1. F ATTY L IVER Shahin Merat, M.D. Associate Professor of Medicine Digestive Disease Research Center, Tehran University of Medical Sciences, 8 th International Congress of Endocrine Disorders Tehran, Oct 2009

2. F ATTY L IVER ( AKA STEATOSIS ) Any amount of fat in liver histology Mirovesicular or macrovesicular With or without inflammation With or without fibrosis Associated with other disease or not Alcohol related or not Alcoholic fatty liver Non alcoholic fatty liver (NAFL) 2

3. N ON -A LCOHOLIC F ATTY L IVER D ISEASE (NAFLD) Defined as: Deposition of fat droplets in hepatocytes AND the absence of significant alcohol intake Generally defined as less than 20gr ethanol per week NAFLD is a range of conditions from near normal liver to cirrhosis 3

4. O THER T ERMS Simple non-alcoholic fatty liver disease (NAFLD) Only deposition of fat in liver No inflammation or fibrosis Non-Alcoholic Steatohepatitis (NASH) NAFLD with inflammation (lobular or portal), hepatocyte ballooning, or fibrosis Absence of serologic evidence of infection with hepatitis B or hepatitis C, … 4

5. NAFLD—S PECTRUM OF D ISEASE Steatosis Steatohepatitis (NASH) NASH with Fibrosis Cirrhosis 5 NAFLD

6. NAFLD, SIMPLE STEATOSIS Fatty Liver Only deposition of fat in liver No inflammation No fibrosis Not believed to progress to cirrhosis Up to 25 % of some populations! 6

7. NAFLD—S TEATOSIS 7 Source: Ibdah 2003

8. NAFLD—NASH ( WITHOUT FIBROSIS ) 8 Source: Ibdah 2003

9. NAFLD—NASH ( WITH FIBROSIS ) Source: Ibdah 2003 9

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11. M ULTIPLE H IT T HEORY 11/22 Normal Liver Fatty Liver Steatohepatitis Cirrhosis Hit 1: ? Insulin resistance, endotoxins, …  Fat accumulation Hit 2: ? Oxidative stress, …  Inflammation Hit 3: ? Oxidative stress, …  Fibrosis May loose fat

12. NAFLD—H ISTOLOGICAL S PECTRUM Macrovesicular Steatosis Lobular Inflammation Fibrosis Cirrhosis Time Progression

13. I MPACT Liver-related death rate: General population: 9.5/100,000 NASH: 11% ! Liver-related deaths were the second most common cause of death in NAFL 13

14. N ATURAL H ISTORY In various follow-up studies (4-18 years) Improved: 0-4% No change: 50-60% Progession: 40-45% Fibrosis: 27% Cirrhosis: 19% Much better than alcoholic hepatitis Approximately 38-50% progress to cirrhosis over seven years 14

15. NAFLD—C LINICAL P REDICTORS Patients at risk to develop NASH with fibrosis: A. Age > 45 B. Obesity (BMI > 31-32) C. Diabetes D. AST/ALT > 1 15

16. S URVIVAL NASH (Hepatology 2001) 5-year all-cause survival: 67% 10-year all-cause survival: 59% Alcoholic hepatitis 5-year survival: 38% 10-year survival: 15% Hepatitis C with compensated cirrhosis 384 cases (Gastroenterology 1997) 5-year survival: 91% 10-year survival: 79% 16

17. H EPATITIS C ( AS A COMPARISON ) 222 cases of Hepatitis C and 377 controls after 25 years of follow-up: (Hepatology 2001) All cause mortality in HCV: 67% In controls: 65% (not significant) 917 women with acute HCV due to contaminated anti-D immune globulin (Hepatology 2000) After 20 yrs: 0.4% cirrhosis Shiraz liver transplant cases (n=207) (2005): Cryptogenic cirrhosis: 23% (most common cause) Hepatitis B: 17% Hepatitis C: 2% 17

19. NASH, E PIDEMIOLOGY ( WORLD ) The most common cause of elevated enzyme levels among asymptomatic patients Only 10% of NAFLD have NASH Among patients who have had liver biopsies, NASH is seen in approximately 7-9% in Western countries 19

20. E PIDEMIOLOGY There are many indications that a large number of patients labeled as cryptogenic cirrhosis have been cases of NASH who have lost indications of NASH. There is evidence that the increased rate of cirrhosis and liver-related death in many conditions such as diabetics and malabsorbtion states (eg celiac disease) is due to NASH 20

21. NASH, P REVALENCE IN I RAN NASH is considered as the hepatic manifestation of the metabolic syndrome (syndrome X). In a large scale study on 10,368 subjects in Tehran, the prevalence of the metabolic syndrome was found to be 30.1% (Azizi et al.) This study did not look to the liver tests or its ultrasonographic appearance, but it can be considered a good estimation of the at-risk population in Iran. 21

22. NASH, P REVALENCE IN I RAN An autopsy series on 895 consecutive deaths from non-medical causes (Sotoudehmanesh et al) 283 (31.6%) had steatosis 19 (2.1%) had steatohepatitis 6.7% of cases of steatosis had steatohepatitis Non had alcohol consumption or diabetes Post-mortem changes ? 22

23. NASH, P REVALENCE IN I RAN 1959 blood donors Subjects with abnormal liver enzymes were invided Further studies performed Viral studies Ultrasonography 2.35% NASH 23

24. NASH, P REVALENCE IN I RAN Only 2.2% of these cases had a BMI of less than 25 Limitations: The population studied was 75.1% male. No histologic confirmation Cases studied were among volunteer blood donors obese subjects are more likely to donate blood high risk subjects are screened out. Nevertheless, this is currently the only published study addressing the prevalence of NASH in Iran’s general population. Another study on 6,000 randomly selected subjects from the general population is on the way 24

25. NASH, D IAGNOSIS Poorly studied Many doctors do not even believe in NASH! Benign compared to other hepatitis One of the most common ways by which NAFLD comes to medical attention is its incidental report during abdominal ultrasonography. Unfortunately some ultrasonographists don’t believe in NAFLD too! 25

26. NASH, D IAGNOSIS Most patients are asymptomatic. Hepatomegaly is the most common physical finding. ALT / AST > 1, usually not so high Ultrasound will demonstrate a fatty or “bright liver.” In CT, the liver is darker than the spleen Liver biopsy is required 26

27. D IAGNOSIS, U LTRASONOGRAPHY Unfortunately many radiologists in Iran do not report mild steatosis Technically unsuitable equipment ? Simple negligence ? They don’t believe in it! 27

28. D IAGNOSIS, U LTRASONOGRAPHY Increased echogenecity of the liver parenchyma, white liver Not the same as coarse echogenicity which is a sign of fibrosis Can be staged to grade I, II, and III according to vascular blurring or visibility of the diaphragm 28

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32. D IAGNOSIS, CT The liver and spleen usually have equal, or near- equal, density In hepatic steatosis the liver is hypodense when compared to the spleen You may see liver angiogram even without contrast injection 32

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34. S UMMARY (1/2) It appears that about 30% of the adult population in Iran is at risk for NAFLD The overweight, obese, and diabetic is more prone. About 10% of these subjects, almost 2-3% of the general adult population, already have NASH. In may be roughly estimated that 10% of NASH cases will progress to cirrhosis. 34

35. S UMMARY (2/2) The prevalence of NASH (2-3%) is comparable to the prevalence of hepatitis B, and much larger than the prevalence of hepatitis C Since hepatitis B is being vaccinated for, we will be seeing less of this disease in the future But obesity is on the rise. (as is hepatitis C) It can be concluded that in the near future, NASH and hepatitis C will be the major liver diseases we will be facing in Iran 35