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. 2020 Jul;86(7):1406-1415.
doi: 10.1111/bcp.14254. Epub 2020 Mar 3.

Metamizole: An underrated agent causing severe idiosyncratic drug-induced liver injury

Marcial Sebode  1   2 , Martin Reike-Kunze  1 , Sören Weidemann  3 , Roman Zenouzi  1   2 , Johannes Hartl  1   2 , Moritz Peiseler  1   2 , Timur Liwinski  1   2 , Lisa Schulz  1   2 , Christina Weiler-Normann  1   2   4 , Martina Sterneck  1   5 , Ansgar W Lohse  1   2 , Christoph Schramm  1   2   4
Affiliations

Metamizole: An underrated agent causing severe idiosyncratic drug-induced liver injury

Marcial Sebode et al. Br J Clin Pharmacol. 2020 Jul.

Abstract

Aims: Drug-induced liver injury (DILI) is a heterogenous entity leading to liver damage. We have analysed the frequency, biochemical and histological patterns and clinical courses of DILI cases due to metamizole at our tertiary care centre in Hamburg, Germany.

Methods: Consecutive patients with DILI who presented to our clinic were analysed retrospectively. Causes of acute hepatitis other than DILI were excluded.

Results: In total, 154 DILI cases were admitted to our centre from 2008 to 2017. After phenprocoumon, metamizole was the second most frequent putative agent causing DILI (23 of all 154 DILI cases, 14,9%). The biochemical pattern on admission of metamizole-induced DILI cases was hepatocellular with median levels of alanine transaminase (779 U/L, 64-3532 U/L) by far exceeding median alkaline phosphatase levels (131 U/L, 42-578 U/L). In 17 of the 23 cases (74%) liver biopsy was performed. Moderate to severe inflammatory histological activity and severe centrilobular necrosis (>30%) was present in 76.5 and 35.3%, respectively. Metamizole was involved in 2 DILI cases progressing to acute liver failure, then receiving liver transplantation and still alive at time of assessment. Our data were supported by re-exposure in 4 patients. Furthermore, a database search for metamizole-induced liver injury in the European Medicines Agency's database identified about 300 reports on suspected metamizole-induced DILI in Europe.

Conclusion: Elevation of liver enzymes or acute liver failure are not mentioned in the German drug label of metamizole as potential side effects. Our study reveals that in Germany and Europe, metamizole is a frequent and underrated agent causing DILI.

Keywords: acute liver failure; drug-induced liver injury; elevated liver enzymes; metamizole; side effects.

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Figures

Figure 1
Figure 1
Liver histology of a representative patients with metamizole‐induced liver injury. Liver histology of a patient with metamizole‐induced liver injury shows infiltration of immune cells: 40× optic magnification and 4.5× digital zoom (A); 40× optic magnification and 14× digital zoom (B); and 40× optic magnification and 20× digital zoom (C)
Figure 2
Figure 2
German‐ and European‐wide database search for metamizole‐induced liver injury. The EudraVigilance data analysis system database search performed by the Bundesinstitut für Arzneimittel und Medizinprodukte identified 143 reports on liver‐related side effects being associated with metamizole in Germany (A) and 296 reports in the European Economic Area (B). The categories of liver‐related side effects are shown, ordered by frequency. Categories that were considered to be unlikely a consequence of metamizole intake and/or did not represent a proper metamizole‐induced liver injury case are not shown
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