CMV-assoziiertes Leberversagen bei einer Patientin mit systemischem Lupus erythematodes unter Immunsuppression mit Tocilizumab

Zusammenfassung

Eine 41-jährige Patientin wurde mit fieberhaftem Ikterus unter dem Bild eines akuten Leberversagens aufgenommen. Der Quick-Wert lag bei 21 %, das Bilirubin bei 258 µmol/l und es bestand eine hepatische Enzephalopathie. GOT und AP lagen max. bei 612 und 215 U/l. Trotz einer starken Linksverschiebung erreichte das CRP nur ein Maximum von 15 mg/l. Wegen eines atypisch verlaufenden systemischen Lupus erythematodes hatte sie bis 12 Tage vor Aufnahme eine Therapie mit Azathioprin, Prednisolon und Tocilizumab erhalten. Die Abklärung erbrachte eine CMV-Hepatitis und einen nekrotisierenden Leberschaden, der als medikamentös-toxisch gewertet wurde. Zum Zeitpunkt der Leberbiopsie, an Tag 3 nach Aufnahme, zeigte sich anhand der Ki-67 Färbung eine ausgeprägte regeneratorische Aktivität in der Leber. Unter einer Therapie mit Valganciclovir, einer Antibiose und einer erhöhten Steroiddosis kam es zur raschen Besserung des Leberversagens. Der Fall unterscheidet sich von den wenigen beschriebenen Fällen einer schweren akuten Leberschädigung unter Tocilizumab. Offensichtlich kam es im Zusammenhang mit der kombinierten Immunsuppression (Steroid, Azathioprin und Tocilizumab) durch die Kombination der CMV-Hepatitis und des medikamentös-toxischen Leberschadens sowie einer möglicherweise passager eingeschränkten Regeneration zum akuten Leberversagen. Andererseits kam es trotz IL6-Blockade durch Tocilizumab zu einer raschen, bioptisch gesicherten Regeneration.

Abstract

A 41-year-old female patient was admitted because of febrile jaundice and acute liver failure. The quick and the bilirubin were 21 % and 258 µmol/l, and there was hepatic encephalopathy I°. AST and AP had a maximum of 612 and 215 U/l. Despite a strong left shift in the differential, the CRP had a maximum of 15 mg/l. Because of an atypically presenting systemic lupus erythematosus, she had been treated with Azathioprine, steroids and Tocilizumab until 12 days before admission. The diagnostic workup revealed CMV hepatitis and necrotizing hepatopathy, which was interpreted as toxic hepatitis. At the time of liver biopsy, on day 3 after admission, staining for Ki-67 indicated strong regenerative activity in the liver. Treatment with Valgancyclovir, antibiotics and steroids led to early recovery from liver failure. The case differs from the few described cases of severe acute liver injury related to Tocilizumab. Apparently, the combined immunosuppression (steroid, Azathioprine and Tocilizumab) led to acute liver failure secondary to CMV hepatitis and acute toxic hepatitis, which may have been aggravated by transiently impaired liver regeneration. On the other hand, stimulated liver regeneration was proven by histology despite previous IL6 blockage by Tocilizumab.

Schlüsselwörter

akutes Leberversagen - Tocilizumab - CMV-Hepatitis - medikamentös-toxischer Leberschaden - Leberregeneration

Key words

acute liver failure - Tocilizumab - CMV hepatitis - toxic hepatitis - liver regeneration

• Literatur

• 1 Alfreijat M. Habibi M. Bhatia P. et al. Severe hepatitis associated with tocilizumab in a patient with rheumatoid arthritis. Rheumatology (Oxford) 2013; 52: 1340-1341
• 2 Alten R. Maleitzke T. Tocilizumab: a novel humanized anti-interleukin 6 (IL-6) receptor antibody for the treatment of patients with non-RA systemic, inflammatory rheumatic diseases. Ann Med 2013; 45: 357-363
• 3 Bari SF. Khan A. Lawson T. C reactive protein may not be reliable as a marker of severe bacterial infection in patients receiving tocilizumab. BMJ Case Rep 2013; pii: bcr2013010423.
• 4 Beisel C. Weiler-Normann C. Teufel A. et al. Association of autoimmune hepatitis and systemic lupus erythematodes: a case series and review of the literature. World J Gastroenterol 2014; 20: 12662-12667
• 5 Campbell L. Chen C. Bhagat SS. et al. Risk of adverse events including serious infections in rheumatoid arthritis patients treated with tocilizumab: a systematic literature review and meta-analysis of randomized controlled trials. Rheumatology (Oxford) 2011; 50: 552-562
• 6 Canbay A. Tacke F. Hadem J. et al. Acute liver failure: a life-threatening disease. Dtsch Arztebl Int 2011; 108: 714-720
• 7 da Silva CG. Studer P. Skroch M. et al. A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signals. Hepatology 2013; 57: 2014-2025
• 8 Drepper M. Rubbia-Brandt L. Spahr L. Tocilizumab-Induced Acute Liver Injury in Adult Onset Still's Disease. Case Reports Hepatol 2013; 2013 Epub 2013 Jul 15
• 9 Hiura M. Abe S. Tabaru A. et al. Case of severe liver damage after the induction of tocilizumab therapy for rheumatoid vasculitis. Hepatol Res 2011; 41: 492-496
• 10 Komura T. Ohta H. Nakai R. et al. Cytomegalovirus Reactivation Induced Acute Hepatitis and Gastric Erosions in a Patient with Rheumatoid Arthritis under Treatment with an Anti-IL-6 Receptor Antibody, Tocilizumab. Intern Med 2016; 55: 1923-1927
• 11 Kotton CN. kumar D. Caliendo AM. et al. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2013; 96: 333-360
• 12 Lee SO. Razonable RR. Current concepts on cytomegalovirus infection after liver transplantation. World J Hepatol 2010; 2: 325-336
• 13 Lepiller Q. Abbas W. Kumar A. et al. HCMV activates the IL-6-JAK-STAT3 axis in HepG2 cells and primary human hepatocytes. PLoS One 2013; 8: e59591
• 14 Ljungman P. Griffiths P. Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis 2002; 34: 1094-1097
• 15 Mahamid M. Paz K. Reuven M. et al. Hepatotoxicity due to tocilizumab and anakinra in rheumatoid arthritis: two case reports. Int J Gen Med 2011; 4: 657-660
• 16 Mori S. Fujiyama S. Hepatitis B virus reactivation associated with antirheumatic therapy: Risk and prophylaxis recommendations. World J Gastroenterol 2015; 21: 10274-10289
• 17 Mourgues C. Henquell C. Tatar Z. et al. Monitoring of Epstein-Barr virus (EBV)/cytomegalovirus (CMV)/varicella-zoster virus (VZV) load in patients receiving tocilizumab for rheumatoid arthritis. Joint Bone Spine 2016; 83: 412-415
• 18 Studer P. da Silva CG. Revuelta Cervantes JM. et al. Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration. Cell Death Differ 2015; 22: 2068-2077
• 19 van DD. Miranda C. Husni E. Cytomegalovirus viremia, pneumonitis, and tocilizumab therapy. Emerg Infect Dis 2011; 17: 754-756