ALKOHOL INDUZIERTE HEPATITIS: PATHOPHYSIOLOGIE UND BEHANDLUNG

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1 ALKOHOL INDUZIERTE HEPATITIS: PATHOPHYSIOLOGIE UND BEHANDLUNG Helmut K. Seitz Zentrum für Alkoholforschung, Lebererkrankungen und Ernährung, Krankenhaus Salem und Universität Heidelberg Falk Symposium 157 : Chronische Hepatitis: metabolisch, cholestatisch, viral und autoimmun Oktober 2006, Freiburg

2 NATURAL COURSE OF ALCOHOLIC LIVER DISEASE Alcohol Normal Liver Alcoholic Fatty Liver ( %) Alcoholic Steato Hepatitis (ASH) (10-35 %) Diet, Genetics, Female gender Alcoholic Cirrhosis (8-20 %) Hepatocellular Cancer (1-2 % p.a.)

3 AFL ASH

4 PATHOGENESIS OF ALCOHOLIC FATTY LIVER AND INFLAMMATION HSF AMP-K Ethanol Acetaldehyde NAD+ ß -OXIDATION GUT FATTY TISSUE Chylomicrones FFA Homocysteine ER-STRESS NADH Acetyl-CoA Cell-Injury Inflammation Endotoxins CYP2E1 FFA ROS ω-oxidation TG IKK-β/NF κ B Activation TNF-α β-oxidation ETHANOL Interleukines Osteopontin Cathepsin B Release PPAR-α VLDL Cholindeficiency MTTP-Defect SREBP-1c Microtubules AA

5 ENDOTOXIN AND ALCOHOLIC LIVER DISEASE GUT BACTERIA + ETHANOL ANTIBIOTICS PROBIOTICS Acetaldehyde Endotoxins ESTROGENS? Fibrosis Hypoxia TGF ß Chemokines Cytokines LPS TLR4/CD14 KC POLYMORPHISM IL-1, 4, 6, 8, 10 TNF α THERAPY TNF α-r Necrosis Apoptosis NF- K B

6 ROLE OF CYP2E1 IN ALCOHOLIC LIVER DISEASE Aceton Ethanol FFA CYP2E1 CYP2E1 AB Chlormethiazole Ethanol Acetaldehyde ROS Fibrogenesis PUFA (Fishoil) Lipids Lipidperoxidation Cell-Injury LPP (4-Hydroxy Nonenal) Carcinogenesis

7 DYNAMICS OF CYP2E1 INDUCTION AND DISAPEARANCE Oneta C, Lieber CS, Ji JJ, Rüttiman S, Rosman J, Seitz HK. J-Hepatol 2002;36:47-52

8 Glassen B, Seitz HK 2006

9 PROGRESSION ON FATTY LIVER ETHANOL FATTY TISSUE IR FATTY LIVER CYP2E1 FFA ETHANOL ENDOTOXINS KC TNFα ROS IRON ETHANOL APOPTOSIS PROLIFERATION SURVIVAL FACTOR NECROSIS FIBROSIS CANCER HEPATITIS CIRRHOSIS

10 GENETIC RISK FACTORS FOR ALD Gene Disease Effect References ADH1B Ethanol consumption + multiple studies ADH 1C HCC + Homann et al ALDH2 Cirrhosis + Enomoto et al.1991 TNFα ASH Grove et al.1997 Bathgate et al Ladero et al IL-10 ALD + - Grove et al Ladero et al CD 14 ASH/Cirrhosis + Järvelainen et al MnSOD Steatosis, ASH + Degoul et al Steward et al. 2002

11 Obesity Fat

12 EFFECT OF GENDER ON THE DEVELOPMENT OF ADVANCED ALD Author Krassner et al Pares et al Marbet et al Time of observation (years) Progression from ASH to cirrhosis male (%) Stop drinking female (%) 50 62

13 PROGNOSIS Discriminant function (DF) 1) 4,6 x (PTT patient PTT control ) + bilirubin (mg%) 32 = 1 month mortality 50 % MELD 2) 9,57 x log e (crea mg%) + 3,78 x log e (bili mg%) + 11,2 x log e (INR) + 6,43 21 = 3 month mortality 20 % 1) Maddrey et al. Gastroenterology 75,193:1978 2) Wiesner et al. Gastroenterology 124,91:2003

14 GLASGOW ALCOHOLIC HEPATITIS SCORE AGE 1 < 50 SCORE 2 > WCC (10 9 /l) < 15 > 15 - Urea (mmol/l) < 5 > 5 - PT ratio < > 2.0 Bilirubin (mg%) < > 14.5 OVERALL ACCURACY OUTCOME ON DAY 84 day 1 GAHS vs. DF day 6-9 (Forrest et al.gut 2005;54: ) 75 % vs. 53 % 78 % vs. 57 %

15 THERAPY OF ASH. ABSTINENCE. NUTRITIONAL THERAPY

16 NUTRITIONAL THERAPY IN ASH (oral/enteral) Cabré et al., Hepatology 32 (2000) RCT (n = 71) severe ASH: NGT 2000 kcal/d 72 g prot./d vs. standard diet (1g prot./d) + 40 g prednisolone 1-year follow up mortality : TEN 8 % PRED 37 % (p = 0.04) 8 drop outs in TEN

17 PARENTERAL NUTRITION 7 RCTs ; n = days outcome: Improvement in albumine and nitrogen balance. No survival benefit.

18 NUTRITIONAL THERAPY Established Oral/enteral nutrition: improves malnutrition and complication rate (A), influence on ASH parenteral nutrition mortality questionable (B) Enteral branched-chain nutrition through amino NG-tube tube: acidseffective, complications not elevated, poor compliance (B) anabolic steroids Parenteral nutrition: insufficient data No advantage on survival by vitamin supplementation Stickel F., Hoehn B., Schuppan D., Seitz HK., Aliment Pharm Ther 2003;18:357

19 THERAPY OF ASH. ABSTINENCE. NUTRITIONAL THERAPY. DRUGS - ANTIOXIDANTS

20 THERAPY OF ASH. ABSTINENCE. NUTRITIONAL THERAPY. DRUGS - ANTIOXIDANTS -STEROIDS

21 THERAPY OF ASH WITH GLUCOCORTICOSTEROIDS Glucocorticosteroids Kupffer cells neutrophilic granulocyts proinflammatory cytokines (TNFα, TGFβ,, IL-1, IL-8) humoral immun response (acetaldehyde adducts)

22 EFFECTIVENESS OF GLUCOCORTICOSTEROIDS IN ASH Metaanalysis: therapeutic benefit (Imperiale & McCullough, Ann Int Med 1990;113:299) Metaanalysis: no therapeutic benefit (Christensen & Gluud,, Gut 1995;37:113) Metaanalysis: therapeutic benefit (Mathurin et al., J Hepatol 2002;36:480)

23 CORTICOSTEROIDS IN ASH Corticosteroids seem to be effective in a subgroup of patients with ASH No G.I. bleeding. No infection Severe ASH with DF > 32 Early change in bilirubin predicts response to treatment Major complication sepsis

24 THERAPY OF ASH. ABSTINENCE. NUTRITIONAL THERAPY. DRUGS - ANTIOXIDANTS -STEROIDS - PENTOXIFYLLINE

25 PENTOXIFYLLINE IN ASH: CLINICAL STUDY Design: Pat. with ASH (DF > 32) double-blind, blind, placebo-controlled controlled TX 3 x 400 mg/ d for 28 days Primary endpoint: short-time time survival,, HRS Results: improved survival by PTX, mainly due to reduction of HRS Suppression of TNFa Effect exceeds expected benefit by glucocorticosteroids % days mortality p = 0,037 PTX CTR Akriviadis et al., Gastroenterology2000;119:1637

26 THERAPY OF ASH. ABSTINENCE. NUTRITIONAL THERAPY. DRUGS - ANTIOXIDANTS -STEROIDS - PENTOXIFYLLINE -TNF-α ANTIBODY

27 TNF-α ANTIBODYTHERAPY IN ASH Spahr et al. J Hep 37,448:2002 Patients Therapy Results 20 (DF > 32, biopsy proven) Infliximab 5 mg/kg b. wt mg prednisone no survival difference decrease in IL6, IL8 and DF Tilg et al. J Hep 38, 415:2003 Patients Therapy 12 (DF > 32, biopsy proven) Infliximab 5 mg/kg b.wt Norfloxacin (Ascites) Results Survival (15 months) 10/12 (83 %) 2 deaths due to septicemia

28 TNF-α ANTIBODYTHERAPY IN ASH Patients 36 (DF > 32) Therapy 40 mg prednisolone (28 days) + 3x (week 0,2,4) 10 mg/kg infliximab vs 40 mg prednisolone (28 days) + placebo Results Mortality 39 % vs. 18 % (NS) Mortality due to infections 22 % vs. 11 % Severe infections 83 % vs. 28 % (pc 0.002) no difference in DF at any time Naveau et al., Hepatology 39, 1390:2004

29 PROBLEMS 1. Dosis 5 mg/kg b.wt. vs. 3 x 10 mg/kg b.wt. 2. Combined therapy with steroids 3. Different degrees of severity of ASH DF: 70 ± 15 (severe infections) 37 ± 18 (remaining patients) Tilg-study: DF: 54 Spahr-study: DF: 39

30 ETANERCEPT THERAPY IN ASH. Etanercept: soluble TNF-receptor: FC Fusion protein. 13 patients with ASH (DF > 15 and/or HE). 2 weeks treatment. 32 mg/kg b.wt. as loadine dose followed by 25 mg s.c. a day 4, 8 and 12 RESULTS: 30 day survival = 92 % 90 day suvival = 83 % Adverse Effects = 23 % Menon et al. Am J Gastroenterol 99,255,2004

31 THERAPY OF ASH. ABSTINENCE. NUTRITIONAL THERAPY. DRUGS - ANTIOXIDANTS -STEROIDS -PENTOXIFYLLINE -TNF-α ANTIBODY. EXTRACORPOREAL DETOXIFICATION (MARS)

32 MARS AND ASH 8 Patients (all HE, 5 HRS 1, 2 HRS 2) 5 HRS1 2HRS2 2 (<30 Tage) 1 (<90 Tage) 1 OLT (21 Tage) 1 alive (90 Tage) 1 alive (90 Tage) mortality 50%/63% No HRS alive (90 Tage) Predicted mortality 90 days (MELD) 76 % Jalan et al. J Hep 38,24-31:2003

33 THERAPY OF ASH. ABSTINENCE. NUTRITIONAL THERAPY. DRUGS - ANTIOXIDANTS -STEROIDS - PENTOXIFYLLINE -TNF-α ANTIBODY. EXTRACORPOREAL DETOXIFICATION (MARS). LIVER TRANSPLANTATION

34 LIVER TRANSPLANTATION IN ALCOHOLIC LlVER DISEASE Tome et al. J Hep 36,793,2002

35 FUTURE PERSPECTIVES 1. Antiinflammatory compounds IL10, thalidomid (Kupffer cell sensibilization) 2. Misoprostol (down regulation of TNF-a production) 3. Adiponectin (AMP activated kinase) 4. CYP2E1 inhibitors (chlomethiazole!) 5. PPAR α stimulation (Wy 14,643) 6. IKK-β inhibitors (aspirin)

36 CONCLUSION I 1. Major pathophysiological factors in ASH are the production of fatty liver due to various ethanol associated mechanisms, oxidative stress predominantly generated by CYP2E1 and TNF-a mainly from Kupffer cells. 2. Diets (polyunsaturated vs. saturated fat) may modulate pathogenesis. Obesity and female gender are risk factors.

37 CONCLUSION II 3. Therapy of ASH includes abstinence, nutritional therapy as well as drug therapy. A subgroup of patients with severe ASH (DF>32) jaundice and encephalopathy may respond to steroids with an increased survival. Early change in bilirubin levels may be predictor for response. Pentoxifylline has also improved survival by reducing hepatorenal syndrome, however, this needs further confirmation. Data on the effect of TNF alpha antibodies are controversial and need reconsideration.

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40 ETHANOL METABOLISM AND ALCOHOLIC LIVER DISEASE Toxicity Proliferation Carcinogenesis COX2 Prostaglandins Drugs, Retinoids, Carcinogen DNA-Damage Lipidperoxidation Arachidonic Acid ROS Oxidized proteins Proteinbinding loss of function neoantigens Metabolite O 2 CYP2E1 Hypoxia Fatty Liver Blood flow Ethanol NAD + ADH Acetaldehyde NADH Mitochondrial Damage Apoptosis NF- K B ALDH Glutathion Polymorphism MnSOD Acetate Methyl-Transfer Carcinogenesis Phospholipids (Membrane Alteration)

41 COMPARISON OF EXPERIMENTAL NASH WITH ASH PATHOGENESIS Lipogenic factors PPARγ, LXRα, SREBP1c Lipolytic factors PPARα PPARβ PTEN AMPK TNF α IL-1β CYP2E1 ETHANOL (35%) NAFLD Tsukamoto et al., ACER 30 (Suppl)89A:2006

42 ENCEPHALOPATHY AND ASCITES 90 DAYS MORTALITY E A days mortality Dunn et al. Hepatology 41, 353: 2005

43 ANTIOXIDANTS 1. Mezey et al., J. Hepatol. 40 (2004) Vitamin E (1000 IU) per day has no beneficial effect on hepatic function or mortality in patients with mild to moderate AH (DF ca. 19) 2. Phillips et al., J. Hepatol. 44 (2006) Antioxidant Vit. C / Vit. E / Se / methionine / allopurinol / desferrioxamine/ N-acetylcystein / β-carotin vs 30 mg predisolone In 101 patients with severe AH (DF ca. 60) for 1 month mortality AO vs CS 46 % vs. 30 % (p = 0.05)

44 PENTOXIFYLLINE non-selective phosphodiesterase inhibitor improves rheology and therefore used for peripheral arterial occlusive disease inhibits synthesis and liberation of TNF α decreases granolocyte activation and lymphocyte proliferation antifibrotic effect in animal experiments (Raetsch et al., Gut 2002, 50: 241)