Alcoholic Hepatitis: Management Options

Paul J. Thuluvath, MD. FRCP Institute of Digestive Health & Liver Diseases,

Mercy Medical Center, Baltimore Professor of Surgery & Medicine,

Georgetown University, Washington DC

Disclosure

• I do not have any financial relationships relevant to this topic

• I will discuss off-label use of medications

Case History • 34 yr old man with new onset of jaundice • No previous history. Worked as a

stockbroker, no drug use, admitted drinking wine regularly

• Total bilirubin 15 mg/dl, DB 12 mg/dl, AST 212, ALT 70, alkphosp 125; INR 3.2, Hb14.5, MCV 102, WBC 12000, Plat 120,000

• U/S of liver – steatosis JAMA 2004;291:1238

Alcohol related morbidity and mortality

• 3rd leading preventable cause of death • 2.3 million years lost in 2001 in the USA

JAMA 2004;291:1238

“Beer is living proof that God loves us and wants us to be happy”

Benjamin Franklin

“Always remember that I have taken more out of alcohol than alcohol has taken out of me”

Winston Churchill

“Alcohol may be the man’s worst enemy, but the bible says love your enemy”

Frank Sinatra

• For every 1-liter alcohol consumption, there is 14% increase of cirrhosis in man and 8% in women

• One death every 2 minutes (9.2% of all deaths in the region) in Columbia

• The alcohol pattern in Columbia is similar to that of USA (7.8 L of pure alcohol/person)

• 60% of all traffic deaths in Columbia are related to alcohol

• Regulation and taxation have the highest impact on alcohol use

Alcoholic Liver Disease

Alcoholism

Fatty Liver 90%

20% Alcoholic Hepatitis

15% Alcoholic Cirrhosis

Normal Liver 10%

30%

Alcoholic Hepatitis • A clinical syndrome characterized by rapid onset

of jaundice and liver failure after decades of alcohol use – may also present with fever, ascites, myopathy,

hepatomegaly and HE • Age: 40-60 yrs, M>F (but women are more

prone) • AST/ALT >2.0 (presumed mechanisms include

decreased hepatic ALT or pyridoxal 5-phosphate, or increased hepatic mitochondrial aspartate)

Alcoholic Hepatitis • Symptomatic alcoholic hepatitis

– 50% will have concomitant cirrhosis • 50% of mild alcoholic hepatitis will progress to

cirrhosis – About a quarter will have normal histology if they abstain from

alcohol – Recidivism is common (67-81%) – Naltrexone or acamprosate may reduce recidivism – Baclofen may be helpful

Predictors of Outcome

• Maddrey’s score: 4.6 x PT {patient PT-control PT} + serum total bilirubin (in mg/dl) – DF>32 associated with high mortality

• 30-day mortality ~30% • Higher in the presence of encephalopathy

• Glasgow alcoholic hepatitis score (age, WBC, BUN, bilirubin, PT/INR)

• MELD score (bilirubin, creatinine, INR) – >21 associated with 20% 90-day mortality

• Lille score

Alcoholic Hepatitis - Treatment

• Nutritional supplementation (enteral + supplements)

– Discordant results • Current SOC is steroid therapy (prednisone 40 mg

daily for 28 days) in those with Maddrey’s score (DF) > 32 – 1-month survival higher in treated group (85% vs. 65%)

J Hepatol 2002:36:480 (analysis of 3 trials) – non-responders (~40% do not respond) have a 6-month

mortality of 70%

• Other treatment options include pentoxifylline, N-acetyl cysteine (NAC), liver transplantation

Pentoxifylline improves survival

N=49

N=52

Hepatorenal syndrome is lower in treated group compared to placebo (12% vs. 42%, p <0.001)

Pentoxifylline

• Cochrane database analysis – 5 trials including 336 patients – Mortality: RR 0.64 (CI0.46-0.89) – Evidence was not firm

Whitfield K et al Cochrane Databse Syst Rev 2009 Oct 7

Could be used when corticosteroid is contraindicated

**Infection was more common in Infliximab group Infliximab 10 mg/kg at week 0,2,4

Lille Score

• The model uses 6 variables – age, creatinine, albumin, PT – baseline bilirubin (Day 0) – bilirubin at day 7 (on treatment)

Louvet A et al Hepatology 2007;45:1348-54

Louvet A et al Hepatology 2007;45:1348-54

M O R T A L I T Y

Lille Score

• Lille Score’ is an excellent predictor of survival at day-7 on treatment with steroids – Non-response (Lille score > 0.45 or

worsening liver disease on day-7) to steroid at day-7 is associated with a high mortality

Louvet A et al Hepatology 2007;45:1348-54

Louvet A et al. J Hepatol 2008:48:465

Pentoxifylline in non-responders

• 2-step strategy • Early (day-7) withdrawal in some non-

responders followed by pentoxifylline for another 28 days (n=29)

• Comparison to 58 matched non-responders to corticosteroid

• No survival advantage at 2 months

Louvet A et al. J Hepatol 2008:48:465

Louvet A et al. J Hepatol 2008:48:465

Pentoxifylline is ineffective in non-responders to corticosteroids

Enteral Nutrition +/- NAC • Randomized, controlled trial in 52 patients (28

NAC, 24 placebo) in biopsy proven alcoholic hepatitis

• N-acytyl cysteine (IV) for 14 days or placebo; all have enteral nutrition support

• Survival – 1 month: 70.2% (NAC), 83.8% (control) – 6 month: 62.4% (NAC), 67.1% (control) Moreno C et al J Hepatol 2010 August1

Other Treatments • Corticosteroids + Pentoxifylline

– No advantage (Sidhu SS et al DDS 2012) • Antoxidant therapy

– No advantage (Stewart S et al 2007 J Hepatol)

Steroid + N-acetyl cysteine (NAC) vs. Steroids alone

• 174 patients with DF >32 + histology consistent with alcoholic hepatitis were randomized from 11 centers in France – Group 1: Prednisone 40 mg daily for 4

weeks – Group II: Prednisone 40 mg daily for 4

weeks + NAC for 5 days

Nguyen-Khac E et al N Engl J Med 2011;365:1871-9

• Prednisone group – Day1-5:

• 1000 ml of D5 in 24 hours

• N-Acetyl Cysteine + Prednisone – Day1:

• 150 mg/kg (in 250 ml of 5% dextrose) in 30 minutes followed by 50 mg/kg in 4 hrs (500 ml D5), 100 mg/kg in 16 hrs (1000 ml D5)

– Day 2-5 • 100 mg/kg in 1000 ml D5 over 24 hrs

Nguyen-Khac E et al N Engl J Med 2011;365:1871-9

• Mortality

Nguyen-Khac E et al N Engl J Med 2011;365:1871-9

Prednisone+ NAC

Prednisone

Month 1 Month 2 Month 3 Month 6

8.2% 15.3% 22.4% 27.1%

23.6%* 32.6%* 33.7% 38.2%

* P <0.005

Nguyen-Khac E et al N Engl J Med 2011;365:1871-9

Liver Transplantation?

• Case control study of LT in patients with non-response to steroids (NRS) at day-7 (Lille score 0.88)

• 26 listed within 13 days of NRS – Selected by consensus (social, co-morbidities..) – Less than 2% of patients admitted with alcohlolic

hepatitis were selected. – 6 month survival (77% vs. 23%) – Three patients resumed drinking at 720, 740 and

1140 days

Liver Transplantation for Alcoholic Hepatitis

Mathurin P et al N Engl J Med 2011;365:1790

Kaplan–Meier Estimates of Survival among the 26 Study Patients and Randomly Selected Matched Controls.

Mathurin P et al. N Engl J Med 2011;365:1790-1800.

Long term survival in severe alcoholic hepatitis

• 272 with severe alcoholic hepatitis treated with steroids

• 6 month survival – responders (Lille <0.45) 82.7% – non-responders (Lille >0.45) 27.6%

Louvet A et al Hepatology 2010;52:381a

Long term survival in severe alcoholic hepatitis treated with steroids

• Overall 5-year survival: 32.6% – responders and abstinent 80.4% – responders and not abstinent 39% – Non-responders who drank 0%

• Recidivism – heavy drinking 53.6% after median time of

180 days (60-180 days) – If patients survived 6 months and they

abstained, 5-year survival was 75.9% vs. 32.6% if they drank

Louvet A et al Hepatology 2010;52:381a

Conclusions • Severe alcoholic hepatitis (DF>32) should

be given a trial of corticosteroids – combination of prednisone and NAC is an

option – Pentoxifylline 400 mg TID for 28 days if

steroid is contraindicated • Those who do not respond at day-7 should

be considered for alternate treatment strategies

• In selected cases, liver transplantation may be considered (?)