Alcholic hepatitis

1. Current Management of Alcoholic
Hepatitis and Future Therapies
Behnam Saberi, Alia S. Dadabhai, Yoon-Young Jang, Ahmet
Gurakar and Esteban Mezey
Journal of Clinical and Translational
Hepatology
2016

2. INTRODUCTION
Alcoholic hepatitis(AH) is distinct manifetation of Alcoholic liver disease and the
conditin ranges from mild to severe form.
AH occurs in 10-35% of alcoholic patients.
Definition (acc. to NIAAA)
1) Recent onset of jaundice within 60days of heavy alcohol consumption (>50/day)
of alcohol for minimum of 6 months.
2) Serum bilirubin >3m/dl
3) AST levels elevated (50-400)
4) AST/ALT >1.5
5) No obvious cause for hepatitis

3. Severe Alcoholic hepatitis(SAH):
Modified MADDEY’S DISCIMINANT FUNCTION(mDF) ≥ 32 or
Model for End-stage Liver Disease (MELD) ≥ 21 or
Presence of hepatic encephalopathy
Severe AH is associated with significant mortality with 1 month mortality rates
35-50%.
Currently, there is no ideal medical treatment for this condition.

4. MANAGEMENT OF ALCOHOLIC HEPATITIS
• ALCOHOLIC ABSTINENCE
Alcohol abstinence is the most important predictor for
determining long-term survival in patients with AH.
In the study by Potts et al.(2013), 5 year survival was
significantly higher in AH patients who remained
abstinent compared to those AH patients who relapsed
or continued to drink (75% vs. 27% and 21%,
respectively, p = 0.005).
Potts JR. Determinants of long-term outcome in severe alcoholic
hepatitis. Aliment Pharmacol Ther 2013

5. • NUTRITIONAL SUPPORT
The degree of malnutrition is correlated closely
with the development of all the serious
complications of liver disease (e.g., ascites,
encephalopathy, and hepatorenal syndrome) as
well as the overall mortality.
2000-2500kcal/day and 1.2-1.5g/kg bdy weight is
recommended

6. • NUTRITIONAL SUPPORT
Despite improvement in nutritional
parameters and liver tests in most studies,
only a few studies have shown survival benefit
with nutritional supplementation, and the
majority of studies have not demonstrated a
change in mortality.

7. • CORTICOSTEROIDS
Corticosteroids are the current main treatment
for severe AH in patients who do not have any
contraindications for steroid treatment.
CONTRAINDIATIONS for steroid therapy:
Renal failure, active GI bleed, Uncontrolled
hyperglycemia, acute pancreatitis, infections- SBP,
pneumonia, UTI, skin infections.

8. • CORTICOSTEROIDS
Data from clinical trials and meta-analyses of corticosteroids
have been conflicting.
To overcome this issue, Mathurin et al. analyzed individual
data from five randomized controlled trials and showed
that steroids have survival advantage for severe AH with a
28 day survival of 85% among treated patients compared to
65% for patients receiving placebo (p =0.001). Prednisolone
40 mg for a total of 4 weeks (28 days)
Mathurin P. Corticosteroids improve short-term survival in patients
with severe alcoholic hepatitis (AH): individual data analysis of the last
three randomized placebo controlled double blind trials of
corticosteroids in severe AH. Journal of Hepatology 2002

9. • RESPONSE TO STEROIDS
LILLE SCORE
Lille score primarily described to assess the steroid response in
patients with severe AH after 7 days of treatment.
In a study conducted by Louvet A et al(2007), patients were classified
into three groups according to their percentile distribution of Lille
score and survival analysis
1)Complete responders (Lille score ≤ 0.16; ≤ 35th percentile),
2)Partial responders (Lille score 0.16–0.56; 35th-70th percentile),
3)Null responders
Louvet A et al. The Lille model: a new tool for therapeutic
strategy in patients with severe alcoholic hepatitis treated
with steroids. Hepatology 2007

10. • RESPONSE TO STEROIDS
The study showed that steroid therapy is
beneficial mainly in complete responders and
partial responders but not in null responders.
Therefore, steroids should not be continued
beyond 7 days in null responders based on
their Lille score.

11. • PENTOXIFYLLINE(PTX)
• Pentoxifylline (PTX) is a phosphodiesterase inhibitor and a
possible TNF-α inhibitor.
• A study conducted by Akriviadis et al(2000), in 101 patients
with severe AH , a 4 week double-blind randomized trial
(PTX 400 mg orally, three times daily) compared to placebo.
The study confirmed that treatment with PTX improves
short-term survival in patients with AH, and the benefit was
attributed to a decrease in the risk of developing
hepatorenal syndrome.
Akriviadis et al. Pentoxifylline improves short-term survival in
severe acute alcoholic hepatitis: a double-blind,placebo-
controlled trial. Gastroenterology 2000

12. • PENTOXIFYLLINE(PTX)
• A prospective randomised control trial conducted
in North India by Sandeep SS (2012) concluded
that, at 4 weeks mortality in PTX group was 20%
and that in controls was 40%. Also there was
significant hepatic and renal improvement in PTX
group at end of 4 weeks .
Sandeep SS et al. Pentoxifylline in severe alcoholic
hepatitis: A prospective,randomised trial: JAPI 2012

13. • PENTOXIFYLLINE(PTX) vs CORTICOSTEROIDS
• In a RCT conducted by De BK (2009), the PTX group was
compared with corticosteroid group and the result was
significantly reduced mortality seen among patients in the
PTX group (14.71%) as compared to those receiving
prednisolone (35.29%).
De BK et al. Pentoxifylline versus prednisolone for severe
alcoholic hepatitis: A randomized controlled trial. World J
Gastroenterol 2009

14. • PENTOXIFYLLINE(PTX) vs CORTICOSTEROIDS
• In a multicenter randomized noninferiority trial
conducted by Park SH(2014), comparing PTX vs.
prednisolone, the authors concluded that the efficacy of
PTX is not statistically equivalent to the efficacy of
prednisolone .
Park SH et al. Pentoxifylline vs. corticosteroid to treat severe
alcoholic hepatitis: a randomised, non-inferiority, open trial.
Journl of Hepatology 2014

15. • PENTOXIFYLLINE(PTX) vs CORTICOSTEROIDS
• STOPAH trial by Thursz MR et al 2015:
A multicentre double blinded randomized trial to study benefit of both
prednisolone 40 mg and/or PTX 400 mg TID for 4 weeks. In total, 1,103 patients with
a clinical diagnosis of severe AH (DF ≥ 32) were randomized into four arms:
A. Placebo/Placebo;
B. Prednisolone/Placebo;
C. PTX/Placebo;
D. PTX/Prednisolone.
At 28 days, the percentage of death in the arms were 17%, 14%, 19%, and 13%,
respectively.
Thursz MR et al. Prednisolone or pentoxifylline for alcoholic
hepatitis. The New England Journal of Medicine 2015

16. • STOPAH trial by Thursz MR et al 2015:
Prednisolone reduced the risk of 28-day mortality,
but this benefit was not sustained at 3 months and
1 year. As expected, infection was more common in
the prednisolone group (13%) than in the no
prednisolone group (7%) (p = 0.002).
This study clearly shows that PTX did not improve
survival in patients wit AH.
Thursz MR et al. Prednisolone or pentoxifylline for alcoholic
hepatitis. The New England Journal of Medicine 2015

17. • COMBINATION THERAPY (PTX PLUS CORTICOSTEROIDS)
VS. CORTICOSTEROID MONOTHERAPY:
In a multicenter randomized control trial conducted in
2013 by Mathurin et al , consisting of 270 patients with
severe AH, there was no statistical difference in 6-month
survival between 4 weeks of dual therapy with
prednisolone and PTX vs. prednisolone monotherapy.
Mathurin P et al. Prednisolone with vs without pentoxifylline
and survival of patients with severe alcoholic hepatitis: a
randomized clinical trial. JAMA 2013

18. • In a study by Louvet A et al , PTX was also
studied as a salvage option in steroid null
responders, but there was no benefit. These
findings were confirmed in the multicenter
European STOPAH trial.
Louvet A et al. Early switch to pentoxifylline in patients with
severe alcoholic hepatitis is inefficient in non-responders to
corticosteroids. Journal of Hepatology 2008

19. • ANTI- TNFs
A) Etanercept
• In a multicenter study by Boetticher et al., 48 patients
with severe AH were randomized to receive either
etanercept or placebo for 3 weeks. The results showed
similar 1-month mortality in both the groups. The
6-month mortality was significantly higher in the
etanercept group than in the placebo group.
Boetticher NC et al. A randomized, double-blinded, placebo-
controlled multicenter trial of etanercept in the treatment of
alcoholic hepatitis. Gastroenterology 2008

20. • ANTI- TNFs
B) INFLIXIMAB
• In a multicenter study by Naveau et al., 36 patients with
severe AH were randomized to receive intravenous infliximab
(10 mg/kg) in weeks 0, 2, and 4 or placebo. All patients
received prednisolone 40 mg/day for 4 weeks. The
probability of death at 2 months was higher in patients who
received infliximab than in those who received placebo, but
the difference was not statistically significant.
Naveau S et al. A double-blind randomized controlled trial of
infliximab associated with prednisolone in acute alcoholic
hepatitis. Hepatology 2004

21. • N-ACETYLCYSTEINE (NAC)
A study evaluating combination therapy with prednisolone
plus NAC in comparison to prednisolone monotherapy
showed a significant decrease in mortality with combination
therapy at 1 month (8% vs. 24%, p = 0.006) but not at 6
months (27% vs. 38%, p = 0.07). Death due to hepatorenal
syndrome was less frequent in the combination group than in
the steroid monotherapy group at 6 months (9% vs. 22%, p =
0.02).
It is not clear if dual therapy with steroid and NAC should
become the standard of care in the management of patients
with AH.
Lake-Bakaar G. Glucocorticoids plus N-acetylcysteine in
alcoholic hepatitis. The New England J ournal of Med 2012.

22. • LIVER TRANSPLANTATION
Early liver transplant is effective in the
management of patients with severe AH who failed
steroid treatment. The patients should be selected
based on strict criteria, and it should be
emphasized that patients with severe AH who do
not respond to steroids have a very short-term
mortality rate without liver transplantation.
Mathurin P et al. Early liver transplantation for severe
alcoholic hepatitis. N Engl J Med 2011

23. • ANTI- TNFs
B) INFLIXIMAB
• In a multicenter study by Naveau et al., 36 patients with
severe AH were randomized to receive intravenous infliximab
(10 mg/kg) in weeks 0, 2, and 4 or placebo. All patients
received prednisolone 40 mg/day for 4 weeks. The
probability of death at 2 months was higher in patients who
received infliximab than in those who received placebo, but
the difference was not statistically significant.
Naveau S et al. A double-blind randomized controlled trial of
infliximab associated with prednisolone in acute alcoholic
hepatitis. Hepatology 2004

24. • FURTURE THERAPIES:
A) GUT LIVER AXIS
Currently there are ongoing clinical trials evaluating the
effect Probiotics( Lactobacillus rhamnosus,Lactobacillus
plantarum Bifidobacterium bifidum), ciprofloxacin,
amoxicillin clavulanate, zinc, and rifaximin in the
management of patients with AH.

25. • FURTURE THERAPIES:
B) INNATE IMMUNE SYSTEM
Activation of the innate immune system is one of the main steps in
the development of AH. Activation of kupffer cells causes release of
IL-1β. It was shown recently that an IL1β receptor antagonist was
protective against alcoholic liver injury in an animal model.
Use of the IL1β receptor antagonist Anakinra in combination with
PTX and zinc is currently being tested in the management of AH.

26. • FURTURE THERAPIES:
C) FARNESOID X RECEPTOR(FXR)
FXR is a nuclear receptor for bile acids. Obeticholic acid
(OCA) is a semi-synthetic analogue of the primary bile acid
chenodeoxycholic acid (CDCA), which selectively activates
FXR.110 In the FLINT trial, treatment with OCA improved
insulin resistance and liver histology in patients with NASH.
A phase II clinical trial of OCA in AH is currently underway.

27. • CONCLUSION
1) Steroids have some short term benefit in treatment of
severe AH, but long term effect is unclear.
2) PTX does not improve outcomes in patients with severe AH.
3) Liver transplant has shown good results in the management
of AH patients who have failed medical therapy, however
patient selection remains a major challenge.
4) There are multiple ongoing clinical trials targeting novel
pathways involved in the pathogenesis of AH.
5) Human iPSCs (induced pluripotent stem cell) are currently
being used as a novel technology for studying the
pathogenesis of ALD with potential for drug discovery.

28. • TAKE HOME MESSAGE: