Liver Injury Associated with Metamizole Exposure: Features of an Underestimated Adverse Event

Sabine Weber, Andreas Benesic, Jens Neumann, Alexander L Gerbes, Sabine Weber, Andreas Benesic, Jens Neumann, Alexander L Gerbes

Abstract

Introduction and objective: The potential of metamizole to cause drug-induced liver injury (DILI) has received increasing attention. We investigated the distinguishing features of a case series comprising 32 patients with suspected metamizole-induced DILI.

Methods: For the current analysis, 32 of 238 patients with DILI included in our prospective study on drugs potentially causing DILI were included. Diagnosis of DILI was based on expert opinion and RUCAM (Roussel Uclaf Causality Assessment Method) score and supported by an in vitro test using monocyte-derived hepatocyte-like cells.

Results: Suspected metamizole-DILI was characterised by a female predominance, hepatocellular pattern of injury, high proportion of antinuclear antibody positivity, and predominance of eosinophilic cell infiltration and necrosis in the histopathological analysis. With 22%, a high proportion of these metamizole-associated liver injury cases developed acute liver failure, which was characterised by a longer latency of metamizole use and more pronounced liver biochemistry abnormalities at onset and peak levels. Furthermore, jaundice was a common finding in the metamizole-associated liver injury cases with 66% presenting with peak bilirubin levels of 3 mg/dL or higher, which was associated with a worse outcome and a higher frequency of acute liver failure.

Conclusions: Our analysis of a well-characterised DILI cohort further supports the potential of metamizole causing DILI and provides important features for the establishment of a signature pattern of liver injury observed in patients treated with metamizole.

Clinical trial registration: ClinicalTrials.gov: NCT02353455.

Conflict of interest statement

Andreas Benesic has a patent held/filed, is a stock shareholder and had a former management position in MetaHeps GmbH. Alexander L. Gerbes has a patent held/filed and is a stock shareholder of MetaHeps GmbH. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Sabine Weber has no conflicts of interest that are directly relevant to the content of this article.

Figures

Fig. 1
Fig. 1
Histology of liver biopsy. Liver biopsy revealed moderate portal and lobular hepatitis with liver cell drop out, confluent necrosis and mild fibrosis (a, haematoxylin and eosin stain, 25-fold). In a larger magnification (b, haematoxylin and eosin stain, 100-fold), lymphohistiocytic infiltrates with scattered eosinophils and apoptosis of liver cells could be obtained. In c (haematoxylin and eosin stain, 200-fold), aggregated eosinophil granulocytes and in d (haematoxylin and eosin stain, 200-fold) apoptotic bodies (‘Councilman bodies’) are shown

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