Advances in the Treatment of Alcoholic Liver Disease

1
Advances in the Treatment of Alcoholic Liver
Disease

• Dr Allister J Grant
• Consultant Hepatologist
• Leicester Liver Unit
• University Hospitals Leicester NHS Trust

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

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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
  AE attendances were shown to be directly related
  to alcohol
• In inner city AE 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

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Alcohol Related Deaths EW 1991-2004
http//www.statistics.gov.uk/cci/nugget.asp?id109
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UHL Med/AE 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

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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

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UHL Alcohol Admissions 2004-8
Monthly admission rate
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Spectrum of Alcoholic Liver Disease

• The most common manifestations of alcoholic liver
  disease are
• Alcoholic steato-hepatitis
• Acute alcoholic hepatitis
• Cirrhosis due to alcohol

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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

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Symptoms

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

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Investigation

• Biochemistry
• AST/ALT ratio gt1.5
• ALT usually lt100 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)

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Investigations 2

• Other
• Hyperuricaemia
• Hypertriglyceridaemia
• Raised IgA
• Hyperglycaemia

• Perform a liver screen
• Liver Biopsy

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Pathology of Alcoholic Hepatitis
Mallorys Hyaline Centrilobular necrosis Fatty
change Hepatocyte ballooning PMN
infiltrate Pericellular fibrosis
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Alcoholic Hepatitis Mechanisms of liver injury
TNFa
Genetics Polymorphisms Male vs Female Race
Damage
Acetaldehyde
Ethanol
TNFa IL-1, IL-8
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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 survival
• mDFlt32 93 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
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• 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
  20055411741179.

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.
Factors independently associated with mortality
at-
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Glasgow Alcoholic Hepatitis Score
Patients score from 5-12 points. Score gt8 was
used to define the high risk population and
maximised sensitivity and specificity.
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GAHS Validation Cohort

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

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Survival from Alcoholic Hepatitis
Derivation and validation datasets combined 436
patients
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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

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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

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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

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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

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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

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Pentoxifylline

• PTX is a phosphodiesterase inhibitor which
  modulates the transcription of the TNFa-gene,
  lowers blood viscosity and reduces portal
  hypertension.
• RCT
• 101 patients with severe alcoholic hepatitis
  (mDFgt32).
• Given 400mg tds for 28 days vs placebo
• Mortality 24 vs 46 at 28 days
• Significant reduction in hepatorenal syndrome

Acriviadis E, Gastro 2000 1191637-48
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Corticosteroids

• Prednisolone 40mg/day for 28 days with a 20mg
  taper
• Evaluated in 13 RCTs
• 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 (mDFgt32)
• Rambaldi A APT 2008271167-78

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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 200848635A

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Corticosteroids

• If the patient has severe alcoholic hepatitis
  mDFgt32, MELD gt11, GAHSgt8
• Therapeutic trial of prednisolone 40mg PO
• 7 days
• If no improvement in bilirubin then discontinue
• Mathurin P Hepatol 2003381363-9
• Louvet A Hepatol 2008451348-54

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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
  (GAHSgt8, mDFgt32) consider starting prednisolone
  40mg/d
• Reassess after 7 days
• The results with pentoxifylline need
  corroboration in further trials

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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!
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Corticosteroids
RCTs 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 113299-307 Poynard T, Hepatology
199114234A Raymond MJ, NEJM 1992
26507-12 Mathurin P, J Hepatol 2002
36480-7 Equivocal Christiansen E, Gut 1995
37113-8