1. NONALCOHOLIC STEATOHEPATITIS (NASH), NAFLD, ASH J. Horák Department od Medicine I Department od Medicine I Third Faculty of Medicine Third Faculty of Medicine Charles University

2. HEPATIC STEATOSIS macrovesicular in long-standing disorders of hepatic lipid metabolism (obesity, DM type II, alcohol) in long-standing disorders of hepatic lipid metabolism (obesity, DM type II, alcohol)microvesicular impaired ß-oxidation of FA – abnormal metabolism of VLCFA, LCFA, DCA and other substrates for peroxisomal FA-CoA oxidase that activate PPAR-α (peroxisome proliferator- activated receptor)

4. NASH First described by Ludwig et al. (Mayo Clin. Proc. 55, 1980, 434 - 438) NASH is a part of Nonalcoholic Fatty Liver Disease (NAFLD) Defined clinically (alcohol intake < 20 g/day) and histologically; liver biopsy is necessary for reliable diagnosis Predisposing factors: obesity, adult age, diabetes mellitus type II, female sex Lab: AST > ALT, hypertriacylglycerolemia

5. NAFLD Is a result of insulin resistance Histological findings: 1. Simple steatosis 2. Steatosis plus inflammation 3. Steatosis plus balloon degeneration 4. Steatosis, sinusoidal fibrosis and polymorphonuclear cell infiltrate, sometimes together with Malloryho hyaline Only stages 3 and 4 correspond with NASH

6. PREVALENCE Whole population: NAFLD ~ 20% NASH ~ 2 – 3% The highest occurrence of NAFLD: 5th – 6th decade, females (65 – 83%), diabetes mellitus type II (28 – 55%), obesity (60 – 95%), hyperlipidemia (20 – 92%)

7. THE METABOLIC SYNDROME AND NAFLD 67% patients with NAFLD and 88% with NASH have MS MS increases risk of NASH (OR 3.2) and hepatic fibrosis (OR 3.5) prevalence of MS in NAFLD increases with BMI in NAFLD prevalence of NASH increases with BMI ~ 66% patients with NAFLD have hypertriacylglycerolemia Marchesini et al, Hepatology 2003

8. CAUSES OF NAFLD Metabolic syndrome –Insulin resistance is an important part of NAFLD and is found also in patients with normal weight and glucose tolerance –NAFLD increases exponentially přibývá exponenciálně with type II DM, hyperlipidemia, visceral obesity and hypertension Drugs (steroids, amiodaron, diltiazem) Chronic inflammation Total parenteral nutrition Short-bowel syndrome Inborn errors of lipid metabolism (abetalipoproteinemia etc.)

9. ETIOPATHOGENESIS OF NASH (1) Defined causes The initial lesion is simple steatosis; episodes of steatohepatitis lead to cirrhosis (cirrhosis prevalence up to 25%) Insulin resistance of any cause Rapid weight loss in obesity Total parenteral nutrition Drugs and other toxins Jejunoileal bypass TNF-α polymorfisms Copper intoxication

10. ETIOPATHOGENESIS OF NASH (2) NASH might be due to liver lesion in frame of a systemic disease Industrial toxins –dimetylformamid –toxic oil syndrome

11. ETIOPATHOGENESIS OF NASH (3) Drugsamiodaronperhexillin dilthiazem, niphedipin synthetic estrogens, tamoxiphen chloroquinesalicylates glucocorticoids (high doses) tetracycline

12. ETIOPATHOGENESIS OF NASH (4) Others Gluten-sensitive enteropathy Abetalipoproteinemia Wilson disease Colon diverticulosis

13. PATHOGENESIS OF NASH insulin resistance simple hepatic steatosis reactive oxygen species lipid peroxidation NASH ?

14. HISTOLOGY OF NASH steatosis (100%) balloon degeneration of hepatocytes (100%) mild diffuse infiltration by PMNs (56 – 100%) perivenular and perisinusoidal collagen deposition (41 – 100%) cirrhosis (0 – 26%) Mallory hyaline (0 – 90%) glycogen nuclei (35 – 100%) focal necroses (25 – 57%)

17. MINIMAL DEMANDS FOR DIAGNOSIS mainly macrovesicular steatosis mild lobular infiltration by PMNs and mononuclears balloon degeneration of hepatocytes with a maximum around steatotic hepatocytes in zone 3

22. CLINICAL AND LABORATORY FINDINGS Asymptomatic course - in 45 – 100% Symptomes: right epigastric pain, abdominal dyscomfort, fatigue, malaise Objective findings: hepatomegaly (12 – 75%), abnormal liver fubction tests, precoccious atherosclerosis in NASH US, CT, NMR: hepatic steatosis In advanced cases hepatic cirrhosis („cryptogenic“)

23. Adams et al, Gastroenterology, 2005, 129:113-121 NAFLD MORTALITY

24. TREATMENT OF NASH (1) treatment of associated conditions (metabolic syndrome, obesity, hyperglycemia, hyperlipidemia) treatment of associated conditions (metabolic syndrome, obesity, hyperglycemia, hyperlipidemia) aerobic exercise aerobic exercise avoid suspected drugs avoid suspected drugs in terminal stage of cirrhosis liver transplantation in terminal stage of cirrhosis liver transplantation

25. TREATMENT OF NASH (2) UDCA (Ursofalk), N-acetylcystein (ACC), α-tocoferol statines sibutramin (Meridia), orlistat (Xenical) metformin thiazolidindiones – pioglitazone - Actos, rosiglitazone - Avandia

26. TREATMENT OF NASH (3) anti-TNF drugs: pentoxiphyllin, adiponectine phenofibrate In extreme obesity (BMI > 40 or BMI > 35 + risk factors): bariatric surgery

27. NASH: before and after treatment with pioglitazone + vitamin E Sanyal et al, Clin Gastroenterol and Hepatol, Dec 2004 Pre treatment (10 X)Post treatment (10 X)