1. Advances in the Treatment of Alcoholic Liver Disease
Dr Allister J Grant
Consultant Hepatologist
Leicester Liver Unit
University Hospitals Leicester NHS Trust

2. Background Alcoholic Hepatitis National and local perspective
Presentation
Pathophysiology
Prognosis
Management
Corticosteroids and pentoxifylline

3. The Burden of Alcohol
9 million adults in the UK who are drinking over the recommended daily limits
people aged 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

4. Alcohol Related Deaths
E&W

5. UHL Med/A&E Directorate
Alcoholic Hepatitis
Alcoholic Liver Disease
Alcohol Intoxication
Alcohol Withdrawal
Alcohol Withdrawal Fits
Cirrhosis due to alcohol
DTs
June July 2007
942 admissions
4544 bed days
12.5 beds permanently occupied

6. 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………

7. UHL Alcohol Admissions 2004-8
Monthly admission rate

8. Spectrum of Alcoholic Liver Disease
The most common manifestations of alcoholic liver disease are:
Alcoholic steato-hepatitis
Acute alcoholic hepatitis
Cirrhosis due to alcohol

9. 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

10. Symptoms Fever Hepatomegaly Jaundice Coagulopathy
Features of hepatic decompensation
However, milder forms of alcoholic hepatitis often do not cause any symptoms

11. Investigation Biochemistry Haematology 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)

12. Investigations 2 Other Perform a liver screen Liver Biopsy
Hyperuricaemia
Hypertriglyceridaemia
Raised IgA
Hyperglycaemia
Perform a liver screen
Liver Biopsy

13. Pathology of Alcoholic Hepatitis
Mallorys Hyaline
Centrilobular necrosis
Fatty change
Hepatocyte ballooning
PMN infiltrate
Pericellular fibrosis

14. Mechanisms of liver injury
Alcoholic Hepatitis
Mechanisms of liver injury
Free radicals
Oxidative injury
Heat
Gut Permeability Endotoxaemia Kupfer cell activation
Gultathione
depletion
ROS &
Free radicals
TNFα
Genetics
Polymorphisms
Male vs Female
Race
Alcohol dehydrogenase (ADH)
Peroxisomal Catalase
Miscrosomal ethanol-oxidising system (CYP 2E1)
Damage
Ethanol
Acetaldehyde
Altered membrane proteins
Neoantigens formation
Impaired cytoskeletal transport
Stimulation of HSC
Immunological injury
Damage to cell
membranes
Acetate
Acetaldehyde
dehydrogenase
TNFα IL-1, IL-8
Downregulated in
chronic alcohol use

15. Prognosis Scoring Systems DF = (4.66PT)+serum bilirubin (mg/dl)
mDF = 4.6 (PTpatient-PTcontrol)+ serum bilirubin (mmol/l)/17.1
mDF≥ % 28 day survival
mDF< % 28 day survival
MELD = 3.86loge(bilirubin (mg/dl))+1.26 loge(INR)+ 9.66loge(creatinine (mg/dl))
Maddrey WC Gastro 1978
Mathurin P J Hepatol 2002

16. 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.
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.
Bilirubin
Albumin
Urea
WCC PT
Encephalopathy
Age
AST/ALT ratio
28 days 84 days
Factors
independently
associated with
mortality at-

17. Glasgow Alcoholic Hepatitis Score
Age < ≥ 50
WCC(109/l) < ≥15
Urea (mmol/l) < ≥5
PT ratio < >2.0
Bili (mol/l) < >250
Score
Patients score from 5-12 points.
Score >8 was used to define the high risk population
and maximised sensitivity and specificity.

18. GAHS Validation Cohort
195 patients with Alcoholic Hepatitis
GAHS score calculated on days 1,7 and correlated with outcome
28 day outcome (%)
Sensitivity Specificity Accuracy
Day 1
GAHS </≥
mDF </≥
Day 7
GAHS</≥
mDF </≥

19. Survival from Alcoholic Hepatitis
Derivation and validation datasets combined – 436 patients
28 day survival (%) day survival(%)
Day 1
GAHS <
GAHS ≥
Day 7
GAHS<
GAHS ≥

20. 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

21. 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

22. 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

23. 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

24. 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
g protein and 35-40Kcal/kg ideal body weight/d

25. Pentoxifylline
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
Acriviadis E, Gastro ;

26. 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:

27. 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

28. 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:

29. 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

30. 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!

31. Corticosteroids Mortality % Meta analyses: 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 mo yr 2yr
Meta analyses:
In support: Imperiale T, Ann Int Med 1990 ;113:
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