Advances in the treatment of alcoholic liver disease
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Advances in the Treatment of Alcoholic Liver Disease. Dr Allister J Grant Consultant Hepatologist Leicester Liver Unit University Hospitals Leicester NHS Trust. Background National and local perspective Alcoholic Hepatitis Presentation Pathophysiology Prognosis Management

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Advances in the treatment of alcoholic liver disease

Advances in the Treatment of Alcoholic Liver Disease

Dr Allister J Grant

Consultant Hepatologist

Leicester Liver Unit

University Hospitals Leicester NHS Trust


Advances in the treatment of alcoholic liver disease

  • Background

    • National and local perspective

  • Alcoholic Hepatitis

    • Presentation

    • Pathophysiology

    • Prognosis

    • Management

      • Corticosteroids and pentoxifylline


The burden of alcohol

The Burden of Alcohol

9 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


Advances in the treatment of alcoholic liver disease

Alcohol Related Deaths

E&W 1991-2004

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


Uhl med a e directorate

UHL Med/A&E Directorate

Alcoholic Hepatitis

Alcoholic Liver Disease

Alcohol Intoxication

Alcohol Withdrawal

Alcohol Withdrawal Fits

Cirrhosis due to alcohol

DTs

June 2006- July 2007

942 admissions

4544 bed days

12.5 beds permanently occupied


Uhl alcohol admissions 2004 8

alcohol induced chronic pancreatitis

alcoholic liver disease

alcoholic gastritis

alcohol abuse counselling & surveillance

alcohol rehabilitation

alcohol abuse without diagnosis of alcoholism

history of alcohol abuse

oesophageal varices in alcoholic liver disease

and others………

UHL Alcohol Admissions 2004-8


Uhl alcohol admissions 2004 81

UHL Alcohol Admissions 2004-8

Monthly admission rate


Spectrum of alcoholic liver disease

Spectrum of Alcoholic Liver Disease

  • The most common manifestations of alcoholic liver disease are:

    • Alcoholic steato-hepatitis

    • Acute alcoholic hepatitis

    • Cirrhosis due to alcohol


Alcoholic hepatitis

Alcoholic Hepatitis

  • Most florid manifestation of ALD

  • Cholestatic liver disease associated with the long term heavy use of alcohol

  • Often a precursor to the development of cirrhosis

  • More severe forms are associated with a high mortality

  • 1yr mortality after initial hospitalisation is 40%

  • Best treatment

    • Stop drinking

    • Resolution occurs within weeks-months +/- cirrhosis


Symptoms

Symptoms

Fever

Hepatomegaly

Jaundice

Coagulopathy

Features of hepatic decompensation

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


Investigation

Investigation

  • Biochemistry

    • AST/ALT ratio >1.5

    • ALT usually <100 IU/ml

    • Raised GT (variable)

    • Raised ALP (variable)

    • Low Albumin (advanced disease)

    • Bilirubin (≥80 mol/l)

  • Haematology

    • Prolonged INR (advanced disease)

    • Macrocytosis / anaemia

    • Leukocytosis

    • Thrombocytopenia (advanced disease)


Investigations 2

Investigations 2

  • Other

    • Hyperuricaemia

    • Hypertriglyceridaemia

    • Raised IgA

    • Hyperglycaemia

Perform a liver screen

Liver Biopsy


Pathology of alcoholic hepatitis

Pathology of Alcoholic Hepatitis

Mallorys Hyaline

Centrilobular necrosis

Fatty change

Hepatocyte ballooning

PMN infiltrate

Pericellular fibrosis


Advances in the treatment of alcoholic liver disease

Altered membrane proteins

Neoantigens formation

Impaired cytoskeletal transport

Stimulation of HSC

Immunological injury

Damage to cell

membranes

Alcoholic Hepatitis

Mechanisms of liver injury

Free radicals

Oxidative injury

Heat

Gut PermeabilityEndotoxaemia Kupfer cell activation

Gultathione

depletion

ROS &

Free radicals

TNFα

Alcohol dehydrogenase (ADH)

Peroxisomal Catalase

Genetics

Polymorphisms

Male vs Female

Race

Damage

Acetaldehyde

Ethanol

Miscrosomal ethanol-oxidising system (CYP 2E1)

Acetaldehyde

dehydrogenase

Downregulated in

chronic alcohol use

TNFα IL-1, IL-8

Acetate


Prognosis

Prognosis

Maddrey WC Gastro 1978

Mathurin P J Hepatol 2002

Scoring Systems

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

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

    • mDF≥32 68% 28 day survival

    • mDF<32 93% 28 day survival

  • MELD = 3.86loge(bilirubin (mg/dl))+1.26 loge(INR)+ 9.66loge(creatinine (mg/dl))


Advances in the treatment of alcoholic liver disease

241 patients with alcoholic hepatitis were studied on day 1, 6-9 and

variables 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.

28 days84 days

Bilirubin

Albumin

Urea

WCC

PT

Encephalopathy

Bilirubin

Albumin

Urea

WCC

PT

Age

AST/ALT ratio

Factors

independently

associated with

mortality at-

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 O’Grady, C P Day, P C Hayes, L S Murray, A J Morris Gut 2005;54:1174–1179.


Glasgow alcoholic hepatitis score

Glasgow Alcoholic Hepatitis Score

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.

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


Gahs validation cohort

GAHS Validation Cohort

28 day outcome (%)

Sensitivity Specificity Accuracy

Day 1

GAHS </≥9 81 61 67

mDF </≥32 96 27 48

Day 7

GAHS</≥9 93 68 75

mDF </≥32 90 45 56

195 patients with Alcoholic Hepatitis

GAHS score calculated on days 1,7 and correlated with outcome


Survival from alcoholic hepatitis

Survival from Alcoholic Hepatitis

Derivation and validation datasets combined – 436 patients

28 day survival (%) 84 day survival(%)

Day 1

GAHS <987 79

GAHS ≥9 46 40

Day 7

GAHS<99386

GAHS ≥94737


Why is a prognostic score important

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 hepatitis

Management of Alcoholic Hepatitis

  • General

    • Stop drinking alcohol

    • Treat alcohol withdrawal

    • Thiamine/Vit B

    • Pabrinex

    • Treat malnutrition (po/ng)

    • Vit K if INR prolonged

    • Treat hepatic decompensation


Therapy

Therapy

The following therapeutic agents have been used in alcoholic hepatitis

  • Evidence

  • to support the use of:

  • Corticosteroids

  • Pentoxifylline

  • Nutritional support

  • Insufficient evidence to support the use of:

  • Anabolic steroids

  • Infliximab

  • Etanercept

  • Malotilate

  • No evidence

  • to support the use of:

  • PTU

  • Insulin & glucose

  • Colchicine

  • Antioxidants


Nutritional support

Nutritional support

  • Multifactorial-

    • poor intake/malabsorption/catabolism

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

  • Mortality is significantly associated with

    protein-energy malnutrition

    • Mild vs. severe nutritional deficiency

    • 30 day mortality= 2% vs. 52% Meadenhall CL Am.J.Clin.Nut 1986


Nutritional support1

Nutritional support

  • PEM is virtually universal- refeeding!

  • Evaluated in several clinical trials

    • Results in a more rapid improvement in liver disease

    • Does not improve survival

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

      Stickel F, APT 2003

    • 1.2-1.5g protein and 35-40Kcal/kg ideal body weight/d


Pentoxifylline

Pentoxifylline

Acriviadis E, Gastro 2000 119;1637-48

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

  • RCT

    • 101 patients with severe alcoholic hepatitis (mDF>32).

    • Given 400mg tds for 28 days vs placebo

    • Mortality 24% vs 46% at 28 days

    • Significant reduction in hepatorenal syndrome


Corticosteroids

Corticosteroids

  • Prednisolone 40mg/day for 28 days with a 20mg taper

  • Evaluated in 13 RCT’s

  • Evaluated in at least 4 Meta Analyses

  • Results are confounded by methodology.

    Cohen SM APT 2009 March (Review)

  • Cochrane review 2008 of 15 trials.

    • If take low bias trials

    • survival benefit for prednisolone in patients with severe alcoholic hepatitis (mDF>32)

      Rambaldi A APT 2008;27:1167-78


Corticosteroids1

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 benefit

      Mathurin P, Hepatology 2008:48;635A


Corticosteroids2

Corticosteroids

  • 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 discontinue

      Mathurin P Hepatol 2003;38;1363-9

      Louvet A Hepatol 2008;45:1348-54


Conclusion

Conclusion

  • Severe 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 end

The 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!


Corticosteroids3

Corticosteroids

RCT’s using Pred 40mg

or equivalent for 28 days

have been shown to

increase both short and

long term survival for

patients with severe

alcoholic hepatitis

Mortality %

1mo 2mo 1yr 2yr

Meta analyses:

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

Poynard T, Hepatology 1991;14:234A

Raymond MJ, NEJM 1992 ; 26:507-12

Mathurin P, J Hepatol 2002; 36:480-7

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


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