OBESITYObesity is a substantial public-health crisis in the United States and in the rest of the developed world. The prevalence is increasing rapidly in numerous developing nations worldwide. This growing rate represents a pandemic that needs urgent attention if its potential morbidity, mortality, and economic tolls are to be avoided.

The image below shows central nervous system neurocircuitry for satiety and feeding cycles.

Central nervous system neurocircuitry for satiety and feeding cycles.

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The annual cost of managing obesity in the United States alone amounts to approximately $100 billion, of which approximately $52 billion are direct costs of healthcare. These costs amount to approximately 5.7% of all US health expenditure. The cost of lost productivity due to obesity is approximately $3.9 billion, and another $33 billion is spent annually on weight-loss products and services.

Body fat percentage, body mass index, skin thicknesses, and anthropomorphic measures

Obesity represents a state of excess storage of body fat. Although similar, the term overweight is puristically defined as an excess body weight for height. Although men have a body fat percentage of 15-20%, women have approximately 25-30%.[1]

Because differences in weight among individuals are only partly due to variations in body fat, body weight is a limited, though easily obtained, index of obesity.

The body mass index (BMI), also known as the Quetelet index, is used far more commonly than body fat percentage to define obesity. BMI is closely correlated with the degree of body fat in most settings. BMI = weight/height2, where weight is in kilograms and height is in meters.

The body fat percentage can be estimated by using the Deurenberg equation, as follows: body fat percentage = 1.2(BMI) + 0.23(age) - 10.8(sex) - 5.4, where age is in years and sex is 1 for male and 0 for female. This equation has a standard error of 4% and accounts for approximately 80% of the variation in body fat.

Although the BMI is typically closely correlated with percentage body fat in a curvilinear fashion, some important caveats to its interpretation apply. In mesomorphic (muscular) persons, BMIs that usually indicate overweight or mild obesity may be spurious, whereas in some persons with sarcopenia (especially among persons of Asian descent), a typically normal BMI may conceal underlying excess adiposity characterized by increased percentage fat mass and reduced muscle mass.

In view of these limitations, some authorities advocate a definition of obesity based on percentage body fat. For men, percentage body fat greater than 25% defines obesity, and 21-25% is borderline. For women, over 33% defines obesity, and 31-33% is borderline.

Taller children generally tend to be more obese than shorter peers, are more insulin-resistant, and have increased leptin levels.[2]

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Other indices used to estimate the degree and distribution of obesity include the 4 standard skin thicknesses (ie, subscapular, triceps, biceps, suprailiac) and various anthropometric measures, of which waist and hip circumferences are the most important.

Classifications and definitions of obesity

Although several classifications and definitions for degrees of obesity are accepted, the most widely accepted is the World Health Organization (WHO) criteria based on BMI. Under this convention for adults, grade 1 overweight (commonly and simply called overweight) is a BMI of 25-29.9 kg/m2. Grade 2 overweight (commonly called obesity) is a BMI of 30-39.9 kg/m2. Grade 3 overweight (commonly called severe or morbid obesity) is a BMI greater than or equal to 40 kg/m2.

The surgical literature often uses a different classification to recognize particularly severe obesity. In this setting, a BMI greater than 40 kg/m2 is described as severe obesity, a BMI of 40-50 kg/m2 is termed morbid obesity, and a BMI greater than 50 kg/m2 is termed super obese.

The definition of obesity in children involves BMIs greater than the 85th (commonly used to define overweight) or the 95th (commonly used to define obesity) percentile, respectively, for age-matched and sex-matched control subjects.

Comorbidities associated with obesity

Apart from total body fat mass, accumulating data suggest that regional fat distribution substantially affects the incidence of comorbidities associated with obesity.[3] High abdominal fat content (including visceral and, to a lesser extent, subcutaneous abdominal fat) is strongly correlated with worsened metabolic and clinical consequences of obesity. As a result, android obesity, which is predominantly abdominal, is more predictive of adipose-related comorbidities than gynecoid obesity, which has a relatively peripheral (gluteal) distribution. See image below.

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Comorbidities of obesity.

Waist circumferences greater than 94 cm in men and greater than 80 cm in women and waist-to-hip ratios greater than 0.95 in men and greater than 0.8 in women are the thresholds for significantly increased potential cardiovascular risk. Circumferences of 102 cm in men and 88 cm in women indicate a markedly increased potential risk requiring urgent therapeutic intervention; these are the thresholds used in the Adult Treatment Panel III (ATPIII) definition of the metabolic syndrome.

A study by Losina et al explored the association of obesity and knee osteoarthritis.[4] The study found that a substantial number of quality-adjusted life-years were lost due to knee osteoarthritis and obesity, most notably among black and Hispanic women.

An elevated BMI during adolescence (within the range currently considered normal) strongly associates with the risk of developing obesity-related disorders later in life.[5] Although the BMI closer to onset of diabetes predicts risk of diabetes, elevated BMI both during adolescence and adulthood strongly predict the risk of CAD later in life. This observation lends support to the notion that process of atherogenesis CAD begins earlier than the manifestation of diabetes.

Obesity is associated with a host of potential comorbidities that significantly increase the potential morbidity and mortality associated with the condition. Although no cause-and-effect relationship is exhaustively demonstrated for all these comorbidities, amelioration of these conditions after substantial weight loss suggests that obesity probably plays an important role in their development.

PathophysiologyThe pathogenesis of obesity is far more complex than the simple paradigm of an imbalance between energy intake and energy output. Although this concept allows easy conceptualization of the various mechanisms involved in the development of obesity, obesity is far more than the mere result of too much eating and/or too little exercise. However, the prevalence of inactivity in developed countries is considerable and relevant. In the United States, only approximately 22% of adults and 25% of adolescents report notable regular physical activity. Approximately 25% of adults in the United States report no remarkable physical activity during leisure, while approximately 14% of adolescents have similar reports of inactivity. See energy balance equation below.

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Energy balance equation.

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Two major groups of factors with a balance that variably intertwines in the development of obesity are genetics, which is presumed to explain 40-70% of the variance in obesity, and environmental factors. Although the high prevalence of obesity in the children of parents who are obese and the high concordance of obesity in identical twins suggest a substantial genetic component to the pathogenesis of obesity, the secular trends of the last few decades, which have been coincident with changes in dietary habits and activity, also suggest an important role for environmental factors.

Leptin

Friedman and colleagues discovered leptin (from the Greek word leptos, meaning thin) in 1994 and ushered in an explosion of research and a great increase in knowledge about regulation of the human feeding and satiation cycle. Since this discovery, neuromodulation of satiety and hunger with feeding has been found to be far more complex than the old, simplistic model of the ventromedial hypothalamic nucleus and limbic centers of satiety and the feeding centers of the lateral hypothalamus. Leptin is a 16-kD protein produced predominantly in white adipose tissue and, to a lesser extent, in the placenta, skeletal muscle, and stomach fundus in rats. Leptin has a myriad of functions in carbohydrate, bone, and reproductive metabolism that are still being unraveled, but its role in body weight regulation is the main reason it came to prominence.

The major role of leptin in body-weight regulation is to signal satiety to the hypothalamus and, thus, reduce dietary intake and fat storage while modulating energy expenditure and carbohydrate metabolism to prevent further weight gain. Unlike the Ob/Ob mouse model in which this peptide was first characterized, most humans who are obese are not leptin deficient but rather leptin resistant. Therefore, they have elevated circulating levels of leptin.

Lieb et al assayed plasma leptin in 818 elderly participants in the Framingham Heart Study.[8] Leptin levels, which were higher in women, were strongly correlated with BMI. On follow-up (mean, 8 y), it was found that congestive heart failure had developed in 129 participants (out of 775 individuals who had been free of congestive heart failure), a first cardiovascular disease event had occurred in 187 participants (out of 532 individuals who had been free of cardiovascular disease), and 391 persons had died. The authors' data indicated that higher circulating leptin levels were associated with a greater risk of congestive heart failure and cardiovascular disease but that leptin did not offer incremental prognostic information beyond BMI.

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Although more than 90% of human cases of obesity are polygenic, the recognition of monogenic variants has greatly enhanced our knowledge about the etiopathogenesis of obesity.[9]

Epidemiology

Frequency

International

The prevalence of obesity worldwide is increasing, particularly in the developed nations of the Northern hemisphere, such as the United States, Canada, and most countries of Europe. Available data from the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) project suggest that at least 15% of men and 22% of women in Europe are obese.

Similar data now are being reported from many developing countries, particularly in those in Asia and, to a lesser extent, those in Africa. Reports from countries such as Malaysia, Japan, Australia, New Zealand, and China detail an epidemic of obesity in the past 2-3 decades. Data from the Middle Eastern countries of Bahrain, Saudi Arabia, Egypt, Jordan, Tunisia, and Lebanon, among others, indicate this same disturbing trend, with alarming levels of obesity often exceeding 40% and particularly worse in women than in men.

Data from the Caribbean and from South America also highlight similar trends. Although data from Africa on this issue are scant, a clear and distinct secular trend of profoundly increased BMIs is clearly observed when people from Africa immigrate to northwestern hemispheric countries. Comparisons of these indices among Nigerians and Ghanaians residing in their native countries with indices in recent immigrants to the United States show this trend poignantly.

Conservative estimates suggest that as many as 250 million people (approximately 7% of the estimated current world population) are obese. Two- to three-times more people than this are probably overweight. Although socioeconomic class and the prevalence of obesity are negatively correlated in most developed countries, including the United States, this correlation is distinctly reversed in many relatively undeveloped areas, including China, Malaysia, parts of South America, and sub-Saharan Africa.

Finucane et al conducted a comprehensive, constructive study that revealed growing global trends in BMI. This study may serve as wake-up call and initiate

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large-scale interventions in an effort to combat increasing body weight and associated adverse health consequences.[12]

Mortality/Morbidity

Some evidence suggests that, if unchecked, trends in obesity in the United States may be associated with overall reduced longevity of the population in the next few years. Data also show that obesity is associated with an increased risk and duration of lifetime disability. Furthermore, obesity in middle age is associated with poor indices of quality of life at old age.

The mortality data appear to have a U - or J -shaped conformation in relation to weight distribution.[14] However, the degree of obesity (generally indicated by the BMI) at which mortality discernibly increases in African Americans and Hispanic Americans than in white Americans; this observation suggests a notable racial spectrum and difference in this effect. Underweight was associated with substantially high risk of death in a study of Asian populations. A high BMI is also associated with an increased risk of death, except in Indians and Bangladeshis.[15]

The optimal BMI in terms of life expectancy is about 23-25 for whites and 23-30 for blacks. Emerging data suggest that the ideal BMI for Asians is substantially lower than that for Caucasians. For subjects with severe obesity (BMIs ≥40), life expectancy is reduced by as much as 20 years in men and by about 5 years in women. Coexisting obesity and smoking are associated with even greater risks than these for premature mortality.

A study by Berrington de Gonzalez et al confirms health advantages of normal BMI (20-24.9) and reinforces that both overweight and underweight have deleterious consequences—increased death risk.[16]

Several factors modulate the morbidity and mortality associated with obesity. They include age of onset and duration of obesity, severity of obesity, amount of central adiposity, other comorbidities, sex, and level of cardiorespiratory fitness.

Race

Obesity is a cosmopolitan disease that affects all races worldwide. However, certain ethnic and racial groups appear to be particularly predisposed. The Pima Indians of Arizona and other ethnic groups native to North America have a particularly high prevalence of obesity. In addition, Polynesians, Micronesians, Anurans, Maoris of the West and East Indies, African Americans in North

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America, and the Hispanic populations (both Mexican and Puerto Rican in origin) in North America also have particularly high predispositions to developing obesity.

Secular trends clearly emphasize the importance of environmental factors (particularly dietary issues) in the development of obesity. In many genetically similar cohorts of the high-risk ethnic and racial groups mentioned above, the prevalence for obesity in their countries of origin might be low, but this rate considerably changes when such groups emigrate to the affluent countries of the Northern hemisphere, where they alter their dietary and activity habits. These findings form the core concept of the thrifty gene hypothesis that Neal and colleagues espoused.

See also Mortality/Morbidity above.

Sex

No significant sex difference is reported in the prevalence of obesity.

Age

The prevalence and age distribution of obesity has substantially changed in the last 2-3 decades.

Although the prevalence has remained at 30-50% of the adult population in the United States, the prevalence in children has increased to 15-25%.

As evidenced in secular trends, children and particularly adolescents who are obese have a high probability of growing to be adults who are obese; hence, the bimodal distribution of obesity portends a large-scale obesity epidemic in the next few decades.

Adolescent obesity poses a serious risk for severe obesity during early adulthood, particularly in non-Hispanic black women. This would call for stronger emphasis on reduction during early adolescence specifically targeting groups with greater risk.[17]

History

In most patients, the presentation is straightforward, with the patient indicating problems with weight or repeated failure in achieving sustained weight loss.

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However, in other cases, the subject may present with complications and/or associations of obesity.

A full history must include a dietary inventory and an analysis of the subject's activity level.

Screening questions to exclude depression are vital because this may be a consequence or a cause of excessive dietary intake and reduced activity.

Because almost 30% of patients who are obese have eating disorders, screen for these in the history. The possibility of binging, purging, lack of satiety, food-seeking behavior, and other abnormal feeding habits must be identified because management of these habits is crucial to the success of any weight-management program.

Also, determine if any of the previously mentioned comorbidities have occurred, and include questions to exclude the possible and rare secondary causes of obesity. See image below.

Secondary causes of obesity.

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When asking patients about their history, investigate whether the rest of the patient's family has weight problems, inquire about the patient's expectations, and estimate the patient's level of motivation.

Comorbidities related to obesity include the following:

Cardiovascular - Essential hypertension, coronary artery disease,[18] left ventricular hypertrophy, cor pulmonale, obesity-associated cardiomyopathy, accelerated atherosclerosis, pulmonary hypertension of obesity

CNS -Stroke, idiopathic intracranial hypertension, meralgia paresthetica GI - Gall bladder disease (cholecystitis, cholelithiasis), nonalcoholic

steatohepatitis (NASH), fatty liver infiltration, reflux esophagitis Respiratory -Obstructive sleep apnea,[19]obesity hypoventilation syndrome

(Pickwickian syndrome), increased predisposition to respiratory infections, increased incidence of bronchial asthma

Malignant - Association with endometrial, prostate, gall bladder, breast, colon, and, possibly, lung cancer[20]

Psychologic - Social stigmatization, depression Orthopedic -Osteoarthritis, coxa vera, slipped capital femoral epiphyses,

Blount disease and Legg-Calvé-Perthes disease, chronic lumbago Metabolic -Insulin resistance, hyperinsulinemia, type 2 diabetes mellitus

(see image below), dyslipidemia (characterized by high total cholesterol, high triglycerides, normal or elevated low-density lipoprotein, and low high-density lipoprotein)

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Simplified scheme for the pathophysiology of type 2 diabetes mellitus.

Reproductive - Anovulation, early puberty, infertility, hyperandrogenism and polycystic ovaries in women, hypogonadotropic hypogonadism in men

Obstetric and perinatal -Pregnancy-related hypertension, fetal macrosomia, pelvic dystocia[21]

Surgical - Increased surgical risk and postoperative complications, including wound infection, deep venous thrombosis, pulmonary embolism, and postoperative pneumonia

Pelvic - Stress incontinence Cutaneous - Intertrigo (bacterial and/or fungal), acanthosis nigricans,

hirsutism, increased risk for cellulitis and carbuncles Extremity - Venous varicosities, lower extremity venous and/or lymphatic

edema Miscellaneous - Reduced mobility, difficulty maintaining personal hygiene

PhysicalIn the clinical examination, measure anthropometric parameters and perform the standard, detailed examination required in evaluating people with any chronic multisystemic disorder, such as obesity. Waist and hip circumference are useful

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surrogates in estimating visceral fat. Serial tracking of these measurements helps in estimating the clinical risk over time.

Neck circumference is predictive of a risk of sleep apnea, and its serial measurement in the individual patient is clinically useful for risk stratification.[19]

In the skin examination, include a search for hirsutism in women, intertriginous rashes, acanthosis nigricans, and possible contact dermatoses.

A detailed cardiac and respiratory evaluation is crucial to exclude cardiomegaly and respiratory insufficiency.

In the abdominal examination, attempt to exclude tender hepatomegaly (which may suggest nonalcoholic steatohepatitis [NASH]) and distinguishing the striae distensae from the pink and broad striae that suggest cortisol excess.

When examining the extremities, search for joint deformities (eg, coxa vara), evidence of osteoarthrosis, and any pressure ulcerations.

CausesThe etiology of obesity is multifactorial.

Among the facets to be considered in the development of obesity are the following:

Metabolic factors Genetic factors Level of activity Behavior Endocrine factors Race, sex, and age factors Ethnic and cultural factors Socioeconomic status Dietary habits Smoking cessation Pregnancy and menopause Psychologic factors History of gestational diabetes Lactational history in mothers

Secondary causes of obesity may include the following (see also the image below):

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Secondary causes of obesity.

Diagnostic Considerations

Adiposa dolorosa (Dercum disease) Partial lipodystrophies associated with localized lipohypertrophy

Mesomorphic body states, as seen in body builders and people in related occupations (eg, professional wrestling) may be associated with elevated BMIs because of increased muscle mass rather than excess adiposity.

Various causes of anasarca may be mistaken as obesity if not carefully evaluated clinically.

 

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Laboratory Studies

Full lipid panel, at minimum, test of fasting cholesterol, triglycerides, and high-density lipoprotein cholesterol (HDL-C) levels

These levels may be normal, or the typical dyslipidemia associated with metabolic syndrome X may be found.

This is characterized by reduced HDL-C, increased low-density lipoprotein cholesterol (LDL-C), normal-to-marginally increased total cholesterol, and elevated fasting triglyceride concentrations.

Hepatic panel

This test is expected to yield normal results, but findings may be abnormal (eg, elevated transaminase levels in the setting of NASH or fatty infiltration of the liver).

Thyroid function tests

The results are typically normal, but checking them to detect primary hypothyroidism (characterized by increased serum thyrotropin and normal or reduced levothyroxine and/or triiodothyronine levels) is worthwhile.

Screening with a serum thyrotropin level is usually sufficient. Of importance, hypothyroidism itself rarely causes more than mild obesity.

For screening purposes, 24-hour urinary free cortisol test

This test is needed only when Cushing syndrome or other hypercortisolemic states are clinically suspected.

Approximately 4% of patients with Cushing syndrome have normal urinary free cortisol values.

Fasting glucose and insulin test

Obesity is associated with insulin resistance, though these levels are normal in many subjects who are obese.

In other people, insulin levels may be elevated.

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In those with impaired glucose tolerance, the fasting serum glucose level is elevated to higher than 100 mg/dL.

ProceduresAmong the various procedures relevant to the treatment of patients who are obese are procedures to estimate the degree of visceral and subcutaneous fat.

These procedures include the standard anthropometric measurements and caliper-derived estimates of skin thickness.

 

 Medical CareAlthough obesity in itself is associated with increased morbidity and mortality, massive poorly monitored weight loss and/or weight cycling can have equally dire consequences. Among the important potential complications to watch out for in the setting of weight loss are cardiac arrhythmias; electrolyte derangements, of which hypokalemia is the most important; hyperuricemia; and psychologic sequelae, including depression and the development of eating disorders (particularly binge-eating disorders).

The 3 major phases of any successful weight-loss program are (1) a preinclusion screening phase; (2) a definitive weight-loss program; and (3) a maintenance phase, which can conceivably last for the rest of the subject's life but which must last for at least 2 years after the weight-loss program is completed.

Weight loss as medical treatment

A reasonable goal for weight-loss in the setting of a medical treatment program is approximately 0.9-1.5 kg/wk. The concept that the weight-loss goal for each subject must be individualized and cannot be unilaterally based on standard weight-for-height norms is becoming increasingly apparent.

One must consider the family's weight, as well as the patient's weight and cultural, ethnic, and racial background in setting individualized goals of weight loss. In a study of approximately 200 obese black women, the Obesity Reduction Black Intervention Trial (ORBIT) investigated whether greater weight loss could be achieved with a culturally adapted weight-loss program than with a more general health program.[22]

The women were randomly divided into a general health program or a 6-month culturally adapted program aimed at altering the women's dietary and physical

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activity patterns (followed by 1 year of maintenance intervention). Women in the latter group lost significantly more weight than did participants in the general program, although the report also found that, despite this success, the average weight loss in the culturally adapted program was still relatively modest and that the amount of weight loss varied greatly among the women in the program.

Like all chronic medical conditions, effective management of obesity must be based on a partnership between a highly motivated patient and a committed team of health professionals, including the physician, psychologists or psychiatrist, physical and exercise therapists, dietitians, and other subspecialists, depending on the comorbidities of the individual patient.

Results of weight-loss management

Results of most weight loss management programs are dismal. On average, participants in the best weight-loss programs lose approximately 10% of their body weight, but people generally regain two thirds of the weight lost within a year, and they regain almost all of it within 5 years.

When defined as sustained weight loss over a 5-year follow-up period, the success of even the best medical weight-loss programs is next to nil. Most available data indicate that, irrespective of the method of medical intervention, 90-95% of the weight lost is regained in 5 years.

In general, body weight and body fat generally tenaciously regulated. Available data suggest that a loss of approximately 10% of body weight in subjects who are obese (BMI < 40) is associated with virtually maximal benefits regarding obesity-elated comorbidities; therefore, further attempts at weight loss beyond this level are generally spurred by cosmetic considerations that may be not only unrealistic but also potentially dangerous. This possibility is the basis of a shift in paradigms in the medical management of obesity from a goal of massive weight loss to a goal of maintaining the highest weight possible while still eliminating obesity-related comorbidities or reducing them to minimum.

A study by Rock et al found that a structured weight loss program resulted in greater risk reduction than usual care.[23]

Childhood obesity

For childhood obesity,[24, 25, 26] the goal is to reduce the rate of weight gain to fit the profile expected based on normal growth curves. The intent here is not to cause weight loss.

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The basic principles of management include (1) modifying diet, (2) increasing appropriate physical activity and exercise, (3) reducing time spent in sedentary activities (eg, watching television), and (4) modifying behavior.

Added to these principles is medication therapy. However, such therapy is still rudimentary in the management of pediatric obesity, and close combination with all the aforementioned modalities is required to achieve substantial and sustained weight loss. At the present, orlistat is the only medication the US Food and Drug Administration (FDA) has approved for use as an adjunct for weight loss in adolescents.

Dietary programs

Starvation is a caloric intake of less than 200 kcal/d and is not medically indicated. Starvation is potentially dangerous and can lead to clinically significant starvation ketosis; electrolyte derangements; vitamin, mineral, and other micronutrient deficiencies; and a marked potential for morbidity and mortality. Starvation is not validated as an effective method of achieving substantial and sustained weight loss.

Achieving a caloric deficit is still the most important component to achieving sustained weight loss. However, the considerable variance in individual energy expenditures and compliances to calorie-deficient plans make it difficult to reliably predict how much weight an individual subject may lose.

Among the caveats are the fact that energy expenditure is related to body weight; about 22 kcal/kg of energy required for basal maintenance of 1 kg of weight in a typical adult. Therefore, obese subjects tend to reduce their energy expenditure as they lose weight, dampening the effect of caloric deficits as weight loss progresses.

Presumably because of their greater lean mass proportions, men tend to lose more weight than women do when caloric deficits are similar.

Because of their lowered energy expenditure, older subjects have increased difficulty is achieving sustained weight loss. The estimated reduction in energy expenditure is 100 kcal per decade after the age of 30 years.

Dennis et al found that in overweight and obese middle-aged and older adults on a hypocaloric diet, drinking water before each main meal aided weight loss. In 48 adults aged 55-75 years with a BMI of 25-40 kg/m2, those who consumed 500 mL of water prior to each daily meal had a 44% greater decline in weight over 12 weeks than did individuals on a hypocaloric diet without premeal water consumption.[27]

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Very–low-calorie diets

Very–low-calorie diets (VLCDs) are best used in an established, comprehensive program. VLCDs involve reducing caloric intake to 800 kcal/d or less. When used in optimal settings, they can achieve weight loss of 1.5-2.5 kg/wk, with a total loss of as much as 20 kg over 12 weeks. No good-quality evidence suggests that a daily calorie intake of less than 800 kcal/d achieves any additional weight loss.

Use special caution whenever VLCDs are prescribed to children, adolescents, or elderly subjects. Use is contraindicated in pregnancy and in protein-wasting states; clinically significant cardiac, renal, hepatic, psychiatric, or cerebrovascular disease; or any other chronic disease. VLCDs are associated with profound initial weight loss, much of which is from lean mass loss in the first few weeks. However, this loss rapidly ceases, and weight-loss velocity then flattens. Although these diets associated with notable short-term weight loss sometimes less than 15% of baseline weight and though they are associated with improved blood pressure and glycemic control, they cannot be sustained longer than 3-6 months. Compliance beyond a few weeks is poor, and close supervision is required to avoid mishaps.

Unless a long-term maintenance calorie-deficit program is developed and adhered, to recidivism after the diet is stopped is rapid. Most subjects quickly regain all the weight they lose and often gain more.

Among the major complications to monitor are hair loss, skin thinning, hypothermia, cholelithiasis, and electrolyte derangement. VLCDs have little or no utility in long-term weight management and are probably best used as stop-gap measures before bariatric surgery or a long-term comprehensive weight-loss program in subjects with very severe or morbid obesity and associated comorbidities (BMI ≥50).

Conventional diets

Conventional diets can be broadly subclassified as (1) balanced, low-calorie diets (or reduced portion sizes), (2) low-fat diets, (3) low-carbohydrate diets, (4) midlevel diets (eg, Zone diet in which the 3 major macronutrients [fat, carbohydrate, protein] are eaten in similar proportions of 30-40%), and (5) fad diets.

Balanced LCDs or reduced portion sizes diets are the types that dietitians and other weight-management professionals most commonly prescribe. These diets underlie most of the popular, commercial weight-loss programs such as those advocated by Jenny Craig, Weight Watchers, Take Off Pounds Sensibly (TOPs), and Overweight

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Anonymous. The basic premise involves obtaining a detailed dietary inventory of the subject, which is used to estimate his or her mean daily caloric intake.

A reasonable goal for the caloric deficit is based on the new goal for total daily calories. Meal plans are then devised to provide this total in ≥3 divided meals throughout the day. Although the meals may be based on regular, everyday foods (with which strategies for effective reduction of portion sizes become central), meal-replacement shakes, bars, prepackaged meals, frozen entrees, and other meals also have adequate amounts of the major macronutrients based on the food pyramid from the US Department of Agriculture and recommended daily allowances (RDAs). These sources also have adequate micronutrients and trace elements. Because alcohol, sodas, most fruit juices, and highly concentrated sweets are generally calorie dense and nutrient deficient (empty calories), these are generally prohibited or reduced to the minimum.

Low-calorie diets involve a caloric intake of 800-1200 kcal/d and are associated with a mean weight loss of 0.4-0.5 kg/wk, with a total loss of 6-8 kg in ideal settings. With any low-calorie diet, maintaining intake of protein with high biologic value of ≥1 g/kg is vital to preserve lean body mass. Major potential complications to watch for include vitamin deficiency, starvation ketosis, electrolyte derangements, and cholelithiasis. Although these diets are useful for short-term weight loss, none alone is associated with reliable, sustained weight loss.

Normal-calorie diets involve diets with a caloric intake greater than 1200 kcal/d. The aim with this type of diet is to reduce the caloric intake by 500-1000 kcal/d from the patient's current dietary intake. The suggested composition for the best-validated dietary programs are protein intake of 0.8-1.5 g/kg of body weight (not to exceed 100 g/d), 10-30% of total calories from fat (preferably ≥90% as polyunsaturated fat and < 10% as saturated fat), carbohydrate intake of ≥50 g/d, and water intake of ≥1 L. Ensure that the dietary plan provides adequate micronutrients and macronutrients based on RDAs.

Low-carbohydrate diets have become popular in the past few decades, with the Atkins diet being the most popular. Little rigorous scientific data supports the use of the Atkins diet. It is a high-protein and/or high-fat, very-low-carbohydrate diet that induces ketosis. The very low carbohydrate content is critical in inducing short-term weight loss in the first 2-4 weeks; this is largely due to fluid mobilization. Ketone bodies tend to be generated with daily dietary carbohydrate intake of < 50 g, force sodium diuresis, which causes most of the short-term weight loss. No robust data about the safety or long-term effectiveness of this diet are available. The premise of the diet is that caloric intake as protein is less prone to fat

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storage than the equivalent caloric intake as carbohydrate; however, no physiologic data support this premise.

Data on the long-term effects of a high-protein in rodents causes concern because these diets may be associated with a reduced life span and predisposition to neoplasia.

In 2 randomized trials weight loss with Atkins-type diets were compared with conventional low-fat or balanced calorie-deficit diets. Although the Atkins-type diet had the greatest initial weight loss, weight loss became similar within 1 year. Furthermore, though lipids did not appear to be deleteriously affected, follow-up was only about 1 year, and noncompliance rates in the Atkins-type group was close to 50%.

The South Beach diet is another low-carbohydrate diet. This program is more liberal than the Atkins diet in its carbohydrate allowance; therefore, compliance rates are enhanced. The South Beach diet distinguishes between what it considered to be good and bad carbohydrates on the basis of their glycemic index. Although the relevance and importance of the glycemic index is controversial, the diet encourages increased fiber intake, which is associated with lowered weight even when total caloric intake is relatively unchanged. Low-glycemic index diets plus modest increase in protein intake are better at helping maintain weight loss.[28]

The National Weight loss database, tracks indices and predictors in subjects with sustained (≥5 y) weight loss of 15% or greater. The data indicate that sustained compliance to diet programs is by far a more important predictor of sustained weight loss than consistently increased levels of physical activity. Caloric deficits are more important than any specific composition of dietary macronutrient. When types of diets are compared, low-fat diets are better than low-carbohydrate diets in achieving sustained weight loss (probably because of generally improved compliance).

Dansinger and colleagues (2005) compared the Zone, Ornish, and Atkins diets and a typical balanced, calorie-restricted (Weight Watchers) diet.[29] The Ornish diet, very-low-fat diet, and the Atkins diets had the poorest compliance rates. The researchers observed no significant differences in weight loss based on the diet. Compliance and caloric deficits were more important predictors of weight loss and improvement in cardiovascular risk surrogates than specific dietary composition. However, a recent study found low-carbohydrate and low-fat diets equally efficacious in inducing weight loss but that fuel partitioning may impact cardiovascular markers differently.[30]

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For subjects who decide to use a low-carbohydrate diet, they should choose heart-healthy sources of fat (monounsaturated fats, polyunsaturated fats, and fats rich in omega 3 fatty acids rather than saturated fat) and protein (fish, nuts, legumes, and lean poultry rather than pork chops, steak, or mutton).

Exercise programs

Before receiving an exercise-program prescription, patients should undergo screening for cardiovascular and respiratory adequacy. Any clinically significant anomalies found require full evaluation by appropriate subspecialist physicians, and only after these issues are adequately managed and stabilized should an active exercise program be begun.

Aerobic isotonic exercise is of the greatest value for subjects who are obese. The ultimate minimum goal should be to achieve 30-60 minutes of continuous aerobic exercise 5-7 times per week.

Anaerobic isometric exercise, including resistance training, can be cautiously added as an adjunct after the aerobic goal described above is achieved.

Exercise is vital to any weight-management program because it helps build muscle mass, increasing metabolic activity of the whole-body mass. Exercise also helps reduce body-fat proportions and decreases the amount of compensatory muscle mass loss that is typical in the setting of weight loss. Although most laypersons may be unable to sustain enough regular exercise to achieve weight loss, consistent moderate exercise is important in maintaining weight and in improving overall cardiorespiratory fitness.

A study by Goodpaster et al showed that patients with severe obesity who introduced exercise concurrently with or after dietary intervention had significant weight loss and modification of cardiometabolic risk factors.[31] Furthermore, a study by Hankinson et al indicated that benefits of exercise in young age may translate into benefits beyond, particularly in young women.[32] This information is useful for patients and physicians who may be discouraged by the initial inability of patients to engage in exercise.

A combination of weight loss and exercise is better than either alone in improving physical fitness.[33]

Behavioral changes

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This treatment requires a trained professional to have an in-depth discussion with the patient regarding the changes required, subsequent to a detailed inventory of the patients' daily activities. This inventory is used to identify activities, cues, circumstances, and practices that favor nonmeal eating and snacking. An individualized plan to change these practices is then developed in conjunction with the subject. The effectiveness of this modality depends on both a highly motivated subject and a dedicated counselor who is willing to maintain long-term follow-up.

A sufficient amount of human sleep favorably impacts maintenance of fat-free mass during times of decreased energy intake. On the contrary, insufficient sleep would undermine the body's ability to limit expansion of fat mass. A healthy sleep pattern would be important to harness weight loss benefits from other interventions.[34]

A 3-month intervention (face-to-face education sessions) led to significant weight loss and better health-related outcomes in fathers and improved eating and physical activity among children.[35] Involvement of fathers in the weight management of children needs to be encouraged and further explored.

Medications

Not many medications are available for the treatment of obesity, and those that are available have minimal long-term effectiveness.

The increasing knowledge that has come on the heels of the discovery of leptin by Friedman and colleagues in 1994 has spurred a whirlwind of research, with several potential pharmaceuticals now being evaluated in various phases of clinical trial.

Murray et al first reported on a sequence variant within the leptin gene that enhances the intrinsic bioactivity of leptin, leading to reduced weight rather than obesity.[36] This sequence variant within the leptin gene is associated with delayed puberty as well.

The major groups of drugs used to manage obesity are (1) centrally acting medications that impair dietary intake, (2) medications that act peripherally to impair dietary absorption, and (3) medications that increase energy expenditure.

Standards for the development of obesity medications are necessarily high because most persons who are obese are fairly healthy in the short-term and must take these medications for extended periods (possibly for the rest of their lives).

The history of obesity medications is replete with numerous disasters that have taught us caution in the use of this group of medicines.

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Among the initial medications used for obesity management were amphetamine, methamphetamine, and phenmetrazine. These were all withdrawn because of their high potential for abuse.

Other former antiobesity medications are thyroid hormone (which caused hyperthyroidism with its attendant sequelae), dinitrophenol (which caused cataracts and neuropathy), rainbow pills (which are a mixture of digitalis and diuretics [which caused deaths from arrhythmias and electrolyte derangements]), aminorex (which caused pulmonary hypertension), and collagen-based VLCDs (which caused sudden deaths).

D-fenfluramine was withdrawn because of problems with cardiac valvulopathies and primary pulmonary hypertension (PPH).

Fluoxetine is not approved for use in achieving weight loss, but it has been known to cause minimal weight loss as an adverse effect, which is sometimes exploited.

Fenfluramine, although effectively used in combination with phentermine, was withdrawn in 1997 (along with D-fenfluramine) because of the potential for adverse cardiac, valvular, and pulmonary hypertensive effects.

The combination of fenfluramine and phentermine was used in some long-term trials with fair results.

The combination of low-dose phentermine and topiramate in conjunction with office-based lifestyle intervention might improve the success rate in the treatment of obesity.[37]

Diethylpropion (25 mg 3 times/d [tid]) and phentermine are available in the US for short-term use.

Phendimetrazine (30 mg/d) and benzphetamine (20-50 mg tid) are not longer available in the US.

Mazindol, which was withdrawn from the US market in 2001, was another drug that was only for short-term use (1 mg tid).

Phenylpropanolamine, which was also for short-term use (25 mg tid), was recalled from the US market. Phenylpropanolamine is an alpha-adrenoreceptor agonist. Some reports suggested a potential association between the use of phenylpropanolamine and ischemic stroke; therefore, this drug should be used with caution in elderly individuals and only after carotid atherosclerosis is excluded.

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Methylphenidate is not approved by the FDA for obesity management, although several anecdotal reports have described it as having variable success for this purpose.[38]

Sibutramine (Meridia) is a centrally acting appetite suppressant that inhibits reuptake of noradrenalin, serotonin, and dopamine.[39] The Sibutramine Trial of Obesity Reduction and Maintenance (STORM) revealed that a 9% weight loss persisted for as long as 18 months after the start of therapy. Sibutramine is fraught with adverse cardiovascular outcomes, and the drug has been withdrawn from the market in Europe. The US FDA is asking its advisory panel to review sibutramine safety in light of the recently published Sibutramine Cardiovascular Outcomes (SCOUT) trial.[40]

On October 8, 2010, Abbott and the US Food and Drug Administration (FDA) announced sibutramine (Meridia) is being withdrawn from the market because of increased risk of myocardial infarction (MI) and stroke. Europe suspended sibutramine from the market earlier this year.

The FDA requested the market withdrawal after reviewing data from the Sibutramine Cardiovascular Outcomes Trial (SCOUT). SCOUT was initiated as part of a postmarket requirement to look at cardiovascular safety of sibutramine after the European approval of this drug. The trial demonstrated a 16% increase in the risk of serious heart events, including nonfatal MI, nonfatal stroke, the need to be resuscitated once the heart stopped, and death, in a group of patients given sibutramine and another given placebo. A very small difference (2.5%) in weight loss was noted between the placebo group and the group that received sibutramine.[41]

Orlistat is the only FDA-approved antiobesity drug on the market. Orlistat (Xenical) blocks the action of pancreatic lipase, reducing triglyceride digestion and, thus, absorption.[42] Two major clinical trials showed sustained weight loss of 9-10% over 2 years.

Ephedrine and caffeine are second-line options in the medical management of obesity. They both act by increasing energy expenditure, but they are associated with the potential for tachycardia, hypertension, and palpitations. These medications are associated with more weight loss when used in combination than when used alone. They cause 25-40% of their weight loss by inducing thermogenesis, but they also decrease food intake, which accounts for 60-75% of the weight-loss effect.

Although not FDA approved for this purpose, several selective serotonin reuptake inhibitors (SSRIs; eg, fluoxetine, paroxetine) may cause anorexia as one of their

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major adverse effects. Some of these medications have been used as adjuncts in the medical management of obesity, with variable success.

Bupropion, which is licensed for use as an antidepressant and in smoking cessation, is associated with minimal to moderate weight loss.[43] Preliminary reports have suggested similar findings with venlafaxine.

Topiramate, licensed as an adjunctive antiepileptic agent, was associated with profound weight loss of as much as 15-18% of the baseline weight. The amount of weight loss appears to be greater with greater baseline weights. The exact mechanism of this effect is being actively investigated. Although the degree of efficacy is exciting, the propensity for adverse effects, especially CNS effects such as drowsiness, paresthesias, memory loss, and confusion, is concerning. Doses for weight management are lower than those for seizure management (usually 25-100 mg/day in divided doses). Doses >200 mg/d are rarely tolerated when administered for weight loss. Topiramate does not have an FDA-approved indication for weight loss at this time.[44]

The central cannabinoid system and feeding disorders

The importance of the central cannabinoid system in the understanding and management of feeding disorders has increased.[45, 46, 47, 48]

In particular, activation of the cannabinoid type 1 (CB1) receptor is associated with increased appetite and appears to be the basis for the effectiveness of dronabinol in enhancing diet in AIDS and other wasting syndromes. CB1 antagonists showed great potential for weight management in several human trials.

Rimonabant, the most-developed CB1 antagonist, caused mean weight loss of 3-6 kg over 1-year follow-up at doses of 5-20 mg/d. Adverse effects, which were most prevalent at high doses, included dizziness, mood swings, headaches, nausea, vomiting, and diarrhea. Rimonabant may obtain FDA approval as an adjunct for weight loss in the next 2-3 years based on the accumulating data from phase 3 trials of human obesity.

Investigational drugs

Agents in early phases of investigation that may yet prove of use include ghrelin antagonists, alpha-MSH analogs, enterostatin, neuropeptide YY antagonists, beta3-adrenergic agonists, and various nutraceuticals and herbal products (including the extract from the African cactus Hoodia gordonii, which may cause clinically significant appetite suppression).

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Metformin does not have an indication for obesity, but it was useful in preventing diabetes and improving insulin resistance in conditions such as polycystic ovary syndrome [PCOS]. Its use was associated with weight neutrality or mild weight loss.[49]

Gadde and colleagues reported that randomized use of the antiepileptic drug zonisamide in a cohort of 60 obese subjects was associated with a weight loss of about 6% of baseline weight, with few adverse effects.[50]

Lustig and colleagues reported the potential utility of octreotide in ameliorating the distinct subclass of hypothalamic obesity.[51]

The first glucagon-like peptide (GLP)-1 analog, exenatide, although not FDA approved for obesity management, has been associated with modest weight loss in subjects with type 2 diabetes.

Peptide YY (3-36) is being developed as a nasal inhaler. Preliminary, ongoing phase 1 and 2 trials yielded encouraging results.[52, 53, 54]

Amylin is the synthetic version of pramlintide and does not have an FDA indication for obesity management. However, this drug is clearly associated with variable weight loss in people with type 1 or 2 diabetes, while improving overall glycemic control.

Drugs no longer used

Some agents that initially showed promise were later demonstrated to be poor prospects in rigorous randomized intervention trials. These include guar gum, chitosan, axokine (or ciliary neurotrophic factor, the use of which was associated with development of autoantibodies and marked reduction in anorexiant potency in about 30% of subjects), leptin (except in the rare subclass of leptin-deficient obesity), St John's wort, psyllium, conjugated linoleic acid, chromium, and ginseng, among others.

Comorbidities

The management of obesity is not complete without attention being paid to various potential comorbidities.

Addressing these issues can have profound effects on the patient's well-being and risk of morbidity and mortality.

Public policy and obesity management

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Although management of obesity in the individual subject is important, realizing that obesity is a public-health problem is vital. Successful management of the obesity pandemic requires public health professionals and administrators to make tough policy decisions.

The multibillion-dollar food industry and the link between this industry and the consumer (including retailers and caterers) must be included in this public-health effort. The high-density foods, snacks, and drinks that are so common in the developed world and that now are infiltrating developing countries must be recognized as major factors in this pandemic.

Large-scale public-health education aimed at all age groups must be implemented with the same fervor and zeal that characterized past advertisements for tobacco. Such public-health initiatives must be accompanied by an equally spirited effort to educate the public and to encourage regular participation in exercise and outdoor recreational activities among individuals of all ages.

Fat substitutes

One strategy to prevent obesity that is being explored in the dietary industry involves use of fat substitutes.

Olestra (Olean) has been approved for use as a dietary supplement and additive in various fast foods, such as potato chips and crackers. Olestra has a calorie value of 0 kcal/g, whereas fat has approximately 9.1 kcal/g. Olestra consists of a sucrose polyester backbone with 6-8 fatty-acid side chains; this structure making it too large for digestive enzymes of the gut to hydrolyze it. In many trials, olestra had fairly good tolerability, though it apparently is less tasty than materials cooked in regular fat. The major adverse effects reported were flatulence, bloating, diarrhea, and loose stools. Because of the concern for possible malabsorption of fat-soluble vitamins, the FDA requires all olestra-prepared foods to be supplemented with these vitamins.

Sitostanol (Benecol) is a plant stanol ester preparation that is used as a spread similar to margarine. It blocks cholesterol absorption in the intestine, with no clinically significant alterations in triglyceride or HDL-C values.

Preliminary reports suggest the potential utility of agents that impede dietary carbohydrate absorption. Tagatose is one of the agents in this class that is undergoing trials.

 

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Surgical Care

Surgical therapy for obesity (bariatric surgery) is the only available therapeutic modality associated with clinically significant and sustained weight loss in subjects with morbid obesity associated with comorbidities. Evidence shows that well-performed bariatric surgery in carefully selected patients and a good multidisciplinary support team substantially ameliorates the morbidities associated with severe obesity. Although bariatric surgery is the only therapeutic method associated with consistently demonstrable sustained weight loss, it is expensive, highly procedure and surgeon specific, and certainly not the solution for the burgeoning obesity epidemic.

Patient selection for these procedures must be addressed along the same stringent lines as those discussed above for potential patients for medical weight-management programs (see Medical Care).

The presence of comorbidities is not a contraindication to these surgical procedures; however, the patient's condition must be stabilized and adequately treated before surgery. At a minimum, consider these procedures only in subjects with a BMI greater than 40 kg/m2 and/or a weight greater than 45 kg above the age-defined and sex-defined ideal weight. For subjects with BMIs of 35-40 kg/m2, several other comorbidities must be present to justify these procedures.

Among the comorbidities reported to be ameliorated and/or resolved by bariatric surgery are type 2 diabetes mellitus, hypertension, heart failure, peripheral edema, respiratory insufficiency, asthma, dyslipidemia, esophagitis, pseudotumor cerebri, sleep disorders, operative risk, osteoarthrosis, thromboembolism, and urinary incontinence. Other reports suggest improved quality of life and fertility among postsurgical patients. Although other outcomes are difficult to demonstrate and are awaiting clear documentation, these procedures may substantially reduce macrovascular complications (eg, myocardial infarction); stroke; amputations; obesity-related malignancies; and a predisposition to infection, hernias, and varicose veins.

Although most bariatric procedures were initially developed in the setting of laparotomies, they now are increasingly performed laparoscopically, with reduced postoperative morbidity. The laparoscopic approach to bariatric surgery is particularly well developed in Europe.

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Among the standard bariatric procedures are (1) horizontal gastroplasty, (2) roux-en-Y gastric bypass, (3) biliopancreatic bypass, (4) silicone gastric banding, (5) adjustable gastric banding, (6) jejunoileal bypass procedures, and (7) biliopancreatic bypass with duodenal-switch procedures.

Although available data on the effectiveness of all these procedures are still relatively scant, anecdotal reports of individual patients and a few reports of the most commonly performed procedures (gastric restriction and gastric bypass procedures) lend veracity to the long-term effectiveness of bariatric surgery.

Ashley and colleagues (1993) examined 114 subjects who underwent vertical-band gastroplasty.[55] About 60% lost more than 50% of their excess body weight over 1 year. No patient lost less than 25%, and, within a year of the surgery, mean BMI had decreased from 44.8 to 32.5 kg/m2.

Flickinger and associates (1984) examined 210 subjects who received roux-en-y gastric bypass.[56] The mean weight loss was 51 kg in 18 months, which was then maintained over 36 months of follow-up. Only 4% required a repeat operation.

Sugerman and colleagues (1992) reported that, among patients undergoing gastric bypass, two thirds of their excess body weight was lost over 2 years, 60% of the excess body weight lost was maintained, and more than 50% of excess body weight lost was maintained at 9-years follow-up.[57]

Roux-en-y and other gastric-bypass procedures generally result in more weight loss than gastric-restriction procedures. When 329 subjects receiving vertical gastroplasty procedures were compared with 623 subjects undergoing roux-en-Y gastric bypass, weight loss was maintained in 47% and 62%, respectively, over 5-9 years of follow-up.[57]

Other adjunctive procedures that may be performed but that have an unclear utility include visceral fat removal, omentectomy, subcutaneous fat panniculectomy, and large-volume subcutaneous fat liposuction. Klein and colleagues (2004) indicated that liposuction in itself has no utility in improving cardiac risk factor among subjects with obesity.[58]

Previous procedures, such as jaw wiring, insertions of gastric balloon, and insertions of gastric wrap are no longer popular because of their poor results compared with those newer procedures and because of their high complication rates.

Vagotomy has declined in popularity. On its own, vagotomy is associated with some weight loss, but the weight is typically regained within a few years. A few

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reports suggest that, when vagotomy is performed with gastric bypass, it increases weight loss by as much as 20%, but this finding has not been consistently replicable.

Among the major procedure-specific postoperative complications to watch for are wound dehiscence, stomal strictures, erosions or ulcers, postprocedure diarrhea, malabsorption, dumping syndrome, and anastomotic leaks with a potential for mediastinitis or peritonitis. In addition, gastric-specific operations can be associated with persistent vomiting, metabolic alkalosis, thiamine deficiency, and malabsorption of iron and vitamin B-12. These operations are more commonly associated with weight-loss failure and inadvertent splenectomy than other methods.

Prevalences for adverse events are approximately 70% for dumping, 50% for dairy intolerance, 40% for constipation and headaches, 15% for depression, and 33% for hair loss. Vitamin B-12 deficiency was found in 25% of patients; incisional hernias, anemia, diarrhea, or abdominal pain, in 15% each; and arrhythmias or single or multiple vitamin deficiencies not involving vitamin B-12, in 10% each.

The mortality rate associated with standard bariatric surgical procedures in an experienced center should not exceed 1.5-2%. The surgical mortality rate is less than 0.5% at centers specializing in bariatric surgery. Mortality rates exceeding this rate suggest a risk-to-benefit ratio that probably is unacceptable.

Subjects who receive bypass procedures are particularly prone to micronutrient deficiency states, especially of calcium, vitamin B-12, folate, and iron.

Among the major specific complications associated with malabsorptive operations are uncontrolled diarrhea, steatorrhea, malabsorption of fat-soluble vitamins, potassium and/or magnesium deficiency, blind-loop syndrome (which includes enteritis, arthropathy, and liver cirrhosis), gallstone development, urolithiasis, and metabolic encephalopathy.

If failure is defined as an inability to ameliorate comorbidities or prevent recurrence of such comorbidities, gastric bypass appears to have a failure rate of approximately 20%. Failure rates based on weight loss are controversial. The overall failure rates for malabsorptive procedures are relatively low, though the need for reversal of the surgery because of resulting adverse effects appears to be relatively high.

Despite the morbidity and mortality risk associated with bariatric surgery, the few reports on the follow-up of subjects undergoing these procedures suggest overall improvement in quality of life. Even more convincing than this finding is that most

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subjects who undergo these procedures, irrespective of their postoperative complications and difficulties, indicate that they would undergo the procedures again if necessary.

Emerging data suggest that gastric pacing achieved by using implantable electrodes may have substantial significant weight-loss effects. This outcome was initially discovered with the use of gastric pacemaker–devices for gastroparesis in subjects with diabetes.

Transneuronix conducted the first set of trials of a device, and findings were largely reported in abstracts. Medtronic, an established company in the arena of medical devices that developed continuous, subcutaneous insulin-pump technology, acquired Transneuronix, as seen in the image below. Recruitment is ongoing for the Appetite Suppression Induced by Stimulation Trial (ASSIST) to evaluate this technology in patients with obesity and type 2 diabetes.

Gastric electrical-stimulation device.

Cigaina (2002) reported that 10 patients in whom the pacing device was laparoscopically implanted showed a mean excess weight loss of about 25% at 3-year follow-up.[59]

Similar findings were replicated in several European studies with a total cohort of about 50 patients.

Consultations

Psychiatrist: Consultation with a psychiatrist is vital for identifying persons with psychiatric disorders and personality disorders such as depression, mania, and obsessive disorders that may be worsened by attempts at weight loss if not adequately treated and controlled.

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Dietitians Exercise and physical therapists Behavioral scientists and/or psychologists Bariatric surgeon, in appropriate setting

DietSee Medical Care.

ActivitySee Medical Care.

Medication Summary

Few medications are available for the management of obesity. The list of putative therapeutic agents being investigated has increased considerably with the explosion in our knowledge of the pathogenesis of obesity. Improved understanding of the neurocircuitry of the feeding-satiety cycle has provided many potential targets for designer therapeutic agents that are being developed (see image below).

Central nervous system neurocircuitry for satiety and feeding cycles.

Most medications available for managing obesity are approved only for short-term use. Available literature indicates that their utility is severely limited when they are given in this fashion. Obesity is a chronic medical condition. As with similar chronic conditions (eg, diabetes, hypertension), after therapeutic agents are stopped, the relapse rate is high. The need for any pharmaceutical regimen to be combined with a sustained exercise, dietary adjustment, and a behavioral-change

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regimen to sustain weight loss further complicates the successful management of obesity.

The only FDA-approved medication for long-term management of obesity in adults and adolescents is orlistat. Adolescents represent the next wave of the obesity pandemic that is anticipated in the next few decades.

A Japanese study found evidence that beverages containing high amounts of catechin, a flavonoid found in green tea, may aid in preventing obesity.[60] Patients in the investigation, all of whom had type 2 diabetes mellitus, ingested either 582.8 mg or 96.3 mg of catechins per day, by drinking green tea. By the 12th week, participants receiving the higher catechin dose had undergone a significantly greater reduction in waist circumference than did patients receiving the lower dose.

Anorexiants

Class Summary

Anorexiants are administered to manage obesity. Indications included weight loss and maintenance of weight loss, in conjunction with a reduced calorie diet, specifically in patients who are obese with an initial BMI of 30 or 27 mg/m2 and other risk factors (eg, diabetes mellitus, dyslipidemia, hypertension).

Orlistat (Xenical)

 GI lipase inhibitor that induces weight loss by inhibiting nutrient absorption. Effectiveness in producing weight loss does not depend on systemic absorption. May reduce absorption of some fat-soluble vitamins (A, D, E, K) and beta-carotene. Administer multivitamin supplement containing fat-soluble vitamins PO qd 2 h ac or 1 h pc.

Adrenergic Agonists

Class Summary

Stimulants release tissue stores of epinephrine, causing subsequent alpha- and/or beta-adrenergic stimulation, have provided benefits to patients with obesity. Approved in adults for short-term use (8-12 wk).

Caffeine

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 Natural xanthine derivative that directly stimulates all levels of CNS, cardiovascular system, and voluntary muscles. Increases gastric acid secretion and renal blood flow. Has mild diuretic activity.

Phentermine (Adipex-P)

 Sympathomimetic amine that increases release and reuptake of norepinephrine and dopamine. Anorexiant effect occurs as result of satiety-center stimulation in hypothalamic and limbic areas of brain. Pharmacologic component of comprehensive weight-reduction program (including behavioral modification, caloric restriction, exercise) intended for patients with initial BMI 30 or 27 kg/m2 and other risk factors (eg, diabetes, hyperlipidemia, hypertension).

Diethylpropion

 Sympathomimetic amine effective as adjunct anoretic therapy of exogenous obesity. Anorexiant effect occurs as a result of satiety-center stimulation in hypothalamic and limbic areas of brain. Controlled substance with high potential for abuse and addiction.

Further Inpatient Care

Although weight-management programs may be based in an outpatient or inpatient setting, no rigorous evidence suggests that inpatient programs are necessarily superior to outpatient programs of similar structure and content.

Inpatient programs may offer the convenience of easy access to patients and ease of monitoring, but they are expensive to run, difficult to reimburse, and generally considerably disrupt the patients' regular routine. In addition, they offer little guarantee of sustained effect.

The major role for inpatient evaluations is in the immediate postoperative period after antiobesity surgery and in the management of major complications, such as clinically significant respiratory or cardiac compromise.

Further Outpatient CareAs with the management of other chronic medical conditions that are not presently curable (eg, diabetes mellitus, hypertension, bronchial asthma), long-term success

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in the management of obesity is contingent on long-standing follow-up with the program.

Visits may not need to occur as frequently during follow-up as during the initial weight-loss phase, but they are paramount if the lessons learned regarding diet, exercise habits, and behavioral patterns are to be maintained.

Experience from the lifestyle intervention group of subjects in the Diabetes Prevention Program and the ongoing Diabetes Prevention Program Observation study have borne out the importance of regular follow-up.

Deterrence/PreventionBecause of the sheer prevalence of obesity and the anticipated worsening of the pandemic in the next few decades, prevention is by far the most desirable means to curb the consequences and economic load of obesity. However, few trials have addressed this issue, and those performed thus far have had mixed results.

Results of some public health education initiatives in Singapore and parts of China that are only now being evaluated suggest, as hoped, that such programs have the potential for reducing the incidence and prevalence of obesity and the major comorbidities of obesity, such as type 2 diabetes and hypertension.

Until recombinant DNA methods are developed enough to enable the alteration of genes that predispose individuals to obesity, the only options available are to develop a massive public health education program aimed at both adults and children to change their eating, activity, and behavioral habits.

The potential for possible leptin sensitizers may assist in changing feeding habits.

Given the global proportions of obesity, a concerted approach is needed and should involve cooperative efforts among public health authorities, caterers, the fast food industry, and organizers of sports and outdoor games.

In 2010, the American Heart Association-American Stroke Association (AHA-ASA) issued guidelines for the primary prevention of stroke, with the following recommendations:[61]

Diet and nutrition: A diet that is low in sodium and high in potassium is recommended to reduce blood pressure. Diets that promote the consumption of fruits, vegetables, and low-fat dairy products such as the DASH-style diet help lower blood pressure and may lower risk of stroke.

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Physical inactivity: Increasing physical activity is associated with a reduction in the risk of stroke. The goal is to engage in at least 30 minutes of moderate intensity activity on a daily basis.

Obesity and body fat distribution: Weight reduction among overweight and obese persons, is recommended to reduce blood pressure and risk of stroke.

ComplicationsThe potential complications and associations of obesity are detailed in the image below.

Comorbidities of obesity.

The so-called Pickwickian syndrome named after the boy who was obese in Charles Dickens’ Pickwick Papers is a combined syndrome of obesity-related hypoventilation (related to the severe mechanical respiratory limitations to chest excursion from severe obesity) and sleep apnea (which may be from obstructive, central, or both mechanisms).

Apart from the metabolic complications associated with obesity, a paradigm of increased intra-abdominal pressure has been recognized. This pressure effect is most apparent in the setting of marked obesity (BMI ≤50) and is espoused by bariatric surgeons, including Sugerman and colleagues (1992).[57]

Given findings from bariatric surgery and animal models, this change in pressure may play a (potentially major) role in the pathogenesis of comorbidities of obesity, such as pseudotumor cerebri, lower-limb stasis, ulcers, dermatitis, thrombophlebitis, reflux esophagitis, abdominal hernias, and possibly hypertension and nephrotic syndrome.

Some reports, including those by Adelman and colleagues and Kasiske and Jennette, suggest an association between severe obesity and focal

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glomerulosclerosis.[62, 63, 64] These complications, in particular, improve substantially or resolve early after bariatric surgery, well before clinically significant weight loss is achieved.

PrognosisThe association between obesity and morbidity is not in doubt.

However, the previous notion that the increased mortality and morbidity in patients who are obese was not entirely due to comorbidities was controversial.

Results of several observational studies detailed by the Expert Panel on the Identification, Evaluation, and Treatment of Overweight Adults and results from other reports by Allison, Bray, and others exhaustively show that obesity, on its own, is associated with increased cardiovascular morbidity and mortality and increased all-cause mortality.

For a person with a BMI of 25-28.9 kg/m2, the relative risk for coronary heart disease is 1.72. This risk progressively increases with an increasing BMI. Therefore, with BMIs greater than 33 kg/m2, the relative risk is 3.44.

Similar trends were demonstrated in the relationship between obesity and stroke or congestive heart failure.

Overall, obesity is estimated to increase the cardiovascular mortality rate 4-fold and the cancer-related mortality rate 2-fold.[20]

As a group, people who are severely obese have a 6- to 12-fold increase in the all-cause mortality rate.

A longitudinal study by Stessman et al of more than 1000 individuals indicated that a normal BMI, rather than obesity, is associated with a higher mortality rate in elderly people. The investigators determined that a unit increase in BMI in female members of the cohort could be linked to hazard ratios (HRs) of 0.94 at age 70 years, 0.95 at age 78 years, and 0.91 at age 85 years. In men, a unit increase in BMI was associated with HRs of 0.99 at age 70 years, 0.94 at age 78 years, and 0.91 at age 85 years. According to a time-dependent analysis of 450 cohort members followed from age 70 to age 88 years, a unit increase in BMI produced an HR of 0.93 in women and in men.[65]

Similar results to those in the Stessman study were found in a Japanese investigation of 26,747 older persons (aged 65-79 years at baseline). Tamakoshi et al found no elevation in all-cause mortality risk in overweight (measured as BMI 25.0-29.9 in this study) or obese (BMI ≥ 30.0) males; slightly elevated hazard

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ratios were found in women in the obese group, but not in the overweight group, in comparison with women in the mid – normal-range group. In contrast, an association was found between a low BMI and an increased risk of all-cause mortality, even among persons in the lower-normal BMI range.[66]

Patient EducationIn studies among low-income families, both adults and adolescents noted caloric information when reading labels.[67] However, it did not affect food selection by adolescents or the parental food selections for their children. It appears that the caloric content and distribution did not impact decision-making.

http://emedicine.medscape.com/article/123702-overview

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