Understanding Obesity and Metabolic Syndrome: Medical Insights and Guidelines

1. بسم الله الرحمن الرحيم

2. Obesity and diseases of civilization By Amr Abdelmonem,MD. Assistant professor of anesthesia ,surgical intensive care and clinical nutrition in faculty of medicine, Cairo university Member of North American Association For The Study Of Obesity Member of the American society of regional anesthesia and pain medicine

3. The O Word:Obesity 1998, world health organization defined overweight and obesity based on Body Mass Index ( BMI Kg / m2) Over weight : 25.0 to 29.9 Class 1 obesity: 30.0 to 34.9 Class 2 obesity: 35.0 to 39.9 Class 3 obesity : 40.0 or greater BMI is not a measure of body composition BMI is an important correlate of impaired HRQL(health related quality of life)

4. National institutes of health of the US have recently recommended weight Management based on Standardized cut- offs for BMI at 25 and 30 Kg/m2 and • On waist circumference ( action levels) • Minimum circumference between lower rib margin and iliac crest • Action level 1 at 94 cm in men and 80 cm in women • Action level 2 at 102 cm in men and 88 cm in women • Greater than action level 1 : individuals are at • increased health risk ,should avoid weight gain • Greater than action level 2 : are at high health risk , • should seek Professional help NICK CIRCUMFERENCE measurement is a simple and time-saving screeningmeasure that can be used to identify overweight and obese patients. Men with NC <37 cm and women with NC <34 cm are not tobe considered overweight

6. Adipose Tissue vs. Fat

7. Traditional Adipose Tissue Classification • Classical anatomy was mainly organ-centered, without recognizingthe specialized organ-like functions of different tissues • Thiswas especially true of adipose tissue, which only recently hasbeen recognized as an "endocrine organ “ N Engl J Med .2001;345:1345 • Simple anatomic adipose tissue groupings :subcutaneous adipose tissue, organ-surrounding adiposetissue, interstitial adipose and adipose tissue in bone marrow • Adipose tissue is also named according to special biologicalfunctions, such as white, mammary gland, brown, and bone marrowadipose tissues

8. Recent proposed Classification of total body adipose tissue Shen et al,Obes Res.2003;11:1 Subcutaneous Internal Superficial Visceral Non- visceral Deep Intramuscular Perimuscular Orbital Intrathoracic Intraabdominopelvic Intrapricardial Intraperitoneal Extrapritoneal Extrapricardial Intraabdominal Intrapelvic Parametrial Retropubic Paravesical Retrouterine Pararectal Retrorectal Preperitoneal Retrroperitoneal

9. Metabolic syndrome

10. What is metabolic syndrome? • Metabolic syndrome is a collection of health risks that increase the chance of developing heart disease, stroke, and diabetes. • The condition is also known by other names including Syndrome X, insulin resistance syndrome, and dysmetabolic syndrome.

11. What are these health risks? ATP III Guidelines WHO Guidelines Abdominal Obesity Waist CircumferenceWaist/Hip Ratio Men > 40 inches  >0.90 Women > 35 inches  >0.85 Other Variables Triglycerides150 mg/dL 150 mg/dL HDL-Cholesterol Men < 40 mg/dL <35 mg/dL  Women < 50 mg/dL <39 mg/dL Blood Pressure130/ 85 mm Hg >140/>90 mm Hg Fasting Glucose110 mg/dL 110 mg/dL WHO guidelines also include microalbuminuria (>20 µg/min or albumin:creatinine ratio >30 mg/g).

12. The pathogenesis of metabolic syndrome Complex interplay of a still largely unknown genetic background with environmental lifestyle- related factors

13. Genetic Background

14. Environmental lifestyle-related factors: When we eat ,our bodies break down the food into its basic components ( protein-carbohydrates- fat), and absorbs them into blood stream  rise in blood sugar  pancreas will release insulin moves sugar into cells either burned for energy or stored away as fat in fat cells or glycogen in liver and muscles Years of dietery abuse in susceptible patients  malfunctioning of insulin sensors  hyperinsulinemia Continued dietery abuse  insulin sensors to sluggish  insulin resistance

15. The link between visceral adipose tissue and metabolic syndrome • Direct exposure of liver cells through the portal circulation to high concentrations of free fatty acids derived from visceral adipose tissue is responsible for metabolic complications of abdominal obesity Gabrielsson et al,Obes Res.2003;11:699 • Adipocytokines (leptin ,adiponectin) factors released from adipose tissue responsible for mediating insulin resistance. Pischon et al,Obes Res.2003;11:1055

16. Markers of insulin resistance : • Hypertriglyceridemia • HDL • Hypertension • Hyperinsulinemia • Abdominal obesity • Hyperglycemia • Recently Marjo etal , proven liver fat accumulation as an important marker • ( Obes Res 2002; 10: 859)

17. Obesity Lets walk through the fat metabolism pathway and follow the flow of fat molecules: Fat travels in the form of triglycerides at cells  ezymatic breakdowen fatty acids enter the cells mitochondria  breakdowen fat  in order to enter mitochondria ,fats need carnitine  insulin inhibitsFat- carnitine shuttle system  fats move back into blood Glucagon accelerates this shuttle system Muscle ,liver, kidney, lung, heart and other cells break down fat

18. Fat cells merely store the fat molecules ! Two enzyme systems on the surface of fat cells regulated by insulin and glucagon Insulin stimulates lipoprotein lipase that transports fatty acid into fat cells Glucagon stimulates sensitive lipase that releases the fat from fat cells into the blood Although we cannot control lipoprotein lipase directly, we can control It indirectly by cotrolling the metabolic hormones ,insulin and glucagon

19. DYSLIPIDEMIA Functions of cholesterol : • Adrenal hormones and sex hormones • Main component of bile acids • Essential for normal growth and development of brain and nervous tissue • Gives the ability of skin to shed water • Precursor of vitamine D in the skin • Normal growth and repair of tissues • Transportation of triglycerides

20. Where does cholesterol come from? 80 % comes from the body itself , every cell in the body is capable of making its own cholesterol , most don’t and rely instead on that made in the liver and skin. Cholesterol and triglycerides are insoluble in blood Lipoproteins are envelops that enclose cholesterol and triglycerides Making them soluble in blood,so that they can be transported to tissues

21. Sequence of events in the life of lipoproteins Liver Makes and release VLDL HDL Released to tissues Deposited in coronary arteries TRIGLYCERIDES WITH CHOLESTEROL Scavenges cholesterl From tissues carries Through blood Hands it off to VLDL Removed by liver TRI AND CHOLES CholesteroL rich MATURE VLDL Triglycerides Released to blood And tissues LDL Cholesterol Bulk +tri LDL More triglycerides release

22. When the level of cholesterol inside the cells falls  LDL receptors Attach to the surfaces of the hepatic cells invaginate LDL cholesterol By endocytosis Obese patients with insulin resistance have LDL receptors dysfunction Cholesterol synthesis inside the cells depends on an enzyme named 3- hydroxy-3 methyl-glutaryl-coenzyme A reductase Couple of hormones affect the activity of the rate limiting enzymeHMG-CoA reductase INSULIN AND GLUCAGON

23. Diet and cholesterol quiz

24. Patient with the following findingTotal cholesterol: 240 LDL : 160 HDL:35Total/ HDL: 6.85 LDL/HDL: 4.57

25. Hypertension Data from NHANES III show that the (age – adjusted prevalence) Of high blood pressure increases progressively with higher levels Of BMI in men and women High blood pressure is defined as SBP 140 mm Hg or MBP  90 mm Hg or currently taking antihypertensives

26. What is the etiology that connects obesity and hypertension? Hyperinsulinemia and insulin resistance

27. Mechanism • Increased sodium retention • Increased sympathetic nervous system activity • Alteration in the mechanics of blood vessels

28. The precise mechanism whereby weight loss results in a decrease in Blood pressure is unknown . • However • It is known that weight loss is associated with •  vascular resistance,total blood volume and cardiac output • Improvement in hyperinsulinemia and insulin resistance •  sympathetic nervous system activity • Suppression of the activity of renin angiotensin aldosterone system • Recently ,serum angiotensin converting enzyme activity declines with modest weight loss.

29. Type II Diabetes mellitus • It represents 90% of all cases of diabetes. • Requires years of underlying metabolic disturbance before symptoms become apparent • The development and diagnosis usually follows weight gain • In Type I and Type II diabetes blood sugar is elevated but for different reasons • Type I there is no insulin to hold it down by moving it into cells

30. Type II the cells become resistant to insulin that even large amounts cant adequately move the sugar into cells • In early stages there is hyperinsulinemia ,later pancreatic beta cells wear out from constantly producing insulin under stimulation of hyperglycemia • Resistin is aprotein secreted by fat cells as a signal from adipose tissue linking obesity to insulin resistance and type II diabetes • Liese et al,Eur J Nutr.2001;40:282 • Increased White blood cell count is correlated with insulin resistance in diabetic obese females • Pannacciulli et al,Obes Res.2003;11:1232

31. Coronary artery disease • Observational studies have shown that overweight,obesity, and VAT are directly related to cardiovascular risk factors (  cholesterol ,  LDL,  triglycerides, hypertension,  fibrinogen,hyperinsulinemia ,  HDL, plasminogen activator inhibitor ) The term "Syndrome X" refers to a heart condition where chest pain and electrocardiographic changes that suggest ischemic heart disease are present, but where there are no angiographic findings of coronary disease. RECENTLY Complement 3 and acute phase proteins is the immunological link between central obesity and CHD

32. Recent studies have shown that risks of nonfatal myocardial infarction and CHD death increase with increasing levels of BMI • In British, Swedish, Japanese and US populations , CHD incidence increased at BMIs above 22 and an increase of 1 BMI unit was associated with • 10 % increase in the rate of coronary events • Recent study has found that obese CHD patients are younger and and are hospitalized more frequently during the first 10 years of their illness than the non-obese

33. Obesity and cardiac dysrhythmias(prolonged Q-T interval) • Q-T interval is usually measured in lead II , and is corrected for heart rate . • Q-Tc= measured Q-T  square root of R-R interval • Prolonged Q-T interval reflects prolonged repolarization of the ventricle • Proposed mechanism is increased SNS activity • Recent study had found that Prolonged Q-T interval is associated with abnormal WHR ,higher levels of FFA and hyperinsulinemia in obese women . • Wight loss leads to normalization of Q-Tc with attenuation of hyperinsulinemia Esposito et al,Obes Res.2003;11:653-659

34. Oxidant Stress Imbalance Between Formation Of Reactive oxygen/nitrogen species (ROS/RNS) And Antioxidants

35. Pathologic stress Induces monocytes to release mediators (TNF and interleukins 1-6-8)  Activates PMNs  Release ROS(superoxide (O2·-), hydrogen peroxide, hypochlorite, nitricoxide (NO), hydroxyl radical  Induce tissue injury by: • damaging DNA • Cross linking cellular proteins • Peroxidation of membrane lipids  • Diminishing membrane fluidity • Increasing membrane permeability

36. Oxidant Stress and Obesity • Adipocytes and preadipocytes have been identifiedas sources of inflammatory cytokines: • including TNF- , interleukin(IL)1-ß, and IL-6. • Stimuli capable of inducingcytokine release from adipocytes may include: • lipopolysaccharides,intracellular triglycerides, and catecholamines

38. We could predict that: •The accumulation of intracellular triglycerides or tissueadiposity promotes increased oxidant stress •Therefore reductionof total body fat through diet and/or exercise may be an effectivemeans of reducing systemic inflammation and oxidant stress. Consistent with this prediction Reductions in plasma markersof oxidant stress and in ROS generation by isolated leukocyteshave been observed after 4 weeks of energy restriction and weightloss. Dandona et al. J Clin Endocrinol Metab,2001; 86:355-363

39. Good news Physical activity •Decreases adipose derived inflammatory mediators •Activates signaling pathways that lead to increasedsynthesis of intracellular antioxidants and antioxidant enzymesand decreased ROS production Miyazaki et al, Eur Appl Physiol.2001; 84:1-6 Pischon et al, Obes Res.2003;11:1055

41. Obesity And Diseases

42. Obesity and cancer • Strong risk factor for esophageal cancer • Uterine and gall bladder cancer in obese women • High risk for colon and prostate cancer in obese males • Breast cancer for obese postmenopausal women

43. Obesity and muscles and bones • Obesity places stress on bones and muscles • High risk for hernias ,low back pain and aggravation of arthritic conditions • High risk for carpal tunnel syndrome

44. Obesity and gallstones • The incidence of gallstones is significantly higher in obese women and men • The risk of stone formation is also high if a person loses weight too quickly

45. Obesity and lungs • Strong risk factor for adult onset asthma. • Increased risk of hypoxemia and detrimental work of breathing • Pickwickian syndrome

46. Obesity and sleep apnea and sleep disorders • Obese tend to fall asleep faster and sleep longer during the day • At night ,it takes them longer to fall asleep they sleep less than others. • When the upper airways relaxes and collapses at intervals during sleep ,thereby temporary blocking the passage of air (sleep apnea) • Symptoms :morning headach,fatigue and irritability • Side effects :dysrhythmias,stroke ,right sided heart failure and car accidents • Sleep apnea deprives patients from REM sleep • REM sleep: the dreaming phase of sleep,necessry for emotional wellbeing • Obesity leads to sleep apnea which leads to loss of REM sleep which leads to raising of BMI

47. OBESITY AND EATING DISORDERS • Binge eating : about 30% of obese are binge eaters ,who typically consume 5000 to 15000 calories in one sitting • To be diagnosed as a binge eater ,person has to binge twice a week for 6 months • Bulimia : binge eating followed by purging in order to lose weight • Anorexia : severe weight loss and is life threatening

48. Why treat overweight and obesity? Not only to improve the BODY IMAGE But also to reduce the OBESITY –RELATED COMORBIDITIES

49. THANK YOU