Alcoholic Hepatitis

Christian Doppler Research Laboratory for Gut Inflammation

Medical University Innsbruck

Herbert Tilg

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

Abnormal production ofcytokines/mediators that

regulate inflammatory responses

PRO-

inflammatory

ANTI-

inflammatory

Alcoholic steatohepatitis (ASH) -a prototypic „cytokine-driven“ disease

Chronic Alcoholic Liver Disease

Modulating influence,e.g. Endotoxaemia

Kupffer Cell

Activation of

Pro-inflammatory Cytokines

INFLAMMATORY RESPONSE

HEPATOCYTE INJURY

IL-8 production

NeutrophilRecruitment

Neutrophilactivation

Pathophysiology of ASH

• Fever (typicallymodest)

• Hepatomegaly• Jaundice• Anorexia• Coagulopathy

• Encephalopathy• Leukocytosis

(correlates withseverity of hepatocyte injury)

• AST/ALT < 400 IU/L

Clinical and laboratory signs of ASH

• Polymorphisms in alcohol-metabolizingenzymes (?)

• Obesity• Exposure to other hepatotoxins (e.g.

acetaminophen)• Hepatitis C virus infection

Aggravating factors: risk factors forserious liver damage

• Clinical and laboratory features oftenadequate 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

Diagnosis of ASH

• Defines severity and mortality risk• DF = (4.6 x (prothrombin time - control PT)

+ (serum bilirubin))• DF > 32 associated with high short-term

mortality

Discriminant Function Formula (DF)(Maddrey Score)

• 320 patients with severe ASH and steroidtreatment studied

• Model combines six reproduciblevariables: age, renal insufficiency, albumin, prothrombin time, bilirubin and evolution of bilirubin at day 7

• Area under the receiver operatingcharacteristic curve (AUROC) higher thanChild-Pugh classification, MELD and Glasgow scores … a better score?

New scores: how to assess severity?The Lille Model (Hepatology 2007)

• Maddrey• Glasgow• Lille• MELD• Child-Pugh

• … we do not know!

Which Clinical Score should be used?

• Treatment of alcohol withdrawal(benzodiazepines)

• Administration of fluid, calories, vitamins(vitamin K, thiamine, folate) and minerals

• Airway protection (encephalopathy)• Managment of ascites (paracentesis,

cultures)

General Management (1)

• Prompt antibiotic treatment in case of proven infection

• Fresh frozen plasma (only if activehemorrhage)

• Nutritional therapy, correction of pre-existing protein calorie malnutrition

General Management (1)

• 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

Treatment of 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!)

Corticosteroids in ASH

• 238 patients studied; 6-months survival as end-point

• 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 prognosticvalue

• Treatment reconsideration on day 7?

Predictive parameters for steroid response?Early change in bilirubin levels

Mathurin P, Hepatology 2003

• Randomized trials published before July 2007• 15 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 notsupport the use of corticosteroids in alcoholichepatitis!

Corticosteroids in ASH: Recent meta-analysisRambaldi A et al, APT 2008

• 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)

Which patient may benefit from Corticosteroids?

• 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 branched-

chain amino acids

Nutritional Therapy in ASH

Steroids versus Enteral Nutrition:Effects on Survival

Cabre et al, Hepatology 2000

• Nuclear factor-erythroid 2-related factor 2 (Nrf2): essential transcription factorprotecting cells against oxidative stress

• Nrf2 -/- mice are extremely sensitive against ethanol and die rapidly of liverfailure

• Activation of TNFα, IL-6 and Stat3• Central role for Nrf2 in the protection

against ethanol-induced liver injury

Nrf2 prevents alcohol-induced fulminant liver injuryLamle J et al, Gastroenterology 2008

• 101 patients; antioxidants versus steroids• Primary endpoint 30-day mortality• At 30-days 16 deaths (30%) in the steroid

group versus 22 deaths (46%) in theantioxidant group (P=0.05)

• Odds of dying by 30 days 2.4 greaterfor patients on antioxidants

• Survival advantage lost at 1 year follow-up

Antioxidants vs Corticosteroids in ASHPhillips et al, J Hepatol 2006

• 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, whitecell count, and age

• NO effect on 6-month survival

A randomized trial of antioxidants aloneor with corticosteroids in ASH

Stewart et al, J Hepatol 2007

• Transition into clinical reality?• Pentoxifylline: A cytokine modulating

drug?• Anti-TNF treatment: a concept loosing

its attraction?

The cytokine concept of ASH

Pathophysiological relevance of cytokinesin liver disease

Tilg H, Diehl AM. New Engl J Med 2000

• Increased serum/plasma levels of various cytokines (Steatohepatitis)

• Decreased levels after achievingclinical remission (Steatohepatitis)

• Levels correlate with mortality• Levels of TNF and TNF soluble

receptors correlate with amount of endotoxemia

Cytokine studies in patients with ASH

(A) wild-type mice, (B) TNF-R1 knockout mice, (C) wild-type miceand (D) TNF-R1 knockout mice given an ethanol diet.

E and F show inflammation and necrosis in wild-type animals fedethanol; G and H depict no inflammation or necrosis in TNF-R1-

deficient mice fed ethanol.

Role of TNF in mouse models

Survival curves for the PTX-treated (solid line) and control (dotted line) groups

Pentoxifylline in severe ASH

Akriviadis et al, Gastroenterology 2000

101 patients4-week treatmentShort-term survival:24.5% vs 46.1%

• 29 non-responders treated with PTX vs 58 matched non-responders treated withcorticosteroids alone

• PTX treatment for 1 month• No survival improvement at 2 months• Non-responders to corticosteroids do not

benefit from consecutive therapy wit PTX

Early switch to pentoxifylline in corticosteroid non-respondersLouvet A et al, J Hepatol 2008

• Aims• Clinical

– Tolerability– Adverse Effects– Biochemistry

• Cytokine Response

A single dose of Infliximab (Remicade, 5mg/Kg) in patients with Severe Alcoholic Hepatitis

Pilot study of Infliximab in severe ASH

Tilg H, J Hepatol 2003

Total bilirubin levels after Inflixmab

White blood cell counts after Infliximab

Liver cytokine mRNA expression

d0 d28

Liver Histology after Infliximab

• 10/12 patients survived (median 12 months; range 6-18)

• 2 patients died within the first monthtoo due infectious complications(staphyloccoccal infection, candidasepticemia)

Summary of our pilot study

• 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/prednisonegroup

• Criticism: extremely high infliximab dose!

Infliximab in ASH: A French Mulitcentre StudyNaveau S et al, Hepatology 2004

• 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?

Etanercept: controlled study in ASHBoetticher NC et al, Gastroenterology 2008; 134: A-765

• Neutrophil oxidative burst and function assessedby FACS analysis in patients with cirrhosis +/-ASH

• Ex vivo studies with removal of endotoxinrestored neutrophil dysfunction (decreasedoxidative burst and increased phagocytosis)

• Endotoxin may be a driving force in neutrophildysfunction …is it more an infectious disease?

Neutrophil dysfunction in ASHMookerjee RP et al. Hepatology 2007

• ASH (n=23), normal livers (n=6)• 46 genes studied• Genes involved in fibrogenesis,

inflammatory response, and oxidativestress overexpressed

• Nicotinamide adenine dinucleotidephosphate (NADPH) oxidase weremarkedly upregulated; many targets forpotential therapies?

Colmenero J. Gastroenterology 2006

Hepatic expression of candidate genesin patients with ASH

• ASH (n=8), alcoholic steatosis (ASH, n=9), controls (n=7)

• ASH 211 differently expressed genes fromthat of controls

• ASH: claudins, osteopontin, CD209, selenoprotein, genes related to bile ductproliferation, IL-8

Seth D et al, J Hepatol 2006

Hepatic expression of candidate genesin patients with ASH

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

• Prevention of gut-derived endotoxemia(Antibiotics, lactobacillus)

• Inhibition of TNFαactivity (Anti-TNFantibodies, TNF receptor antagonists, Pentoxifylline)?

• Generalized inhibition of inflammation(Glucocorticoids)

• Decrease in reactiveoxygen speciesproduction: Glutathioneprodrugs (S-adenosylmethionine, betaine, choline, vitamin E, silymarin, propylthiouracil)

• Enhancing neutrophilfunction or correcting itsdefects?

• Probiotics?

Potential beneficial treatmentsin patients with severe ASH

• Common disease with high mortality and no satisfactory, established therapy

• Better understanding of immunopathogenesismay lead to new therapies targeting selectiveinflammatory pathways e.g. anti-TNFapproaches?

• More basic and clinical research urgentlyneeded in this neglected disease to definenew potential therapies

Conclusions