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DOI: 10.1055/s-0043-109370
Erhöhte Leberwerte bei einem Rheumapatienten. Was nun?
Elevated liver Enzymes in Patients with a Rheumatic Disease. What Comes Next?Publikationsverlauf
Publikationsdatum:
08. Juni 2017 (online)
Zusammenfassung
Regelmäßige Kontrollen der Leberwerte sind ein fester Bestandteil der rheumatologischen Routine. Erhöhte Transaminasen sind dabei ein häufiger Befund, für den viele verschiedene Gründe in Frage kommen. Als Erstes muss die Möglichkeit einer unerwünschten Wirkung eines der rheumatologischen Medikamente erwogen werden. Am häufigsten sind dies NSAR, vor allem Diclofenac, gefolgt von den DMARD Methotrexat oder Leflunomid. Die Kombination der letztere beiden verursacht besonders häufig Transaminasenanstiege. Der aktive Metabolit von Leflunomid muss dann unter Umständen mit Colestyramin aus dem enterohepatischen Kreislauf ausgewaschen werden. Leberwerterhöhungen durch Sulfasalazin sind selten, schwere nekrotisierende Hepatitiden als Teil einer systemischen Medikamentenreaktion können jedoch auftreten. Unter den biologischen DMARD sind es v. a. die TNF-alpha-Hemmer Infliximab und Adalimumab welche Hepatitiden verursachen können. Bei Patienten mit ankylosierender Spondylitis waren aber auch unter Etanercept Leberwertanstiege beobachtet worden. Als weitere Substanz kann der Interleukin-6-Rezeptor Antikörper Tocilizumab zu einem Anstieg der Transaminasen führen, selten auch zu schweren Leberreaktionen. Schließlich gibt es noch eine ganze Reihe von anderen Ursachen für Anstiege der Leberwerte bei Rheumapatienten, die von einer Reaktivierung oder Neuinfektion einer Virushepatitis, dem Auftreten einer Autoimmunhepatitis bis zu Begleiterkrankungen der Leber reichen. Dies alles macht ein systematisches differentialdiagnostisches Vorgehen notwendig.
Abstract
The monitoring of liver enzymes in blood on a regular basis is an established part of routine care in rheumatology. Elevated transaminases are a frequent finding, which may be attributed to various causes. Firstly, the possibility of an adverse event of a rheumatologic drug should be considered. The most common drugs causing elevated liver enzymes are NSAIDs, especially diclofenac, followed by the DMARDs methotrexate and leflunomide. The combination of the latter two causes elevated transaminase levels more frequently than the same drugs given in monotherapy. When there are strong signs of liver damage, the active metabolite of leflunomide has to be eliminated from the enterohepatic circulation by colestyramin. Elevations of liver enzymes caused by sulfasalazine are rare, but there is a possibility of severe necrotising hepatitis occurring as part of a systemic drug reaction. Biologic DMARDs may induce increased liver enzymes as well: Most commonly, it is the TNF-alpha inhibitors infliximab and adalimumab that have been reported to cause drug-induced hepatitis. However, in patients with ankylosing spondylitis, etanercept has also been reported to induce elevated transaminases. Further on, the interleukin-6 receptor antibody tocilizumab may induce elevated transaminases and, rarely, it may cause severe liver reactions. Finally, there are a number of other causes for elevated transaminases in patients with rheumatic diseases, e. g. reactivated or new viral hepatitis infection, autoimmune hepatitis or comorbid disorders of the liver. All of this requires a systematic differential diagnostic procedure in this clinical situation.
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Literatur
- 1 Albrecht K, Huscher D, Eidner T et al. Versorgung der rheumatoiden Arthritis 2014. Aktuelle Daten aus der Kerndokumentation. Z Rheumatol 2016 E-Pub
- 2 Rostom A, Goldkind L, Laine L. Nonsteroidal anti-inflammatory drugs and hepatic toxicity: a systematic review of randomized controlled trials in arthritis patients. Clin Gastroenterol Hepatol 2005; 3: 489-498
- 3 McKenna F, Borenstein D, Wendt H. et al. Celecoxib versus diclofenac in the management of osteoarthritis of the knee. Scand J Rheumatol 2001; 30: 11-18
- 4 Tarner IH, Manger B, Fleck M et al. Evidenzbasierte Empfehlungen einer nationalen Expertenrunde zum Einsatz von Methotrexat bei entzündlich-rheumatischen Erkrankungen. Akt Rheumatol 2009 (Online-Publikation)
- 5 Salliot C, van der HD. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis 2009; 68: 1100-1104
- 6 Kent PD, Luthra HS, Michet Jr C. Risk factors for methotrexate-induced abnormal laboratory monitoring results in patients with rheumatoid arthritis. J Rheumatol 2004; 31: 1727-1731
- 7 Schmajuk G, Miao Y, Yazdany J. et al. Identification of risk factors for elevated transaminases in methotrexate users through an electronic health record. Arthritis Care Res (Hoboken) 2014; 66: 1159-1166
- 8 Verstappen SM, Bakker MF, Heurkens AH. et al. Adverse events and factors associated with toxicity in patients with early rheumatoid arthritis treated with methotrexate tight control therapy: the CAMERA study. Ann Rheum Dis 2010; 69: 1044-1048
- 9 Ortiz Z, Shea B, Suarez-Almazor ME. et al. The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis. A metaanalysis of randomized controlled trials. J Rheumatol 1998; 25: 36-43
- 10 Conway R, Low C, Coughlan RJ. et al. Risk of liver injury among methotrexate users: A meta-analysis of randomised controlled trials. Semin Arthritis Rheum 2015; 45: 156-162
- 11 Quintin E, Scoazec JY, Marotte H. et al. Rare incidence of methotrexate-specific lesions in liver biopsy of patients with arthritis and elevated liver enzymes. Arthritis Res Ther 2010; 12: R143
- 12 Curtis JR, Beukelman T, Onofrei A. et al. Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide. Ann Rheum Dis 2010; 69: 43-47
- 13 Kremer JM, Genovese MC, Cannon GW. et al. Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2002; 137: 726-733
- 14 Kremer J, Genovese M, Cannon GW. et al. Combination leflunomide and methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing MTX monotherapy: open-label extension of a randomized, double-blind, placebo controlled trial. J Rheumatol. 2004; 31: 1521-1531
- 15 Krüger K, Bolten W. Behandlung der rheumatoiden Arthritis mit Leflunomid. Z Rheumatol. 2005; 64: 96-101
- 16 Queyrel V, Catteau B, Michon-Pasturel U. et al. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome after sulfasalazine and carmazepine: report of two cases. Rev Med Interne. 2001; 22: 582-586
- 17 Jobanputra P, Amarasena R, Maggs F. et al. Hepatotoxicity associated with sulfasalazine in inflammatory arthritis: A case series from a local surveillance of serious adverse events. BMC Musculoskelet Disord 2008; 9: 48
- 18 Sokolove J, Strand V, Greenberg JD. et al. Calabrese L, Hooper M, Baumgartner S, Furst DE; CORRONA Investigators. Risk of elevated liver enzymes associated with TNF inhibitor utilisation in patients with rheumatoid arthritis. Ann Rheum Dis. 2010; 69: 1612-1617
- 19 Carlsen KM, Riis L, Madsen OR. Toxic hepatitis induced by infliximab in a patient with rheumatoid arthritis with no relapse after switching to etanercept. ClinRheumatol 2009; 28: 1001-1003
- 20 van Denderen JC, Blom GJ, van der Horst-Bruinsma IE. et al. Elevated liver enzymes in patients with ankylosing spondylitis treated with etanercept. Clin Rheumatol 2012; 31: 1677-1682
- 21 Curtis JR, Perez-Gutthann S, Suissa S. et al. Tocilizumab in rheumatoid arthritis: a case study of safety evaluations of a large postmarketing data set from multiple data sources. Semin Arthritis Rheum 2015; 44: 381-388
- 22 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
- 23 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
- 24 Grasland A, Sterpu R, Boussoukaya S. et al. Autoimmune hepatitis induced by adalimumab with successful switch to abatacept. Eur J Clin Pharmacol 2012; 68: 895-898
- 25 Barone M, Notarnicola A, Lopalco G. et al. Safety of long-term biologic therapy in rheumatologic patients with a previously resolved hepatitis B viral infection. Hepatology 2015; 62: 40-46
- 26 Chung SJ, Kim JK, Park MC. et al. Reactivation of hepatitis B viral infection in inactive HBsAg carriers following anti-tumor necrosis factor-alpha therapy. J Rheumatol 2009; 36: 2416-2420
- 27 Iannone F, La Montagna G, Bagnato G. et al. Safety of etanercept and methotrexate in patients with rheumatoid arthritis and hepatitis C virus infection: a multicenter randomized clinical trial. J Rheumatol 2014; 41: 286-292
- 28 Chen YM, Chen HH, Chen YH. et al. comparison of safety profiles of tumour necrosis factor α inhibitors and rituximab therapy in patients with rheumatoid arthritis and chronic hepatitis C. Ann Rheum Dis 2015; 74: 626-627
- 29 Brunasso AM, Puntoni M, Gulia A. et al. Safety of anti-tumour necrosis factor agents in patients with chronic hepatitis C infection: a systematic review. Rheumatology (Oxford) 2011; 50: 1700-1711