Glucocorticosteroids for people with alcoholic hepatitis (Cochrane review)

  • Authors: Pavlov C.S1,2, Varganova D.L2,3, Casazza G.4, Tsochatzis E.5, Nikolova D.6, Gluud C.6
  • Affiliations:
    1. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital
    2. Center for Evidence Based Medicine, Sechenov First Moscow State Medical University
    3. Department of Gastroenterology, Ulyanovsk Regional Clinical Hospital
    4. Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Università degli Studi di Milano
    5. Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health
    6. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital
  • Issue: Vol 91, No 8 (2019)
  • Pages: 52-66
  • Section: Editorial
  • URL: https://journals.rcsi.science/0040-3660/article/view/33614
  • DOI: https://doi.org/10.26442/00403660.2019.08.000354
  • ID: 33614

Cite item

Full Text

Abstract

Alcoholic hepatitis (AH) is a form of alcoholic liver disease. Glucocorticosteroids (GCS) are used as anti - inflammatory drugs for people with alcoholic hepatitis. Aim. To assess the benefits and harms of GCS in people with AH. Material and methods. We identified trials through electronic searches in Cochrane Hepato-Biliary's (CHB) Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, and Science Citation Index Expanded. We considered for inclusion randomised clinical trials (RCTs) assessing GCS versus placebo/no intervention in adult participants with AH. We allowed co - interventions in the trial groups if they were similar. We followed Cochrane methodology, CHB Group methodology using Review Manager 5 and Trial Sequential Analysis(TSA) to perform meta - analysis (M-A), assessed bias risk of the trials, certainty of evidence using GRADE. Results and discussion. Sixteen trials fulfilled the inclusion criteria. Fifteen trials provided data for analysis (927 participants received GCS, 934 - placebo/no intervention). The GCS were administered to adult participants at different stages of AH orally or parenterally for a median of 28 days. There was no evidence of effect of GCCs on our primary outcomes all - cause mortality up to 3 months following randomisation (RR 0.90, 95% CI 0.70-1.15; n=1861), on health - related quality of life (MD - 0.04 points; 95% CI -0.11-0.03; n=377; trial = 1) (EQ-5D-3L scale), on the occurrence of serious adverse events during treatment (RR 1.05, 95% CI 0.85-1.29; n=1861). We found no evidence of a difference between the intervention groups. The risk of bias was high in all the trials except one. The certainty of evidence was very low or low. One of the trials seems to be not industry - funded. Conclusion. We found no evidence of a difference between GCS and placebo or no intervention on all - cause mortality, health - related quality of life, and serious adverse events during treatment. We cannot exclude increases in adverse events and cannot rule out significant benefits and harms of GCSs. Future trials ought to report depersonalised individual participant data.

About the authors

Chavdar S Pavlov

The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital; Center for Evidence Based Medicine, Sechenov First Moscow State Medical University

Email: chpavlov@mail.ru
д.м.н., проф., директор центра доказательной медицины технопарка биомедицины, проф. каф. пропедевтики внутренних болезней ФГАОУ ВО «Первый МГМУ им. И.М. Сеченова»; ORCID: 0000-0001-5031-9798 Russia

Daria L Varganova

Center for Evidence Based Medicine, Sechenov First Moscow State Medical University; Department of Gastroenterology, Ulyanovsk Regional Clinical Hospital

м.н.с. центра доказательной медицины технопарка биомедицины ФГАОУ ВО «Первый МГМУ им. И.М. Сеченова», врач-гастроэнтеролог ГУЗ «Ульяновская ОКБ»; ORCID: 0000-0002-5745-7605 Russia

Giovanni Casazza

Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Università degli Studi di Milano

проф., отд. биомедицинской статистики, Клиника Л. Сакко; ORCID: 0000-0003-3718-1784 Italy

Emmanuel Tsochatzis

Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health

д.м.н., проф., Гепатологический центр Шейлы Шерлок; ORCID: 0000-0001-5069-2461 London, UK

Dimitrinka Nikolova

The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital

правляющий редактор, Гепатобилиарная группа Кокрейна, Университетский госпиталь Копенгагена; ORCID: 0000-0001-5976-6762 Denmark

Christian Gluud

The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital

рук. Гепатобилиарной группы Кокрейна, Университетский госпиталь Копенгагена; ORCID: 0000-0002-8861-0799 Denmark

References

  1. WHO. Global status report: Alcohol and health, 2018. Available from: https://www.who.int/substance_abuse/publications/global_alcohol_report/gsr_2018/en/ (Ссылка активна на 19.04.2019).
  2. EASL Clinical Practice Guidelines: Management of alcohol - related liver disease. J Hepatol. 2018;69:154-81. doi: 10.1016/j.jhep.2018.03.018
  3. WHO. Global status report: Alcohol and health, 2014. Available from: http://www.who.int/substance_abuse/publications/ global_alcohol_report/en/ (Ссылка активна на 21.03.2019).
  4. Ellis E.L, Mann D.A. Clinical evidence for the regression of liver fibrosis. J Hepatol. 2012;56(5):1171-80. doi: 10.1016/j.jhep.2011.09.024
  5. Maddrey W.C, Boitnott J.K, Bedine M.S, Weber F.L. Jr, Mezey E, White R.I. Jr. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology. 1978;75(2):193-9.
  6. Dunn W, Jamil L.H, Brown L.S, Wiesner R.H, Kim W.R, Menon K.V.N, et al. MELD accurately predicts mortality in patients with alcoholic hepatitis. Hepatology (Baltimore, Md.). 2005;41:353-8. doi: 10.1002/hep.20503
  7. Forrest E.H, Evans C.D, Stewart S, Phillips M, Oo Y.H, Mc Avoy N.C, et al. Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score. Gut. 2005;54:1174-9. doi: 10.1136/gut.2004.050781
  8. Dominguez M, Rincon D, Abraldes J.G, Miquel R, Colmenero J, Bellot P, et al. A new scoring system for prognostic stratification of patients with alcoholic hepatitis. Am J Gastroenterol. 2008;103:2747-56. doi: 10.1111/j.1572-0241.2008.02104.x
  9. Carithers R.L. Jr, Herlong H.F, Diehl A.M, Shaw E.W, Combes B, Fallon H.J, et al. Methylprednisolone therapy in patients with severe alcoholic hepatitis. A randomized multicenter trial. Ann Intern Med.1989;110:685-90. doi: 10.7326/0003-4819-110-9-685
  10. Phillips M, Curtis H, Portmann B, Donaldson N, Bomford A, O’Grady J. Antioxidants versus corticosteroids in the treatment of severe alcoholic hepatitis - a randomised clinical trial. J Hepatol. 2006;44:784-90. doi: 10.1016/j.jhep.2005.11.039
  11. O'Shea R.S, Dasarathy S, Mc Cullough A.J. Alcoholic liver disease. Hepatology (Baltimore, Md.). 2010;51:307-28. doi: 10.1002/hep.23258
  12. Ивашкин В.Т., Маевская М.В., Павлов Ч.С., Сиволап Ю.П., Луньков В.Д., Жаркова М.С., Масленников Р.В. Клинические рекомендации Российского общества по изучению печени по ведению взрослых пациентов с алкогольной болезнью печени. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2017;27(6):20-40. doi: 10.22416/1382-4376-2017-27-6-20-40
  13. www.lillemodel.com
  14. Louvet A, Naveau S, Abdelnour M, Ramond M.J, Diaz E, Fartoux L. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology (Baltimore, Md.). 2007;45(6):1348-54. doi: 10.1002/hep.21607
  15. Lefkowitch J.H. Morphology of alcoholic liver disease. Clin Liv Dis. 2005;9(1):37-53. doi: 10.1016/j.cld.2004.11.001
  16. Christensen E, Gluud C. Glucocorticoids are ineffective in alcoholic hepatitis: a meta - analysis adjusting for confounding variables [see comments]. Gut. 1995;37(1):113-8. doi: 10.1136/gut.37.1.113
  17. Rambaldi A, Saconato H.H, Christensen E, Thorlund K, Wetterslev J, Gluud C. 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(12):1167-78. doi: 10.1111/j.1365-2036.2008.03685.x
  18. Reynolds T.B, Benhamou J.P, Blake J, Naccarato R, Orrego H. Treatment of acute alcoholic hepatitis. Gastroenterol Int. 1989;2(4):208-16.
  19. Imperiale T.F, Mc Cullough A.J. Do corticosteroids reduce mortality from alcoholic hepatitis? A meta - analysis of the randomized trials. Ann Intern Med. 1990;113(4):299-307. doi: 10.7326/0003-4819-113-4-299
  20. Daures J-P, Peray P, Bories P, Blanc P, Yousfi A, Michel H, et al. Steroid therapy in acute alcoholic hepatitis: a pooled estimate based on published randomized controlled trials [Place de la corticotherapie dans le traitement des hépatites alcooliques aiguës. Résultants d'une méta - analyse]. Gastroenterologie Clinique et Biologique. 1991;51:223-8.
  21. Christensen E, Gluud C. Glucocorticosteroids are not effective in alcoholic hepatitis. Am J Gastroenterol. 1999;94(10)(3065):66.
  22. Mathurin P, O'Grady J, Carithers R.L, Phillips M, Louvet A, Mendenhall C.L, et al. Corticosteroids improve short - term survival in patients with severe alcoholic hepatitis: meta - analysis of individual patient data. Gut. 2011;60(2):255-60. doi: 10.1136/gut.2010.224097
  23. Louvet A, Thursz M, Kim D.J, Labreuche J, Atkinson S.R, Sidhu S.S, et al. Corticosteroids reduce risk of death within 28 days for patients with severe alcoholic hepatitis, compared with pentoxifylline or placebo - a meta - analysis of individual data from controlled trials. Gastroenterology. 2018;155:458-68. doi: 10.1053/j.gastro.2018.05.011
  24. Pavlov C.S, Varganova D.L, Casazza G, Tsochatzis E, Nikolova D, Gluud C. Glucocorticosteroids for people with alcoholic hepatitis. Cochrane Database Syst Rev. 2017;(11):Art. No.: CD001511. doi: 10.1002/14651858.CD001511.pub3
  25. Pavlov C.S, Tsochatzis E, Casazza G, Nikolova D, Volcek E, Gluud C. Glucocorticosteroids for people with alcoholic hepatitis [Protocol]. Cochrane Database Syst Rev. 2016;(6). doi: 10.1002/14651858
  26. International Conference on Harmonisation Expert Working Group. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Guideline for good clinical practice CFR & ICH Guidelines. Vol. 1. Philadelphia (PA): Barnett International/PAREXEL, 1997.
  27. Higgins J.P.T, Altman D.G, Sterne J.A.C (eds). Chapter 8: Assessing risk of bias in included studies. In: Higgins J.P.T, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from: handbook.cochrane.org
  28. Gluud C, Nikolova D, Klingenberg S.L. Cochrane Hepato-Biliary Group. About Cochrane (Cochrane Review Groups (CRGs)) 2017, Issue 2. Art. No.: LIVER 2017.
  29. Jakobsen J, Wetterslev J, Winkel P, Lange T, Gluud C. Thresholds for statistical and clinical significance in systematic reviews with meta - analytic methods. BMC Med Res Methodol. 2014;14:120. doi: 10.1186/1471-2288-14-120
  30. Higgins J.P.T, Thompson S.G. Quantifying heterogeneity in a meta - analysis. Stat Med. 2002;21(11):1539-58. doi: 10.1002/sim.1186
  31. GRADE [Computer program]. Available from: http://www.gradeworkinggroup.org/
  32. Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, the Cochrane Collaboration; 2014. Available from: https://community.cochrane.org/help/tools-and-software/revman-5. Accessed Sep 9, 2018.
  33. TSA - Trial Sequential Analysis [Computer program]. Version 0.9 Beta. Copenhagen: Copenhagen Trial Unit, 2011. Available from: www.ctu.dk/tsa/downloads.aspx
  34. Wetterslev J, Jakobsen J.C, Gluud C. Trial Sequential Analysis in systematic reviews with meta - analysis. BMC Med Res Methodol. 2017;17(1):39. doi: 10.1186/s12874-017-0315-7
  35. Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G, Gluud C. User manual for Trial Sequential Analysis (TSA). Available from: ctu.dk/tsa/files/tsa_manual.pdf
  36. Brok J, Thorlund K, Gluud C, Wetterslev J. Trial Sequential Analysis reveals insufficient information size and potentially false positive results in many meta - analyses. J Clin Epidemiol. 2008;61:763-9. doi: 10.1016/j.jclinepi.2007.10.007
  37. Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta - analyses may be inconclusive - Trial Sequential Analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta - analyses. Int J Epidemiol. 2009;38(1):287-98. doi: 10.1093/ije/dyn188
  38. Thorlund K, Devereaux P.J, Wetterslev J, Guyatt G, Ioannidis J.P, Thabane L, et al. Can trial sequential monitoring boundaries reduce spurious inferences from meta - analyses. Int J Epidemiol. 2009;38(1):276-86. doi: 10.1093/ije/dyn179
  39. Thorlund K, Anema A, Mills E. Interpreting meta - analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV-infected individuals. Clin Epidemiol. 2010;2:57-66. doi: 10.2147/СLEP.S9242
  40. Helman R.A, Temko M.H, Nye S.W, Fallon H.J. Alcoholic hepatitis. Natural history and evaluation of prednisolone therapy. Ann Intern Med. 1971;74(3):311-21. doi: 10.7326/0003-4819-74-3-311
  41. Porter H.P, Simon F.R, Pope C.E. II, Volwiler W, Fenster L.F. Corticosteroid therapy in severe alcoholic hepatitis. A double - blind drug trial. N Engl J Med. 1971;284(24):1350-5. doi: 10.1056/NEJM197106172842404
  42. Blitzer B.L, Mutchnick M.G, Joshi P.H, Phillips M.M, Fessel J.M, Conn H.O. Adrenocorticosteroid therapy in alcoholic hepatitis. A prospective, double - blind randomized study. Dig Dis. 1977;22(6):477-84.
  43. Mendenhall C.L, Goldberg S. Risk factors and therapy in alcoholic hepatitis (AH). Gastroenterology. 1977;72(5):1100.
  44. Mendenhall C.L, Anderson S, Garcia-Pont P, Goldberg S, Kiernan T, Seeff L.B, et al. Short - term and long - term survival in patients with alcoholic hepatitis treated with oxandrolone and prednisolone. N Engl J Med. 1984;311(23):1464-70. doi: 10.1053/jhep.2000.8627
  45. Shumaker J.B, Resnick R.H, Galambos J.T, Makopour H, Iber F.L. A controlled trial of 6-methylprednisolone in acute alcoholic hepatitis. With a note on published results in encephalopathic patients. Am J Gastroenterol. 1978;69(4):443-9.
  46. Depew W, Boyer T, Omata M, Redeker A, Reynolds T. Double - blind controlled trial of prednisolone therapy in patients with severe acute alcoholic hepatitis and spontaneous encephalopathy. Gastroenterology. 1980;78(3):524-9.
  47. Ramond M.J, Poynard T, Rueff B, Mathurin P, Theodore C, Chaput J.C, et al. A randomized trial of prednisolone in patients with severe alcoholic hepatitis. New Engl J Med. 1992;326:507-12. doi: 10.1056/NEJM199202203260802
  48. De B.K, Mandal S.K, Sau D, Mani S, Chatterjee S, Mondal S.S, et al. Pentoxifylline plus prednisolone versus pentoxifylline only for severe alcoholic hepatitis: a randomized controlled clinical trial. Ann Med Health Sci Res. 2014; 4(5):810-16. doi: 10.4103/2141-9248.141562
  49. Thursz M.R, Richardson P, Allison M, Austin A, Bowers M, Day C.P, et al. Prednisolone or pentoxifylline for alcoholic hepatitis. New Engl J Med. 2015;372(17):1619-28. doi: 10.1056/NEJMoa1412278
  50. Campra J.L, Hamlin E.M. Jr, Kirshbaum R.J, Olivier M, Redeker A.G, Reynolds T.B. Prednisone therapy of acute alcoholic hepatitis. Report of a controlled trial. Ann Intern Med. 1973;79(5):625-31. doi: 10.7326/0003-4819-79-5-625
  51. Theodossi A, Eddleston A.L, Williams R. Controlled trial of methylprednisolone therapy in severe acute alcoholic hepatitis. Gut. 1982;23(1):75-9. doi: 10.1136/gut.23.1.75
  52. Bories P, Guedj J.Y, Mirouze D, Yousfi A, Michel H. Prednisolone treatment of alcoholic hepatitis: forty - five patients [Traitement de l'hepatite alcoolique aigue par la prednisolone. Quarante - cinq malades]. La Presse Medicale. 1987;16:769-72.
  53. Richardet J.P, Dehoux M, Mal F, Roulot D, Labadie H, Pol S, et al. Influence of corticosteroids (CS) on plasma cytokines concentrations in patients with severe alcoholic hepatitis (HA): results of a randomized study. J Hepatol. 1993;18:S75.
  54. Lesesne H.R, Bozymski E.M, Fallon H.J. Treatment of alcoholic hepatitis with encephalopathy. Comparison of prednisolone with caloric supplements. Gastroenterology. 1978;74(2 Pt 1):169-73.
  55. Cabré E, Rodríguez-Iglesias P, Caballería J, Quer J.C, Sánchez-Lombraña J.L, Parés A, et al. Short - and long - term outcome of severe alcohol - induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial. Hepatology (Baltimore, Md.). 2000;32:36-42. doi: 10.1053/jhep.2000.8627
  56. Harbord R.M, Egger M, Sterne J.A.C. A modified test for small - study effects in meta - analyses of controlled trials with binary endpoints. Statist Med. 2006;25(20):3443-57. doi: 10.1002/sim.2380
  57. Student. The probable error of a mean. Biometrika. 1908;6(1):1-25.
  58. Buzzetti E, Kalafateli M, Thorburn D, Davidson B.R, Thiele M, Gluud L.L, et al. Pharmacological interventions for alcoholic liver disease (alcohol - related liver disease). Cochrane Database System Rev. 2017;(3):Art. No.: CD011646. doi: 10.1002/14651858
  59. Chan A.W, Tetzlaff J.M, Altman D.G, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200-7. doi: 10.7326/0003-4819-158-3-201302050-00583

Copyright (c) 2019 Consilium Medicum

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
 
 


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies