Login Register Cart 0
Current Drug Safety

Current Drug Safety

Editor-in-Chief

ISSN (Print): 1574-8863
ISSN (Online): 2212-3911

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Case Report

Azathioprine-induced Veno-occlusive Hepatotoxicity in a Patient with Myasthenia Gravis

Author(s): Nikhil Dongre, Jayantee Kalita* and Usha K. Misra

Volume 20, Issue 1, 2025

Published on: 23 January, 2024

Page: [68 - 73] Pages: 6

DOI: 10.2174/0115748863272041231116104839

Price: $65

Become a Editorial Board Member
Become a Reviewer
Become a Editor
Become a Section Editor

Abstract

Introduction: Myasthenia gravis (MG) is an autoimmune disorder of post-synaptic neuromuscular junction characterised by fatigable muscle weakness and is treated with prednisolone with or without other immunosuppressants, including azathioprine (AZA). Veno-occlusive hepatotoxicity of AZA is a rare complication in MG.

Case Report: We report a 35-year-old man with MG, was treated with pyridostigmine, prednisolone, and AZA for 5 years. He presented with abdominal pain and increased fatiguability for 7 days. His serum bilirubin and liver enzymes were elevated, and ultrasound revealed a dilated hepatic vein and portal vein suggestive of veno-occlusive liver disease. The clinical symptoms, liver functions, and ultrasound of the hepatobiliary system normalized after withdrawal of AZA.

Conclusion: A possibility of AZA veno-occlusive hepatoxicity should be considered in a MG patient if presented with abdominal pain, elevated bilirubin and transaminases, and ultrasound showing dilatation of hepatic veins. Physicians should be aware of this complication because this toxicity is reversible following dose reduction or withdrawal of AZA.

Keywords: Azathioprine, myasthenia gravis, vena-occlusive, hepatotoxicity, AChR, MuSK, dilatation of hepatic veins.

« Previous Next »

Graphical Abstract

Graphical abstract illustrating key findings of the study

[1]
Cai XJ, Li ZW, Xi JY, et al. Myasthenia gravis and specific immunotherapy: Monoclonal antibodies. Ann N Y Acad Sci 2019; 1452(1): 18-33.
[http://dx.doi.org/10.1111/nyas.14195] [PMID: 31393614]
[2]
Deenen JCW, Horlings CGC, Verschuuren JJGM, Verbeek ALM, van Engelen BGM. The epidemiology of neuromuscular disorders: A comprehensive overview of the literature. j Neuromuscul Dis 2015; 2(1): 73-85.
[http://dx.doi.org/10.3233/JND-140045] [PMID: 28198707]
[3]
Walker MB. Treatment of myasthenia gravis with physostigmine. Lancet 1934; 223(5779): 1200-.
[http://dx.doi.org/10.1016/S0140-6736(00)94294-6]
[4]
Tindall RSA, Phillips JT, Rollins JA, Wells L, Hall K. A clinical therapeutic trial of cyclosporine in myasthenia gravis. Ann N Y Acad Sci 1993; 681(1): 539-51.
[http://dx.doi.org/10.1111/j.1749-6632.1993.tb22937.x] [PMID: 8357194]
[5]
Tindall RSA, Rollins JA, Phillips JT, Greenlee RG, Wells L, Belendiuk G. Preliminary results of a double-blind, randomized, placebo-controlled trial of cyclosporine in myasthenia gravis. N Engl J Med 1987; 316(12): 719-24.
[http://dx.doi.org/10.1056/NEJM198703193161205] [PMID: 3547126]
[6]
Lindberg C, Andersen O, Lefvert AK. Treatment of myasthenia gravis with methylprednisolone pulse: a double blind study. Acta Neurol Scand 1998; 97(6): 370-3.
[http://dx.doi.org/10.1111/j.1600-0404.1998.tb05968.x] [PMID: 9669469]
[7]
Palace J, Newsom-Davis J, Lecky B. A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis. Neurology 1998; 50(6): 1778-83.
[http://dx.doi.org/10.1212/WNL.50.6.1778] [PMID: 9633727]
[8]
Meriggioli MN, Ciafaloni E, Al-Hayk KA, et al. Mycophenolate mofetil for myasthenia gravis. Neurology 2003; 61(10): 1438-40.
[http://dx.doi.org/10.1212/01.WNL.0000094122.88929.0B] [PMID: 14638974]
[9]
Nagane Y, Utsugisawa K, Obara D, Kondoh R, Terayama Y. Efficacy of low-dose FK506 in the treatment of Myasthenia gravis--a randomized pilot study. Eur Neurol 2005; 53(3): 146-50.
[http://dx.doi.org/10.1159/000085833] [PMID: 15900097]
[10]
Sanders DB, Hart IK, Mantegazza R, et al. An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology 2008; 71(6): 400-6.
[http://dx.doi.org/10.1212/01.wnl.0000312374.95186.cc] [PMID: 18434638]
[11]
Heckmann JM, Rawoot A, Bateman K, Renison R, Badri M. A single-blinded trial of methotrexate versus azathioprine as steroid-sparing agents in generalized myasthenia gravis. BMC Neurol 2011; 11(1): 97.
[http://dx.doi.org/10.1186/1471-2377-11-97] [PMID: 21819556]
[12]
Howard JF Jr, Barohn RJ, Cutter GR, et al. A randomized, double‐blind, placebo‐controlled phase II study of eculizumab in patients with refractory generalized myasthenia gravis. Muscle Nerve 2013; 48(1): 76-84.
[http://dx.doi.org/10.1002/mus.23839] [PMID: 23512355]
[13]
Pasnoor M, He J, Herbelin L, et al. A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis. Neurology 2016; 87(1): 57-64.
[http://dx.doi.org/10.1212/WNL.0000000000002795] [PMID: 27306628]
[14]
Farmakidis C, Pasnoor M, Dimachkie MM, Barohn RJ. Treatment of myasthenia gravis. Neurol Clin 2018; 36(2): 311-37.
[http://dx.doi.org/10.1016/j.ncl.2018.01.011] [PMID: 29655452]
[15]
Matell G. Immunosuppressive drugs: Azathioprine in the treatment of myasthenia gravis. Ann N Y Acad Sci 1987; 505(1): 588-94.
[http://dx.doi.org/10.1111/j.1749-6632.1987.tb51327.x] [PMID: 3479940]
[16]
Abramsky O, Tarrab-Hazdai R, Aharonov A, Fuchs S. Immunosuppression of experimental autoimmune myasthenia gravis by hydrocortisone and azathioprine. J Immunol 1976; 117(1): 225-8.
[http://dx.doi.org/10.4049/jimmunol.117.1.225] [PMID: 932425]
[17]
Sheiko MA, Sundaram SS, Capocelli KE, Pan Z, McCoy AM, Mack CL. Outcomes in pediatric autoimmune hepatitis and significance of azathioprine metabolites. J Pediatr Gastroenterol Nutr 2017; 65(1): 80-5.
[http://dx.doi.org/10.1097/MPG.0000000000001563] [PMID: 28272159]
[18]
Wee JS, Marinaki A, Smith CH. Life threatening myelotoxicity secondary to azathioprine in a patient with atopic eczema and normal thiopurine methyltransferase activity. BMJ 2011; 342(mar25 1): d1417.
[http://dx.doi.org/10.1136/bmj.d1417] [PMID: 21441287]
[19]
Joshi R, Singh S. Plica neuropathica (Plica polonica) following Azathioprine-induced pancytopenia. Int J Trichology 2010; 2(2): 110-2.
[http://dx.doi.org/10.4103/0974-7753.77523] [PMID: 21712900]
[20]
Broekman MMTJ, Coenen MJH, van Marrewijk CJ, et al. More dose-dependent side effects with mercaptopurine over azathioprine in ibd treatment due to relatively higher dosing. Inflamm Bowel Dis 2017; 23(10): 1873-81.
[http://dx.doi.org/10.1097/MIB.0000000000001163] [PMID: 28644183]
[21]
Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: Monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980; 32(5): 651-62.
[PMID: 7191632]
[22]
Nielsen OH, Vainer B, Rask-Madsen J. The treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine. Aliment Pharmacol Ther 2001; 15(11): 1699-708.
[http://dx.doi.org/10.1046/j.1365-2036.2001.01102.x] [PMID: 11683683]
[23]
Anthony Saway P, Heck LW, Bonner JR, Kirklin JK. Azathioprine hypersensitivity. Am J Med 1988; 84(5): 960-4.
[http://dx.doi.org/10.1016/0002-9343(88)90079-4] [PMID: 3284343]
[24]
Fuggle NR, Bragoli W, Mahto A, Glover M, Martinez AE, Kinsler VA. The adverse effect profile of oral azathioprine in pediatric atopic dermatitis, and recommendations for monitoring. J Am Acad Dermatol 2015; 72(1): 108-14.
[http://dx.doi.org/10.1016/j.jaad.2014.08.048] [PMID: 25440430]
[25]
Van Geenen EJM, De Boer NKH, Stassen P, et al. Azathioprine or mercaptopurine‐induced acute pancreatitis is not a disease‐specific phenomenon. Aliment Pharmacol Ther 2010; 31(12): 1322-9.
[http://dx.doi.org/10.1111/j.1365-2036.2010.04287.x] [PMID: 20222913]
[26]
Gupta P, Shaffrali F. An unusual side effect of azathioprine. Clin Exp Dermatol 2015; 40(8): 929-30.
[http://dx.doi.org/10.1111/ced.12639] [PMID: 25810100]
[27]
Chen SC, Cummings OW, Hartley MP, Filomena CA, Cho WK. Hepatocellular carcinoma occurring in a patient with Crohn’s disease treated with both azathioprine and infliximab. Dig Dis Sci 2006; 51(5): 952-5.
[http://dx.doi.org/10.1007/s10620-005-9009-9] [PMID: 16670938]
[28]
Brinkert F, Arrenberg P, Krech T, Grabhorn E, Lohse A, Schramm C. Two cases of hepatosplenic T-cell lymphoma in adolescents treated for autoimmune hepatitis. Pediatrics 2016; 138(3): e20154245.
[http://dx.doi.org/10.1542/peds.2015-4245] [PMID: 27516526]
[29]
Gisbert JP, González-Lama Y, Maté J. Thiopurine-induced liver injury in patients with inflammatory bowel disease: A systematic review. Am J Gastroenterol 2007; 102(7): 1518-27.
[http://dx.doi.org/10.1111/j.1572-0241.2007.01187.x] [PMID: 17391318]
[30]
Read A, Wiesner RH, LaBrecque DR, et al. Hepatic veno-occlusive disease associated with renal transplantation and azathioprine therapy. Ann Intern Med 1986; 104(5): 651-5.
[http://dx.doi.org/10.7326/0003-4819-104-5-651] [PMID: 3008617]
[31]
Katzka DA, Saul SH, Jorkasky D, Sigal H, Reynolds JC, Soloway RD. Azathioprine and hepatic venocclusive disease in renal transplant patients. Gastroenterology 1986; 90(2): 446-54.
[http://dx.doi.org/10.1016/0016-5085(86)90947-9] [PMID: 3510146]
[32]
Zafrani ES, von Pinaudeau Y, Dhumeaux D. Drug-induced vascular lesions of the liver. Arch Intern Med 1983; 143(3): 495-502.
[http://dx.doi.org/10.1001/archinte.1983.00350030109018] [PMID: 6338851]
[33]
Lorenzoni Paulo José, Cláudia Suemi Kamoi Kay, Zanlorenzi Marcelo Farago, Ducci Renata Dal-Prá, Werneck Lineu Cesar, Scola Rosana Herminia. Myasthenia gravis and azathioprine treatment: Adverse events related to thiopurine S-methyl-transferase (TPMT) polymorphisms. J Neurol Sci 2020; 412: 116734.
[http://dx.doi.org/10.1016/j.jns.2020.116734]
[34]
Ansari A, Hassan C, Duley J, et al. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther 2002; 16(10): 1743-50.
[http://dx.doi.org/10.1046/j.1365-2036.2002.01353.x] [PMID: 12269967]
[35]
Bouhnik Y, Lémann M, Mary JY. Long-term follow-up of patients with Crohn's disease treated with azathioprine or 6-mercaptopurine Lancet 1996; 347(8996): 215-9.
[http://dx.doi.org/10.1016/S0140-6736(96)90402-X]
[36]
Caprilli R, Carratù R, Babbini M. A double-blind comparison of the effectiveness of azathioprine and sulfasalazine in idiopathic proctocolitis. Am J Dig Dis 1975; 20(2): 115-20.
[http://dx.doi.org/10.1007/BF01072336] [PMID: 235835]
[37]
Bastida G, Nos P, Aguas M, et al. Incidence, risk factors and clinical course of thiopurine-induced liver injury in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2005; 22(9): 775-82.
[http://dx.doi.org/10.1111/j.1365-2036.2005.02636.x]
[38]
Romagnuolo J, Sadowski DC, Lalor E, Jewell L, Thomson ABR. Cholestatic hepatocellular injury with azathioprine: A case report and review of the mechanisms of hepatotoxicity. Can J Gastroenterol 1998; 12(7): 479-83.
[http://dx.doi.org/10.1155/1998/294752] [PMID: 9812167]
[39]
Gross R, Scapa E. Hepatotoxicity of 6-mercaptopurine in Crohn’s disease. Am J Gastroenterol 1992; 87(12): 1885-6.
[PMID: 1449165]
[40]
de Boer NK, Mulder CJ, van Bodegraven AA. Myelotoxicity and hepatotoxicity during azathioprine therapy. Neth J Med 2005; 63(11): 444-6.
[PMID: 16397313]
[41]
Russmann S, Zimmermann A, Krähenbühl S, Kern B, Reichen J. Veno-occlusive disease, nodular regenerative hyperplasia and hepatocellular carcinoma after azathioprine treatment in a patient with ulcerative colitis. Eur J Gastroenterol Hepatol 2001; 13(3): 287-90.
[http://dx.doi.org/10.1097/00042737-200103000-00013] [PMID: 11293451]
[42]
Holtmann M, Schreiner O, Köhler H, et al. Veno-occlusive disease (VOD) in Crohn’s disease (CD) treated with azathioprine. Dig Dis Sci 2003; 48(8): 1503-5.
[http://dx.doi.org/10.1023/A:1024755521423] [PMID: 12924643]
[43]
Wanless IR, Godwin TA, Allen F, Feder A. Nodular regenerative hyperplasia of the liver in hematologic disorders: A possible response to obliterative portal venopathy. A morphometric study of nine cases with an hypothesis on the pathogenesis. Medicine 1980; 59(5): 367-79.
[http://dx.doi.org/10.1097/00005792-198009000-00004] [PMID: 7432153]
[44]
Seiderer J, Zech CJ, Diebold J, et al. Nodular regenerative hyperplasia: A reversible entity associated with azathioprine therapy. Eur J Gastroenterol Hepatol 2006; 18(5): 553-5.
[http://dx.doi.org/10.1097/00042737-200605000-00018] [PMID: 16607155]
[45]
de Boer NKH, Reinisch W, Teml A, et al. 6-Thioguanine treatment in inflammatory bowel disease: A critical appraisal by a European 6-TG working party. Digestion 2006; 73(1): 25-31.
[http://dx.doi.org/10.1159/000091662] [PMID: 16493198]
[46]
Hohlfeld R, Michels M, Heininger K, Besinger U, Toyka KV. Azathioprine toxicity during long-term immunosuppression of generalized myasthenia gravis. Neurology 1988; 38(2): 258-61.
[http://dx.doi.org/10.1212/WNL.38.2.258] [PMID: 3340289]
[47]
Booth RA, Ansari MT, Loit E, et al. Assessment of thiopurine S-methyltransferase activity in patients prescribed thiopurines: A systematic review. Ann Intern Med 2011; 154(12): 814-23.
[http://dx.doi.org/10.7326/0003-4819-154-12-201106210-00009]
[48]
Arber N, Zajicek G, Nordenberg J, Sidi Y. Azathioprine treatment increases hepatocyte turnover. Gastroenterology 1991; 101(4): 1083-6.
[http://dx.doi.org/10.1016/0016-5085(91)90737-6] [PMID: 1889701]
[49]
Samarasena J, Borgaonkar M. Development of hepatocellular carcinoma in a patient with Crohn’s disease treated with azathioprine. Dig Dis Sci 2007; 52(10): 2748-50.
[http://dx.doi.org/10.1007/s10620-006-9613-3] [PMID: 17404860]

Rights & Permissions Print Cite
Article Metrics
Pdf icon 58
Html icon 2
Find your institution