Advances in the Treatment Advances in the Treatment of Alcoholic Liver Diseaseof Alcoholic Liver Disease

Dr Allister J GrantDr Allister J GrantConsultant HepatologistConsultant Hepatologist

Leicester Liver UnitLeicester Liver UnitUniversity Hospitals Leicester NHS TrustUniversity Hospitals Leicester NHS Trust

BackgroundBackground National and local perspectiveNational and local perspective

Alcoholic HepatitisAlcoholic Hepatitis Presentation Presentation PathophysiologyPathophysiology PrognosisPrognosis ManagementManagement

• Corticosteroids and pentoxifyllineCorticosteroids and pentoxifylline

The Burden of AlcoholThe Burden of Alcohol

9 million adults in the UK who are drinking over the 9 million adults in the UK who are drinking over the recommended daily limits recommended daily limits

people aged 16-24 are the heaviest drinkerspeople aged 16-24 are the heaviest drinkers

The Royal Liverpool University Hospital, 12% of A&E The Royal Liverpool University Hospital, 12% of A&E attendances were shown to be directly related to alcoholattendances were shown to be directly related to alcohol

In inner city A&E departments approximately 75% of In inner city A&E departments approximately 75% of

patients attending after midnight are drunkpatients attending after midnight are drunk

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

Alcohol Related Deaths Alcohol Related Deaths E&W 1991-2004E&W 1991-2004

http://www.statistics.gov.uk/cci/nugget.asp?id=1091

UHL Med/A&E DirectorateUHL Med/A&E Directorate

Alcoholic Hepatitis Alcoholic Hepatitis Alcoholic Liver DiseaseAlcoholic Liver Disease Alcohol IntoxicationAlcohol Intoxication Alcohol WithdrawalAlcohol Withdrawal Alcohol Withdrawal Fits Alcohol Withdrawal Fits Cirrhosis due to alcoholCirrhosis due to alcohol DTsDTs

June 2006- July 2007June 2006- July 2007

942 admissions942 admissions

4544 bed days4544 bed days

12.5 beds permanently 12.5 beds permanently occupiedoccupied

alcohol induced chronic pancreatitisalcohol induced chronic pancreatitis alcoholic liver diseasealcoholic liver disease alcoholic gastritisalcoholic gastritis alcohol abuse counselling & surveillancealcohol abuse counselling & surveillance alcohol rehabilitationalcohol rehabilitation alcohol abuse without diagnosis of alcoholismalcohol abuse without diagnosis of alcoholism history of alcohol abusehistory of alcohol abuse oesophageal varices in alcoholic liver diseaseoesophageal varices in alcoholic liver disease and others………and others………

UHL Alcohol Admissions 2004-8UHL Alcohol Admissions 2004-8

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UHL Alcohol Admissions 2004-8UHL Alcohol Admissions 2004-8

Spectrum of Alcoholic Liver DiseaseSpectrum of Alcoholic Liver Disease

The most common manifestations of alcoholic The most common manifestations of alcoholic liver disease are:liver disease are:

Alcoholic steato-hepatitisAlcoholic steato-hepatitis Acute alcoholic hepatitisAcute alcoholic hepatitis Cirrhosis due to alcoholCirrhosis due to alcohol

Alcoholic HepatitisAlcoholic Hepatitis

Most florid manifestation of ALDMost florid manifestation of ALD Cholestatic liver disease associated with the long term Cholestatic liver disease associated with the long term

heavy use of alcoholheavy use of alcohol Often a precursor to the development of cirrhosisOften a precursor to the development of cirrhosis More severe forms are associated with a high mortalityMore severe forms are associated with a high mortality 1yr mortality after initial hospitalisation is 40%1yr mortality after initial hospitalisation is 40%

Best treatmentBest treatment Stop drinkingStop drinking Resolution occurs within weeks-months +/- cirrhosisResolution occurs within weeks-months +/- cirrhosis

SymptomsSymptoms

FeverFever HepatomegalyHepatomegaly JaundiceJaundice CoagulopathyCoagulopathy Features of hepatic decompensationFeatures of hepatic decompensation

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

InvestigationInvestigation

BiochemistryBiochemistry AST/ALT ratio >1.5AST/ALT ratio >1.5 ALT usually <100 IU/mlALT usually <100 IU/ml Raised Raised GT (variable)GT (variable) Raised ALP (variable)Raised ALP (variable) Low Albumin (advanced Low Albumin (advanced

disease)disease)

Bilirubin (≥80 Bilirubin (≥80 mol/l)mol/l)

HaematologyHaematology Prolonged INR Prolonged INR

(advanced disease)(advanced disease) Macrocytosis / Macrocytosis /

anaemiaanaemia LeukocytosisLeukocytosis Thrombocytopenia Thrombocytopenia

(advanced disease)(advanced disease)

Investigations 2Investigations 2

OtherOther HyperuricaemiaHyperuricaemia HypertriglyceridaemiaHypertriglyceridaemia Raised IgARaised IgA HyperglycaemiaHyperglycaemia

Perform a liver screenPerform a liver screen

Liver BiopsyLiver Biopsy

Pathology of Alcoholic HepatitisPathology of Alcoholic Hepatitis

Mallorys Hyaline

Centrilobular necrosis

Fatty change

Hepatocyte ballooning

PMN infiltrate

Pericellular fibrosis

Ethanol

Alcohol dehydrogenase (ADH)Peroxisomal Catalase

Miscrosomal ethanol-oxidising system (CYP 2E1)

Acetaldehyde

Acetate

Acetaldehyde dehydrogenase

Damage

Gultathione depletion

ROS &Free radicals

Altered membrane proteinsNeoantigens formation

Impaired cytoskeletal transportStimulation of HSC

Immunological injuryDamage to cell

membranes

Alcoholic HepatitisMechanisms of liver injury

Free radicalsOxidative injuryHeat

Downregulated inchronic alcohol use

TNFα IL-1, IL-8

Gut Permeability Endotoxaemia Kupfer cell activation

TNFα

GeneticsPolymorphismsMale vs Female

Race

PrognosisPrognosis

Scoring SystemsScoring Systems

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

mDF = 4.6 (PTmDF = 4.6 (PTpatientpatient-PT-PTcontrolcontrol)+ serum bilirubin (mmol/l)/17.1)+ serum bilirubin (mmol/l)/17.1

mDF≥32 mDF≥32 68% 28 day survival68% 28 day survival mDF<32 mDF<32 93% 28 day survival93% 28 day survival

MELD = 3.86logMELD = 3.86logee(bilirubin (mg/dl))+1.26 log(bilirubin (mg/dl))+1.26 logee(INR)+ (INR)+ 9.66log9.66logee(creatinine (mg/dl))(creatinine (mg/dl))

Maddrey WC Gastro 1978

Mathurin P J Hepatol 2002

Analysis of factors predictive of mortality in Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score.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, 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 O’Grady, C P Day, P C Hayes, L S Murray, A J Morris J O’Grady, C P Day, P C Hayes, L S Murray, A J Morris

Gut 2005;54:1174–1179. Gut 2005;54:1174–1179.

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-

BilirubinAlbuminUreaWCCPTEncephalopathy

BilirubinAlbuminUreaWCCPTAgeAST/ALT ratio

28 days 84 days

Glasgow Alcoholic Hepatitis ScoreGlasgow Alcoholic Hepatitis Score

Age <50 ≥ 50

WCC(109/l) <15 ≥15

Urea (mmol/l) <5 ≥5

PT ratio <1.5 1.5-2.0 >2.0

Bili (mol/l) <125 125-250 >250

Score 1 2 3

Patients score from 5-12 points.

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

GAHS Validation CohortGAHS Validation Cohort

195 patients with Alcoholic Hepatitis195 patients with Alcoholic Hepatitis GAHS score calculated on days 1,7 and correlated with GAHS score calculated on days 1,7 and correlated with

outcomeoutcome

28 day outcome (%)Sensitivity Specificity AccuracyDay 1

GAHS </≥9 81 61 67mDF </≥32 96 27 48

Day 7

GAHS</≥9 93 68 75mDF </≥32 90 45 56

Survival from Alcoholic HepatitisSurvival from Alcoholic Hepatitis

28 day survival (%) 84 day survival(%)Day 1

GAHS <9 87 79 GAHS ≥9 46 40

Day 7

GAHS<9 93 86GAHS ≥9 47 37

Derivation and validation datasets combined – 436 patients

Why is a prognostic score Why is a prognostic score important?important?

Patients with mild alcoholic hepatitis will improve Patients with mild alcoholic hepatitis will improve spontaneously upon cessation of alcoholspontaneously upon cessation of alcohol

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

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

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

Management of Alcoholic Management of Alcoholic HepatitisHepatitis

GeneralGeneral Stop drinking alcoholStop drinking alcohol Treat alcohol withdrawalTreat alcohol withdrawal Thiamine/Vit B Thiamine/Vit B PabrinexPabrinex Treat malnutrition (po/ng)Treat malnutrition (po/ng) Vit K if INR prolongedVit K if INR prolonged Treat hepatic decompensationTreat hepatic decompensation

TherapyTherapy

The following therapeutic agents have been used in alcoholic hepatitis

Evidenceto support the use of:

1.Corticosteroids

2.Pentoxifylline

3.Nutritional support

Insufficient evidence to support the use of:

1.Anabolic steroids

2.Infliximab

3.Etanercept

4.Malotilate

No evidenceto support the use of:

1.PTU

2.Insulin & glucose

3.Colchicine

4.Antioxidants

Nutritional supportNutritional support

Multifactorial- Multifactorial- poor intake/malabsorption/catabolismpoor intake/malabsorption/catabolism

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

Mortality is significantly associated with Mortality is significantly associated with

protein-energy malnutritionprotein-energy malnutrition Mild vs. severe nutritional deficiency Mild vs. severe nutritional deficiency 30 day mortality= 2% vs. 52% 30 day mortality= 2% vs. 52% Meadenhall CL Meadenhall CL Am.J.Clin.NutAm.J.Clin.Nut

19861986

PEM is virtually universal- refeeding!PEM is virtually universal- refeeding!

Evaluated in several clinical trialsEvaluated in several clinical trials

Results in a more rapid improvement in liver diseaseResults in a more rapid improvement in liver disease Does not improve survivalDoes not improve survival

Henkel AS, Henkel AS, Nat.Clin.Pract.Gastroenteol.HepatolNat.Clin.Pract.Gastroenteol.Hepatol 2006 2006

Stickel F, Stickel F, APTAPT 2003 2003

1.2-1.5g protein and 35-40Kcal/kg ideal body weight/d1.2-1.5g protein and 35-40Kcal/kg ideal body weight/d

Nutritional supportNutritional support

PentoxifyllinePentoxifylline

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

RCT RCT 101 patients with severe alcoholic hepatitis (mDF>32).101 patients with severe alcoholic hepatitis (mDF>32). Given 400mg tds for 28 days vs placeboGiven 400mg tds for 28 days vs placebo Mortality 24% vs 46% at 28 daysMortality 24% vs 46% at 28 days Significant reduction in hepatorenal syndromeSignificant reduction in hepatorenal syndrome

Acriviadis E, Gastro 2000 119;1637-48

Prednisolone 40mg/day for 28 days with a 20mg taper Prednisolone 40mg/day for 28 days with a 20mg taper Evaluated in 13 RCT’sEvaluated in 13 RCT’s Evaluated in at least 4 Meta AnalysesEvaluated in at least 4 Meta Analyses Results are confounded by methodology.Results are confounded by methodology.

Cohen SM Cohen SM APTAPT 2009 March (Review)2009 March (Review)

Cochrane review 2008 of 15 trials.Cochrane review 2008 of 15 trials. If take low bias trialsIf take low bias trials survival benefit for prednisolone in patients with severe alcoholic survival benefit for prednisolone in patients with severe alcoholic

hepatitis (mDF>32)hepatitis (mDF>32)Rambaldi A Rambaldi A APTAPT

2008;27:1167-782008;27:1167-78

CorticosteroidsCorticosteroids

Mathurin P et al 2002 Mathurin P et al 2002 J HepatolJ Hepatol

Data from the 3 largest trials Pred vs. placeboData from the 3 largest trials Pred vs. placebo

Analysed patients with mDF ≥ 32Analysed patients with mDF ≥ 32

28 day survival 28 day survival 85% vs 65%85% vs 65%

NNT 5NNT 5

2008, 5 largest trials reanalysed- confirmed the survival benefit2008, 5 largest trials reanalysed- confirmed the survival benefitMathurin P, Mathurin P,

HepatologyHepatology 2008:48;635A 2008:48;635A

CorticosteroidsCorticosteroids

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

Therapeutic trial of prednisolone 40mg POTherapeutic trial of prednisolone 40mg PO

7 days7 days

If no improvement in bilirubin then discontinueIf no improvement in bilirubin then discontinueMathurin P Mathurin P HepatolHepatol

2003;38;1363-92003;38;1363-9

Louvet A Louvet A HepatolHepatol 2008;45:1348-542008;45:1348-54

CorticosteroidsCorticosteroids

ConclusionConclusion

Severe alcoholic hepatitis is life threateningSevere alcoholic hepatitis is life threatening

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

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

Reassess after 7 daysReassess after 7 days

The results with pentoxifylline need corroboration in The results with pentoxifylline need corroboration in further trialsfurther trials

The EndThe End“All right, let's not panic.

I'll make the money by selling one of my livers.I can get by with one “

Doh!

CorticosteroidsCorticosteroids

Mor

talit

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1mo 2mo 1yr 2yr

Meta analyses:In support: Imperiale T, Ann Int Med 1990 ;113:299-307

Poynard T, Hepatology 1991;14:234ARaymond MJ, NEJM 1992 ; 26:507-12Mathurin P, J Hepatol 2002; 36:480-7

Equivocal: Christiansen E, Gut 1995; 37:113-8

RCT’s 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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