OBESITY.

DISEASE OF THE

XXI CENTURY

OBESITY

• significant public health crisis in the United States and the rest of the developed world.

• The prevalence is also increasing rapidly in numerous developing nations worldwide.

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• This growing incidence represents a pandemic that needs urgent attention if the potential morbidity, mortality, and economic tolls that will be left in its wake are to be avoided.

OBESITY TREATMENT

• The cost of obesity management in the United States alone amounts to approximately $100 billion annually, of which approximately $52 billion are from the direct costs of health care.

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• These costs amount to approximately 5.7% of the entire US health expenditure. The cost of lost productivity due to obesity amounts to approximately $3.9 billion, while another $33 billion is spent annually on various weight loss products and services.

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Obesity represents a state of excess storage of body fat.

Overweight puristically is defined as an excess body weight for height.

While adult men have a body fat percentage of 15-20%, women have a higher proportion (approximately 25-30%).

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

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• Body mass index (BMI), also known as the Quetelet index, is far more commonly used to define obesity and has been found to closely correlate with the degree of body fat in most settings.

•

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• BMI = (weight [kg]) / (height [m])2.

• Body fat percentage can be estimated using the Deurenberg equation.

• Body fat percentage = 1.2(BMI) + 0.23(age [y]) – 10.8(sex) – 5.4, with males coded as 1 and females as 0.

• This formula has a standard error of 4% and explains approximately 80% of the variation in body fat.

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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.

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• World Health Organization (WHO) criteria

based on BMI. for adults:

• grade 1 (overweight ) BMI of 25-29.9 kg/m2.

• Grade 2 overweight (obesity) BMI of 30-39.9

kg/m2.

• Grade 3 overweight (severe or morbid obesity)

BMI greater than or equal to 40 kg/m2.

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• Surgical literature ( different classification) for recognize severe obesity.

• BMI greater than 40 kg/m2 (severe obesity)

• BMI of 40-50 kg/m2 (morbid obesity) • BMI greater than 50 kg/m2 ( super

obese)

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• Adipocyte: is the cellular basis for obesity, is being found to be an increasingly complex and metabolically active cell.

• the adipocyte is being perceived more frequently as an endocrine gland with several peptides and metabolites that may have relevance to the control of body weight.

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• products of the adipocyte involved in the complex intermediary metabolism:

• cytokines • tumor necrosis factor-alpha• interleukin-6 • lipotransin, • adipocyte lipid-binding protein• acyl stimulation protein• prostaglandins• adipsin• perilipins• lactate• adiponectin• monobutyrin• phospholipid transfer protein

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• critical enzymes involved in adipocyte metabolism:

• endothelial lipoprotein lipase (involved in lipid storage)

• hormone-sensitive lipase (involved in lipid elaboration and release from adipocyte depots)

• acylcoenzyme A (acyl-CoA) synthetases (involved in fatty acid synthesis),

• and a cascade of enzymes (involved in beta oxidation and fatty acid metabolism)

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• Another area of actively progressing research is the cues for the differentiation of preadipocytes to adipocytes.

• identified factors involved in this process:• transcription factors peroxisome proliferator-

activated receptors gamma (PPAR-gamma), retinoid-X receptor ligands, perilipin, adipocyte differentiation-related protein (ADRP).

Obesity Pathophysiology:

• The pathogenesis of obesity is far more complex than the simple paradigm of an imbalance between energy intake and energy output.

Obesity Pathophysiology:

• obesity obviously is far more than the mere result of excess eating and/or too little exercise.

• in USA, 22% of adults and 25% of adolescents report significant regular physical activity.

• 25% of adults in the United States report no significant physical activity during leisure

• 14% of adolescents have similar reports of inactivity.

Obesity

• 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 variability in obesity variance, and environmental factors.

Obesity

• The high prevalence of obesity in the children of parents who are obese and the high concordance of obesity in identical twins suggest a significant genetic component to the pathogenesis of obesity, the secular trends of the last few decades, which are coincident with recent changes in dietary habits and activity, also suggest a significant role for environmental factors.

Leptin

• Leptin was discovered in 1994 by Friedman et al and ushered in an explosion of research and a great increase in knowledge about regulation of the human feeding and eating cycle.

• 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.

• Unfortunately, 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 and, thus, have elevated circulating leptin levels.

• While most human obesity is polygenic (>90% of cases), the recognition of monogenic variants has greatly enhanced our knowledge about the etiopathogenesis of obesity.

Monogenic models for obesity in humans and experimental

animals

• The various available monogenic models have greatly increased our knowledge about mechanisms for the development of obesity, and they also have provided multiple potential targets for future antiobesity medications.

• Proopiomelanocortin (POMC) and alpha–melanocyte-stimulating hormone (alpha-MSH) both act centrally on the melanocortin receptor 4 (MC 4) to reduce dietary intake.

• Genetic defects in POMC production and mutations in the MC4 gene both have been described as monogenic causes of obesity in humans.

• Of particular interest is the fact that patients with POMC mutations, because of the deficiency in MSH production that results, tend to have red-colored hair. Also, because of their diminished adrenocorticotropic hormone (ACTH) levels, they tend to have central adrenal insufficiency.

• Some recent data suggest that as many as 5% of children who are obese have MC4 or POMC mutations. If confirmed, these would be the most common identifiable genetic defects associated with obesity in humans (band 2p23 for POMC and band 18q21.3 for MC4).

• The Ob/Ob mice are the prototypical mice that set the stage for the discovery of leptin.

• These mice lack the leptin gene and are overweight and hyperphagic.

• A few humans have been identified who have a similar genetic defect with similar phenotypic consequences.

• This variant of obesity, although minor in the grand scheme of human obesity, is exquisitely sensitive to leptin injection, with reduced dietary intake and profound weight loss (band 7q31).

• The Db/Db mice have mutations of the leptin receptor in the hypothalamus.

• Fa/Fa mice also have leptin-receptor mutations. • These mice have early-onset obesity and

hyperphagia like the Ob/Ob mice, but they also have normal or elevated leptin levels.

• Human counterparts of this model are very rare and are associated with hyperphagia, hypogonadotrophic hypogonadism, and defective thyrotropin secretion, but they are not associated with hypercortisolism, hyperglycemia, and hypothermia as occurs in Db/Db mice (band 1p31).

•

• Prohormone convertase is an enzyme that is critical in protein processing, and it appears to be involved in the conversion of POMC to alpha-MSH.

• Patients identified to have this, although rare, have significant obesity, hypogonadotrophic hypogonadism, and central adrenal insufficiency.

• It is one of the few obesity models not associated with insulin resistance (band 5q15-21).

• PPAR-gamma is a transcription factor that is involved in adipocyte differentiation. All humans with mutations of the receptor described so far have severe obesity (band 3p25).

• In addition to the above monogenic models of obesity, genome-wide linkage analyses and microarray technology have revealed a rapidly growing list of potential susceptibility obesity genes. Among those identified that are being actively studied are genes on chromosome arms 2p, 10p, 5p, 11q, and 20q.

• In the same line as the evidence that proved Helicobacter pylori as the cause for peptic ulcer disease, some evolving data suggest that a significant inflammatory and possibly infective etiology may exist for obesity. Adipose tissue is known to be a repository of various cytokines, especially interleukin-6 and tumor necrosis factor-alpha

• Some data have shown that adenovirus 36 infection is associated with obesity in chickens and mice.

• Other data also suggest that while humans who are not obese have a 5% prevalence rate of adenovirus 36 infection, humans who are obese have a prevalence rate of 20-30%.

Frequency:

• 100 million adults in the United States are at least overweight or obese.

• 35% of women and 31% of men older than 19 years are obese or overweight.

• The prevalence of obesity in children in the United States has increased markedly between the time of the National Health and Nutrition Examination Survey (NHANES) 2 and 3 trials.

• 20-25% of children are either overweight or obese, and the prevalence is even greater in some minority groups, including Pima Indians, Mexican Americans, and African Americans.

• Internationally: The prevalence of obesity worldwide is increasing, and this is particularly occurring in the developed nations of the Northern Hemisphere, including the United States, Canada, and most of Europe.

• Available data from the MONICA (monitoring cardiovascular) disease study in Europe 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 Asia and, to a lesser extent, in Africa.

• Reports from countries such as Malaysia, Japan, Australia, New Zealand, and China detail an epidemic of obesity in the last 2-3 decades.

• Data from the Middle Eastern countries of Bahrain, Saudi Arabia, Egypt, Jordan, Tunisia, and Lebanon, among others, exhibit this same disturbing trend, with alarming levels of obesity often exceeding 40%, particularly worse in women.

• Data from the Caribbean and South America also highlight similar trends. While data from Africa on this issue are scant, a clear and distinct secular trend of profoundly increased BMIs clearly exists when people from Africa immigrate to northwestern hemispheric countries. Studies comparing these indices among Nigerians residing in Nigeria and recent immigrants to the United States show this trend very poignantly.

• Conservative estimates suggest that as many as 250 million people (approximately 7% of the estimated current world population) are obese.

• Mortality/Morbidity:

• Data available from insurance company databases and large prospective cohorts such as the Framingham and NHANES studies clearly indicate that obesity is associated with a significant increase in both morbidity and mortality.

• The degree of obesity (generally indicated by the BMI) at which a discernible increase in mortality occurs is, however, higher for African Americans and Hispanic Americans than for white Americans, suggesting a significant racial spectrum and difference in this effect.

• Race: • Obesity is a cosmopolitan disease that affects all races

worldwide. • However, certain ethnic and racial groups appear to be

particularly predisposed.• Pima Indians of Arizona and other ethnic groups native to

North America have a particularly high prevalence of obesity.

• Polynesians, Micronesians, Anurans, Maoris of the West and East Indies, African Americans in North America, and the Hispanic populations (both Mexican and Puerto Rican in origin) in North America also have particularly high predispositions to developing obesity.

• Secular trend studies clearly underline the marked importance of environmental factors (particularly dietary issues) in the development of obesity. Many of the genetically similar cohorts of the above named high-risk ethnic and racial groups have far less prevalence for obesity in their countries of origin, but this changes significantly when such groups have immigrated to the affluent Northern Hemisphere, with altered dietary and activity habits. These findings form the core concept of the thrifty gene hypothesis espoused by Neal et al.

Sex:

• No significant sex difference exists in the prevalence of obesity.

Age:

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

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

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

• 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 this in the history. The possibility of binging, purging, lack of satiety, food-seeking behavior, and other abnormal feeding habits need to be identified because management of these habits is crucial to the success of any weight management program.

• Also, investigate whether any of the previously mentioned comorbidities have occurred, and include questions to exclude the possible rare causes of secondary obesity

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

Comorbidities related to obesity include the following

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

– Central nervous system - Stroke, idiopathic intracranial hypertension, meralgia, paresthetica

– Gastrointestinal - Gall bladder disease (cholecystitis, cholelithiasis), nonalcoholic steatohepatitis (NASH), fatty liver infiltration, reflux esophagitis

– Respiratory tract - Obstructive sleep apnea, obesity hypoventilation syndrome (Pickwickian syndrome), increased predisposition to respiratory infections, increased incidence of bronchial asthma

• Malignancies - Association with endometrial, prostate, gall bladder, breast, colon, and, possibly, lung cancer

• Psychologic - Social stigmatization, depression

• Orthopedic - Osteoarthritis, coxa vera, slipped capital femoral epiphyses, Blount disease and Legg-Calvé-Perthes disease, chronic lumbago

Orthopedic - Osteoarthritis,

– Metabolic - Insulin resistance, hyperinsulinemia, type 2 diabetes mellitus, dyslipidemia (characterized by high total cholesterol, high triglycerides, normal or elevated low-density lipoprotein, and low high-density lipoprotein)

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

– Obstetric and perinatal - Pregnancy-related hypertension, fetal macrosomia, pelvic dystocia

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

– Pelvic problems - Stress incontinence– Cutaneous - Intertrigo (bacterial and/or

fungal), acanthosis nigricans, hirsutism, increased risk for cellulites and carbuncles

• Extremities - Venous varicosities, lower extremity venous and/or lymphatic edema

• Miscellaneous - Reduced mobility, difficulty maintaining personal hygiene

• Physical:

• In the clinical examination, include measurement of the anthropometric parameters and the standard detailed examination required for the evaluation of persons with any chronic multisystemic disorder such as obesity.

• 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, include an attempt at excluding tender hepatomegaly and distinguishing the striae distensae from the pink and broad striae that would suggest cortisol excess.

• When examining the extremities, include a search for joint deformities such as coxa vara, evidence of osteoarthrosis, and any pressure ulcerations.

• Causes: The 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:– Hypothyroidism– Cushing syndrome– Insulinoma

– Hypothalamic obesity– Polycystic ovarian syndrome – Genetic syndromes (eg, Prader-Willi

syndrome, Alström syndrome, Bardet-Biedl syndrome, Cohen syndrome, Börjeson-Forssman-Lehmann syndrome, Fröhlich syndrome)

– Growth hormone deficiency – Oral contraceptive use

• Medication-related (eg, phenothiazines, sodium valproate, carbamazepine, tricyclic antidepressants, lithium, glucocorticoids, megestrol acetate, thiazolidine diones, sulphonylureas, insulin, andrenergic antagonists, serotonin antagonists [especially cyproheptadine])

• Eating disorders (especially binge-eating disorder, bulimia nervosa, night-eating disorder)

• Hypogonadism • Pseudohypoparathyroidism • Obesity related to tube feeding

• Lab Studies:

• Full lipid panel (at minimum, fasting cholesterol, triglycerides, and high-density lipoprotein [HDL])– These may be normal, or the typical dyslipidemia

associated with metabolic syndrome X may be found.– This is characterized by reduced HDL cholesterol (HDL-

c), increased low-density lipoprotein cholesterol (LDL-c), normal-to-marginally increased total cholesterol, and elevated fasting triglycerides.

• Hepatic panel: This is expected to be normal but may be abnormal (elevated transaminases in the setting of NASH).

• Thyroid function tests– These typically are normal but checking them in

order to detect cases of primary hypothyroidism (characterized by increased serum thyrotropin and normal or reduced levothyroxine and/or triiodothyronine levels) is worthwhile.

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

• For screening purposes, 24-hour urinary free cortisol– This test only needs to be performed when

Cushing syndrome or other hypercortisolemic states are clinically suspected.

– Approximately 4% of patients with Cushing syndrome have normal urinary free cortisols.

• Fasting glucose and insulin

– Obesity is associated with insulin resistance, even though these levels are normal in a significant proportion of subjects who are obese.

– In other people, insulin levels may be elevated.

– In those with impaired glucose tolerance, the fasting serum glucose level is elevated to higher than 110 mg/dL.

• Procedures:

• Among the various procedures relevant to the management of patients who are obese are procedures to estimate the degree of visceral and subcutaneous fat. These include the standard anthropometric measurements and caliper-derived skin thickness estimates.

• Histologic Findings: Hypertrophic obesity characterized by enlarged fat cells is typical of android abdominal obesity. Hypercellular obesity, on the other hand, is more variable, and it is typical of obesity with an onset in childhood or adolescence but invariably also is found in subjects with severe obesity.

• Medical Care: While 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).

3 major phases of any weight loss program

• (1) preinclusion screening phase

• (2) definitive weight loss program

• (3) maintenance phase, which conceivably can last for the rest of the subject's life, but must last for at least 2 years after the weight loss program is completed.