Advances in the Treatment of Alcoholic Liver Disease

Advances in the Treatment of Alcoholic Liver DiseaseDr Allister J GrantConsultant HepatologistLeicester Liver UnitUniversity Hospitals Leicester NHS Trust

BackgroundNational and local perspective

Alcoholic HepatitisPresentation PathophysiologyPrognosisManagementCorticosteroids and pentoxifylline

The Burden of Alcohol9 million adults in the UK who are drinking over the recommended daily limits

people aged 16-24 are the heaviest drinkers

The Royal Liverpool University Hospital, 12% of A&E attendances were shown to be directly related to alcohol In inner city A&E departments approximately 75% of patients attending after midnight are drunk

20% of patients admitted to hospital for illnesses unrelated to alcohol, are drinking at hazardous levels

Alcohol Related Deaths E&W 1991-2004http://www.statistics.gov.uk/cci/nugget.asp?id=1091

UHL Med/A&E Directorate

Alcoholic Hepatitis Alcoholic Liver DiseaseAlcohol IntoxicationAlcohol WithdrawalAlcohol Withdrawal Fits Cirrhosis due to alcoholDTs

June 2006- July 2007

942 admissions

4544 bed days

12.5 beds permanently occupied

alcohol induced chronic pancreatitisalcoholic liver diseasealcoholic gastritisalcohol abuse counselling & surveillancealcohol rehabilitationalcohol abuse without diagnosis of alcoholismhistory of alcohol abuseoesophageal varices in alcoholic liver diseaseand others

UHL Alcohol Admissions 2004-8

Monthly admission rateUHL Alcohol Admissions 2004-8

Spectrum of Alcoholic Liver Disease

The most common manifestations of alcoholic liver disease are:

Alcoholic steato-hepatitisAcute alcoholic hepatitisCirrhosis due to alcohol

Alcoholic HepatitisMost florid manifestation of ALDCholestatic liver disease associated with the long term heavy use of alcoholOften a precursor to the development of cirrhosisMore severe forms are associated with a high mortality1yr mortality after initial hospitalisation is 40%

Best treatmentStop drinkingResolution occurs within weeks-months +/- cirrhosis

SymptomsFeverHepatomegalyJaundiceCoagulopathyFeatures of hepatic decompensation

However, milder forms of alcoholic hepatitis often do not cause any symptoms

Investigation

BiochemistryAST/ALT ratio >1.5ALT usually

Investigations 2

OtherHyperuricaemiaHypertriglyceridaemiaRaised IgAHyperglycaemia

Perform a liver screen

Liver Biopsy

Pathology of Alcoholic Hepatitis

Mallorys Hyaline

Centrilobular necrosis

Fatty change

Hepatocyte ballooning

PMN infiltrate

Pericellular fibrosis

EthanolAcetaldehydeDamageAlcoholic HepatitisMechanisms of liver injuryTNF IL-1, IL-8TNF GeneticsPolymorphismsMale vs FemaleRace

Prognosis

Scoring Systems

DF = (4.66PT)+serum bilirubin (mg/dl)

mDF = 4.6 (PTpatient-PTcontrol)+ serum bilirubin (mmol/l)/17.1

mDF32 68% 28 day survivalmDF

Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score.E H Forrest, C D J Evans, S Stewart, M Phillips, Y H Oo, N C McAvoy, N C Fisher, S Singhal,A Brind, G Haydon, J OGrady, C P Day, P C Hayes, L S Murray, A J Morris Gut 2005;54:11741179. 241 patients with alcoholic hepatitis were studied on day 1, 6-9 andvariables that predicted outcome at days 28 and 84 were sought.

These variables were included in the Glasgow alcoholic hepatitis score (GAHS)and validated against a further 195 patients.

Factors independentlyassociated withmortality at-

Glasgow Alcoholic Hepatitis ScorePatients score from 5-12 points.

Score >8 was used to define the high risk population and maximised sensitivity and specificity.

GAHS Validation Cohort195 patients with Alcoholic HepatitisGAHS score calculated on days 1,7 and correlated with outcome

Survival from Alcoholic HepatitisDerivation and validation datasets combined 436 patients

Why is a prognostic score important?Patients with mild alcoholic hepatitis will improve spontaneously upon cessation of alcohol

Patients with severe alcoholic hepatitis should be monitored in level 2 care or above

A significant percentage of patients will deteriorate some time after initial presentation

Patients with severe alcoholic hepatitis benefit from the initiation of specific therapies

Management of Alcoholic HepatitisGeneralStop drinking alcoholTreat alcohol withdrawalThiamine/Vit B PabrinexTreat malnutrition (po/ng)Vit K if INR prolongedTreat hepatic decompensation

TherapyThe following therapeutic agents have been used in alcoholic hepatitisEvidenceto support the use of:

Corticosteroids

Pentoxifylline

Nutritional supportInsufficient evidence to support the use of:

Anabolic steroids

Infliximab

Etanercept

MalotilateNo evidenceto support the use of:

PTU

Insulin & glucose

Colchicine

Antioxidants

Nutritional supportMultifactorial- poor intake/malabsorption/catabolism

No published guidance (Vit B/ Vit K/ Zinc)

Mortality is significantly associated with protein-energy malnutritionMild vs. severe nutritional deficiency 30 day mortality= 2% vs. 52% Meadenhall CL Am.J.Clin.Nut 1986

PEM is virtually universal- refeeding!

Evaluated in several clinical trials

Results in a more rapid improvement in liver diseaseDoes not improve survivalHenkel AS, Nat.Clin.Pract.Gastroenteol.Hepatol 2006Stickel F, APT 2003

1.2-1.5g protein and 35-40Kcal/kg ideal body weight/dNutritional support

PentoxifyllinePTX is a phosphodiesterase inhibitor which modulates the transcription of the TNF-gene, lowers blood viscosity and reduces portal hypertension.

RCT 101 patients with severe alcoholic hepatitis (mDF>32).Given 400mg tds for 28 days vs placeboMortality 24% vs 46% at 28 daysSignificant reduction in hepatorenal syndromeAcriviadis E, Gastro 2000 119;1637-48

Prednisolone 40mg/day for 28 days with a 20mg taper Evaluated in 13 RCTsEvaluated in at least 4 Meta AnalysesResults are confounded by methodology.Cohen SM APT 2009 March (Review)

Cochrane review 2008 of 15 trials.If take low bias trialssurvival benefit for prednisolone in patients with severe alcoholic hepatitis (mDF>32)Rambaldi A APT 2008;27:1167-78

Corticosteroids

Mathurin P et al 2002 J Hepatol

Data from the 3 largest trials Pred vs. placebo

Analysed patients with mDF 32

28 day survival 85% vs 65%

NNT 5

2008, 5 largest trials reanalysed- confirmed the survival benefitMathurin P, Hepatology 2008:48;635ACorticosteroids

If the patient has severe alcoholic hepatitis mDF>32, MELD >11, GAHS>8

Therapeutic trial of prednisolone 40mg PO

7 days

If no improvement in bilirubin then discontinueMathurin P Hepatol 2003;38;1363-9Louvet A Hepatol 2008;45:1348-54

Corticosteroids

ConclusionSevere alcoholic hepatitis is life threatening

The GAHS is clinically useful and more accurate than mDF and MELD at predicting outcome

If the patient has severe alcoholic hepatitis (GAHS>8, mDF>32) consider starting prednisolone 40mg/d

Reassess after 7 days

The results with pentoxifylline need corroboration in further trials

The EndAll right, let's not panic.I'll make the money by selling one of my livers.I can get by with one Doh!

CorticosteroidsMortality %1mo 2mo 1yr 2yrMeta analyses:In support:Imperiale T, Ann Int Med 1990 ;113:299-307Poynard T, Hepatology 1991;14:234ARaymond MJ, NEJM 1992 ; 26:507-12Mathurin P, J Hepatol 2002; 36:480-7

Equivocal:Christiansen E, Gut 1995; 37:113-8RCTs using Pred 40mgor equivalent for 28 dayshave been shown to increase both short andlong term survival for patients with severe alcoholic hepatitis

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