OBESITY'

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OBESITY.

• DISEASE OF THE
• XXI CENTURY

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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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OBESITY

• 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.

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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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OBESITY

• 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

• 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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OBESITY

• 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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OBESITY

• 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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OBESITY

• 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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OBESITY

• 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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OBESITY

• 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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OBESITY

• 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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OBESITY

• 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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OBESITY

• 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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OBESITY

• 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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OBESITY

• 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).

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Obesity Pathophysiology

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

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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.

However, the prevalence of
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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.

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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.

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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.

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• 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.

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• 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.

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• While most human obesity is polygenic (gt90 of
  cases), the recognition of monogenic variants has
  greatly enhanced our knowledge about the
  etiopathogenesis of obesity.

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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.

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• Proopiomelanocortin (POMC) and alphamelanocyte-st
  imulating 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.

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• 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.

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• 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).

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• 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).

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• 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).

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• 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).

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• 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).

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• 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.

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• 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

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• 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.

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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.

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• 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.

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• 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.

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• 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.

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

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• 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.

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• 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.

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• 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.

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• 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.

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Sex

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

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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.

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• 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.

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• 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.

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• 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.

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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
  
  
  
  

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• 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

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• 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,
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• 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

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• 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

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• Extremities - Venous varicosities, lower
  extremity venous and/or lymphatic edema
• Miscellaneous - Reduced mobility, difficulty
  maintaining personal hygiene

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• 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.

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• 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.

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• 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.

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• Causes The etiology of obesity is
  multifactorial. Among the facets to be considered
  in the development of obesity are the following

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• Metabolic factors
• Genetic factors
• Level of activity
• Behavior
• Endocrine factors
• Race, sex, and age factors

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• Ethnic and cultural factors
• Socioeconomic status
• Dietary habits
• Smoking cessation
• Pregnancy and menopause
• Psychologic factors

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• History of gestational diabetes
• Lactational history in mothers
• Secondary causes of obesity may include the
  following
• Hypothyroidism
• Cushing syndrome
• Insulinoma

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• 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

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• 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

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• 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.

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• 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.

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• 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

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• 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.

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• 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.

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• 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.

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• 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).

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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.