1. Epidemiology of the Metabolic Syndrome in the USA Incidence ? Prevalence Distribution Control ? Incidence ? Prevalence Distribution Control ? Epidemiology Evaluates a Disease

2. Epidemiology of the Metabolic Syndrome What is It ? Why are its Limitations ? Why is It Important ? What is its Prevalence ? What are its Clinical Outcomes ? - Cardiac - Diabetes - Nonalcoholic Fatty Liver Disease

3. The Metabolic Syndrome ObesityDiabetes HyperlipidemiaHypertension Insulin Resistance

4. Epidemiology of the Metabolic Syndrome What is It ? Why are its Limitations ? Why is It Important ? What is its Prevalence ? What are its Clinical Outcomes ? - Cardiac - Diabetes - Nonalcoholic Fatty Liver Disease

5. Metabolic Syndrome World Health Organization (WHO) International Diabetes Association (IDF) Adult Treatment Panel (ATP III) - National Cholesterol Education Program Expert Panel World Health Organization (WHO) International Diabetes Association (IDF) Adult Treatment Panel (ATP III) - National Cholesterol Education Program Expert Panel There are 3 Definitions

6. Three Different Definitions Obesity BP Fasting Glucose Triglycerides HDL Cholesterol Micro Albumin BMI Similar IPG/HOMA Same Not Used Used BMI Similar IPG/HOMA Same Not Used Used Central Same >6.1mol/L Same Similar Not Used Central Same >6.1mol/L Same Similar Not Used IDFWHOATP Central Same >5.6mol/L Same Similar Not Used Central Same >5.6mol/L Same Similar Not Used

7. Concerns About the Metabolic Syndrome Criteria are Ambiguous Rationale for Thresholds ill defined Inclusion of Diabetes Questionable Importance of Insulin Resistance Unclear Questions about CVD Risk Factors Remain Treating MS no different than treating its parts Medical Value of Diagnosing MS is Unclear Criteria are Ambiguous Rationale for Thresholds ill defined Inclusion of Diabetes Questionable Importance of Insulin Resistance Unclear Questions about CVD Risk Factors Remain Treating MS no different than treating its parts Medical Value of Diagnosing MS is Unclear (ADA and EASD)

8. Epidemiology of the Metabolic Syndrome What is It ? Why are its Limitations ? Why is It Important ? What is its Prevalence ? What are its Clinical Outcomes ? - Cardiac - Diabetes - Nonalcoholic Fatty Liver Disease

9. Prevalence (%) of Metabolic Syndrome Country ATP IDF WHO South Asia 26 18 23 Australia 19 16 21 France 9 13 18 Italy 18 34

10. Prevalence (%) of Metabolic Syndrome United States and China County ATP IDF WHO USA National 24 40 Texas 25 25 China Hong Kong 17 21 InterAsia 14

11. Epidemiology of the Metabolic Syndrome What is It ? Why are its Limitations ? Why is It Important ? What is its Prevalence ? What are its Clinical Outcomes ? - Cardiac - Diabetes - Nonalcoholic Fatty Liver Disease

12. Metabolic Syndrome Predicts All Cause Mortality (13 year Follow up) Metabolic Syndrome No Yes ATP III (%) 10 21 p<0.01 WHO (%) 10 18 p<0.05

13. Metabolic Syndrome and Cardiac Death Years Of Follow-Up NCEP-MetS

14. Metabolic Syndrome Predicts Diabetes (8 year Follow up) Diabetes No Yes ATP III (%) 14.4 28.7 p<0.0001 WHO (%) 12.5 41.3 p<0.0001

15. Epidemiology of the Metabolic Syndrome What is It ? Why are its Limitations ? Why is It Important ? What is its Prevalence ? What are its Clinical Outcomes ? - Cardiac - Diabetes - Nonalcoholic Fatty Liver Disease

16. Non-Alcoholic Fatty Liver Disease What is it? Why is it Important? How do you treat it? What is it? Why is it Important? How do you treat it?

17. Proposed Classification for NAFLD* Conditions associated with an insulin resistance syndrome - Diabetes mellitus (type II) - Obesity - Hyperlipidemia Conditions associated with an insulin resistance syndrome - Diabetes mellitus (type II) - Obesity - Hyperlipidemia Primary Secondary DRUGS - Corticosteroids - Synthetic Estrogens - Amiodarone - Perhexiline - Nifedipine DRUGS - Corticosteroids - Synthetic Estrogens - Amiodarone - Perhexiline - Nifedipine SURGICAL PROCEDURES - Gastroplexy - Jejunoileal bypass - Extensive small bowel resection - Bilio-pancreatic Diversion SURGICAL PROCEDURES - Gastroplexy - Jejunoileal bypass - Extensive small bowel resection - Bilio-pancreatic Diversion MISCELLANEOUS - Abeta/ hypobeta - Weber-Christian Disease - TPN with glucose - Environmental toxins - S. Bowel Diverticulosis MISCELLANEOUS - Abeta/ hypobeta - Weber-Christian Disease - TPN with glucose - Environmental toxins - S. Bowel Diverticulosis

18. Non-Alcoholic Fatty Liver Disease NASH INFLAMMATION STEATOSIS

19. Non-Alcoholic Fatty Liver (NAFL) Type 1 Type 2 Type 3 Type 4 Type 1 Type 2 Type 3 Type 4 - Fat alone - Fat + Inflammation - Fat + Hepatocyte Injury - Fat + Fibrosis and/ or Mallory Bodies - Fat alone - Fat + Inflammation - Fat + Hepatocyte Injury - Fat + Fibrosis and/ or Mallory Bodies

20. NAFLD Activity Score (NASH CRN) Grade Steatosis Inflammation Ballooning Injury Maximum Score Steatosis Inflammation Ballooning Injury Maximum Score 0 - 3 0 - 2 8 0 - 3 0 - 2 8 Histologic Finding NASH Requires a Score of  4 with at least 1 Point from Ballooning Injury NASH Requires a Score of  4 with at least 1 Point from Ballooning Injury

21. WHAT IS NON-ALCOHOLIC?

24. Benefits of Beer Religion Patriot Government Religion Patriot Government 9 Patron Saints Ben Franklin NIAAA 9 Patron Saints Ben Franklin NIAAA

25. Beer Is Proof That God Loves Us And Wants Us To Be Happy Beer Is Proof That God Loves Us And Wants Us To Be Happy - Ben Franklin

26. Relative Mortality (All Causes) Wine Drinkers 0 1-7 8-21 22-35 35 1.6 1.4 1.2 1.0 0.8 0.6 0.4 1.6 1.4 1.2 1.0 0.8 0.6 0.4 Non Wine Drinkers Non Wine Drinkers

28. Risk Factors for Fibrosis in NAFLD OR95%CIP Age, years 1.07 1.04 – 1.08 <0.0001 Diabetes, yes vs. no 2.54 1.75 – 3.69 <0.0001 Alcohol usage, not abstinent vs abstinent 0.53 0.37 – 0.75 0.0004

29. Benefits of Alcohol in NonAlcolic Fatty Liver Disease Improves Insulin Resistance Decreases ALT Less NASH in Bariatric Surgery Pts Less Fibrosis in Nash CRN Improves Insulin Resistance Decreases ALT Less NASH in Bariatric Surgery Pts Less Fibrosis in Nash CRN

30. Practical Conclusions Histologic Definition Fat + Ballooning Degeneration Fat + Fibrosis Exclusion Limit for Daily Alcohol Use 7 units per wk for women 14 units per wk for men Histologic Definition Fat + Ballooning Degeneration Fat + Fibrosis Exclusion Limit for Daily Alcohol Use 7 units per wk for women 14 units per wk for men

31. Non-Alcoholic Fatty Liver Disease What is it? Why is it Important? How do you treat it? What is it? Why is it Important? How do you treat it?

32. The Importance of Any Disease Natural History Prevalence Natural History Prevalence Determined by:

33. Progressive Fibrosis Steatosis Alone Teli (1995) 1/40 Teli (1995) 1/40 (10 Year Follow-Up) Matteoni (1999) 2/49 Matteoni (1999) 2/49 Dam-Larsen (2003) 1/109 Dam-Larsen (2003) 1/109

34. Matteoni Follow-up (n = 174) NASHSteatosisIndeterminant (66) (75)(32) Mortality 16% 2% 0% (LR) Confirmed by Kaplan Meier.0043

35. Natural History of NASH Sub-Acute Failure Sub-Acute Failure CIRRHOSIS HCC Post-OLTX Recurrence Post-OLTX Recurrence Liver Related Death Liver Related Death NASH 20% 30 - 40% (2%) (8%) ? ?

36. Survival (%) 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 0 2 4 6 8 10 12 14 16 Time (years) Expected Observed p = 0.005 Adams, 2005 Survival in NAFLD

37. Time (years) 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 NAFLD patients Reference population NAFLD patients Reference population Ekstedt, 2006 Survival in NAFLD n=129

38. Time (years) 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 Steatosis Reference population Steatosis Reference population Ekstedt,2006 Survival in Steatosis

39. Time (years) 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 NASH Reference population NASH Reference population Ekstedt, 2006 Survival in NASH p<0.01

40. Subjects with NAFLD have a greater than expected mortality compared to matched controls Risk factors for mortality: –Diabetes (p< 0.005) – Age (p < 0.001) –Cirrhosis (p< 0.02) Increased mortality:* –cardiovascular disease – liver disease Adams et al, Gastroenterology, 2005, 129:113-121 * Ekstedt et al, Hepatology, 2006, 44:865-873 * Sanyal et al, Hepatology, 2006, 43:682-689

41. SUMMARY NASH is Not a Benign Disease Cirrhosis Develops in 20-25% of Cases -Liver Related Deaths in 10% The Prevalence is High and Increasing World Wide NASH is Not a Benign Disease Cirrhosis Develops in 20-25% of Cases -Liver Related Deaths in 10% The Prevalence is High and Increasing World Wide

42. The Importance of Any Disease Prevalence Natural History Prevalence Natural History Determined by:

43. Metabolic Syndrome (NHANES III, 1988-1994) OVERALL PREVALENCE 24% Diagnosis Based on Elevated Serum Enzymes

44. Dallas Heart Study Hepatic Triglyceride Content (%) * Hepatic Triglyceride Content (%) * Hepatic Steatosis (%) Hepatic Steatosis (%) All Black White Hispanic All Black White Hispanic 3.6 (2.1 – 6.6) 3.2 (2.0 – 5.3) 3.6 (2.1 – 7.3) 4.6 (2.6 – 10.3) 3.6 (2.1 – 6.6) 3.2 (2.0 – 5.3) 3.6 (2.1 – 7.3) 4.6 (2.6 – 10.3) 31 24 33 45 31 24 33 45 Browning, 2005 * Based on NMR and presented as Median (interquartiles) Subjects

45. Prevalence of NAFLD (Updated) Steatosis 30% Steatosis 30% NASH 6-8% NASH 6-8%

46. Epidemiology of NAFLD USA Italy Japan Taiwan India USA Italy Japan Taiwan India Cases (in millions) Cases (in millions) Country 90 17 78 8 240 90 17 78 8 240 30 37 24.5 30 37 24.5 Prevalence (%) Prevalence (%)

47. SUMMARY NASH is Not a Benign Disease Cirrhosis Develops in 20-25% of Cases -Liver Related Deaths in 10% The Prevalence is High in the United States and Increasing World Wide

48. The Metabolic Syndrome NAFLDDiabetes CancerCardiovascular Metabolic Syndrome

49. Patient Demographics in NAFLD Patients StudyNAge Female Diabetic Obese ↑TGs (%) (%) (%) (%) Matteoni13253 53 3370 92 (1999) Angulo14451 67 2860 27 (1999) Marchesini30442 17 725 3 (2003) Angulo73348 47 3060 60 (2007) NASH CRN 1,26650 64 3162 55 (2010)

50. Metabolic Syndrome BMI Waist(cm) % Hypertension % Low HDL % Hyperglycemia HOMA-R % Metabolic Syndrome(%) Fatty Liver (n=63) NASH (n=110) 28 96 53 57 60 3.2 67 29 100 72 76 91 4.2 88 Marchesini, 2003

51. The Metabolic Syndrome NAFLDDiabetes CancerCardiovascular Metabolic Syndrome

52. NAFLD Age at Diagnosis Females BMI Triglycerides Development of Cirrhosis Liver Related Deaths Age at Diagnosis Females BMI Triglycerides Development of Cirrhosis Liver Related Deaths Diabetes (n=42) Diabetes (n=42) 37 ± 11 67% 31 ± 5 489 ± 312 23.9% 19% 37 ± 11 67% 31 ± 5 489 ± 312 23.9% 19% 54 ± 14 47% 29 ± 6 226 ± 115 10.6% 2% 54 ± 14 47% 29 ± 6 226 ± 115 10.6% 2% NS.04.02.04.05.02 NS.04.02.04.05.02 No Diabetes (n=42) No Diabetes (n=42) P Value

53. The Metabolic Syndrome NAFLDDiabetes CancerCardiovascular Metabolic Syndrome

54. RISK OF CARDIOVASCULAR DISEASE Type 2 Diabetes Odds ratio NAFLD present 1.84 (2.4-2.1) p <.04 1.96(1.4-2.7) p <.001 Adjusted for 1.54 (1.2-1.7) p =.02 Metabolic 1.87 (1.2-2.6) p>.001 Syndrome Targher, 2005,2007

55. Non-Alcoholic Fatty Liver Disease What is it? Why is it Important? How do you treat it? What is it? Why is it Important? How do you treat it?

56. Emerging Therapies Revisit Common Sense Revisit Common Sense Current Strategies Current Strategies New Ideas Diet Supplements Co-Morbidities Diet Supplements Co-Morbidities Insulin Resistance Anti-cytokines Anti-oxidants Insulin Resistance Anti-cytokines Anti-oxidants Inflammation Apoptosis Nuclear Receptor Ligands Inflammation Apoptosis Nuclear Receptor Ligands

57. Weight Loss and NASH Weight Improved Loss(%) Histology Life Style Change 9.3 Yes Control 0.25 No Hepatology 2010;51:121-129

58. Primary Outcome –Vitamin E alone met the pre-specified primary endpoint P< 0.001(P< 0.04) 36/84 NNT=4.4 26/80 NNT= 6.6 16/83

59. Vitamin E for NASH Vitamin E (800 IU/day), but not pioglitazone (30 mg/day), was superior to placebo for histological improvement as defined as the primary outcome Both vitamin E and pioglitazone significantly improved: –Steatohepatitis –Steatosis grade –Inflammation grade –NAFLD activity score Neither drug improved fibrosis scores

60. Prevention of Insulin Mediated Disease Environment / Genes Normal IR OS ObesityDiabetes Hypertension Dyslipidemia Vascular disease Liver disease Cancer National Screening Early Counseling X