Alcoholic Hepatitis. Christian Doppler Research Laboratory for Gut Inflammation Medical University Innsbruck. Herbert Tilg

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1 Alcoholic Hepatitis Christian Doppler Research Laboratory for Gut Inflammation Medical University Innsbruck Herbert Tilg

2 Overview Background I: Alcoholic steatohepatitis (ASH) is a severe and often life-threatening disease Background II: Treatment of this disease is still not satisfactory although corticosteroids show some efficacy in certain patient groups Background III: Immunopathogenesis better understood Pro-inflammatory cytokines play a critical role New-anti-inflammatory strategies needed

3 Alcoholic steatohepatitis (ASH) - a prototypic cytokine-driven disease Abnormal production of cytokines/mediators that regulate inflammatory responses inflammatory ANTIinflammatory PRO-

4 Pathophysiology of ASH Chronic Alcoholic Liver Disease Modulating influence, e.g. Endotoxaemia Kupffer Cell Activation of Neutrophil activation Neutrophil Recruitment Pro-inflammatory Cytokines IL-8 production INFLAMMATORY RESPONSE HEPATOCYTE INJURY

5 Clinical and laboratory signs of ASH Fever (typically modest) Hepatomegaly Jaundice Anorexia Coagulopathy Encephalopathy Leukocytosis (correlates with severity of hepatocyte injury) AST/ALT < 400 IU/L

6 Aggravating factors: risk factors for serious liver damage Polymorphisms in alcohol-metabolizing enzymes (?) Obesity Exposure to other hepatotoxins (e.g. acetaminophen) Hepatitis C virus infection

7 Diagnosis of ASH Clinical and laboratory features often adequate for diagnosis Biopsy: (i) in patients who have evidence of liver failure and high transaminases (> 400 IU/L) (ii) more than one type of liver disease (e.g. hepatitis C) (iii) clinical studies

8 Discriminant Function Formula (DF) (Maddrey Score) Defines severity and mortality risk DF = (4.6 x (prothrombin time - control PT) + (serum bilirubin)) DF > 32 associated with high short-term mortality

9 New scores: how to assess severity? The Lille Model (Hepatology 2007) 320 patients with severe ASH and steroid treatment studied Model combines six reproducible variables: age, renal insufficiency, albumin, prothrombin time, bilirubin and evolution of bilirubin at day 7 Area under the receiver operating characteristic curve (AUROC) higher than Child-Pugh classification, MELD and Glasgow scores a better score?

10 Which Clinical Score should be used? Maddrey Glasgow Lille MELD Child-Pugh we do not know!

11 General Management (1) Treatment of alcohol withdrawal (benzodiazepines) Administration of fluid, calories, vitamins (vitamin K, thiamine, folate) and minerals Airway protection (encephalopathy) Managment of ascites (paracentesis, cultures)

12 General Management (1) Prompt antibiotic treatment in case of proven infection Fresh frozen plasma (only if active hemorrhage) Nutritional therapy, correction of preexisting protein calorie malnutrition

13 Treatment of ASH Mortality in severe ASH: 30-50% Current therapeutic options Corticosteroids: Daures et al, Gastroenterol Clin Biol 1991 Ramond et al, NEJM 1992; Christensen et al, GUT 1995 Imperiale et al, Ann Intern Med 1990 Mathurin P et al, J Hepatol 2002 Rambaldi A et al. APT 2008 Pentoxifylline:? Shakil et al, Gastroenterology 2000 Louvet A et al, J Hepatol 2008

14 Corticosteroids in ASH Most intensively studied treatment option (15 controlled trials) Several controlled trials produced variable results Meta-analyses to date failed to show a clear benefit of such therapies (heterogeneity of studies!)

15 Predictive parameters for steroid response? Early change in bilirubin levels Mathurin P, Hepatology patients studied; 6-months survival as endpoint Early change in bilirubin levels (ECBL) at 7 days (defined as levels lower than at treatment start) was observed in 73% After 6-months survival of patients with ECBL was 83% vs 23% ECBL had the most important prognostic value Treatment reconsideration on day 7?

16 Corticosteroids in ASH: Recent meta-analysis Rambaldi A et al, APT 2008 Randomized trials published before July trials, 721 patients; overall mortality rate 40% 12/15 trials at risk of bias Corticosteroids did not reduce mortality compared to placebo or no intervention Benefit: DF > 32, encephalopathy? Conclusion: current evidence base of mainly heterogenous with high bias risk trials does not support the use of corticosteroids in alcoholic hepatitis!

17 Which patient may benefit from Corticosteroids? ECBL DF > 32 and encephalopathy Mortality in steroid-treated patients still high (up to 40%) 40 mg Prednisolone daily for 4 weeks and then tapering Prednisolone preferred to prednisone (requires conversion to prednisolone in the liver)

18 Nutritional Therapy in ASH Evaluated in many clinical trials Several studies have reported improvement in liver function and histology Protein should not be restricted in patients with alcoholic hepatitis (use as tolerated) In case of encephalopathy, use branchedchain amino acids

19 Steroids versus Enteral Nutrition: Effects on Survival Cabre et al, Hepatology 2000

20 Nrf2 prevents alcohol-induced fulminant liver injury Lamle J et al, Gastroenterology 2008 Nuclear factor-erythroid 2-related factor 2 (Nrf2): essential transcription factor protecting cells against oxidative stress Nrf2 -/- mice are extremely sensitive against ethanol and die rapidly of liver failure Activation of TNFα, IL-6 and Stat3 Central role for Nrf2 in the protection against ethanol-induced liver injury

21 Antioxidants vs Corticosteroids in ASH Phillips et al, J Hepatol patients; antioxidants versus steroids Primary endpoint 30-day mortality At 30-days 16 deaths (30%) in the steroid group versus 22 deaths (46%) in the antioxidant group (P=0.05) Odds of dying by 30 days 2.4 greater for patients on antioxidants Survival advantage lost at 1 year follow-up

22 A randomized trial of antioxidants alone or with corticosteroids in ASH Stewart et al, J Hepatol 2007 N-acetyl cysteine for 1 week; vitamins A-E, biotin, selenium, zinc, manganese, copper, folic acid and Coenzyme Q for 6 months 36 received active drug, 34 placebo (all steroids) Predictors of survival: initial bilirubin, white cell count, and age NO effect on 6-month survival

23 The cytokine concept of ASH Transition into clinical reality? Pentoxifylline: A cytokine modulating drug? Anti-TNF treatment: a concept loosing its attraction?

24 Pathophysiological relevance of cytokines in liver disease Tilg H, Diehl AM. New Engl J Med 2000

25 Cytokine studies in patients with ASH Increased serum/plasma levels of various cytokines (Steatohepatitis) Decreased levels after achieving clinical remission (Steatohepatitis) Levels correlate with mortality Levels of TNF and TNF soluble receptors correlate with amount of endotoxemia

26 Role of TNF in mouse models (A) wild-type mice, (B) TNF-R1 knockout mice, (C) wild-type mice and (D) TNF-R1 knockout mice given an ethanol diet. E and F show inflammation and necrosis in wild-type animals fed ethanol; G and H depict no inflammation or necrosis in TNF-R1- deficient mice fed ethanol.

27 Pentoxifylline in severe ASH Survival curves for the PTX-treated (solid line) and control (dotted line) groups 101 patients 4-week treatment Short-term survival: 24.5% vs 46.1% Akriviadis et al, Gastroenterology 2000

28 Early switch to pentoxifylline in corticosteroid non-responders Louvet A et al, J Hepatol non-responders treated with PTX vs 58 matched non-responders treated with corticosteroids alone PTX treatment for 1 month No survival improvement at 2 months Non-responders to corticosteroids do not benefit from consecutive therapy wit PTX

29 Pilot study of Infliximab in severe ASH Aims Clinical Tolerability Adverse Effects Biochemistry Cytokine Response A single dose of Infliximab (Remicade, 5mg/Kg) in patients with Severe Alcoholic Hepatitis Tilg H, J Hepatol 2003

30 Total bilirubin levels after Inflixmab

31 White blood cell counts after Infliximab

32 Liver cytokine mrna expression

33 Liver Histology after Infliximab d0 d28

34 Summary of our pilot study 10/12 patients survived (median 12 months; range 6-18) 2 patients died within the first month too due infectious complications (staphyloccoccal infection, candida septicemia)

35 Infliximab in ASH: A French Mulitcentre Study Naveau S et al, Hepatology 2004 Prednisone 40 mg/kg + infliximab (10 mg/kg KG; weeks 0, 2 und 4) End-point: 2-month mortality After inclusion of 36 patients interim analysis 2-fold increase of death in the infliximab group (NS) Frequency of severe infections within 2 months significantly higher in the infliximab/prednisone group Criticism: extremely high infliximab dose!

36 Etanercept: controlled study in ASH Boetticher NC et al, Gastroenterology 2008; 134: A-765 Randomized, placebo-controlled trial Etanercept, twice weekly for 3 weeks Moderate to severe AH (MELD score > 15) Mortality 1 month: no difference Mortality 6 months: higher in the etanercept group (58% vs 23%)... End of the anti-tnf concept?

37 Neutrophil dysfunction in ASH Mookerjee RP et al. Hepatology 2007 Neutrophil oxidative burst and function assessed by FACS analysis in patients with cirrhosis +/- ASH Ex vivo studies with removal of endotoxin restored neutrophil dysfunction (decreased oxidative burst and increased phagocytosis) Endotoxin may be a driving force in neutrophil dysfunction is it more an infectious disease?

38 Hepatic expression of candidate genes in patients with ASH ASH (n=23), normal livers (n=6) 46 genes studied Genes involved in fibrogenesis, inflammatory response, and oxidative stress overexpressed Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were markedly upregulated; many targets for potential therapies? Colmenero J. Gastroenterology 2006

39 Hepatic expression of candidate genes in patients with ASH ASH (n=8), alcoholic steatosis (ASH, n=9), controls (n=7) ASH 211 differently expressed genes from that of controls ASH: claudins, osteopontin, CD209, selenoprotein, genes related to bile duct proliferation, IL-8 Seth D et al, J Hepatol 2006

40 Tilg H, Day CP. Nat Clin Pract Gastroenterol Hepatol 2007

41 Potential beneficial treatments in patients with severe ASH Prevention of gutderived endotoxemia (Antibiotics, lactobacillus) Inhibition of TNFα activity (Anti-TNF antibodies, TNF receptor antagonists, Pentoxifylline)? Generalized inhibition of inflammation (Glucocorticoids) Decrease in reactive oxygen species production: Glutathione prodrugs (S-adenosyl methionine, betaine, choline, vitamin E, silymarin, propylthiouracil) Enhancing neutrophil function or correcting its defects? Probiotics?

42 Conclusions Common disease with high mortality and no satisfactory, established therapy Better understanding of immunopathogenesis may lead to new therapies targeting selective inflammatory pathways e.g. anti-tnf approaches? More basic and clinical research urgently needed in this neglected disease to define new potential therapies