Prednisolone or pentoxifylline for alcoholic hepatitis

Dr. Paul Mullins MBBS DM FRCP (biography, no disclosures)

What I did before

Alcoholic hepatitis (AH), perhaps more accurately described as alcohol-related cholestatic liver failure (1), is a clinical syndrome in those chronically consuming alcohol to excess presenting with jaundice and liver failure. Challenges for clinicians in managing these patients include making an accurate diagnosis, assessment of severity and the approach to treatment (2). Mortality at 28 days in severe AH is 30-40% (3, 4).

Diagnosis
A patient presenting with decompensated alcoholic liver disease may have co-existing AH, alcoholic fatty liver, cirrhosis and/or other liver disease, making a clear diagnosis of AH difficult. A diagnosis of predominant AH is made when certain clinical, biochemical, and imaging features are present in chronic excess alcohol consumption. Typically there is recent onset jaundice, ascites and/or other features of liver failure (5, 6), hepatomegaly, which may be tender, and clinical features of chronic liver disease and/or portal hypertension, confirmed by imaging. Biochemical tests supporting the diagnosis include Bilirubin >80 µmol/L, increased AST<300 IU/L, AST: ALT ratio >2, increased INR, and an increased blood neutrophil count. Liver biopsy, by the trans-jugular route in significant coagulopathy, is more often used to assist in diagnosis in Europe whereas in North America, and the UK, its use is generally restricted to cases where an alternative diagnosis is considered.

Assessment of severity
Several scoring systems have been used to identify severe AH, which has a higher mortality, for which specific drug treatment may improve survival. Scores are not used for diagnosis of AH, and have limitations (2):

• A modified Discriminant Function (mDF) score >32 is the most widely used to guide treatment initiation. Limitations of mDF include that the prothrombin time used in the score underestimates severity of disease (7).
• The MELD score has been shown to predict survival overall (8). Guidelines from the American Association of the Study of the Liver recommend a MELD score >18 as sufficient to initiate treatment (5).
• The Glasgow Alcoholic Hepatitis Score (GAHS) (9) and Age Bilirubin INR Creatinine (ABIC) Score (10), which are not validated internationally, also assess severity of AH. GAHS may be superior in identifying those who will benefit from corticosteroid treatment (11).
• I have used an mDF >32, or GAHS ≥9, with/without hepatic encephalopathy, to decide whether to commence specific drug treatment.

Treatment

• General
  Supportive care and management of associated problems encountered in these patients includes the following: alcohol withdrawal; alcohol-related neurological complications; complications of cirrhosis: sepsis; hepatorenal syndrome; acute bleeding; acute kidney injury; hepatic encephalopathy. Once the patient is clinically stable nutritional support, via oral or nasogastric route, is commenced.
• Specific
  A number of drugs have been considered as specific treatment for severe AH. Guidelines recommend Prednisolone 40 mg a day PO, or Pentoxifylline 400 mg three times a day PO, for four weeks (5, 6, 12). If active sepsis, pancreatitis, bleeding and/or renal failure is present Pentoxifylline, rather than Prednisolone, is preferred. I ensure that there has been no active sepsis or acute bleeding for 48 hours before commencing specific drug treatment for severe AH.
• Cessation
  A decrease of Bilirubin level by 25% after seven to nine days confirms a corticosteroid response. The Lille score identifies corticosteroids non-responders (13), corticosteroids are stopped on day seven of treatment if the Lille score is >0.45.The benefit of corticosteroids and Pentoxifylline in severe AH is controversial. There is a lack of definitive evidence for reduction in mortality with corticosteroids (14, 15, 16, 17, 18), Pentoxifylline (19, 20, 21), or in combination (22, 23, 24, 25).

What changed my practice

STOPAH is a UK multi-centre, double-blind, randomized trial in severe AH to assess the effect of Prednisolone and/or Pentoxifylline on mortality at 28 days, and mortality or liver transplantation at 90 days and at one year.

Mortality at 28 days was 17% in the placebo–placebo group, 14% in the Prednisolone–placebo group, 19% in the Pentoxifylline–placebo group, and 13% in the Prednisolone–Pentoxifylline group. Odds ratios were as follows: Pentoxifylline 1.07 (95% confidence interval (CI), 0.77-1.49; P = 0.69); Prednisolone 0.72 (CI 0.52-1.01; P = 0.06). There were no significant differences in outcomes between the groups at 90 days, and at 1 year. Serious infections occurred in 13% of patients treated with Prednisolone, compared with 7% of those who were not treated with Prednisone (P = 0.002).

Power and limitations of the study
A power calculation was performed with the following parameters: Power = 90% (to allow for secondary outcomes); two-sided significance level of 5%; an estimated 28-day mortality rate for each treatment group, based upon a reduction in the 28-day mortality rate at the margins from 30% to 21%. According to this power calculation, a sample size of 513, per group of single agent versus no single agent, would be required, thus the overall trial sample size would require 1,026 patients. The power calculation assumed no interaction between the treatments.

A limitation of the trial is that the mortality rate was lower, at 13-19%, compared to previous trials. In response the authors state that mortality rates are similar to trials published in recent years, and that differences in mortality between studies are most likely to reflect variations in patient factors and improvements in general management over the years. These factors include greater number of well-nourished younger patients, improvements in supportive care, lower incidence of infection, acute kidney injury and hepatic encephalopathy. Other factors predicting mortality in this study, Prednisolone use, levels of INR, Bilirubin, Creatinine, Urea, white blood cell count, compared to previous trials were similar. Absence of liver biopsy in this trial may have resulted in inaccurate diagnosis leading to a reduced power of the study to detect a therapeutic effect. The authors state, however, that use of liver biopsy, except when an alternative diagnosis is suspected, is controversial, and is not performed routinely in most units managing patients with AH.

Results from this pragmatic clinical trial provide evidence that Pentoxifylline does not improve mortality in severe AH. Use of Prednisolone does not improve mortality either, except in the short term in a small proportion of patients, and that the reduced mortality rate is not maintained at one year.

What I do now

I do not use Pentoxifylline in the treatment of severe AH and restrict the use of corticosteroid therapy in this condition. My approach to corticosteroid therapy in severe AH is as follows:

• Use diagnostic criteria as defined above with emphasis on presence of features indicating predominant AH, tender hepatomegaly, persistent high WBC in absence of active sepsis/other cause.
• Use mDF >32 or GAHS> 9, with or without hepatic encephalopathy to identify severe AH.
• Ensure general management has been established, the patient is clinically stable with absence of active sepsis or hemorrhage for 48 hours.
• Make a general assessment of patient fitness to withstand complications and side effects of corticosteroids eg. sepsis.
• Cessation: <25% reduction of Bilirubin at day seven to nine; or Lille score >0.45 at day seven.

The importance of general management of associated conditions, and the need for new treatments to reduce short-term mortality in severe AH, is emphasised (26). Reduction of long-term mortality remains dependent upon maintained abstinence.

Scores:

• mDF: http://www.mdcalc.com/maddreys-discriminant-function-for-alcoholic-hepatitis/
• MELD: http://www.mdcalc.com/meld-score-model-for-end-stage-liver-disease-12-and-older/
• GAHS: (http://www.mdcalc.com/glasgow-alcoholic-hepatitis-score/
• ABIC Score: (age × 0.1) + (serum bilirubin × 0.08) + (serum Creatinine × 0.3) + (INR × 0.8)
• Lille: http://www.lillemodel.com/score.asp

References:

1. Hazeldine S, Sheron N. Current treatment options for alcohol-related liver disease. Curr Opin Gastroenterol 2014 30: 238-44. (View with CPSBC or UBC)
2. Singal AK, Kamath PS, Gores GJ, et al. Alcoholic Hepatitis: current challenges and future directions. Clin Gastroenterol Hepatol 2014 12: 555-64. (View with CPSBC or UBC)
3. Yu VH, Xu CF, Ye H, et al. Early Mortality of alcoholic hepatitis: a review of data from placebo-controlled clinical trials. World J Gastroenterol 2010 16: 2435-39. (View)
4. Mathurin P, Lucey MR. Management of alcoholic hepatitis. J Hepatol 2012 56 (suppl 1): S39-45. (View with CPSBC or UBC)
5. O’Shea RS, Dasarthy S, McCullough AJ, et al. Alcoholic Liver Disease AASLD Practice Guidelines. Hepatol 2010 51(1): 307-28. (Request with CPSBC or view UBC)
6. Mathurin P, Hadengue A, Bataller R, et al. EASL Clinical Practice Guidelines: Management of Alcoholic Liver Disease. J Hepatol 2012 57: 399-420. (View with CPSBC or UBC)
7. Maddrey C, Boitnott JK, Bedine MS, et al. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology 1978 75: 193-99. (Request with CPSBC)
8. Dunn W, Jamil LH, Brown S, et al. MELD accurately predicts mortality in patients with alcoholic hepatitis. Hepatology 2005 41: 353-58. (View)
9. Forrest EH, Evans CD, Stewart S, et al. Analysis of factors predictive of mortality and derivation of and validation of the Glasgow alcoholic hepatitis score. Gut 2005 54: 1174-79. (View)
10. Dominguez M, Rincon D, Abraldes JG, et al. A new scoring system for prognostic stratification of patients with alcoholic hepatitis. Am J Gastroenterol 2008 103: 2747-56. (View with CPSBC or UBC)
11. Forrest EH, Morris AJ, Stewart S, et al. the Glasgow alcoholic hepatitis score identifies patients who may benefit from corticosteroids. Gut 2007 56: 1743-46. (View)
12. Alcohol-use disorders: Diagnosis and clinical management of alcohol-related physical complications. NICE Guideline 100. 2010. (View)
13. Louvet A, Naveau S, Abdelnour M, et al. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology 2007 45: 1348-54. (Request with CPSBC or view UBC)
14. Rambaldi A, Saconato HH, Christensen E, et al. Systematic review: glucocorticosteroids for alcoholic hepatitis — a Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials. Aliment Pharmacol Ther 2008 27: 1167-78. (View)
15. Mendenhall CL, Anderson S, Garcia-Pont P, et al. Short-term and long-term survival in patients with alcoholic hepatitis treated with oxandrolone and prednisolone. N Engl J Med 1984 311: 1464-70. (Request with CPSBC or view UBC)
16. Ramond MJ, Poynard T, Rueff B, et al. A randomized trial of prednisolone in patients with severe alcoholic hepatitis. N Engl J Med 1992 326: 507-12 (View)
17. Mathurin P, Duchatelle V, Ramond MJ, et al. Survival and prognostic factors in patients with severe alcoholic hepatitis treated with prednisolone. Gastroenterology 1996 110: 1847-53. (Request with CPSBC or view UBC)
18. Mathurin P, O’Grady J, Carithers RL, et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut 2011 60: 255-60. (Request with CPSBC or view UBC)
19. Akriviadis E, Botla R, Briggs W, et al. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology 2000 119: 1637-48. (Request with CPSBC or view UBC)
20. Whitfield K, Rambaldi A, Wetterslev J, et al. Pentoxifylline for alcoholic hepatitis. Cochrane Database Syst Rev 2009 4: CD007339. (View with CPSBC or UBC)
21. Parker R, Armstrong MJ, Corbett C, et al. Systematic review: pentoxifylline for the treatment of severe alcoholic hepatitis. Aliment Pharmacol Ther 2013 37: 845-54. (View)
22. Park SH, Kim DJ, Kim YS, et al. Pentoxifylline vs. corticosteroid to treat severe alcoholic hepatitis: a randomised, noninferiority, open trial. J Hepatol 2014; 61:792-8. (View with CPSBC or UBC)
23. De BK, Gangopadhyay S, Dutta D, et al. Pentoxifylline versus prednisolone for severe alcoholic hepatitis: a randomized controlled trial. World J Gastroenterol 2009 15: 1613-9. (View)
24. Mathurin P, Louvet A, Duhamel A, et al. Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial. JAMA 2013 310: 1033-41. (Request with CPSBC or view UBC)
25. Sidhu SS, Goyal O, Singla P, et al. Corticosteroid plus pentoxifylline is not better than corticosteroid alone for improving survival in severe alcoholic hepatitis (COPE trial). Dig Dis Sci 2012 57: 1664-71. (Request with CPSBC or view UBC)
26. Thursz M, Morgan TR. Treatment of Severe Alcoholic Hepatitis. Gastroenterology 2016 150: 1823-34. (Request with CPSBC or view UBC) DOI: 10.1053/j.gastro.2016.02.074

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Prednisolone or pentoxifylline for alcoholic hepatitis

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