIATION long-term fat loss can decrease the number of fat cells.86 However, it is possible that the marked shrinkage caused by severe weight loss may make some adipocytes visually indiscernible by standard cell-counting techniques, leading to a false perception of decreased fat cell number. Weight loss could eliminate fat cells by 2 possible mechanisms: dedifferentiation and apoptosis. Although adipocyte dedifferentiation, the morphological and biochemical reversion of mature adipocytes to preadipocytes, has been identified in vitro, there is no evidence that this process occurs in vivo.87 In contrast, adipoctye apoptosis can be induced in vitro88 and has been shown to occur in vivo in some patients with cancer.89 However, the possibility that adipocyte apoptosis is induced by weight loss has not been studied. Medical Complications of Obesity Obesity is an important risk factor for many serious medical complications (Table 4), which lead to impaired quality of life, considerable morbidity, and premature death. Many of the complications associated with obesity have been reviewed previously.4,90,91 Gastrointestinal and other selected complications will be discussed in this section. Gastrointestinal Disease Gastroesophageal reflux disease. Most,92–96 but not all,97 large epidemiological studies have found that gastroesophageal reflux disease (GERD) symptoms are more common in obese than in lean persons. However, it is unclear whether obesity actually causes reflux or is simply associated with GERD. The relationship between obesity and known factors that predispose to GERD, such as resting lower esophageal sphincter (LES) pressure and acidic lower esophageal pH, is unclear because of conflicting results from different studies. Several studies found no significant relationship between BMI and GASTROENTEROLOGY Vol. 123, No. 3 esophageal acid reflux evaluated by 24-hour pH monitoring,98 –100 whereas one study, involving extremely obese subjects, revealed that BMI correlated directly with pathologic reflux, defined as an esophageal pH ⬍4 for more than 5% of the time.101 Although increased intra-abdominal pressure induced by excessive abdominal girth may predispose obese persons to reflux, we are unaware of any randomized controlled trials that have evaluated whether weight loss decreases reflux symptoms. In one study, conducted in lean persons, diet-induced weight loss correlated directly with improvement in reflux symptoms.102 However, even modest weight loss of 2 to 3 kg caused a marked improvement in symptom score, suggesting that changes in diet rather than body weight may have been responsible for the beneficial clinical effects. In studies of patients with class I103 and class III104 obesity who had symptoms of GERD, diet-induced weight loss did not improve symptoms or 24-hour esophageal pH values. In contrast, the gastric bypass procedure consistently has been shown to decrease GERD symptoms.105–107 In fact, GERD symptoms often resolve immediately after surgery, before there is significant weight loss,101 suggesting that the elimination of acid or bile reflux, rather than decreased weight, is responsible for the beneficial effect. Although some studies have found that vertical-banded gastroplasty (VBG) and gastric banding, which increase resistance to flow through the proximal pouch, do not alter LES pressure or increase episodes of reflux,108,109 severe gastroesophageal reflux can occur after VBG.110,111 Gallbladder disease. Obesity is an important risk factor for gallbladder disease, particularly in women. The risk of symptomatic gallstones increases linearly with BMI (Figure 3).21,112 Data from the Nurses Health Study demonstrated that, compared with lean women (BMI ⬍24 kg/m2), obese women (BMI ⬎30 kg/m2) had a 2-fold excess risk and extremely obese women (BMI Table 4. Medical Complications Associated With Obesity Gastrointestinal Endocrine/metabolic Cardiovascular Respiratory Musculoskeletal Gynecologic Genitourinary Ophthalmologic Neurologic Cancer Postoperative events Gallstones, pancreatitis, abdominal hernia, NAFLD (steatosis, steatohepatitis, and cirrhosis), and possibly GERD Metabolic syndrome, insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, dyslipidemia, polycystic ovary syndrome Hypertension, coronary heart disease, congestive heart failure, dysrhythmias, pulmonary hypertension, ischemic stroke, venous stasis, deep vein thrombosis, pulmonary embolus Abnormal pulmonary function, obstructive sleep apnea, obesity hypoventilation syndrome Osteoarthritis, gout, low back pain Abnormal menses, infertility Urinary stress incontinence Cataracts Idiopathic intracranial hypertension (pseudotumor cerebri) Esophagus, colon, gallbladder, prostate, breast, uterus, cervix, kidney Atelectasis, pneumonia, deep vein thrombosis, pulmonary embolus September 2002 Figure 3. Relationship between the incidence of symptomatic gallstones (defined as cholecystectomy or newly diagnosed symptomatic unremoved gallstones) and BMI in the Nurse’s Health Study. (Data from Stampfer et al.112) ⬎45 kg/m2) had a 7-fold excess risk of symptomatic gallstones.112 The annual incidence of symptomatic gallstones was 1% in women who had a BMI greater than 30 kg/m2 and 2% in those with a BMI greater than 45 kg/m2. The risk of obesity-related gallbladder disease is smaller in men than in women. Data from 2 large prospective studies of men,113,114 as well as the NHANES III data from men and women, showed the prevalence of gallstones was lower in men than in women when both genders were matched on BMI. The relative increase in risk with increasing BMI was also lower in men. The risk of gallstones increases during weight loss because of increased bile cholesterol supersaturation, enhanced cholesterol crystal nucleation, and decreased gallbladder contractility.115 The incidence of new gallstones is approximately 25% and 35% in obese patients who experience rapid weight loss after treatment with a verylow-calorie (⬍600 kcal per day), low-fat (1 to 3 g per day) diet116 –119 and gastric surgery,120 –123 respectively. The risk of gallstone formation increases exponentially when the rate of weight loss exceeds 1.5 kg (⬃1.5% of body weight) per week.124 Dietary fat content also influences de novo gallstone formation during weight loss induced by a very-low-calorie diet, presumably because of the effect of ingested fat on gallbladder emptying; ingesting a meal with 4 g of fat is a poor stimulus for gallbladder emptying, whereas ingesting a meal with 10 g of fat causes maximal gallbladder contractility.125 Festi et al.126 found that increasing the fat content of a very-low-calorie diet (⬍600 kcal per day) prevented the development of new gallstones. The risk of developing gallstones while dieting is much lower (0%–17%) in patients who consume a low-calorie diet (⬎800 kcal per AMERICAN GASTROENTEROLOGICAL ASSOCIATION 889 day) containing 15 to 30 g of fat per day than a verylow-calorie, low-fat diet.127–130 Moreover, increasing dietary fat content may not be as important for reducing the risk of gallstones in low-calorie compared with verylow-calorie diet therapy.131 Ursodeoxycholic acid therapy markedly decreases gallstone formation caused by either a very-low-calorie diet119 or gastric surgery.121–122 A dose of 600 mg per day provides maximal gallstone prevention and prophylactic therapy is cost-effective in patients who are expected to achieve rapid weight loss.132 Pancreatitis. Although it seems logical that obese patients should be at increased risk for gallstone pancreatitis because of the increased prevalence of gallstones, few studies have evaluated this issue. However, there is evidence from both retrospective and prospective studies that obese patients who develop pancreatitis from any cause experience a worse outcome than lean patients. Most studies found that overweight and obese patients are at higher risk for developing local complications and severe pancreatitis.133–137 Several studies found that obesity also increased the risk of respiratory insufficiency134,136,138 and mortality.133 It has been hypothesized that increased fat deposited in the peripancreatic and retroperitoneal spaces may predispose obese patients to peripancreatic fat necrosis and subsequent local and systemic complications. Liver disease. Obesity is associated with a constellation of liver abnormalities, manifested by hepatomegaly, increased liver biochemistry values, and alterations in liver histology (macrovesicular steatosis, steatohepatitis, fibrosis, and cirrhosis).139 Although these abnormalities have been reported as individual entities associated with obesity, they more likely represent a spectrum of liver disease, now known as nonalcoholic fatty liver disease (NAFLD).140 The exact prevalence of different features of NAFLD in obese patients is not known because of a paucity of data. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are the most commonly elevated liver enzymes but they usually do not exceed twice the upper limit of normal127; enzyme levels often do not correlate with the severity of histological abnormalities.140 Dieting itself often causes a transient increase in serum transaminase concentrations and a decrease in serum alkaline phosphatase concentration during the first 6 weeks of active weight loss.127,141,142 A retrospective analysis of liver biopsy specimens obtained from overweight and obese patients who had abnormal liver biochemistries but who did not have overt findings of liver disease or evidence of acquired, autoimmune, or genetic liver disease, revealed that 30% of patients had septal fibrosis and one-third of 890 AMERICAN GASTROENTEROLOGICAL ASSOCIATION these (10% of the total group) had “silent” cirrhosis.143 In addition, many patients who have histological features of NAFLD are obese. Composite data from a series of studies found that 40% to 100% of patients with NASH were obese.144 Data from autopsy studies, investigations of obese patients undergoing obesity surgery, and crosssectional analyses of liver biopsy samples suggest that steatosis occurs in ⬃75%, steatohepatitis in ⬃20%, and cirrhosis in ⬃2% of obese patients.145–147 Although the clinical, laboratory, and histological features of NAFLD have been documented,138 –150 the pathogenesis and natural history of this disease are not well understood. Most patients with NAFLD are asymptomatic, but some may complain of fatigue, malaise, and vague abdominal discomfort. Hepatomegaly has been reported in up to 75% of patients with NAFLD. In contrast to patients who have alcohol-induced steatohepatitis, the AST:ALT ratio is usually less than 1 in patients who have NAFLD. In studies that observed patients for 1 to 7 years, liver disease progressed in approximately 40%, with cirrhosis occurring in approximately 10% of patients. Moreover, most patients with simple steatosis had a benign clinical course, whereas those with steatohepatitis, fibrosis, and cirrhosis were more likely to develop clinical sequelae of severe liver disease. Although only a small percentage of patients with NAFLD eventually develop cirrhosis, the high prevalence of obesity and obesity-related liver disease makes NAFLD an important cause of cirrhosis in the United States. Furthermore, obesity increases the risk of fibrosis and cirrhosis in patients with alcoholic liver disease151 and hepatitis C.152 The factors responsible for the development of NAFLD in obese persons are not clear. There is increasing evidence that NAFLD is associated with abdominal obesity (assessed by waist circumference), insulin resistance (defined by elevated fasting blood glucose and insulin concentrations), diabetes, hypertriglyceridemia, low serum high-density lipoprotein (HDL) cholesterol concentrations, and hypertension.143,153–155 It has been hypothesized that NAFLD is the result of 2 or more insults to the liver.156 The first “hit” is steatosis, presumably caused by obesity-induced alterations in lipid metabolism, including increased lipolysis of adipose tissue triglycerides, which increases free fatty acid delivery to the liver, increased hepatic de novo lipogenesis, and decreased hepatic fatty acid oxidation. The second “hit” may be peroxidation of hepatic lipids and injury-related cytokines, which can cause direct cellular injury, inflammation, and fibrosis.157 GASTROENTEROLOGY Vol. 123, No. 3 Although weight loss typically is recommended for obese patients with NAFLD, it is not known whether this therapy changes the natural history of disease. A gradual loss of 10% or more of body weight can correct abnormal liver chemistries and decrease liver size, fat content, and features of steatohepatitis.158 –160 However, rapid weight loss after gastric surgery,146 very-low-calorie diets (VLCDs),161 or fasting162 decreases hepatic fat content but can induce hepatic inflammation and exacerbate steatohepatitis. Endocrinologic/Metabolic Disease Metabolic syndrome. The metabolic syndrome, also known as the insulin-resistance syndrome and syndrome X, represents a specific body phenotype in conjunction with a group of metabolic abnormalities that are risk factors for CHD. Characteristics of this syndrome include abdominal obesity, insulin-resistant glucose metabolism (hyperinsulinemia, impaired glucose tolerance, impaired insulin-mediated glucose disposal, type 2 diabetes mellitus), dyslipidemia (hypertriglyceridemia, low serum HDL-cholesterol concentration), and hypertension. Recently, additional metabolic abnormalities associated with abdominal obesity that are also risk factors for CHD have been identified: increased serum concentrations of apolipoprotein B, small, dense low-densitylipoprotein (LDL) particles, and plasminogen activator inhibitor 1 (PAI-1) with impaired fibrinolysis.163,164 Obesity itself is not a requirement for the metabolic syndrome; metabolically obese, normal-weight persons, presumably with increased abdominal fat mass, have been identified.165 It has been hypothesized that insulin resistance is the common pathogenic mechanism underlying the metabolic syndrome.166 However, factor analysis of nondiabetic participants in the Framingham Offspring Study suggests that insulin resistance may not be the only antecedent and that more than one independent physiological process is responsible for the observed cluster of metabolic abnormalities.167 Although abdominal obesity clearly is associated with insulin resistance, it is not clear whether visceral (omental and mesenteric) fat or subcutaneous abdominal fat is more closely associated with insulin resistance because of contradictory data from different studies.168 –173 Moreover, the size of one depot correlates closely with the size of the other,168 making it difficult to separate the relationship of each one with insulin sensitivity. In addition, it is not known whether visceral or abdominal fat actually is involved in the pathogenesis of the metabolic syndrome or whether these are simply markers for persons who are at increased risk for the metabolic complications of obesity.174 September 2002 Type 2 diabetes mellitus. It is likely that the 25% increase in the prevalence of diabetes in the last 20 years in the United States175 is caused by the marked increase in the prevalence of obesity. BMI, abdominal fat distribution, and weight gain are important risk factors for type 2 diabetes mellitus. Data from NHANES III found that two-thirds of adult men and women in the United States diagnosed with type 2 diabetes have a BMI of 27 kg/m2 or greater.91 Moreover, the risk of diabetes increased linearly with BMI; diabetes prevalence was 2%, 8%, and 13% in those with BMI 25 to 29.9 kg/m2 (overweight), 30 to 34.9 kg/m2 (class I obesity), and ⱖ35 kg/m2 (class II/III obesity), respectively.175 Data from the Nurses Health Study proved that the risk of diabetes begins to increase in “normal” weight women when BMI exceeds 22 kg/m2.18,176 Increases in abdominal fat mass, waist circumference, and waist-to-hip-circumference ratio all increase the risk of diabetes at any BMI value.177–179 Weight gain during adulthood also increases the risk of diabetes. For example, men and women 35 to 60 years of age who gained 5 to 10 kg since age 18 to 20 years had a 3-fold greater risk of diabetes than those who maintained their weight within 2 kg.18,19 Dyslipidemia. Obesity, particularly the abdominal obesity phenotype, is associated with hypertriglyceridemia, low HDL2 cholesterol, and an increased proportion of small, dense, LDL particles.180 –182 Most studies also suggest that overweight and obesity are associated with an increase in serum total and LDL-cholesterol concentrations.183 However, BMI-associated differences in total and LDL cholesterol are more pronounced at lower body weights and become blunted with increasing age. Data from NHANES III showed that the prevalence of hypercholesterolemia (total blood cholesterol ⱖ240 mg/dL or 6.21 mmol/L) increased progressively with increasing BMI in men, whereas the prevalence of hypercholesterolemia was highest at a BMI between 25 kg/m2 and 27 kg/m2 and did not increase further with higher BMI values in women.183 The abnormalities in serum lipids associated with obesity are clinically important and are clearly associated with an increased risk of CHD.184,185 Cardiovascular Disease CHD. Obese persons, particularly those with ab- dominal fat distribution and those who gained weight during young adulthood, are at increased risk for CHD. The risk of CHD begins to increase at a “normal” BMI of 23 kg/m2 for men and 22 kg/m2 for women.186 The presence of increased abdominal fat increases the risk of CHD at any given BMI value. In fact, data from the Nurses Health Study showed that women in the lowest AMERICAN GASTROENTEROLOGICAL ASSOCIATION 891 BMI but highest waist-to-hip circumference ratio tertiles had a greater risk of fatal and nonfatal myocardial infarctions than women in the highest BMI but lowest waistto-hip circumference ratio tertiles.187 A weight gain of 5 or more kg after 18 years of age also increases the risk of fatal and nonfatal myocardial infarction.10,16 Most of the increase in CHD is mediated by obesity-related increases in risk factors, particularly hypertension, dyslipidemia, impaired glucose tolerance/diabetes, and the metabolic syndrome. It has been more difficult to show an independent effect of obesity on CHD in epidemiological studies, possibly because of the long follow-up period needed to detect CHD, the confounding effect of CHD risk factors that affect body weight (such as cigarette smoking), and the influence of body fat distribution. Nonetheless, several long-term epidemiological studies disclosed that overweight and obesity increased the risk of CHD, even after correction for other known risk factors.10,188 Therefore, the American Heart Association recently added obesity to its list of major risk factors for CHD189 and developed guidelines for achieving a healthy body weight.190 Cerebrovascular and thromboembolic disease. Overweight and obesity increase the risk of ischemic, but not hemorrhagic, strokes in both men and women.191,192 The risk of fatal and nonfatal ischemic stroke increases progressively with increasing BMI and is approximately 2-fold greater in obese than in lean persons. Obesity, particularly abdominal obesity, also increases the risk of venous stasis, deep vein thrombosis, and pulmonary embolism.193–195 Lower extremity venous disease may be a consequence of increased intra-abdominal pressure, an impaired fibrinolytic system, and increased inflammatory mediators associated with abdominal obesity.196,197 Recent data obtained from California Medicare records revealed that elderly patients who underwent total hip arthroplasty had a 2.5-fold increased risk of subsequent hospitalization for symptomatic thromboembolic disease (deep vein thrombosis or pulmonary embolism) if their BMI was 25 kg/m2 or greater.198 Hypertension. Several large epidemiological studies have documented the linear relationship between hypertension and BMI.188,199 –201 Data from NHANES III demonstrated that the age-adjusted prevalence of hypertension (defined as systolic blood pressure ⱖ140 mm Hg, diastolic blood pressure ⱖ90 mm Hg, or use of antihypertensive medications) was more than 2-fold higher in obese men and women (42% and 38% prevalence rates, respectively) than in lean men and women (⬃15% prevalence rate in both men and women).183 Abdominal fat distribution is an independent risk factor 892 AMERICAN GASTROENTEROLOGICAL ASSOCIATION for hypertension and in some studies was a better predictor of hypertension than BMI.202–204 Weight gain also increases hypertensive risk. Longitudinal assessment of participants in the Framingham Study found that blood pressure increased by 6.5 mm Hg for every 10% increase in body weight.200 Pulmonary Disease Pulmonary Function Obesity is associated with pulmonary function abnormalities, obesity-hypoventilation syndrome, and obstructive sleep apnea.205 However, no epidemiological or longitudinal studies have systematically evaluated the prevalence or natural history of pulmonary disease in obese persons. Obesity, particularly when there is excess abdominal fat, can interfere mechanically with lung function. Increased weight on the chest wall and thoracic cage decreases respiratory compliance, increases the work of breathing, restricts ventilation (measured as decreased total lung capacity, forced vital capacity, and maximal ventilatory ventilation), and limits ventilation of lung bases with subsequent atelectasis, ventilatory-perfusion mismatching, and increases in alveolar-to-arterial gradient. Obesity-hypoventilation. Patients with obesityhypoventilation syndrome have a PCO2 ⬎50 mm Hg because of decreased ventilatory responsiveness to hypercapnea and/or hypoxia and an inability of respiratory muscles to meet the increased ventilatory demand caused by the mechanical effects of obesity. Alveolar ventilation is reduced because of shallow and inefficient breathing related to decreased tidal volume, inadequate inspiratory strength, and an elevated diaphragm. Patients may become more symptomatic when lying down because abdominal pressure pushes up the diaphragm, which increases intrathoracic pressure, causing further compromise in lung function and respiratory capacity. A severe form of the obesity-hypoventilation syndrome, known as the Pickwickian Syndrome after an obese character in Charles Dickens’ Pickwick Papers, is associated with extreme obesity, irregular breathing, somnolence, cyanosis, secondary polycythemia, and right ventricular dysfunction. Obstructive sleep apnea. Obstructive sleep apnea syndrome is characterized by excessive episodes of apnea and hypopnea during sleep caused by partial or complete upper airway obstruction, despite persistent respiratory efforts. The interruption in nighttime sleep and arterial hypoxemia cause daytime sleepiness and cardiopulmonary dysfunction. Most patients with sleep apnea have a BMI ⬎30 kg/m2, abdominal fat distribution, and a large GASTROENTEROLOGY Vol. 123, No. 3 neck girth (ⱖ17 inches in men and ⱖ16 inches in women).206 –210 In addition, midlife waist circumference and an increase in waist circumference over 30 years of adult life are independent risk factors for sleep apnea in old age (75 to 91 years of age).211 However, the presence of sleep apnea in lean persons demonstrates that other factors, such as cephalometric defects that are independent of body weight and regional fat distribution, also contribute to risk.212 Musculoskeletal Disease Gout. Both cross-sectional and longitudinal studies have demonstrated that obesity is associated with hyperuricemia and gout.213–214 Moreover, hyperuricemia is associated with abdominal obesity and the metabolic syndrome,215–216 and insulin resistance decreases renal uric acid clearance.217 Osteoarthritis. Overweight and obesity increase the risk of osteoarthritis of weight-bearing joints, particularly the knees, presumably because body weight exerted across the knee is much greater than that exerted across the hips during weight-bearing activities.218 –219 The relationship between body size and osteoarthritis is stronger in women than in men and even small increases in body weight can cause osteoarthritis in women. A study of twin pairs found that individuals who had symptomatic or asymptomatic lower extremity osteoarthritis were 3 to 5 kg heavier than their paired siblings.220 Data from longitudinal studies suggest that obesity is involved in the pathogenesis of osteoarthritis because obesity can precede osteoarthritis by decades.220 –221 Some studies also have found that obesity is associated with osteoarthritis of the hand, suggesting that increased load across a joint may not be the only pathogenic mechanism responsible for joint disease.222–223 Cancer Overweight and obesity are associated with an increased risk of esophageal, gallbladder, pancreatic, breast, renal, uteral, cervical, and prostate cancer.92,224 –226 A direct relationship between BMI and colon cancer has been observed for both men and women in most,226 –228 but not all,229,230 epidemiological studies. The effect of BMI is strongest for distal cancers and in those with a family history of colorectal cancer.231 Obesity and weight gain after the age of 18 years increase the risk of breast and endometrial cancer mortality.226,232 However, the greater risk of breast cancer with increasing BMI is limited to postmenopausal women, and increased BMI actually may be protective of breast cancer in premenopausal women.233 Moreover, it is difficult to determine how much of the September 2002 association between obesity and cancer is attributable to obesity per se or to a high-fat, high-calorie diet because both factors often are correlated. Reproductive and Urinary Tract Abnormalities in Women Obesity is associated with irregular menses, amenorrhea, and infertility.234 Obesity during pregnancy increases the risk for gestational diabetes and hypertension,235 a complicated delivery,236 and congenital malformations.237 Obesity is an independent risk factor for urinary incontinence, even when the data are adjusted for age and parity.238 –240 In one study, the odds ratio for daily incontinence increased by 1.6 for every 5-unit increase in BMI.240 Presumably, increased intra-abdominal pressure is an important etiologic factor for incontinence, and incontinence usually resolves in extremely obese patients after massive weight loss.241 Neurological Disease Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, is a syndrome of increased intracranial pressure in the absence of hyrocephalus or a space-occupying lesion. This syndrome often causes symptoms of headache, vision abnormalities, tinnitus, and sixth nerve paresis. Increased BMI is associated with an increased prevalence of IIH, and even persons who are as little as 10% above ideal body weight are at increased risk.242,243 The notion of a causal relationship between obesity and IIH is supported by the observation that marked weight loss in extremely obese patients with IIH decreases intracranial pressure and resolves most associated clinical signs and symptoms.244,245 Even modest weight losses of ⬃6% of body weight have been associated with resolution of papilledema.246 Ophthalmological Disease Several epidemiological studies have shown that overweight and obesity are associated with an increased prevalence of cataracts and cataract surgery.247–250 Moreover, excess abdominal fat distribution, assessed by waist-to-hip-circumference ratio, is an additional risk factor.250,251 It is not known whether obesity causes or is simply associated with premature cataracts. However, several obesity-related abnormalities, such as insulin resistance, elevated serum uric acid concentrations, and an increase in inflammatory mediators, may contribute to cataract formation. Psychological Abnormalities Approximately 20% to 30% of obese patients who seek weight reduction at university clinics suffer AMERICAN GASTROENTEROLOGICAL ASSOCIATION 893 from depression or other psychological disturbances.252 However, there is only limited evidence of increased psychiatric or emotional abnormalities in obese compared with normal-weight subjects when both are recruited from the general population.253 Obese women may be at greater risk of psychological abnormalities than obese men, presumably because of the greater social pressure on females to be thin.254 Some behavioral abnormalities may contribute to obesity. Binge eating is defined as eating a large amount of food in a short period of time, accompanied by feelings of loss of control and guilt. The diagnosis of binge-eating disorder is made when these episodes occur at least twice a week for 6 or more months and overeating is not accompanied by compensatory purging behavior to curb weight gain.255,256 Approximately 10% to 15% of obese persons who seek weight reduction have binge-eating disorder compared with only 2% in the general population.257 Patients with this disorder who enroll in weight loss programs typically are more obese and may be more refractory to weight loss than those who do not have the disorder. Pharmacological or behavioral treatment of binge eating can decrease binging episodes but, paradoxically, often do not induce weight loss.258 A second eating disorder, known as the night-eating syndrome, also is linked to obesity, but occurs less frequently than bingeeating disorder.259 Affected patients consume more than 50% of their daily intake after dinner, have delayed sleep onset, report multiple awakenings at night that often are accompanied by eating, and experience morning anorexia. Quality of Life and Function Obesity has been associated with impaired quality of life. One study found that obese persons who sought treatment at an outpatient university-based weight management center had profound abnormalities in healthrelated quality of life, measured by the Medical Outcomes Study Short-Form Health Survey (SF-36).260 Obesity was associated with negative effects on all 8 domains assessed by the SF-36, particularly bodily pain, which measures the severity of pain and the impact of pain on normal function. On all SF-36 domains, higher BMI values were associated with greater adverse effects. Patients with class III obesity exhibited particularly poor scores in physical function, general health perception, vitality, and bodily pain. Obesity also is associated with impairment in productivity in the workplace, manifested by increased sick leave absences and disability claims.261,262 The effect of obesity on workplace function has considerable economic impact. For example, it was estimated that paid sick 894 AMERICAN GASTROENTEROLOGICAL ASSOCIATION leave and disability insurance cost U.S. businesses more than $3 billion in 1994.261 Benefits of Intentional Weight Loss Effect on Mortality There is no conclusive evidence that weight loss decreases mortality in obese persons. In fact, most epidemiological studies have found that weight loss or weight fluctuation was associated with increased mortality.263 However, these studies did not distinguish between intentional and unintentional weight loss, which may have confounded the results because unintentional weight loss often is caused by preexisting illness. Three studies have reported the effect of intentional weight loss on survival.264 –266 Each study reported on a different subgroup within the American Cancer Society’s Cancer Prevention Study I, which obtained baseline data between 1959 and 1960 in mostly white men and women and followed the participants for an average of 12 years. The first study was performed in overweight and obese women.264 In women with obesity-related illnesses, any amount of intentional weight loss was associated with a 20% reduction in all-cause mortality, primarily caused by a decrease in mortality from obesity-related cancers and diabetes. In women who did not have a preexisting illness, there was no overall relationship between intentional weight loss and mortality. However, a loss of ⱖ20 pounds in the preceding year was associated with a 25% reduction in all-cause, cardiovascular, and cancer mortality, whereas a loss of ⬍20 pounds that occurred more than 1 year before the initiation of the study was associated with a small increase in mortality. The second study evaluated overweight and obese men.265 In men with obesity-related illnesses, intentional weight loss did not affect total or cardiovascular mortality, but mortality from cancer was increased in those who had lost ⱖ20 pounds. In men who did not have a preexisting illness, intentional weight loss was not associated with total, cardiovascular, or cancer mortality, but diabetes-associated mortality was increased in those who lost ⱖ20 pounds. The third study evaluated overweight and obese men and women who had diabetes.266 Intentional weight loss was associated with a 25% reduction in total mortality and a 28% reduction in cardiovascular disease and diabetes-related mortality. In aggregate, these studies suggest that intentional (possibly transient) weight loss may improve survival in overweight and obese persons who have an obesity-related illness, particularly type 2 diabetes mellitus. However, these data must be interpreted with caution because weight loss was self-reported and may have occurred at any time before the initial GASTROENTEROLOGY Vol. 123, No. 3 visit. In addition, possible changes in weight that may have occurred in the subsequent 12-year follow-up period were not determined. Moreover, intentional decreases in weight before 1960 may not have the same effect on mortality as intentional decreases in weight today because of improvements in medical care. Effect on Morbidity Intentional weight loss improves many of the medical complications associated with obesity.4,267 Moreover, many of these beneficial effects are apparent after only modest weight losses of 5% to 10% of initial body weight.268 There is also evidence that weight loss can delay or decrease the risk of developing new obesityrelated diseases, such as diabetes.269,270 Cardiovascular disease. Obese persons who develop CHD often have more than one metabolic risk factor for CHD. The hazard of developing CHD is related directly to the concomitant burden of risk factors. Although effective pharmacological approaches are available to treat individual risk factors, modest weight loss can affect the entire cluster of risk factors simultaneously. Data from the Framingham Offspring Study indicate that a weight loss of 5 pounds (2.25 kg) or more over 16 years was associated with a 48% and 40% decrease in the sum of risk factors (highest quintile of systolic blood pressure, serum triglyceride, serum total cholesterol, fasting blood glucose, and BMI and lowest quintile of HDL-cholesterol) in men and women, respectively.271 Weight loss also improves cardiovascular structure and function. Weight loss decreases blood volume and hemodynamic demands on the heart, left ventricular mass and chamber size, and septal wall thickness.272–275 These improvements in cardiac function may be responsible for the decrease in symptoms of chest pain and dyspnea reported in patients who lost 23% (28 kg) of their body weight after gastric surgery for obesity.276 Furthermore, weight loss may decrease the progression of atherosclerosis. B-mode ultrasound assessment of the carotid artery, a surrogate measure of coronary atherosclerosis, was performed at baseline and 4 years later in 3 groups of subjects: (1) obese persons who underwent gastric surgery for obesity and lost 19% of their body weight, (2) obese persons who were not treated and maintained their body weight, and (3) lean volunteers.277 The progression rate of intimal wall thickness was similar in both obese subjects who lost weight and lean volunteers, but was 3 times higher in the obese patients who maintained their body weight. Type 2 diabetes mellitus. Both negative energy balance and weight loss improve insulin sensitivity and glycemic control in obese patients with type 2 diabetes September 2002 mellitus. In one study, as little as a 5% weight loss at the end of 1 year decreased fasting blood glucose, insulin, and hemoglobin A1c concentrations and medication requirements in obese, diabetic patients who were being treated with oral hypoglycemic agents.278 The need for hypoglycemic medication was decreased in all subjects who lost 15% or more of their body weight. An average weight loss of ⬃30% of initial body weight in patients with class III obesity who had gastric bypass surgery resulted in marked long-term improvements in glucose homeostasis; 83% of patients with type 2 diabetes and 99% of patients with impaired glucose tolerance achieved normal fasting blood glucose, insulin, and glycosylated hemoglobin concentrations.279 However, weight loss does not improve glycemic control in all obese patients who have diabetes280 and it is possible that patients with long-term disease and more severe pancreatic failure are resistant to the benefits of weight loss. Sustained weight loss is effective in preventing the development of new cases of diabetes in obese persons.270,281–282 Data from the Framingham Study revealed that the risk of diabetes decreased by 33% in those who lost 3.7 to 6.8 kg and by 51% in those who lost more than 6.8 kg during 16 years of observation.270 Data from the Finnish Diabetes Prevention Study and the United States Diabetes Prevention Program Study demonstrate that changes in lifestyle that result in modest (⬃5%) weight loss decreased the 4- to 6-year cumulative incidence of diabetes by 58% in overweight and obese men and women with impaired glucose tolerance.283,283a A 16% weight loss after gastric surgery in severely obese patients (initial BMI ⫽ 41 kg/m2 participating in the Swedish Obese Subjects (SOS) study was associated with a 5-fold decrease in the risk of diabetes over an 8-year period (diabetes incidence of 18.5% in the control group and 3.6% in the surgery-treated group).282 Achieving weight loss is particularly difficult in patients with type 2 diabetes. Several studies have shown that obese patients with type 2 diabetes lose less weight than obese patients without diabetes.284 –286 Moreover, weight loss success may be inversely related to duration and severity of diabetes. In one study, obese patients with a more severe stage of disease (defined as those controlled by hypoglycemic agents) were more refractory to weight loss than those with a milder form of disease (defined as those controlled by diet therapy alone).286 The reasons for the blunted weight loss response in patients with diabetes is not known but might be related to energy-conserving effects (e.g., reduced glycosuria) and tendency toward weight gain associated with pharmacological diabetes therapy.287 AMERICAN GASTROENTEROLOGICAL ASSOCIATION 895 Dyslipidemia. Most studies have found that weight loss decreases serum triglyceride, total cholesterol, and LDL-cholesterol concentrations and increases serum HDL-cholesterol concentration.4,288 However, the time course of lipid changes is influenced by the state of energy balance and other dietary and physical factors. The greatest improvements in serum triglyceride, total cholesterol, and LDL-cholesterol concentrations tend to occur in the first 4 to 8 weeks of weight loss.289,290 During the period of active weight loss serum HDLcholesterol concentration also decreases, but later increases once weight loss stabilizes.288 In addition, dietinduced weight loss in conjunction with exercise has a greater beneficial effect on LDL-cholesterol than either treatment alone.291 The beneficial effect of weight loss on serum lipids is greater in men than in women,288 but this probably is caused by differences in baseline BMI and serum lipid levels than gender per se.292 Adjustment for body size and initial lipid profile eliminates many of the putative gender differences. In general, the degree of improvement in serum lipids is related to the amount of weight lost, and weight regain will lead to relapse in triglyceride and cholesterol concentrations. At 2 years, a sustained weight loss of 5% is sufficient to maintain the reduction in serum triglyceride concentrations, whereas serum total and LDL cholesterol revert toward baseline if at least a 10% weight loss is not maintained.289,290,293,294 Of the lipid subfractions, HDL cholesterol is the most resistant to change; nonpharmacologic increases in HDL may require a large amount of weight loss, a period of weight stabilization, and concomitant exercise training. Hypertension. Weight loss, independent of sodium restriction, decreases systolic and diastolic blood pressure.295 One of the largest intervention studies, the Trials of Hypertension Prevention Phase II (TOHP II), randomized approximately 1200 overweight and obese participants to a dietary weight loss intervention or usual care.296 The results demonstrated a dose-response relationship between weight loss and blood pressure at 36 months; an average weight loss of 8.8 kg in the highest weight loss quintile was associated with a reduction of 7 mm Hg systolic and 5 mm Hg diastolic blood pressure, a loss of 2.6 kg was associated with a reduction of 4.5 mm Hg systolic and 2.5 mm Hg diastolic blood pressure, and a loss of 0.1 kg was associated with a reduction of 2.0 mm Hg systolic without a change in diastolic blood pressure. Participants who lost a considerable amount of weight in the first 6 months and then regained most or all of their lost weight had a marked decline in blood pressure at 6 months, followed by a steady increase 896 AMERICAN GASTROENTEROLOGICAL ASSOCIATION to near baseline values by the end of the study. In extremely obese patients who already have hypertension, marked weight loss induced by gastric surgery improves or completely resolves hypertension in approximately two-thirds of patients.297,298 Recent data from the SOS study question the duration of the effect of weight loss on blood pressure. The beneficial effect of weight loss on blood pressure observed at 1 and 2 years after gastric surgery disappeared by 3 years, and both systolic and diastolic blood pressure continued to increase gradually for the next 5 years.282 The reason for the discrepancy between studies is not clear but may be related to the larger weight gain from nadir weight in the surgically treated group (⬃11 kg) than in the highest weight loss quintile of the diet-treated group (⬃1 kg) although surgical therapy resulted in greater overall weight loss (16% of initial weight) than did successful diet therapy (⬃10% of initial weight). These data suggest that current energy balance and the direction of weight change are also important factors in controlling blood pressure. The ability of weight loss to prevent the future development of hypertension has also become controversial because of the SOS report. Several large prospective epidemiological and intervention studies found that weight loss decreased the incidence of hypertension. The risk of new cases of hypertension in normotensive women who were followed for 12 to 15 years in the Nurses Health Study correlated directly with changes in body weight; weight losses of 5.0 to 9.9 kg and 10 or more kg were associated with a 15% and 26% decreased risk of hypertension, respectively.20 In TOHP II, persons who maintained a weight loss of at least 4.5 kg at 36 months had a 65% decrease in the risk of hypertension compared with the control group who gained 1.8 kg.296 In contrast, the beneficial effect of weight loss on the risk of hypertension at 2 years after gastric surgery in the SOS study269 disappeared by 3 years; the risk was still the same as that for the control group through 8 years of observation, despite persistent weight loss.282 Surprisingly, the SOS study found a striking differential effect of weight loss on the incidence of obesity-related diseases. Despite the disappointing effect on hypertension, long-term surgically induced weight loss caused a marked and persistent reduction in the risk of diabetes. Respiratory disease. Pulmonary function, obstructive sleep apnea, and obesity hypoventilation improve with weight loss. Marked weight loss of ⬃30% body weight in patients with class III obesity decreases the severity of sleep apnea and often results in complete resolution of obstructive sleep apnea syndrome when the respiratory disturbance index, defined as the average GASTROENTEROLOGY Vol. 123, No. 3 number of apnea or hypopnea episodes per hour of sleep, is ⱕ40.299 –301 However, even modest weight loss of ⬃10% body weight decreases the respiratory disturbance index, improves sleep patterns, and decreases daytime hypersomnolence.302 The weight loss–induced decrease in upper airway collapsibility may be responsible for the decrease in apnea severity, so initial critical upper airway collapsibility pressure may determine how much weight loss is needed to achieve a beneficial effect.303 Surgically induced weight loss has been shown to improve and resolve obesity hypoventilation syndrome, with correction of resting room air arterial blood gases, lung volumes, and cardiac filling pressures.301,304 Improvements in sleep apnea and obesity hypoventilation are maintained with persistent weight loss, but relapse occurs in those who regain lost weight. It is not known whether there is a critical threshold of weight loss, whether this threshold differs among patients, and which patients are likely to achieve benefits in respiratory status from weight loss. Reproductive and urinary tract function in women. Weight loss after gastric bypass surgery has been shown to correct urinary overflow incontinence and eliminate the need for perineal pads.241 Marked weight loss improves fertility and patients who were previously amenorrheic and infertile begin to ovulate and can become pregnant after bariatric surgery. Therefore, sexually active women should take contraceptive precautions after weight loss if pregnancy is not desired. Quality of life and function. Data from several studies suggest that weight loss improves physical function and health-related quality of life. The precise amount of weight loss needed to alleviate symptoms or prevent osteoarthritis in obese persons is not known. However, the magnitude of weight that is lost is directly correlated with improvement in symptoms, increase in pain-free range of motion, and decrease in analgesic use in the obese patient with osteoarthritis.305 Most patients with class III obesity experience relief of pain in one or more joints after marked weight loss induced by obesity surgery.306 In subjects with class I obesity, an average weight loss of 8.6 kg after 13 weeks of treatment with a reduced-calorie diet, physical activity, and behavior therapy was associated with marked improvements in healthrelated quality of life, measured by the physical function, general health perception, vitality, and mental health domains of the SF-36.307 Data obtained at 2 years in the SOS study found that weight loss, induced by gastric surgery, improved health-related quality of life as measured by instruments that evaluated social interaction, anxiety and depression, mood, perceived health, and September 2002 daily activities, whereas no changes in these variables were noted in the control group.308 The improvements in health-related quality of life parameters were directly correlated with the amount of weight lost. In addition, in years 2, 3, and 4 of the SOS study, the number of sick days and disability pension days awarded for short-term and long-term illness or disability was lower in those who lost ⬃20% to 25% of initial body weight after gastric surgery than in the control group, particularly in subjects who were older than 46 years of age.309 Medical Therapy At any given time, approximately 45% of women and 30% of men in the United States are actively trying to lose weight.310 Although many obese persons can lose weight by dieting, successful long-term weight management is much more difficult. Weight loss and subsequent regain is known as “weight cycling” or “yo-yo dieting” and may have adverse psychological311 and medical312 consequences. However, as noted previously, most observations of adverse medical outcomes associated with weight cycling fail to distinguish intentional from unintentional weight loss and include both lean and obese persons. The National Task Force on the Prevention and Treatment of Obesity concluded that the available data regarding effects of weight cycling on health are inconclusive and should not prevent obese persons from trying to lose weight.313 Additional research is still needed to determine whether unsuccessful dieting can cause net harm. The current therapeutic tools that are available for weight management include dietary intervention, physical activity, behavior modification, pharmacotherapy, surgery, and intragastric balloons (not available in the United States). Dietary Intervention Dietary intervention is the cornerstone of weight loss therapy because it is easier for most obese persons to achieve negative energy balance by decreasing food intake than by increasing physical activity. Most diets proposed for losing weight vary in 2 principal dimensions– energy content and macronutrient composition. However, the energy content, and not the relative macronutrient composition of the diet, is the primary determinant of weight loss. Energy content. VLCDs provide ⬍800 kcal per day and usually contain small amounts of fat (ⱕ15 g per day) and large amounts of protein (70 to 100 g per day). These diets may be consumed as commercially prepared liquid formulas, with or without nutritional bars, or as AMERICAN GASTROENTEROLOGICAL ASSOCIATION 897 regular foods consisting of mostly lean meat, fish, or fowl (the latter known as a protein-sparing modified fast). Low-calorie diets (LCDs) contain 800 to 1500 kcal per day, which can be provided as liquid formula, nutritional bars, regular food, or some combination of these. A balanced-deficit diet (BDD) usually provides ⱖ1500 kcal per day of conventional foods, with an appropriate balance of macronutrients. Obesity treatment guidelines issued by the NIH4 recommend that persons who are overweight (BMI of 25.0 to 29.9 kg/m2) and who have 2 or more risk factors should decrease their energy intake by approximately 500 kcal per day. This energy deficit, which is also recommended for persons with class I obesity (BMI of 30 to 34.9 kg/m2), will result in approximately a 1-pound (0.45 kg) weight loss per week and about a 10% reduction of initial weight at 6 months. Persons with class II (BMI of 35.0 to 39.9 kg/m2) or III (BMI ⱖ40 kg/m2) obesity should aim for a more aggressive energy deficit of 500 to 1000 kcal per day, which will produce approximately a 1- to 2-pound weight loss per week and approximately a 10% weight loss at 6 months. To prescribe a diet that induces a specific energy deficit, it is necessary to know the patient’s daily energy requirements. Although REE and TEE can be measured, the technology needed to make these measurements is expensive and not readily available to most clinicians. Total daily energy requirements can be estimated by using standard equations based on the patient’s size, age, gender, and activity level, such as the Harris-Benedict314 or the World Health Organization equations (Table 5).315 However, the use of standard equations is cumbersome and may be unreliable in obese persons because these equations can underestimate or overestimate energy expenditure significantly. We suggest using the simple Table 5. Commonly Used Formulas for Calculating Resting Energy Expenditure Harris-Benedict Equations314 Men ⫽ 66 ⫹ (13.7 ⫻ W) ⫹ (5 ⫻ H) ⫺ (6.8 ⫻ A) Women ⫽ 665 ⫹ (9.6 ⫻ W) ⫹ (1.8 ⫻ H) ⫺ (4.7 ⫻ A) World Health Organization Equations315 Age (yrs) 0–3 3–10 10–18 18–30 30–60 ⬎60 Male (60.9 (22.7 (17.5 (15.3 (11.2 (13.5 ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ W) W) W) W) W) W) ⫺ ⫺ ⫹ ⫹ ⫹ ⫹ 54 495 651 679 879 987 Female (61.0 ⫻ W) ⫺ 51 (22.5 ⫻ W) ⫹ 499 (12.2 ⫻ W) ⫹ 746 (14.7 ⫻ W) ⫹ 996 (8.7 ⫻ W) ⫹ 829 (10.5 ⫻ W) ⫹ 596 W, weight in kg; H, height in cm; A, age in years. An adjusted body weight rather than actual body weight should be used for obese patients. Adjusted body weight ⫽ ideal body weight ⫹ [(actual body weight ⫺ ideal body weight) ⫻ (0.25)]. 898 AMERICAN GASTROENTEROLOGICAL ASSOCIATION Table 6. Suggested Energy and Macronutrient Composition of Initial Reduced-Calorie Diet Body weight (pounds) Suggested energy intake (kcal/d) 150–199 200–249 250–299 300–349 ⱖ350 1000 1200 1500 1800 2000 Macronutrient composition: Total fat Saturated fatty acids Monosaturated fatty acids Polyunsaturated fatty acids Cholesterol Protein Carbohydrate 20%–30% of total calories 8%–10% of total calories Up to 15% of total calories Up to 10% of total calories ⬍300 mg/day 15%–20% of total calories 55%–65% of total calories dietary guidelines outlined in Table 6. Although patients who follow these guidelines usually will lose weight, some may not fully comply with their prescribed diets. Therefore, dietary energy content must be adjusted regularly, based on a trial-and-error approach. The effectiveness of LCDs has been evaluated in more than 30 prospective randomized clinical trials, which demonstrated that a 1000 to 1500 kcal per day LCD produces about an 8% loss of body weight after 16 to 26 weeks of treatment.4 In these studies, diets were prescribed to provide a predetermined calorie target rather than as an estimated energy deficit for each subject. The results from these studies may differ from those obtained by simply prescribing an LCD in clinical practice because the participants in these trials volunteered for a weight loss study and most received some form of behavior modification therapy as part of the study protocol. Although the use of VLCDs usually produces a loss of about 15%–20% of initial weight in 12 to 16 weeks of treatment, this approach is associated with poor maintenance of weight loss.294,316 –320 In several randomized trials,294,316 –320 weight regain was greater after VLCD than after LCD therapy, so that weight loss 1 year after treatment was not different between the 2 diets. Moreover, initial weight loss with a VLCD is similar to that obtained with an LCD when the diets are served in the same manner. Weight loss in patients given a liquid diet containing 420 kcal per day was not significantly greater than that in persons who consumed a liquid diet containing 800 kcal per day,321,322 suggesting that patients treated with VLCDs are either less compliant with their diet or experience a greater decline in energy expenditure than those treated with an LCD. In addition, the use of VLCDs increases the risk of dieting-associated medical complications, such as hypokalemia, dehydration, and gallstone formation. Therefore, patients treated with a GASTROENTEROLOGY Vol. 123, No. 3 VLCD require closer medical monitoring than those treated with an LCD. Meal replacements. The use of portion-controlled servings can enhance weight loss because obese persons who consume a diet of self-selected table foods tend to underestimate their energy intake. For example, one study found that obese persons who claimed they were unable to lose weight on an LCD actually consumed twice as many calories as they recorded in daily food records.66 Underestimation is likely to result from underestimating serving sizes or failing to identify hidden calories from fat and sugar. Providing prepackaged prepared meals can enhance long-term compliance. In a randomized controlled trial conducted in persons with hypertension, dyslipidemia, or diabetes, those who received prepackaged prepared meals lost 3 times as much weight (⬃6 kg) at the end of 1 year as those randomized to a standard exchange system diet (⬃2 kg).323 Jeffery et al.324 found that obese subjects who were prescribed a self-selected LCD of 1000 kcal per day lost less weight than those who were prescribed the same number of calories but were given their breakfast and dinner meals. In a follow-up study, these investigators showed that the provision of a structured meal plan, rather than providing patients the foods per se, was responsible for the success of the portion-controlled diet.325 Subjects who were provided a meal plan that told them precisely what foods to purchase lost more weight than those who were prescribed the same number of calories but consumed a self-selected diet. Providing foods, in addition to the meal plan, did not produce greater weight loss than the meal plan alone. The use of liquid formula meal replacements can be effective for long-term weight management. In a randomized controlled trial conducted in Germany, subjects who replaced 2 meals a day with a liquid formula (SlimFast; SlimFast Foods Co., West Palm Beach, FL) lost 8% of initial weight during the first 3 months compared with a loss of only 1.5% in those randomized to receive the same number of calories as a self-selected diet.326 More importantly, those who continued to use the supplement to replace one meal and one snack a day maintained a weight loss of 11% at 27 months and of 8% at 51 months.327 The long-term effectiveness of a liquidformula meal replacement also has been demonstrated in a large uncontrolled trial performed in the United States.328 Macronutrient composition. Macronutrient composition does not affect weight loss unless it influences total energy intake. Traditionally, low-fat diets are prescribed to help obese patients lose weight because these September 2002 diets facilitate energy restriction. Dietary fat is composed primarily of triglycerides, which increase food palatability and energy density. Data from epidemiological and diet intervention studies suggest that increasing dietary fat increases total energy consumption and body weight.329 In addition, the results from a large number of studies support the notion that decreasing fat intake, while allowing ad libitum intake of carbohydrate and protein, leads to a spontaneous decrease in total energy intake and weight loss. A meta-analysis of 37 intervention studies that prescribed a Step I or Step II low-fat (ⱕ30% kcal as fat) diet recommended by the National Cholesterol Education Program to decrease the risk of cardiovascular disease found a direct relationship between changes in dietary fat and body weight (Figure 4).330 Another meta-analysis of 19 studies showed that weight loss produced by a low-fat ad libitum diet was directly related to the severity of obesity; subjects who were more obese lost greater amounts of weight on this diet than those who were less obese.331 Diets that focus on reducing fat intake alone produce less initial weight loss than those that restrict both fat and total energy intake. Schlundt et al.332 found that obese subjects who were instructed to eat 25 g/day of fat, with ad libitum intake of carbohydrate, lost 4.6 kg in 20 weeks, while those who were prescribed the same fat goal as part of a 1200 to 1500 kcal per day diet lost 8.8 kg. However, it is not clear which dietary approach is superior for long-term weight maintenance because of conflicting data showing worse,332 the same,333 or better334 weight loss at 1 and 2 years with a low-fat ad libitum Figure 4. Relationship between changes in dietary fat intake and body weight from selected dietary intervention studies that were designed to improve plasma lipids by following the National Cholesterol Education Program’s Step I and Step II diets. (Reprinted with permission from Yu-Poth et al.330 © Am J Clin Nutr. American Society for Clinical Nutrition.) AMERICAN GASTROENTEROLOGICAL ASSOCIATION 899 diet than with an LCD. Data from the National Weight Control Registry support the importance of a low-fat diet for long-term weight management.335 Participants in this registry, which is comprised of obese persons who have maintained a weight loss of ⱖ14 kg (30 pounds) for at least 1 year (average weight loss of 29 kg maintained for 6.9 years), reported consuming less than 25% of calories from fat. Energy density. The beneficial effects of a low-fat diet on body weight may be related to the effect of fat on energy density. Dietary fat content and energy density, defined as the energy (i.e., calories) present in a given weight (g) of food, are highly correlated because fat has such a high energy density. A series of elegant, but short-term (up to 14 days), studies have demonstrated that energy intake is regulated by the weight of ingested food, rather than by fat or energy content.336 In one study, both lean and obese subjects given either an ad libitum high-fat/high-energy-density (1.5 kcal/g) diet or a low-fat/low-energy-density (0.7 kcal/g) diet ate the same weight of food, so energy intake on the high-fat/ high-energy-density diet (3000 kcal/day) was almost twice that consumed on the low-fat/low-energy-density diet (1570 kcal/day).337 In other studies, subjects who were given liquid diets that varied in fat content (from 20% to 60%) but had the same energy density also ate the same weight of food, so total energy intake was the same despite large differences in fat intake.338 –341 Finally, several studies have found that the same weight of food is eaten when energy density is manipulated while keeping fat content the same. Therefore, energy intake was inversely correlated with energy density, and subjects who consumed a low-energy-density diet lost weight.341,342 These data demonstrate that dietary fat content itself does not affect total energy intake, independent from its effects on diet energy density and food palatability. The results of short-term studies suggest that manipulating energy density might be a useful approach to regulate total energy intake. However, longterm studies in obese subjects are still needed to confirm that low-energy-density diets can help induce and maintain weight loss. The energy density of a diet can be decreased by adding water to food, increasing the intake of highwater-content foods, such as fruits and vegetables, and by limiting the intake of high-energy-density foods, such as high-fat and dry foods (e.g., crackers and pretzels). The energy density of some low-fat dry foods (e.g., fat-free pretzels) is as high as that of some high-fat foods (e.g., cheese) (Figure 5). Surprisingly, consuming water with a meal may not have the same effect as adding water to the 900 AMERICAN GASTROENTEROLOGICAL ASSOCIATION Figure 5. Energy density of selected commonly consumed foods. Foods that have a high fat content usually have a high energy density, whereas foods that have a high water content usually have a low energy density. (Figure provided courtesy of Liane Roe.) food itself. In one study, eating chicken rice soup before lunch caused a greater decrease in the consumption of lunch calories than eating chicken rice casserole (same calories but greater energy density) or chicken rice casserole with 356 mL of water (same calories and same amount of water).343 These data suggest that adding water to a food influences food intake by its effect on sensory and cognitive factors rather than by its effect on gastric volume. Low-carbohydrate diets. Recently, there has been a renewed interest in the use of low-carbohydrate diets for losing weight. Although these diets were introduced more than 100 years ago to treat obesity,344 and different variations with their own labels continue to resurface, there is a paucity of data from clinical trials of the long-term efficacy of low-carbohydrate diets in obese persons. Several randomized345–347 and nonrandomized348 controlled trials have compared the weight loss effect of short-term (ⱕ12 week) low-carbohydrate with high-carbohydrate diets, when energy intake was identical in both groups. The results from these studies suggest that early (ⱕ4 week) weight loss can be greater with a low- than a with a high-carbohydrate diet despite the same energy intake because of greater water losses in the low-carbohydrate group. However, weight loss between 6 and 12 weeks of treatment is likely to be the same for subjects consuming either diet when energy intake is identical. Many of the current popular low-carbohydrate diets limit carbohydrate intake (e.g., the Atkins diet limits carbohydrate intake to 20 g/day349), but allow unre- GASTROENTEROLOGY Vol. 123, No. 3 stricted amounts of fat and protein. The authors of low-carbohydrate diet books often provide anecdotal case studies to support their diets and have proposed several implausible metabolic mechanisms to explain how their diets cause weight loss. Nonetheless, there may be valid explanations for how low-carbohydrate diets with ad libitum fat and protein intake can generate weight loss, including (1) initial diuresis associated with ketone and urea nitrogen excretion,345 (2) losses of up to 100 kcal/ day in urinary ketones,344 and (3) decreased energy intake, possibly related to ketosis, diet monotony, or other unknown mechanisms. Two recent prospective trials reported that when obese subjects restrict their carbohydrate intake they do not completely compensate for the energy deficit by increased consumption of fat and protein.350,351 In one study, total energy intake decreased by approximately 1000 kcal/day after obese subjects started a low-carbohydrate, ad libitum fat and protein intake diet.350 In a second study, obese subjects lost 10% of their initial body weight 6 months after starting the Atkins diet.351 To date, one randomized controlled trial has evaluated the effectiveness of the Atkins diet.352 At the end of 12 weeks, average weight loss was 3.4% in the Atkins diet group and 8.6% in the traditional highcarbohydrate, low-fat diet group. No randomized controlled trials evaluating the long-term effectiveness of a low-carbohydrate diet have been reported. The possibility that low-carbohydrate with ad libitum fat and protein diets could have harmful effects has not been carefully studied. It has been suggested that highfat and high-protein intake could cause dehydration, electrolyte imbalance, hyperuricemia, calciuria, kidney stones, glycogen depletion with easy fatigue, and hyperlipidemia.344 However, no serious adverse effects were reported in 41 subjects who completed a 6-month trial of the Atkins diet.351 In fact, these subjects experienced a 7% decrease in plasma LDL cholesterol, a 43% decrease in plasma triglycerides, and an 18% increase in plasma HDL cholesterol. Additional long-term studies containing large numbers of subjects are needed to determine whether low-carbohydrate diets could ultimately result in net harm. Physical Activity Body Composition The addition of exercise training to a diet program can affect the composition of weight loss. Two meta-analyses that pooled data from 4682 and 28353 published trials found that exercise can attenuate the loss of FFM. Regular low- or moderate-intensity exercise decreased the percentage of weight lost as FFM by half, September 2002 from approximately 25% to 12%, when diet-induced weight loss was ⬃10 kg. However, this large difference in percentage of weight lost as FFM represented only a small (⬃1 kg) difference in the absolute amount of FFM lost between groups. Moreover, conservation of FFM does not necessarily represent conservation of muscle protein; the greater retention of FFM associated with exercise may be related to increased retention of body water and muscle glycogen. In fact, nitrogen balance studies in women have failed to show any nitrogen-sparing effect of exercise during diet-induced weight loss.354 It is not clear whether there is a difference between endurance and resistance exercise in FFM conservation because of limited and conflicting data.355,356 Metabolic Rate Although exercise has a profound effect on energy expenditure during the actual bout of exercise, the results from most studies suggest that adding regular exercise to a reduced-calorie diet program has little, if any, effect on REE. A meta-analysis of prospective controlled trials that randomized obese subjects to diet alone or diet plus exercise found that exercise training did not prevent the expected decline in REE, when REE was adjusted for loss of body mass.357 Weight Loss Physical activity alone is not an effective method for achieving initial weight loss. The energy deficit generated by physical activity in obese persons is usually much less and requires more effort than the energy deficit generated by a reduced-calorie diet. For example, walking or running 1 mile consumes about 110 kcal of endogenous fuel. Therefore, the loss of 2 pounds per week that typically is induced by a 1000-kcal/day deficit diet would require walking or running 65 miles per week if energy intake remained constant. The results from most studies have shown that moderate endurance exercise such as brisk walking for 45 to 60 minutes 4 times a week for up to 1 year usually induces a weight loss of only a few kilograms.353,358,359 Adding a regular exercise program to short-term (ⱕ6 months) diet intervention does not increase initial weight loss significantly358 unless it is prolonged and vigorous activity (e.g., 88 minutes per day of brisk walking or cycling).360 Moreover, the type of exercise performed while dieting does not seem to make a difference. In one prospective randomized trial, obese subjects who consumed a 925-kcal/day diet for 4 months lost the same amount of weight whether they were assigned to diet alone, diet plus endurance training, diet plus AMERICAN GASTROENTEROLOGICAL ASSOCIATION 901 strength training, or diet plus both endurance and strength training.355 Weight Maintenance Although increasing physical activity is not effective for initial weight loss, physical activity is very important for long-term weight management. Several large-scale cross-sectional case studies found that obese subjects who achieved successful long-term (ⱖ1 year) weight loss participated in regular exercise.335,361–363 Retrospective analyses of prospective clinical weight loss trials also found that subjects who reported exercising regularly maintained their weight losses significantly better than those who remained sedentary.364,365 In addition, several prospective randomized studies found that subjects assigned to diet-plus-exercise conditions who continued to exercise maintained substantially larger weight losses than those randomized to diet alone or to diet plus exercise but who stopped exercising.366 –369 Nonetheless, most prospective randomized trials failed to find a statistically significant long-term beneficial effect of exercise on body weight when data were analyzed on an intention-to-treat basis, presumably because many subjects failed to adhere to their exercise program.358 The beneficial effect of exercise on long-term body weight probably involves both physiological and psychological mechanisms. Physical activity can help prevent weight regain by consuming energy and by enhancing selfesteem and mood, which may improve dietary compliance and the ability to cope with eating-related situations.370 The amount of physical activity required to maintain weight loss appears to be much greater than that recommended by the American College of Sports Medicine and the Centers for Disease Control and Prevention for good health.371 Recent studies indicate that obese patients should expend approximately 2500 kcal/week to maintain weight loss.335,372–374 This amount of energy expenditure can be achieved by moderate activity (brisk walking) for approximately 60 to 75 minutes per day or by more vigorous activity (aerobics, cycling, or jogging) for 30 minutes per day. For most obese persons, this level of activity cannot be reached in a short period of time, so it is important to set modest activity goals initially and increase activity slowly over time. Pedometers provide a reliable and inexpensive method of tracking most forms of physical activity.375 A reasonable goal is to increase the number of steps walked daily by 1000 every month until reaching a total of 15,000 steps per day (equal to approximately 60 to 75 minutes or 3 to 4 miles of walking per day). 902 AMERICAN GASTROENTEROLOGICAL ASSOCIATION The greatest hurdle to increasing long-term physical activity is compliance. This problem has led to evaluation of the merits of programmed vs. lifestyle activities. Programmed activity consists of regularly scheduled bouts of running, swimming, cycling, and other aerobic activities, which usually are engaged in for a discrete period of time (e.g., 30 to 60 minutes) at a relatively high intensity level (e.g., 60% to 80% of maximum heart rate). Lifestyle activity involves increasing energy expenditure during the course of the day by practices such as walking rather than riding, using stairs rather than escalators, and discarding energy-saving devices such as television remote controls and extension telephones. Two approaches may improve adherence to programmed activity. The first is to divide one long bout of exercise activity into several shorter bouts for those who “can’t find the time to exercise.” In one prospective trial, obese women randomized to 3 short (10 minutes) bouts of aerobic exercise (primarily walking) per day, 5 days per week, reported 20% more exercise time per week than obese women randomized to the same total amount of activity but in long (30 minutes) bouts of aerobic exercise per day, 5 days per week.376 There was also a trend toward greater weight loss in the short-bout exercise group. A second method of facilitating exercise adherence is to have patients exercise at home rather than at a health club or similar facility because home exercise is associated with fewer barriers, including costs and travel time. Two prospective randomized trials found that both adherence to a walking program377,378 and maintenance of weight loss378 were significantly better at 1 and 2 years in subjects who were assigned to walk at home compared with those who participated in a supervised on-site program. The use of home exercise equipment, such as a treadmill, has also been shown to improve exercise adherence and long-term weight loss.373 Altering lifestyle activity without emphasizing work intensity may provide more opportunities for increasing physical activity than programmed exercise. In children, instruction in increasing lifestyle activity was associated with significantly better maintenance of weight loss than participation in programmed exercise.379,380 A recent study in obese adults found that weight loss was the same after a 16-week behavioral program that combined a 1200 kcal/day diet with either lifestyle activity or programmed exercise.381 There was also a trend toward better maintenance of weight loss 1 year after treatment in the lifestyle activity participants than in the group that received programmed exercise. Moreover, there was a direct relationship between level of activity and weight GASTROENTEROLOGY Vol. 123, No. 3 maintenance. These findings demonstrate that education to alter lifestyle activities is a reasonable alternative to programmed exercise for properly selected obese patients. Additional health benefits of physical activity. Aerobic exercise has additional health benefits that are independent of weight loss itself. Endurance exercise increases insulin sensitivity and aerobic fitness.382 Increased physical activity and aerobic fitness are associated with a decreased risk of developing diabetes22,383 and dying from cardiovascular disease.23 In fact, the risks of cardiovascular and all-cause mortality are lower in fit obese men than in unfit lean men (Figure 6).23 A large number of studies also have demonstrated psychological benefits of exercise in nonobese individuals. Surprisingly, there have been few studies of the psychological effects of exercise in obese persons.384 In the largest investigation to date, subjects treated by diet plus aerobic activity had significant reductions in depression and fatigue and improvements in vigor.355 However, improvements in psychological functioning were no greater in these participants than in those who lost weight by diet alone. Behavior Modification The purpose of behavior modification therapy is to help patients identify and then modify eating and Figure 6. Relative risk (RR) of cardiovascular disease (CVD) mortality, stratified by body fatness and cardiorespiratory fitness in men. Body fat categories were classified by percentage body fat according to percentile scores: lean (⬍16.7% body fat; ⬍25th percentile), normal (16.7%–24.9% body fat; 25th to ⬍75th percentile), and obese (ⱖ25% body fat; ⱖ75th percentile). Cardiorespiratory fitness was determined by oxygen consumption during a maximal treadmill exercise test. Unfit men (black bars) were defined as those who were in the lowest quartile (20%) of oxygen uptake (expressed as mL consumed/kg FFM/min) in each age group; all other men were considered fit (white bars). (Reprinted with permission from Lee et al.23 © Am J Clin Nutr. American Society for Clinical Nutrition.) September 2002 physical activity habits that contribute to their obesity. This approach is based on the classical conditioning principle that behaviors often are prompted by an antecedent event, and the link between the antecedent event and the behavior becomes stronger with repetition. For example, eating may be triggered by watching television. The more often the two events are paired together, the stronger will be the connection between them; eventually the presence of one automatically triggers the other. Eating often is the consequence of a series of antecedent events. Many factors may contribute to overeating as illustrated in the behavior chain in Figure 7. Disconnecting triggers within the chain (e.g., instructing the patient to limit all eating at home to the kitchen and dining room to break the link between eating and television viewing) will diminish the strength of each trigger over time. In addition, a cognitive component is included in behavioral treatment because it is believed that thoughts (or cognitions) directly affect feelings and behaviors. Therefore, how patients perceive a specific situation will influence their feelings about it and their desire for change. Principles of Therapy There are 3 general principles of behavior modification therapy. First, behavioral treatment is goaldirected and specifies goals in terms that can be easily measured. This is true whether the goal is walking for 20 minutes 3 times per week, limiting the consumption of a specific food to 2 portions per week, or decreasing the number of self-critical comments. Providing specific Figure 7. Example of a behavior change that demonstrates how individual behaviors are linked together to contribute to an episode of overeating. Therefore, dietary indiscretion can be traced to a series of small decisions and behaviors. (Reprinted with permission from Brownell KD. Sample behavioral chain. The LEARN Program for weight management–2000. Dallas, Texas: American Health Publishing Company; 2000:204. All rights reserved. For ordering information, call 1-888-LEARN-41 or visit www.TheLifeStyleCompany.com. AMERICAN GASTROENTEROLOGICAL ASSOCIATION 903 goals facilitates the assessment of goal attainment and the initiation of targeted problem solving. Second, behavioral treatment is process-oriented and helps patients develop realistic goals and a reasonable plan for reaching those goals. Therefore, once a specific goal is identified, patients are encouraged to examine factors that will help or hinder goal achievement and to develop strategies for success. This philosophy holds that planning, not willpower, is the key to weight management. Third, behavioral treatment advocates making small rather than large changes. This is based on the learning principle of successive approximation in which incremental steps are taken to achieve more distant goals. Setting small and achievable goals allows patients to have successful experiences, which can be used as a foundation for additional lifestyle alterations. Drastic behavior change is usually short-lived. Components of Therapy Behavior therapy of obesity usually includes multiple components: self-monitoring (daily records of food intake and physical activity), stimulus control (avoiding triggers that prompt eating), social support (assistance from family members and friends in modifying lifestyle behaviors), cognitive restructuring (thinking in a positive manner), problem-solving skills (systematic methods of analyzing problems and identifying possible solutions), and relapse prevention (methods to help recovery from episodes of overeating or weight regain).385 These strategies are used to modify eating and activity habits. Self-monitoring (i.e., recording one’s behavior) is the cornerstone of behavioral treatment, and several studies have shown that it correlates with successful long-term weight control.386 At first, patients keep daily records of their food intake, including the type, amount, and energy content, without attempting to change their diet. Dietary advice is then given to reduce energy intake by a specific amount (usually 500 –1200 kcal/day) to achieve a gradual rate of weight loss per week (usually 1 pound per week). Record keeping is expanded over time to include information about times, places, and feelings associated with eating. These records provide the information needed to identify different components of the behavior chain that can be targeted for intervention. Accurate record keeping also serves to decrease, although not eliminate, the tendency to underestimate food intake.387 The behavioral approach to physical activity supports the notion that any activity is better than none. Efforts are directed toward increasing activity gradually along a continuum, rather than initially targeting a specific ac- 904 AMERICAN GASTROENTEROLOGICAL ASSOCIATION GASTROENTEROLOGY Vol. 123, No. 3 tivity “threshold” (e.g., 30 minutes of walking at 80% of maximum heart rate). This can be accomplished by increasing programmed or lifestyle activity or both. Clinical experience suggests that lifestyle activity provides an excellent alternative for obese persons who “hate to exercise.” Cognitive restructuring is an important component of behavior therapy because it teaches patients to identify, challenge, and correct the irrational thoughts that frequently undermine weight control efforts. These thoughts usually occur when there are setbacks in maintaining dietary control and when desired weight loss is not achieved. Cognitive restructuring teaches patients to avoid the extremes of catastrophizing (“I’ve blown it”) and denial (“It’s nothing to worry about”), neither of which is helpful for long-term weight control. Cognitive techniques also can help patients accept weight losses that are less than desired but still medically beneficial. Developing realistic goals and responses to counter unrealistic cognitions (e.g., “I won’t be happy until I can wear a size 6 dress”) are important to prevent a feeling of failure, which can lead to relapse and weight regain. Treatment structure. Behavior therapy can be provided in either group or individual sessions. Although obesity is a chronic illness, behavior treatment usually is provided in a time-limited fashion, with predetermined starting and finishing dates, often lasting 16 to 26 weeks.388 There have been no controlled comparisons of the effects on long-term weight loss of timelimited vs. open-ended treatment. Clinical effectiveness. Patients treated by a comprehensive group behavior therapy approach lose about 9% of their initial weight in 20 to 26 weeks of treatment.389 Table 7 summarizes the results of prospective randomized clinical trials published in 4 leading behavioral journals from 1974 to 1995 that evaluated the effectiveness of behavior therapy in achieving weight Table 7. Summary of Randomized Clinical Trials of Group Behavior Therapy for Weight Loss 1974 1984 1990–1995 1996–1999 Number of trials 15 15 Treatment duration (wk) 8 13 Rate of weight loss (kg/wk) 0.5 0.5 Weight loss (kg) 3.8 6.9 Length of follow-up (wk) 6 58 Weight loss at follow-up (kg) 4.0 4.4 14 26 0.4 9.0 40 5.2 9 21 0.5 9.6 74 6.0 All trials evaluated in this Table were published in Addictive Behaviors, Behavior Therapy, Behaviour Research and Training, and Journal of Consulting and Clinical Psychology. Values represent the means across studies, weighted by the number of subjects in each study. Data from Wadden TA, Foster GD. Behavioral treatment of obesity. Med Clin North Am 2000;84:441– 461. loss. Although the mean weekly rate of weight loss remained the same (⬃0.5 kg per week), total weight loss induced by behavior therapy more than doubled over this 20-year period because treatment duration doubled. Weight regain is common after treatment ends. As shown in Table 7, patients typically regain about 30% to 35% of their lost weight in the year following treatment. Nonetheless, most patients still maintain medically significant weight loss of ⱖ5% of initial body weight at the end of 1 year. Efforts to increase total weight loss by increasing the duration of behavior therapy have been only marginally successful. In 2 studies, weekly treatment was provided for 1 year with the expectation that subjects would lose an average of 0.5 kg/week or 25 kg (⬃25% of body weight).316,390 Average weight loss at 1 year, however, was only ⬃14 kg and was achieved within the first 6 months of therapy. Nonetheless, continued therapy probably prevented weight regain that usually occurs after treatment is stopped. In a series of studies, Perri et al.391–393 reported that obese patients who maintained regular biweekly contact with their treatment providers– by telephone, postcards, or in-clinic visits–maintained their full end-of-treatment weight loss for as long as such care was provided. Unfortunately, when contact was withdrawn, patients began to regain weight. These data demonstrate that prolonged treatment is needed to achieve long-term weight management success. Moreover, the benefit of long-term therapy is to improve weight maintenance rather than increase the magnitude of weight loss. Practical considerations. Although long-term group behavior therapy is effective, it is not widely available, so finding a suitable provider can be problematic. Even when a good obesity-behavior therapy program can be identified, it may be unaffordable for many patients because insurance carriers usually do not reimburse treatment. In addition, patients often tire of behavioral treatment after the first 6 to 12 months and it is difficult to maintain long-term interactions. Several studies found that patients attended approximately half as many sessions during the last several months of treatment as compared with the first several months.316,394 Recent data suggest that the Internet might provide a valuable resource for facilitating patients’ adherence to appropriate diet and activity regimens. Participants in a pilot study lost 4.1 kg in 12 weeks, a loss only slightly smaller than that produced with traditional group behavior therapy.395 Providing appropriate behavior modification therapy for obesity within a clinical practice is difficult because September 2002 physicians usually do not have the time or expertise to provide such care. Patients are likely to obtain the best results when they are seen frequently, such as every week or every other week. The anticipation of “weighing-in” and having to submit food records provides important motivation. Some physicians may be able to enlist the support of a nurse, medical technician, or dietitian who could weigh patients, briefly review their food records, and praise their efforts. Alternatively, the physician may refer the patient to a legitimate commercial or self-help program. Weight Watchers, for example, is reasonably priced and provides social support and sound advice on nutrition, exercise, and behavior modification. Take Off Pounds Sensibly (TOPS) is a self-help program that takes a similar approach. Overeaters Anonymous is another self-help option, which is appropriate for persons who binge eat or wish to explore emotional issues related to weight and eating. If patients are referred out, the physician should support their weight loss efforts by asking to see their weight graphs or food records and by inquiring about satisfaction with treatment. Pharmacotherapy General Principles The difficulty in achieving long-term weight management with lifestyle modification has led to an increased interest in pharmacotherapy for obesity. Although pharmacotherapy can help selected patients maintain long-term weight loss, 7 issues regarding the use of drugs should be considered. First, the greatest problem in obesity therapy is the high rate of relapse, so the most important challenge of pharmacotherapy is to maintain long-term weight loss. Therefore, it is inappropriate to consider the use of pharmacotherapy as a shortterm approach to “get patients going,” because patients who respond to drug therapy usually regain weight when therapy is stopped.396 –398 Effective pharmacotherapy for obesity is likely to require long-term, if not lifelong, treatment. Second, the required chronicity of drug treatment for obesity makes it particularly important to analyze carefully the long-term risks of obesity, the beneficial effects of pharmacotherapy on body weight and obesity-associated diseases, and the side effects and costs of treatment. This analysis is difficult because no prospective randomized controlled trials have evaluated the efficacy of any currently approved drugs for obesity for longer than 2 years. Third, some patients are refractory to drug therapy. If a patient does not respond to drug treatment for obesity in the first 4 weeks, long-term success is unlikely399,400 and discontinuation of treat- AMERICAN GASTROENTEROLOGICAL ASSOCIATION 905 ment should be considered. Fourth, drug therapy does not cause an indefinite reduction in body weight; weight loss usually plateaus by 6 months of treatment. Compared with placebo, drug therapy delays the onset and the level at which a plateau in weight loss occurs. Body weight begins to increase after ⬃1 year, despite continued drug treatment, but weight regain is less with drug than placebo.397,401 Therefore, overall weight loss observed in drug-treated patients is still greater than that observed in placebo-treated patients at 2 years. These data demonstrate that pharmacotherapy alone is unable to maintain a long-term plateau in body weight and suggest that either the effectiveness of medication diminishes over time or obesity is a continuously progressive disease, or both. Fifth, pharmacotherapy is not a “cure” for obesity; current medications have clinically significant but moderate effects on body weight and obesity-associated diseases. At the end of 1 year of treatment, the best of the currently available medications increases average weight loss by several percentage points and may double the number of patients who achieve a clinically significant weight loss (ⱖ10%).397,401 Sixth, it is difficult to judge the effectiveness of medications that were approved by the United States Food and Drug Administration (USFDA) for obesity treatment more than 5 years ago (no medications were approved between 1974 and 1996). The criteria required to approve antiobesity agents were much less stringent in the past than they have been in the last 5 years; earlier trials contained considerably fewer subjects and were much shorter than more recent studies. Seventh, pharmacotherapy alone is not as effective as pharmacotherapy given in conjunction with a comprehensive weight-management program (Figure 8).402,403 Therefore, patients given drug treatment without the other standard approaches to weight management, including behavior modification, diet education, and exercise counseling, are exposed to the full risks of drug treatment without the full medical benefits. Criteria for success. To evaluate the effectiveness of drug therapy, it is important to establish criteria for a successful treatment outcome. A clinically useful definition of a successful outcome might be individualized for each patient and, therefore, could involve a range of end points, such as amount of weight loss, prevention of weight gain, slowing the rate of future weight gain, improvement of obesity-associated medical complications, and improvements in quality of life and function. A reasonable and medically significant outcome for many patients is to lose 10% of body weight in the first 6 months of treatment. 906 AMERICAN GASTROENTEROLOGICAL ASSOCIATION Figure 8. Weight loss in women treated with anorexiant medication (sibutramine) alone (diamonds), medication plus group behavior modification therapy (squares), or medication plus group behavior modification therapy and meal replacements (triangles). These data demonstrate that greater weight loss is achieved when anti-obesity medications are used in conjunction with lifestyle modification than when they are used alone. (Reprinted with permission from Wadden et al.403 Arch Intern Med 2001;161:218 –227. Copyrighted 2001, American Medical Association.) Criteria for approval of new anti-obesity medications. The USFDA has proposed that drugs approved for the treatment of obesity demonstrate in a 1-year randomized, double-blind, controlled trial that: (1) weight loss with drug treatment is more than 5 percentage points greater than, and statistically significantly different from, weight loss with placebo; and (2) compared with placebo, drug treatment causes a statistically significantly larger number of subjects to achieve a ⬎5% weight loss.404,405 It is also recommended that studies be performed in year 2 to demonstrate maintenance of weight loss, but there is no proposal for longer studies. However, evaluating the effectiveness of a drug in a randomized controlled clinical trial can be confounded by the choice of adjunctive obesity therapy that is provided as part of the study protocol. Weight loss achieved in placebo-treated groups can vary widely, depending on the type of diet, exercise prescription, and behavior therapy program that is incorporated into the study.406 An effective obesity treatment program will minimize differences between drug and placebo-treatment groups and make seeing an additional effect of a drug on body weight more difficult. Overview of medications and mechanisms of action. Medications approved by the USFDA for the treat- ment of obesity are listed in Table 8. Only sibutramine and orlistat are approved for long-term use. With the exception of orlistat, which inhibits the absorption of dietary fat, all medications approved for obesity treatment act as anorexiants. Methamphetamine and benz- GASTROENTEROLOGY Vol. 123, No. 3 phetamine are addictive and should be avoided. Recently, 3 anorexiant medications have been removed from the marketplace because of increased risks of either valvular heart disease (fenfluramine and dexfenfluramine)407 or hemorrhagic stroke (phenylpropanolamine)408 associated with their use. Anorexiant medications increase satiation (level of fullness during a meal, which regulates the amount of food consumed), or satiety (level of hunger after a meal is consumed, which regulates the frequency of eating), or both, by affecting the monoamine (norepinephrine, serotonin, and dopamine) system in the hypothalamus. All of the anorexiant medications, with the exception of mazindol, are derivatives of the amphetamine precursor -phenylethylamine. Methamphetamine is addictive and should be avoided, whereas the other amphetamine derivatives have been chemically modified to reduce abuse potential. Monoamine neurotransmitters are synthesized from tyrosine and stored in granules that release their contents from presynaptic nerve terminals into the interneuronal cleft between presynaptic and postsynaptic nerves. Most of the monoamines released into the interneuronal cleft are taken back up into the presynaptic nerve terminal, where they are either degraded or repackaged into granules for future release. A small portion of released monoamines bind to postsynaptic receptors, Table 8. Drugs Approved by the United States Food and Drug Administration for the Treatment of Obesity Generic name Methamphetamine hydrochloridea Benzphetamine hydrochlorideb Phendimetrazine tartratec Phentermine Hydrochlorided Resine Diethylpropion hydrochloride Immediate releasef Controlled releasef Mazindolg Sibutramine hydrochloridea Orlistath aAbbott, Trade name(s) Desoxyn 15 Didrex Bontril, Plegine, Prelu-2, X-Trozine 25–150 70–210 Adipex-P, Fastin, Oby-trim Ionamin 15–37.5 Tenuate Tenuate Dospan Sanorex, Mazanor Meridia Xenical Chicago, IL. & Upjohn, Kalamazoo, MI. cAmarin, Warren, NJ. dGate, Sellersville, PA. eCelltech, Rochester, NY. fWatson, Corona, CA. gWyeth-Ayerst, Philadelphia, PA. hRoche Laboratories, Nutley, NJ. bPharmacia Daily dose (mg) 15–30 75 75 1–3 5–15 360 September 2002 thereby transmitting a signal from one nerve to the other. The 2 most commonly prescribed anorexiants are phentermine and sibutramine. Phentermine stimulates the release of norepinephrine and dopamine from nerve terminals. Sibutramine inhibits the reuptake of norepinephrine, serotonin, and, to a lesser degree, dopamine. Sibutramine affects satiation, rather than satiety, and may also cause a small increase in metabolic rate several hours after its administration in humans.409 Orlistat is a synthetic derivative of lipstatin, a product made by the Streptomyces toxytricini mold, which inhibits most mammalian lipases.410 When ingested, orlistat binds to gastric, pancreatic, and carboxylester lipases in the gastrointestinal tract and blocks the action of these lipases on dietary triglycerides and vitamin esters. The inhibition of fat digestion decreases micelle formation and the absorption of long-chain fatty acids, cholesterol, and certain fat-soluble vitamins. The percentage of malabsorbed fat is directly related to drug dose in a curvilinear fashion (Figure 9).411 At a dose of 360 mg/day (120 mg 3 times daily with meals), ⬃30% of ingested triglycerides are excreted in stool, which is near the maximum plateau value. Therefore, ingesting more than 120 mg of orlistat with a meal is unlikely to increase the malabsorption of ingested fat appreciably. The large range in fat malabsorption at any given orlistat dose (shown in Figure 9) is presumably a function of how well orlistat mixes and remains with the fat content of the meal. After ingestion of a meal plus Figure 9. Dose-response relationship between orlistat treatment and fecal fat excretion. Data from individual subjects (open circles) and the curve that best fits the data (continuous line) are shown. Fat malabsorption increased sharply with increasing orlistat dose, up to a near plateau value of 360 mg/day (120 mg 3 times daily with meals). (Reprinted with permission from Zhi et al.411) AMERICAN GASTROENTEROLOGICAL ASSOCIATION 907 orlistat, fat is released slowly from the stomach, while orlistat empties more rapidly.412 Therefore, orlistat may bind only to lipases released during the early portion of a meal and may not be available when the remaining portion of ingested fat enters the duodenum. Enhancing the physical interaction between orlistat and ingested fat increases orlistat’s malabsorptive potency. A 4-hour duodenal perfusion of orlistat during the oral consumption of a test meal containing 10 g of fat and a 4-hour duodenal perfusion of a lipid emulsion containing 30 g of fat resulted in ⬎95% inhibition of triglyceride hydrolysis.413 Less than 1% of ingested orlistat is absorbed; therefore, it has no effect on systemic lipases.414 In general, the approved indications for pharmacotherapy for obesity are a BMI ⱖ30 kg/m2 or a BMI between 27 and 29.9 kg/m2 in conjunction with an obesityrelated medical complication, in patients who have no contraindications to therapy. A comprehensive review of drug therapy for obesity was published recently.405 Only the data from long-term (defined as ⬎6 months) prospective, randomized, controlled trials that evaluated the weight loss efficacy and side effects of the most commonly prescribed medications will be reviewed here. Phentermine. Only one prospective randomized controlled trial has evaluated the effect of at least 6 months of phentermine therapy on body weight.415 In that study, which was published in 1968, 108 obese women were randomized to receive a 1000 kcal/day diet and treatment with either daily phentermine, daily phentermine every other month alternating with daily placebo every other month, or daily placebo for 36 weeks. Of the 64 subjects who completed the study, weight loss in the groups receiving continuous or alternating phentermine (with placebo) therapy were the same (13% of initial weight), and greater than the loss observed in the placebo group (5% of initial weight). Phentermine side effects. The most common side effects of phentermine are related to its sympathomimetic effects and include dry mouth, insomnia, and constipation. Although all sympathomimetic agents can increase blood pressure and heart rate, these abnormalities usually do not occur with phentermine therapy in the presence of weight loss. Sibutramine. Treatment with sibutramine at doses between 1 and 30 mg per day for 24 weeks demonstrated that weight loss was clearly dose-dependent, ranging from 0.9% to 7.7% of initial body weight for placebo and 30 mg per day, respectively.396 The current recommended starting dose is 10 mg per day, which can be decreased or increased by 5 mg in those 908 AMERICAN GASTROENTEROLOGICAL ASSOCIATION GASTROENTEROLOGY Vol. 123, No. 3 Table 9. Summary of 1-year, Randomized, Controlled Trials That Compared Sibutraminea or Orlistatb With Placebo Weight loss at 1 year Mean (% initial weight) First author (ref) Year No. of subjects randomized Sibutramine trials Smith417 McMahon418 2001 2000 485 224 1.8 0.7 Orlistat trials Sjöström397 Davidson420 Rossner290 Finer421 Hauptman422 1998 1999 2000 2000 2000 688 892 487 228 422 Lindgarde424 2000 Hollander423 1998 Placebo ⱖ5% (% subjects) Drug ⱖ10% (% subjects) Placebo Drug Placebo Drug Site Comments 7.3 4.7 20 9 57 40 7 4 34 13 United Kingdom United States Mean BMI ⫽ 33 kg/m2 BMI ⫽ 27–40 kg/m2 HTN 6.1 5.8 6.6 5.4 4.2 10.2 8.8 9.8 8.5 7.9 49 44 44 21 31 69 66 63 35 51 18 25 19 17 11 39 39 38 28 29 Europe United States Europe United Kingdom United States 376 4.6 5.9 41 54 15 19 Sweden 391 4.3 6.2 23 49 9 18 United States BMI ⫽ 28–47 kg/m2 BMI ⫽ 30–43 kg/m2 BMI ⫽ 28–43 kg/m2 BMI ⫽ 28–43 kg/m2 BMI ⫽ 28–43 kg/m2 Primary care setting BMI ⫽ 28–38 kg/m2 Type 2 DM, HTN, dyslipidemia Primary care setting BMI ⫽ 28–40 kg/m2 Type 2 DM DM, diabetes mellitus; HTN, hypertension. 15–20 mg day. bOrlistat, 120 mg 3 times daily. aSibutramine, who do not tolerate or who do not respond adequately to the initial dose.416 Two prospective 1-year randomized controlled trials have been reported that evaluated the efficacy of sibutramine therapy in producing and maintaining weight loss (Table 9).417,418 In both trials, more subjects randomized to 10 to 20 mg/day of sibutramine lost ⱖ5% and ⱖ10% of their initial weight than those in the placebo group. Minimal adjunctive weight management therapy was provided, so the placebo group achieved less weight loss than that usually observed in placebo groups from other trials. The results from another study demonstrated that weight loss with intermittent sibutramine therapy (15 mg/day given during weeks 1 through 12, 19 through 30, and 37 through 48, and placebo administered during the other weeks) was equivalent to weight loss with continuous sibutramine therapy (15 mg/ day).418a Two prospective randomized controlled trials have evaluated the efficacy of sibutramine therapy in longterm weight management after a predetermined amount of weight loss was achieved initially.401,419 In one study, 160 obese subjects who lost 6 kg or more after 4 weeks of treatment with a VLCD resumed a regular diet with diet counseling and were randomly assigned to 1 year of treatment with placebo or sibutramine (10 mg/day) therapy.419 In the year after randomization, subjects given sibutramine lost an additional 5.2 kg (total study weight loss of 12.9 kg), whereas those in the placebo group gained 0.5 kg (total study weight loss of 6.9 kg). Among subjects treated with sibutramine, 74% maintained or increased the weight loss achieved with a VLCD, compared with 41% of placebo-treated patients. In the second study, 467 obese subjects who experienced more than a 5% weight loss at the end of 6 months of treatment with sibutramine (10 mg/day) and a 600 kcal/day deficit diet were randomized to 18 months of dietary counseling and treatment with either sibutramine (increased to 15 or 20 mg/day) or placebo.401 Almost half of the subjects who entered the study dropped out before completing the 18-month treatment program. On average, those randomized to sibutramine treatment maintained their weight loss for 1 year, followed by a slight and progressive increase in weight thereafter; those randomized to placebo treatment experienced a progressive increase in weight as soon as they stopped sibutramine therapy. Of the subjects who completed the study, 43% of sibutramine-treated and 16% of placebo-treated subjects maintained 80% or more of their original 6-month weight loss. Sibutramine side effects. The most common side effects associated with sibutramine therapy are dry mouth, headache, constipation, and insomnia, which are usually mild and transient. Sibutramine also causes a September 2002 dose-related increase in blood pressure and heart rate that usually occurs in the first few weeks of treatment and lasts as long as the drug is taken. A dose of 10 to 15 mg/day causes an average increase in systolic and diastolic blood pressure of 2 to 4 mm Hg and an increase in heart rate of 4 to 6 beats per minute.396,401 However, some patients experience much larger increases in blood pressure or heart rate and require dose reduction or discontinuation of therapy.404 The risk of adverse effects on blood pressure are no greater in patients with controlled hypertension than in those who do not have hypertension.401,418 The use of sibutramine is contraindicated in patients with poorly controlled hypertension. Orlistat. Many of the orlistat clinical trials included treatment arms that provided low doses of orlistat (30 and 60 mg 3 times daily) that were not effective and are not currently available. Therefore, only the data evaluating the standard dose of 120 mg 3 times daily will be reviewed here. Seven prospective randomized controlled trials of ⱖ1 year duration have been published that evaluated the efficacy of orlistat therapy in initiating and maintaining weight loss (Table 9).290,397,420 – 424 Compared with placebo, the efficacy of orlistat in achieving weight loss was consistent across studies. At 1 year, approximately one third more patients treated with orlistat lost 5% or more of their initial body weight than did those treated with placebo; approximately twice as many patients treated with orlistat lost 10% or more of their initial body weight as those in the placebo group. Subjects who were enrolled in a trial conducted within a primary care practice setting, which did not include behavior therapy or interaction with a dietitian,422 did not do as well as those enrolled in trials that provided formal behavior modification and dietary counseling.290,397,420 Successful weight loss also was more difficult to achieve in patients with type 2 diabetes mellitus423 and in those with risk factors for CHD, including hypertension and dyslipidemia.424 Several randomized controlled studies have evaluated the effectiveness of orlistat in maintaining initial weight loss. Four trials represent a second year extension of 1-year studies reviewed previously.397,402,420,422 In these trials, energy intake was liberalized during the second year with a goal of preventing weight regain, rather than inducing further weight loss. Approximately half of the subjects who initially were randomized completed the entire 2 years. In all trials, weight regain occurred in both placebo- and orlistat-treated groups after year 1, but the total percent weight loss at the end of year 2 was greater with orlistat than with placebo therapy. Weight loss at 2 years was better when dietary counseling and AMERICAN GASTROENTEROLOGICAL ASSOCIATION 909 behavior modification therapy were incorporated into the treatment program than when the trial was conducted in a primary care setting without formal behavioral or dietary counseling. At 2 years, 34% of subjects given behavior modification therapy plus orlistat lost 10% or more of their initial weight,420 compared with 19% of subjects given orlistat within a primary care setting.422 One trial evaluated the efficacy of orlistat therapy in weight maintenance after initial weight loss was induced by diet alone.425 A total of 729 obese subjects who lost ⱖ8% of body weight after completing a 6-month weight loss program were prescribed a weight-maintaining diet and randomized to receive orlistat or placebo therapy for 12 months. Compared with placebo, subjects given orlistat had slightly greater total weight loss (8.2% vs. 6.4% of initial body weight) and less weight regain (32% vs. 56% of lost weight). Furthermore, 48% of patients treated with orlistat compared with 30% of patients treated with placebo maintained at least 75% of their lost weight; 24% of patients treated with orlistat compared with 16% of patients treated with placebo did not regain any weight or continued to lose weight. Comparing the results from this latter study425 with data obtained from a similar study that evaluated the effectiveness of sibutramine in weight maintenance419 suggests that orlistat is not as effective as sibutramine in maintaining diet-induced weight loss (Figure 10). How- Figure 10. Weight maintenance during 1 year of treatment with either sibutramine or orlistat after subjects achieved successful initial weight loss by diet alone. The amount of initial weight loss, achieved by 4 weeks of treatment with a very low-calorie diet in the sibutramine trial and after 6 months of treatment with a low-calorie diet in the orlistat trial, is represented by the black bars. Total weight loss 1 year after initial intensive diet therapy was stopped for those randomized to receive placebo (white bars) or drug (striped bars) during the maintenance period. (Data for the sibutramine trial were obtained from Apfelbaum et al.419 and data for the orlistat trial were obtained from Hill et al.425) 910 AMERICAN GASTROENTEROLOGICAL ASSOCIATION ever, differences in dietary instructions make it difficult to compare data reliably between studies, and further evaluation of each medication given as part of a single prospective randomized trial is warranted. Data from several randomized orlistat clinical trials suggest that orlistat may have a beneficial effect on serum cholesterol concentration that is independent of weight loss alone. Subjects administered orlistat had a greater reduction in serum LDL-cholesterol concentrations than those given placebo, even after adjusting for percent weight loss.397,420 The mechanism responsible for this additional lipid-lowering effect may be related to orlistat’s effect on dietary cholesterol absorption. By using cholesterol tracer methods, it was reported that orlistat ingestion with a meal decreased dietary cholesterol absorption by 25%.426 It has been hypothesized that, in addition to blocking the absorption of fat, orlistat helps patients lose weight by encouraging dietary fat restriction to avoid the gastrointestinal side effects of fat malabsorption. In fact, it has been suggested that orlistat may be a behavior modification tool by acting as an “Antabuse” for fat. However, data from 2 prospective trials revealed that, compared with placebo, orlistat therapy did not cause a further decrease in fat intake in subjects prescribed a low-calorie, low-fat diet (⬃60 g of fat per day).425,427 Moreover, the energy lost from malabsorbed fat was greater than expected based on the observed weight loss, suggesting that orlistat’s effect on body weight can be accounted for by fat malabsorption alone, rather than by modification of fat intake. Orlistat side effects. The most common side effects experienced with orlistat therapy are related to orlistat’s action on gastrointestinal lipases. In 1- and 2-year trials,290,397,420 – 424 approximately 70% to 80% of subjects treated with orlistat experienced one or more gastrointestinal events (listed in Table 10) compared with approximately 50% to 60% of those treated with placebo. Gastrointestinal events usually occurred early (within the first 4 weeks), were of mild or moderate intensity, were usually limited to 1 or 2 episodes, and resolved despite continued orlistat treatment. Approximately 4% of subjects treated with orlistat and 1% of subjects treated with placebo withdrew from the studies because of gastrointestinal complaints. The gastrointestinal side effect profile of one illustrative study is shown in Table 10.397 Subjects who completed year 1 on placebo therapy: and switched from placebo to orlistat during year 2 experienced the same number of gastrointestinal side effects during year 2 as those initially treated with orlistat experienced during year 1. Subjects who GASTROENTEROLOGY Vol. 123, No. 3 were given orlistat during both years 1 and 2 had the same number of gastrointestinal side effects in year 2 as those treated with placebo had in year 1. Many of the gastrointestinal side effects of orlistat can be prevented by concomitant therapy with a gel-forming fiber (psyllium mucilloid).428 Long-term orlistat treatment can affect the homeostasis of certain fat-soluble vitamins. Acute absorption studies conducted in normal volunteers showed that orlistat ingestion inhibited the absorption of -carotene429 and vitamin E,430 but not vitamin A.430 Assessment of serum concentrations of fat-soluble vitamins and -carotene during 1- and 2-year orlistat clinical trials showed that mean serum concentrations remained within the normal range, although subjects were not allowed vitamin supplementation. Vitamin concentrations, usually vitamins D, E, and -carotene, decreased below normal limits in approximately 5% more orlistat- than placebo-treated subjects. These abnormalities resolved rapidly with vitamin supplementation.397,290,420 – 423 Therefore, it is recommended that all patients who are treated with orlistat be given a daily multivitamin supplement that is taken at a time when orlistat is not being ingested. Orlistat can have medically significant effects on the absorption of lipophilic medications if both drugs are taken simultaneously. Several cases have been reported of subtherapeutic plasma cyclosporin levels in organ transplant recipients after they began orlisat therapy for obesity.431– 433 Therefore, orlistat should not be taken for at least 2 hours before or after the ingestion of lipophilic drugs, and plasma drug concentrations should be followed to ensure appropriate dosing if possible. The results of pharmacokinetic studies suggest that orlistat does not affect the absorption of selected drugs with a narrow therapeutic index (warfarin, digoxin, phenytoin) and selected drugs that are likely to be taken concomi- Table 10. Gastrointestinal Side Effects of Orlistat Therapy Year 1 Fatty/oily stool Increased defecation Oily spotting Soft stool Liquid stools Abdominal pain Fecal urgency Flatulence Flatus with discharge Fecal incontinence Oily evacuation Year 2 Placebo Orlistat Placebo Orlistat 5 7 1 9 10 9 3 3 0 0 1 31 20 18 15 13 7 10 7 7 7 6 1 2 1 2 5 7 2 2 0 0 0 8 2 6 6 8 7 3 3 1 2 5 Data from Sjöström L, et al.397 September 2002 tantly with orlistat (glyburide, oral contraceptives, furosemide, captopril, nifedipine, atenolol, and alcohol).434 There is a theoretical concern that long-term orlistat therapy may increase the risk of specific gastrointestinal diseases, such as gallstones and colon cancer. Orlistat could increase gallstone formation because inhibition of fat digestion prevents the release of fatty acids into the intestinal lumen, which is needed to stimulate cholecystokinin secretion and gallbladder contraction.413 However, orlistat administered with meals of varying fat content does not reduce gallbladder motility,435 and there is no evidence of increased gallstone formation in the thousands of subjects who have completed 1- and 2year orlistat clinical trials.307,402,420 – 425 The increased delivery of fat to the colon has raised a concern of increased colon cancer risk. However, orlistat administration in obese volunteers does not increase colonocyte proliferation,436 and there is no evidence of an increased incidence of colon cancer in subjects who took orlistat in clinical trials. Nonetheless, studies of longer duration would be useful to confirm these data. Surgical Therapy Indications for Surgery Gastrointestinal surgery is the most effective approach for achieving weight loss in severely obese patients. In 1991, a NIH Consensus Conference established guidelines for the surgical treatment of obesity.437 The panel concluded that patients with class III obesity (BMI ⱖ40 kg/m2) or those with class II obesity (BMI 35.0 –39.9 kg/m2) and one or more severe obesity-related medical complications (e.g., hypertension, type 2 diabetes mellitus, heart failure, or sleep apnea) are eligible for surgery. Moreover, potential candidates should be patients who are unable to lose weight or maintain weight loss with conventional therapy, have acceptable operative risks, and are able to comply with long-term treatment and follow-up. Active substance abuse is an absolute contraindication. Types of Surgical Procedures Surgical therapy for obesity can be classified into 2 general categories: (1) procedures that primarily cause gastric restriction and (2) procedures that primarily cause maldigestion and malabsorption (Table 11). This section will focus particularly on the risks and benefits of the gastric bypass procedure (GBP) because it accounts for more than 90% of the bariatric surgery procedures currently being performed in the United States. GBP. The GBP, also known as a Roux-en-Y gastric bypass, involves construction of a small (10 to 30 AMERICAN GASTROENTEROLOGICAL ASSOCIATION 911 mL) proximal gastric pouch by stapling across the stomach or complete transection from the rest of the stomach (Figure 11A). The pouch empties into a segment of jejunum that is brought up to the gastric pouch as a Roux-en-Y limb. The length of the Roux-en-Y limb is variable, depending on the size of the patient. For example, a 45- to 100-cm limb (proximal or short-limb GBP) often is used in patients with a BMI ⬍50 kg/m2, whereas a limb of 150 cm or more (distal or long-limb GBP) usually is reserved for patients with a BMI ⱖ50 kg/m2. In one study, conducted in patients with BMI ⱖ50 kg/m2, a 150-cm limb achieved greater weight loss than a 75-cm limb, without increasing the risk of nutrient deficiencies.438 Although the gastric bypass is considered a restrictive procedure, it causes some malabsorption as a consequence of the bypassed stomach, duodenum, and upper jejunum. No randomized clinical trials have evaluated the most effective pouch or stomal size for optimal weight loss. However, many bariatric surgeons believe that the gastric pouch should be as small as possible (just large enough to construct a gastrojejunostomy) and that the stoma should be about 1 cm in diameter. Complications specifically related to the GBP procedure include early complications of hemorrhage, gastrointestinal leak leading to peritonitis, splenic injury, wound infection, and late complications of stomal stenosis, marginal ulcers, staple line disruption, dilation of the bypassed stomach, internal hernias, specific nutrient deficiencies, and dumping syndrome. Stomal stenosis occurs in 5% to 15% of patients and is manifested as nausea and vomiting after eating.439 Although stomal stenosis after gastric bypass usually can be treated by endoscopic balloon dilatation, it is occasionally necessary to surgically revise the gastrojejunal anastomosis. If not treated, stomal stenosis can cause serious nutrient deficiencies, including thiamine deficiency with Wernicke-Korsikoff encephalopathy and profound peripheral neuropathy.440,441 Therefore, upper gastrointestinal endoscopy should be performed at the first sign of Table 11. Surgical Procedures for Weight Loss Classification Procedure Primarily gastric restriction Gastric bypass (Roux-en-Y gastric bypass) Gastroplasty (VBG) Gastric banding Biliopancreatic diversion Biliopancreatic diversion with duodenal switch Distal gastric bypass JIB (small bowel bypass)a Primarily maldigestion/ malabsorption aThis procedure is no longer recommended because of unacceptable side effects. 912 AMERICAN GASTROENTEROLOGICAL ASSOCIATION Figure 11. Gastric restrictive surgical procedures: (A) GBP and (B) VBG. recurrent nausea and vomiting, before patients develop dehydration or electrolyte and vitamin deficiencies. Marginal ulcers develop in 5% to 15% of patients and almost always occur on the jejunal side of the gastrojejunostomy.439 Staple line disruption increases the risk of this complication because of persistent bathing of the anastomosis with acid.110 Marginal ulcers usually respond to acid-suppression therapy; however, approximately 10% of patients with ulcers (1% of all patients) will need surgery to resect the ulcer. On rare occasions, ulceration and friability at the anastomosis cause gastrointestinal bleeding, which usually resolves with conservative therapy. Upper gastrointestinal bleeding that cannot be detected by endoscopy usually is caused by a duodenal ulcer that cannot be visualized because of anatomical reconstruction of the intestine. Therefore, empiric acid-reduction therapy is indicated in the absence of endoscopic evidence of a marginal ulcer. Assessment of Helicobacter pylori status, by using a serum or breath test, is useful to identify patients who may benefit from H. pylori eradication. Staple line disruption often is heralded by a marked increase in the ability to eat large volumes of food or by the presence of a marginal ulcer that is refractory to acid-suppression therapy. Surgical revision, which can be technically difficult because of adhesions from the previous surgery, is required.110 Dilation of the bypassed stomach can occur as an acute postoperative problem and usually presents as hiccups and complaints of bloating. The diagnosis can be confirmed with a plain, upright abdominal film showing a dilated, air-filled distal stomach. This complication usually can be treated by percutaneous fine-needle aspiration. However, if dilatation recurs, an endoscopic or surgically placed gastrostomy tube may be necessary to prevent gastric necrosis or disruption of the gastrojejunostomy.111 GASTROENTEROLOGY Vol. 123, No. 3 Internal hernias usually occur at 3 sites: (1) where the Roux limb passes through the mesocolon, (2) at the jejunojejunostomy, and (3) between the jejunal and colonic mesenteries. It is critical to recognize symptoms of an internal hernia (i.e., cramping and periumbilical pain, with or without nausea and vomiting) because emergency surgery is needed to prevent intestinal necrosis from a closed-limb obstruction.111 The decision to operate is based on clinical suspicion because an upper gastrointestinal radiographic (UGI) film may not detect the problem. Certain nutrient deficiencies, particularly iron, calcium, folic acid, and vitamin B12, are common after gastric bypass surgery because of impaired absorption and decreased intake.442– 445 Premenopausal women are particularly susceptible to the development of iron-deficiency anemia because of blood loss during menses, in addition to surgery-induced iron malabsorption caused by both anacidity and duodenal bypass. Osteoporosis can occur because of calcium malabsorption. Serum calcium concentration remains normal because of calcium mobilization from bone but alkaline phosphatase and other markers of bone turnover often are increased. More than 50% of patients become vitamin B12 deficient if they do not take oral supplementation. Vitamin B12 deficiency probably is caused by inadequate acidity needed to release vitamin B12 from food; the Schilling test is generally normal. Folate deficiency is rare and probably occurs because of decreased intake. Many nutrient deficiencies can be prevented by appropriate mineral and vitamin supplementation. All gastric surgery patients should take supplemental calcium and a multivitamin containing folate and vitamin B12 daily. Vitamin B12 also can be provided by oral, intramuscular, or intranasal routes. Menstruating women should also take supplemental iron with meals. Some patients also may require additional magnesium or zinc. Dumping syndrome often occurs after gastric bypass surgery because ingested food traverses directly from the gastric pouch into the jejunum. Patients who eat a large volume of food or energy-dense liquids that have high sugar content or high osmolality often complain of dumping symptoms, including nausea, abdominal pain, flushing, tachycardia, and diarrhea. This “complication” is probably beneficial because it prevents excessive ingestion of carbohydrate-dense foods. Gastroplasty. Gastroplasty (Figure 11B), also known as gastric stapling, can be performed in 2 ways. The first procedure, known as VBG, involves stapling the front to the back of the stomach below the gastroesophageal junction and 1 cm from the lesser curvature with a September 2002 surgical stapling device that cuts out a hole. A vertical staple line is then made from the opening to the left side of the gastroesophageal junction, and the outlet stoma is restricted with a 1-cm diameter polypropylene band.446 The second procedure, known as silastic ring gastroplasty, involves constructing a vertical staple line along the lesser curvature to the left side of the gastroesophageal junction, with a notched stapling device that leaves an opening (stoma) distally. The stoma is then restricted with a 1-cm diameter silastic ring.447 Complications specifically related to gastroplasty include stomal stenosis, staple line disruption, erosion of the band, and increased gastroesophageal reflux. Stomal stenosis prevents adequate nutrient intake and causes dehydration and vitamin deficiencies. Although an attempt to dilate stenoses by endoscopic balloon dilatation should be made, this approach usually is unsuccessful because of the fixed band and generally is best managed by surgical conversion to a gastric bypass.439 Staple line disruption, which can occur in up to 35% of patients, leads to rapid weight regain.448 In some patients, gastroesophageal reflux can be a severe and serious complication, requiring conversion to a gastric bypass.110,111 In contrast to the GBP, gastroplasty does not cause dumping syndrome or iron or vitamin B12 deficiency. Comparison between gastric bypass and gastroplasty on weight loss. Four prospective, randomized tri- als448 – 451 that compared VBG with GBP consistently found that weight loss was greater with the latter procedure. In addition, many,452– 454 but not all,455 retrospective studies found that weight loss with gastric bypass was superior to weight loss with gastroplasty. In the first randomized trial to evaluate the 2 procedures, average loss of excess weight at 1 year after surgery was 42% with VBG and 68% after the GBP; weight loss remained significantly different between groups during a 3-year follow-up period449 (Figure 12). Moreover, independent long-term evaluations of each procedure suggest better results with the GBP than VBG. Average weight loss after the GBP was maintained up to 14 years after surgery,279 whereas a recent study reported poor weight loss at 10 or more years after VBG.456 The mechanism responsible for the difference in weight loss between the 2 procedures is not known, but may be related to increased susceptibility to dumping and lactose intolerance associated with GBP. These symptoms may cause a decrease in the intake of foods with high sugar content and high-calorie milk products, such as ice cream and milkshakes.449,457 In fact, patients who eat a large portion of their calories as sweets (“sweet eaters”) lose substantially more weight with the GBP than with the VBG.449 AMERICAN GASTROENTEROLOGICAL ASSOCIATION 913 Figure 12. Percentage of excess weight (⫾ SD) lost over 36 months after the GBP and VBG. (Adapted with permission from Sugerman et al.449) However, even when “sweet eaters” are excluded, patients who undergo gastric bypass still experience more weight loss than those who have VBG.458 Therefore, gastric bypass is currently considered the gold standard for obesity surgery in many centers. Gastric banding. The laparoscopically inserted adjustable silicone gastric band (LASGB) is currently the most popular bariatric surgical procedure being performed in Europe.459 The LASGB recently was approved for clinical use in the United States by the Food and Drug Administration (USFDA). The band is placed around the upper stomach, just distal to the gastroesophageal junction. A balloon in the band is connected to a subcutaneously implanted port that can be accessed percutaneously to inflate or deflate the band, and thereby change the size of the band circumference. Some studies found that weight loss with this device was equivalent to a VBG,459 whereas other investigators have found the average loss with LASBD was much less than that achieved by GBP.460 Complications of the LASGB are less common and less severe than those that occur with either the GBP or gastroplasty. These complications include band slippage, esophageal dilatation, erosion of the band into the stomach, band or port infections, and balloon or system leaks that lead to inadequate weight loss.461,462 Band slippage occurs when the posterior stomach wall herniates through the band, which can cause gastric obstruction and require surgical revision. Band placement at the gastroesophageal junction can cause esophageal dilatation and dysphagia.461 Loosening the band usually decreases the dilatation but sometimes band removal is required; in some patients, the band erodes into the stomach, which also requires surgical removal.462 Jejunoileal bypass (JIB). The JIB, first reported in 1969, was designed to bypass most of the small 914 AMERICAN GASTROENTEROLOGICAL ASSOCIATION Figure 13. Biliopancreatic diversion with duodenal switch. (Data from Marceau et al.474) intestine and induce weight loss by malabsorption of ingested calories. The original procedure was constructed with 8 inches of jejunum connected end-to-side to the ileum 4 inches from the ileocecal valve.463 To prevent reflux of food into the bypassed intestine and increase weight loss, the operation was then changed to an endto-end jejunoileostomy with the bypassed small bowel drained into the colon.464 The JIB procedures were associated with many serious complications caused by protein-calorie malnutrition, bacterial overgrowth and translocation, and excess oxalate absorption (e.g., cirrhosis, interstitial nephritis, migratory arthritis, bypass enteritis, erythema nodosum, oxalate urolithiasis, hypocalcemia, and electrolyte imbalances).465– 469 These operations are no longer performed because of the unacceptable rate of serious side effects. Patients who experience one or more of the JIB complications that are related to bacterial overgrowth (e.g., migratory arthritis, elevated liver enzymes, bleeding from inflammation in the bypassed intestine) can be treated successfully with oral metronidazole.468 – 469 Patients refractory to antibiotic treatment or who suffer other serious consequences of the procedure, such as progressive liver disease, require surgical revision. If a JIB is surgically corrected, a GBP should be performed at the time of surgery unless the patient has severe cirrhosis with portal hypertension because reversal of the JIB is associated with regain of all lost weight and recurrence of previous obesity-related diseases.470 Biliopancreatic diversion. Biliopancreatic diversion, also known as partial biliopancreatic bypass, is designed to induce gastric restriction, maldigestion, and malabsorption. In this operation, a partial gastrectomy is performed with creation of a 500-mL capacity proximal gastric pouch for patients with a BMI ⬍50 kg/m2 or a 200-mL capacity pouch for those with a BMI ⱖ50 kg/m2. The small intestine is transected 250 cm from the GASTROENTEROLOGY Vol. 123, No. 3 ileocecal valve, and the distal end is anastomosed to the gastric pouch. The proximal limb is then connected to the ileum, 50 cm from the ileocecal valve. These anastomoses create a 200-cm “alimentary tract,” a variable length (300- to 500-cm) “biliary tract,” and a 50-cm “common tract” where digestion and absorption of ingested food occur. The biliopancreatic diversion causes a greater amount of weight loss (⬃75% of excess weight) than gastric restrictive procedures. Biliopancreatic diversion causes more nutritional abnormalities (e.g., osteoporosis) and gastrointestinal complications (e.g., frequent, foul-smelling steatorrheic stools) than gastric restrictive procedures because of malabsorption of protein, fat, fat-soluble vitamins, iron, calcium, and vitamin B12.471– 474 The size of the gastric pouch is inversely correlated with the risk of protein deficiency, which can occur in 100% of patients when the pouch is only 30 mL in size.472,474 In contrast to the JIB, the bypassed intestine produced by this procedure usually does not develop bacterial overgrowth because the bypassed limb is “washed” with bile and pancreatic juices. Consequently, biliopancreatic diversion rarely is associated with liver damage; migratory arthritis and renal disease have not been reported with the procedure. However, after this procedure some patients may develop fever and diarrhea that respond to metronidazole therapy, suggesting the presence of bacterial overgrowth in the biliopancreatic limb.472 Biliopancreatic diversion with duodenal switch. This operation, also known as partial biliopancreatic bypass with duodenal switch, is a modification of the biliopancreatic diversion procedure474 – 476 (Figure 13). The procedure involves removal of approximately 60% of the greater curvature of the stomach (sleeve gastrectomy), which causes gastric restriction but allows better preservation of gastric physiological function than a distal gastrectomy. In addition, the proximal duodenum is transected, the distal end of the duodenum is closed, and the proximal duodenum is anastomosed to distal intestine, 250 cm proximal to the ileocecal valve. The proximal intestine is then connected to the ileum, 100 cm from the ileocecal valve. This procedure causes greater weight loss (⬃75% of excess weight) than a standard gastric bypass. Patients who have this procedure are able to eat normal volumes of food and do not develop dumping syndrome symptoms because of the regulation of gastric emptying by an intact pyloric sphincter. The incidence of protein deficiency is probably less common and gastrointestinal side effects are not as severe after biliopancreatic diversion with duodenal switch than after bilio- September 2002 pancreatic diversion with distal gastric resection. In addition, sparing the pylorus decreases the risk of marginal ulceration. Laparoscopic obesity surgery. All obesity surgical procedures have been performed laparoscopically. The laparoscopic approach is becoming more available because the number of centers performing the procedures is increasing rapidly. The laparoscopic gastric bypass is technically challenging with a steep learning curve. The time needed to perform the procedure and the incidence of complications decrease with increased experience. The results from initial large series477,478 and a randomized controlled trial479 demonstrate that weight loss after the laparoscopic procedure is the same as that after the open procedure.477– 479 The laparoscopic approach is associated with decreased wound complications (infection and incisional hernia), decreased postoperative pain, less blood loss, improved cosmesis, shorter hospital stay, and an earlier return to a functional life. Late anastomotic strictures occur more frequently after laparoscopy than open procedure but the rate of postoperative anastomotic leaks and the costs are the same.479 Complications Associated With All Bariatric Surgical Procedures Perioperative mortality rate after open obesity surgical procedures reported in studies containing large numbers of patients is usually ⬍1.5%.279,448,480 Approximately 75% of the deaths are caused by anastomotic leaks and peritonitis and 25% by pulmonary embolism. Anastomotic leak with peritonitis is a devastating complication that can be very difficult to diagnose because patients rarely develop peritoneal signs despite the presence of peritonitis. Symptoms of a leak include left shoulder pain, tenesmus and urinary urgency, increased back pain, and a feeling of “impending doom.” Signs include fever and tachycardia.111,481 The diagnosis requires a high degree of suspicion and can sometimes be confirmed with a water-soluble contrast UGI series. However, if the patient has had a gastric bypass, the leak may be from the bypassed stomach and will not be seen by a UGI series. If a leak is suspected, the safest course of action is to re-explore the patient. The leak rate after open gastric bypass is approximately 2.5% in most series, and the mortality risk from this complication is approximately 0.3%.279,482 Patients who have sleep apnea or obesity hypoventilation syndrome have a higher mortality risk.299 The risk of pulmonary embolism after surgery is increased in extremely obese patients. Although many surgeons use intermittent venous compression boots, as well as AMERICAN GASTROENTEROLOGICAL ASSOCIATION 915 standard or low-molecular-weight heparin to reduce this risk, no studies have carefully evaluated the risk-reduction of any prophylactic approach. In one series, the risk of a fatal pulmonary embolism was 0.2% and increased to 4% in patients with severe venous stasis disease.483 The presence of severe pulmonary hypertension in association with obesity hypoventilation can increase the risk of fatal pulmonary embolism,304 which raises the consideration of prophylactic Greenfield inferior vena cava filter placement in these patients. Gallstones will form in approximately one third of patients within 6 months after a gastric restrictive procedure; the incidence may be higher in patients who have had a malabsorptive procedure. As noted previously, the incidence of gallstone formation is markedly decreased with ursodeoxycholic acid therapy.122 Although some surgeons perform cholecystectomy routinely at the time of the bariatric surgical procedure, most only perform cholecystectomy in patients who have gallstones already present at the time of the procedure. The risk of incisional hernia is markedly increased after any abdominal surgery in a severely obese patient compared with a lean patient.484 In fact, the risk of incisional hernia after bariatric surgery in extremely obese patients is greater than the risk in patients who undergo a colectomy and ileoanal pouch procedure for ulcerative colitis, despite the latter having a much larger incision and compromised wound healing because of prednisone therapy. Overall, postoperative incisional hernia occurs in 15% to 25% of patients but the risk is higher in patients with a prior incisional herniorrhaphy or patients with diabetes, obesity hypoventilation syndrome, or sleep apnea. Wound infections occur more commonly after any abdominal operation in severely obese than in lean patients, presumably because of the increased amount of deep subcutaneous fat. Inadequate Weight Loss or Weight Regain After Surgery On average, at 1 to 2 years after GBP, patients lose two thirds of their excess weight (one-third of their total weight). At 5 and 10 years after surgery, the average loss of excess weight is 60% and 50%, respectively.279,482 Better long-term weight loss of ⬃75% of excess weight is observed after the partial biliopancreatic bypass or duodenal switch procedures.471,474 – 476 Approximately 15% of patients will fail to lose more than 40% of their excess weight (10% to 15% of total weight) after a GBP,279,482 and an even greater percentage of patients fail to lose this amount of weight after gastroplasty procedures.456 The primary cause of failed weight loss after gastric bypass is the frequent ingestion of high-fat 916 AMERICAN GASTROENTEROLOGICAL ASSOCIATION snacks (e.g., potato or corn chips), fried foods (e.g., french-fried potatoes), and high-calorie soft foods and liquids (sodas, lemonade, milkshakes, cookies, and ice cream). In patients who have undergone either a stapled gastroplasty or gastric bypass, increased food intake may be related to staple line disruption, particularly if the patient is able to eat much larger quantities of food at a time. An UGI series is needed to diagnose this complication, which requires surgical revision. Revisional procedures for bariatric procedures carry a higher risk of complications, including anastomotic leak.485 Dilation of the gastrojejunal stoma can occur, but it probably does not impede weight loss, and surgical revision does not lead to greater weight reduction.486 Patients who have not responded to a standard gastric bypass and have severe obesity-related diseases such as drug-resistant hypertension, obesity hypoventilation, or diabetes are potential candidates for conversion to a malabsorptive procedure. Although converting a standard gastric bypass to a malabsorptive distal gastric bypass is effective for weight loss, this approach increases the risk of development of protein-calorie malnutrition, steatorrhea with foul-smelling stools, and fat-soluble vitamin deficiencies.472 Medical Management of Bariatric Surgery Patients Careful evaluation and management of patients before and after surgery are important to exclude inappropriate surgical candidates, provide counseling regarding postoperative lifestyle, diet, and weight loss expectations, and decrease the risk of postoperative complications. The initial evaluation should include a careful medical assessment with particular attention to concomitant medical illnesses that increase the risk of surgery. A psychological assessment can help identify patients who might experience an adverse outcome because of psychiatric problems, such as severe depression, suicidal ideation, substance abuse, or inadequately treated psychosis. Dietary counseling is needed before and after surgery to help patients adjust to the marked changes required of their dietary habits. Dietary intake after surgery usually progresses from liquids (days 2 to 3), to pureed foods (days 4 to 30), to soft foods (days 31 to 45), to small, 2to 3-oz portions of regular food (after day 45). When dietary intake is stable, patients should consume 6 to 8 cups of fluids per day, ingest high-protein foods, and take vitamin and mineral supplements. After the first postoperative year, a medical examination should be performed annually and should include blood tests to evaluate hemoglobin, plasma mineral concentrations (particularly iron, magnesium, and calcium), and se- GASTROENTEROLOGY Vol. 123, No. 3 lected vitamin concentrations (folate and vitamin B12). Fat-soluble vitamins A, D, and E should also be monitored in patients who have had malabsorptive procedures, such as the long-limb gastric bypass or biliopancreatic diversion. Intragastric Balloon Therapy The observation that gastric bezoars cause weight loss487 led to the concept of using intragastric balloons as a method of obesity therapy. In 1985, the Garren Edwards Gastric Bubble became the first endoscopically placed intragastric balloon approved by the USFDA. However, an unacceptable incidence of gastric erosions and ulcers, balloon deflation, and small bowel obstruction caused by migration of deflated balloons led to the removal of the Garren Edwards Gastric Bubble and later the Wilson-Cook balloon from the marketplace. Nonetheless, continued efforts to develop a safe and effective intragastric balloon have led to a new generation of balloons with a low potential for gastric irritation and deflation. In addition, these balloons have a larger capacity (400 to 800 mL) than earlier models to enhance weight loss, and the volume in selected balloons can be endoscopically adjusted to accommodate for patient size, gastrointestinal symptoms, and rate of weight loss. Currently, intragastric balloons are not available for use in the United States but are being used for weight loss therapy in selected patients in other countries, primarily in Europe. The complication rates observed with these balloons are much lower than those observed with the Garren Edwards Gastric Bubble. The composite of results from several studies showed that mucosal damage occurred in ⬃4% and balloon deflation in ⬃7% of subjects.488 It usually is recommended that the balloon be removed or replaced within 3 to 6 months of insertion to reduce the risk of complications. Longer placement periods might be safe with appropriate monitoring by x-ray or ultrasound to ensure that adequate balloon inflation has been maintained. Recently, colonic impaction caused by migration of a deflated balloon was reported in one patient 9 months after balloon placement.489 Data from published randomized controlled trials of currently available devices, conducted in extremely obese subjects for up to 8 months, have not demonstrated consistent benefits of intragastric balloon therapy on weight loss.490 – 495 Most,490 – 494 but not all495 trials, revealed that weight loss in subjects who had intragastric balloon placement (in conjunction with diet therapy) was similar to that in subjects who had sham endoscopy and diet therapy. In all negative trials, patients randomized to sham balloon placement and diet therapy achieved con- September 2002 siderable weight loss. Therefore, the successful weight-management program in these studies may have made it difficult for balloon therapy to provide additional benefits. For example, in one study of extremely obese patients who had a BMI ⬎50 kg/m2 and weighed ⬎150 kg, the control group lost ⬃50 kg at 8 months of treatment. Additional studies, of much longer duration and in a more typical clinical practice setting, are still needed to determine the long-term efficacy and safety of intragastric balloons. Patient Expectations There is a considerable discrepancy between a realistic weight loss goal and the patient’s expected weight loss goal. Obese persons who seek nonsurgical therapy for obesity typically want to lose 2 to 3 times more weight than usually is achieved with current behavioral and pharmacologic treatments. In a recent study, obese women who were beginning a weight loss program indicated they wanted to lose 38% of their body weight but would be happy with a loss of 31%, satisfied with a loss of 25%, and disappointed with a loss of 17% of initial body weight.496 After 48 weeks of intensive diet and exercise therapy, these women lost an average of 16.4% of their initial weight. In another study, patients who were about to begin treatment with sibutramine and group lifestyle modification expected to lose twice as much weight (25% of initial weight) as they actually lost (11.5% of initial weight) at the end of 1 year.404 Patients who seek bariatric surgery also often have unrealistically high weight loss expectations.497 Many obese patients will accept extraordinary risks and hardships to lose weight. Rand and Macgregor498 found that patients who had maintained a weight loss of ⱖ100 pounds for 3 or more years after gastric surgery would rather lose their hearing, become blind, or lose a leg than regain their lost weight. We found that 1 in 4 obese patients enrolled in our own weight-management program were willing to accept an 8% annual mortality risk to lose 12% of their body weight and a 21% one-time chance of immediate death to obtain their self-described desired weight (B. Weiss, R. Nease, and S. Klein, unpublished observations, 2000). Despite this exceptional desire by many obese patients to lose weight, most are unable to make the necessary long-term changes in daily lifestyle needed for successful weight loss. These findings underscore the importance of carefully reviewing patients’ treatment expectations and setting realistic goals. It is important to clarify what patients can and cannot expect with regard to changes in weight, health complications, body image, and social function- AMERICAN GASTROENTEROLOGICAL ASSOCIATION 917 ing. Moreover, obese patients who are not candidates for bariatric surgery must ultimately be convinced that losing 10% of initial weight is a success, even if they remain overweight or obese after treatment. They should know at the outset that the principal goal of treatment, like that of other medical therapies, is to improve health and well-being, not appearance. Treatment Guidelines for Overweight and Obesity The clinical approach to overweight and obese patients involves many of the same principles used in the management of other chronic diseases, which also rarely are cured but can be controlled with proper treatment. Obesity requires constant vigilance, and its clinical course is often characterized by periods of weight stability and relapse. Unwavering support from physicians and other caregivers, within the context of a long-term treatment program, will enhance the chance for long-term weight management. Appropriate management requires identifying patients who need treatment, developing a realistic treatment plan, and implementing a defined treatment strategy that can be modified as needed during long-term surveillance. A Practical Guide to the management of overweight and obesity, published as a monograph in October 2000, was developed by the North American Association for the Study of Obesity in conjunction with the NIH.416 The Practical Guide was based on earlier clinical guidelines developed by an expert panel convened by the National Heart, Lung and Blood Institute (NHLBI).4 In this section, guidelines for obesity therapy adapted from the Practical Guide with modifications based on recent additional information are presented. Assessment A careful medical evaluation is needed to identify patients who either have, or are at risk for, obesityrelated medical complications. This assessment should include a determination of BMI and other obesity-related risk factors, including the amount of weight gained since young adulthood and the patient’s level of cardiovascular fitness. Although the amount of weight gain that is associated with increased risk of obesity-related diseases has been documented,16 –21 the amount and type of regular physical activity needed to decrease the risk of obesity-related disease are not known. However, in view of the preponderance of evidence that physical activity and aerobic fitness are inversely related to cardiovascular disease,499 it seems prudent to use the recommendations made by the Centers for Disease Control and Prevention, 918 AMERICAN GASTROENTEROLOGICAL ASSOCIATION the American College of Sports Medicine, and the American Heart Association regarding physical activity as criteria for CHD risk.468,500 Based on these recommendations, overweight or obese persons who do not engage in moderate physical activity (e.g., walking) for at least 30 minutes per day, 5 days per week, are at increased risk for CHD. The Practical Guide also recommends that waist circumference be determined because a “large” waist circumference, defined by the NIH guidelines as ⬎102 cm (40 inches) in men and ⬎88 cm (35 inches) in women, is an independent risk factor for a cluster of medical abnormalities, including the components of the metabolic syndrome and cardiovascular disease.4 However, recent data obtained from more than 9000 participants in NHANES III question the clinical utility of measuring waist circumference.501 More than 99% of men and 98% of women in the NHANES III sample would have received the same treatment recommendations proposed by the NHLBI Expert Panel and the Practical Guide without an assessment of waist circumference. It is possible that lower waist circumference cutoff values could be more effective in identifying overweight patients who are at increased risk for obesity-related metabolic complications and, therefore, might benefit from more aggressive obesity therapy. However, this issue requires further study. A history, physical examination, and laboratory tests also should be performed to identify the presence of CHD, other atherosclerotic processes, additional risk fac- GASTROENTEROLOGY Vol. 123, No. 3 tors for CHD, and other obesity-related diseases that may benefit from weight loss (Table 12). In addition, the medical evaluation should be used to identify obesityrelated diseases (see Table 4) that may not necessarily benefit from weight loss, but that require medical treatment. Treatment The goal of weight-loss therapy is to improve or eliminate obesity-related comorbidities or decrease the risk for future obesity-related medical complications. The indications for weight loss therapy proposed by the Practical Guide and the NHLBI Expert Panel focus on the prevention and treatment of CHD. The composite of body weight classification (based on BMI), current cardiovascular illnesses, and risk factors for future CHD (identified by the medical examination) helps determine the need for and aggressiveness of obesity therapy. However, in addition to CHD and its risk factors, obesity causes other serious medical illnesses (Table 4). Therefore, it is reasonable to include other obesity-related illnesses that improve with weight loss as additional indicators for treatment (Table 12). Table 13 provides general guidelines for selecting among treatment options that are available for weight management. An effective treatment plan must consider patients’ willingness to undergo therapy, their ability to comply with specific treatment approaches, access to skilled caregivers, and financial considerations. Weight loss therapy is not recommended for patients with a BMI Table 12. Risk Factors and Diseases That May Influence Obesity Therapy 1. Presence of cardiovascular disease a. CHD (history of myocardial infarction, angina, coronary artery surgery, or coronary artery procedures) b. Other atherosclerotic processes (peripheral arterial disease, aortic aneurysm, and carotid artery disease) 2. Presence of obesity-related diseases that increase CHD risk a. Hypertension (systolic blood pressure ⱖ140 mm Hg, or diastolic blood pressure ⱖ90 mm Hg, or taking antihypertensive medications) b. High serum LDL cholesterol (ⱖ160 mg/dL) c. Low serum HDL cholesterol (⬍35 mg/dl) d. Impaired fasting plasma glucose (110–125 mg/dL) or type 2 diabetes mellitus 3. Presence of additional risk factors for CHD a. Family history of premature CHD (myocardial infarction or sudden death at or before 55 years of age in father or other male firstdegree relative, or myocardial infarction or sudden death at or before 65 years of age in mother or other first-degree female relative) b. Age ⱖ45 years for men and ⱖ55 years for women (or postmenopausal) 4. History of lifestyle-associated risk factors a. Cigarette smoking b. Weight gain of 5 kg or more since the age of 18–20 years c. Sedentary lifestyle (⬍30 min/day of moderate activity 5 days/week) 5. Presence of additional obesity-related diseases that may benefit from weight loss a. NAFLD (steatosis and steatohepatitis) b. Polycystic ovary syndrome c. Venous disease (venous stasis, deep vein thrombosis) d. Pulmonary disease (abnormal pulmonary function, obstructive sleep apnea, obesity hypoventilation syndrome) e. Musculoskeletal abnormalities (osteoarthritis, low back pain) f. Gynecologic abnormalities (abnormal menses, infertility) g. Urinary stress incontinence September 2002 AMERICAN GASTROENTEROLOGICAL ASSOCIATION 919 Table 13. Suggested Weight Loss Treatment Options Based on BMI and Risk Factors BMI category (kg/m2) Treatment 25.0–26.9 27.0–29.9 30.0–34.9 35.0–39.9 ⱖ40.0 Diet, physical activity, and behavior therapy Pharmacotherapya Surgeryb With risk factor With risk factor Yes Yes Yes With obesity-related disease Yes Yes With obesity-related disease Yes Yes aPharmacotherapy should be considered only in patients who are not able to achieve adequate weight loss by available conventional therapy (diet, physical activity, and behavior therapy) and who do not have any absolute contraindications for drug therapy. bBariatric surgery should be considered only in patients who are unable to lose weight with available conventional therapy and do not have any absolute contraindications for surgery. ⬍25 kg/m2; however, providing recommendations for a healthy lifestyle, including dietary and physical activity modification, is reasonable for lean persons who have, or are at increased risk for, metabolic and cardiovascular diseases. Characteristics of Successful Weight Maintenance Certain characteristics are common among patients who have achieved successful long-term weight loss without bariatric surgery. Persons who maintain their weight loss report that they: (1) monitor their food intake, physical activity, and body weight regularly; (2) consume a diet that is low in calories (1300 to 1400 kcal/day) and fat (⬃25% kcal as fat); (3) eat breakfast daily; and (4) engage in high levels of regular physical activity (expending ⬃2800 kcal/week equivalent to walking ⬃4 miles per day).335,335a In addition, successful weight loss often was preceded by a medical or emotional triggering event and was followed by improvements in energy level, physical mobility, mood, self-confidence, and physical health. Future Research Directions Future research in obesity should be directed toward the following: (1) developing more effective prevention strategies, (2) improving obesity treatment, and (3) improving our understanding of the pathophysiological effects of excess adiposity. Prevention and treatment efforts in children and adolescents are particularly important because successful weight management in these age groups will help prevent obesity in adulthood. The current obesity epidemic can be attributed, in large part, to a “modern” environment that implicitly discourages physical activity and explicitly encourages the consumption of supersized portions of high-fat, highsugar foods. Therefore, to be successful, prevention efforts will need to target the “modern” environment. Traditional approaches that have emphasized education and individual responsibility have not been, and are unlikely to be, effective. Many people know what they must do to prevent or eliminate obesity but simply are unable to implement the lifestyle changes needed to lose weight permanently or prevent weight gain. Obesity prevention strategies should involve public and private sector partnerships between community leaders, school administrators, employers, health care providers, and governmental agencies. Such an approach must be sensitive to issues of individual rights and freedom of choice. Nonetheless, it is likely that successful prevention will require bold public policy initiatives to enhance safe and easy access for physical activity and to facilitate lowcalorie food choices. Reasonable concepts should be tested carefully for feasibility and effectiveness in clinical trials that involve varied ethnic and socioeconomic groups. Additional research efforts are needed to improve treatment for persons who are already obese. These studies should further define the roles of macronutrient composition, meal replacement therapy, specific exercise/activity programs, and innovative technological approaches (e.g., the Internet) in achieving and maintaining long-term weight loss. The most exciting new developments in obesity therapy probably will be derived from research that improves our understanding of the molecular mechanisms responsible for regulating energy balance. This information may lead to the development of new and effective pharmacologic agents that decrease energy intake and/or increase energy expenditure. The use of individual medications, combinations of medications, and medications plus other treatment tools will need to be studied in long-term (⬃5 year) clinical trials. Finally, the long-term effectiveness and safety of new surgical approaches (e.g., gastric pacing and laparoscopic techniques) and efforts to decrease postoperative complications need to be studied in randomized controlled trials. The mechanisms responsible for the link between excess adiposity and many obesity-related diseases are not clear. Therefore, additional research is needed to identify 920 AMERICAN GASTROENTEROLOGICAL ASSOCIATION the cellular and physiological factors that are responsible for organ and tissue damage related to excess total body fat and specific fat distribution patterns. The recent mapping of the human genome provides exciting new opportunities for understanding the pathogenesis and pathophysiology of obesity, which could lead to improved therapeutic approaches for both obesity and obesity-related medical complications. GASTROENTEROLOGY Vol. 123, No. 3 12. 13. 14. SAMUEL KLEIN Department of Internal Medicine and Center for Human Nutrition Washington University School of Medicine St. Louis, Missouri 15. THOMAS WADDEN Department of Psychiatry University of Pennsylvania Philadelphia, Pennsylvania 17. HARVEY J. 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Dr. Klein has received honoraria for speaking engagements on obesity from Roche Laboratories and R. W. Johnson; is a member of the Obesity and Diabetes Educational Council, which is funded by an unrestricted educational grant provided by Roche Laboratories; and has received research support for clinical studies from Roche Laboratories, R.W. Johnson, DMV International, Regeneron Pharmaceuticals, Novartis Nutrition, and GlaxoSmithKline. These funds were used for participating in multicenter clinical research trials and for investigatorinitiated research in obesity. Dr. Wadden serves on the speakers’ bureau for Abbott Laboratories and Roche Laboratories, which manufacture the weight-loss medications sibutramine and orlistat, respectively. He has received research support from Schering-Plough, GlaxoSmithKline, and Abbott Laboratories.