Mohssen Nassiri Toosi, MD Associated Professor of Internal Medicine Imam Khomini Hospital

1. Mohssen Nassiri Toosi, MD Associated Professor of Internal Medicine Imam Khomini Hospital TUMS, Tehran, Iran mohsen_nasiri@yahoo.com

2. Terminology Brief History of Non-AlcoholicFattyLiverDisease (NAFLD) NASH was first described by Ludwiget al (1980) by two main diagnostic criteria: 1. fatty changes with lobular hepatitis on liver biopsy, 2. absence of alcoholism • 1980~ 8 papers published • 1998 First NIH conference • 1999 First Clinical Trials • 2002~ 60 papers published • Release of first book on NAFLD / NASH • 2005~ 354 papers published

3. Terminology Non-AlcoholicFattyLiverDisease (NAFLD) A young syndrome of some common clinico-pathological features Non-Alcoholic Fatty liver (NAFL) (Steatosis) Fibrosis Cryptogenic Cirrhosis Non-Alcoholic Steatohepatitis (NASH)

4. Terminology • Non-AlcoholicFattyLiverDisease • (NAFLD) • A clinico-pathologic term • Clinical: • Liver abnormality in lack of significant alcohol consumption • Exclusion of other liver dis. (HBV / HCV infection) • Pathological: • Liver biopsy with histologic spectrum of liver damage • NAFL (Only moderate to gross macrovesicular fatty change) • NASH (Steatosis + inflammation ± mallory bodies or fibrosis) • Cirrhosis (regenerative nodules + fibrosis)

5. Terminology Steatosis, macro > micro accentuated in zone 3 Mild scattered PMN, monocytes, ballooning near steatotic liver cells, in zone 3 simple steatosis + lobular inflammation + ballooned hepatocytes + mallory hyaline or fibrosis Zone 3 Perisinusoidal / pericellular fibrosis Periportal / bridging fibrosis

6. Terminology

7. Terminology

8. Terminology No clinical or histopathological "markers," predicting risk for progression

9. Terminology

10. Epidemiology obesity NAFLD diabetes dyslipidemia • NAFLD the epidemic and its cause 1998

11. Terminology Non-AlcoholicFattyLiverDisease NAFLD, Walking To Death Cirrhosis Non-AlcoholicSteatoHepatitis with fibrosis (NASH) Non-AlcoholicSteatoHepatitis (NASH) Non-AlcoholicFattyLiver Disease (NAFLD) Epidemics of obesity, type 2 diabetes and dyslipidemias

12. Terminology • Non-AlcoholicFattyLiverDisease • (NAFLD) • Common , but underappreciated liver disease • Relatively recent coining of terms (1998) • Clinico-pathologic term need liver biopsy for definitive diagnosis • Lack of consensus regarding histologic diagnosis / management • Indolent nature of the disease

13. Epidemiology • NAFLD the epidemic and its cause • Obesity is the single most common consistent association with NAFLD. • A high degree of correlation between total fat mass and severity of hepatic steatosis and fibrosis has been reported. • Abnormal regional body fat by an elevated waist-hip ratio is predictor of hepatic steatosis. • Weight loss has been shown to result in biochemical and histological improvement in patients with NAFLD.

14. Epidemiology Non-AlcoholicFattyLiverDisease (NAFLD) A new disease or A consequence of recent obesity epidemic

15. Epidemiology Human ages – Old time

16. Epidemiology Human ages – Old time

17. Epidemiology Human ages – New time

18. Epidemiology • NAFLD the epidemic and its cause

19. Epidemiology • NAFLD the epidemic and its cause

20. Epidemiology • NAFLD the epidemic and its cause Human ages

21. How common is NAFLD? • The most common cause of abnormal liver function tests. • Affect 10 - 24% of population • 58-74% obese population • Affect 2.6% of children • 23-53% obese children • 10% NAFLD and 1% NASH in population predisposing to cirrhosis and HCC. Epidemiology

22. Epidemiology

23. Epidemiology

24. Epidemiology

25. Epidemiology

26. Epidemiology

28. Epidemiology

29. How common is NAFLD? Epidemiology CDC estimates of incidence of HCV and obesity in US, 1982–2000.

30. Epidemiology How common is NAFLD? Projected relative frequencies of NASH and HCV as indications for liver transplantation (LT).

31. Epidemiology

32. Epidemiology

33. Non-AlcoholicFattyLiverDisease (NAFLD) Conditions associated with steatohepatitis Primary conditions Secondary causes • TPN, Refeeding syndrome • Severe weight loss • a. Jejunoileal bypass • b. Gastric bypass* • c. Severe starvation • IBD, HCV, Wilson, • Iatrogenic, or toxic exposure • Amiodarone Valporic acid • Diltiazem Aspirin • Tamoxifen MTX • Steroids Tetracyclin • Antiretroviral therapy • Environmental toxins • Workplace toxins or solvents • MetabolicSyndrome • Obesity • Diabetes • Hypertriglyceridemia • Hypertension • Disordersoflipidmetabolism • Abetalipoproteinemia • Hypobetalipoproteinemia • lipoathrophy

34. Non-AlcoholicFattyLiverDisease (NAFLD) Pathogenesis The Two-Hit Hypothesis Predisposition FIRST HIT: Obesity, diabetes, etc Development of fatty liver SECOND HIT: Free radicals STEATOHEPATITIS

35. Pathophysiology

36. Pathophysiology

40. Pathophysiology

41. Pathophysiology

42. Pathophysiology Diabetes (34-75%) Abdominal obesity (69-100%) NAFLD Hypertension Dyslipidemia (20-80%) 2007 The Deadly Quartet Metabolic Syndrome Insulin resistance syndrome Obesity dyslipidemia syndrome

43. Non-AlcoholicFattyLiverDisease • (NAFLD) • This underappreciating would be change • NAFLD recognized as a common liver disease • May affect otherwise lean, healthy patients • May result in cirrhosis and even HCC • One major cause of liver transplantation

44. Thank you for your attention

46. Epidemiology

47. Epidemiology