Phenprocoumon-induced liver disease ranges from mild acute hepatitis to (sub-) acute liver failure

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Abstract

Background/Aims

Except for bleeding complications, other serious adverse reactions of coumarin anticoagulants such as hepatotoxicity or skin necrosis are comparatively rare. Nonetheless, a small number of coumarin-induced (sub-) acute liver failures has been published.

Methods

A retrospective analysis was performed of patients treated for liver disease between 1992 and 2002 at our department to evaluate the incidence, clinical findings and histopathology of coumarin-induced hepatotoxicity.

Results

The retrospective analysis revealed eight cases of phenprocoumon-induced hepatotoxicity, including three cases of (sub-) acute liver failure which resulted in two orthotopic liver transplantations and one fatal outcome. Five patients with phenprocoumon-induced hepatitis recovered well after anticoagulation was switched to another coumarin derivate or subcutaneous low molecular weight heparin. In all patients liver injury was predominantly of an hepatitic type. In the cases of (sub-) acute liver failure massive confluent liver cell necroses were histologically present, whereas among patients without liver failure mild portal to moderate active lobular hepatitis were observed.

A retrospective analysis by BfArM (German Federal Institute for Drugs and Medical Devices) revealed 4390 cases of possible phenprocoumon-related adverse reactions since 1990, 2% of which had presented with hepatitis and 0.2% with liver failure.

Conclusions

Phenprocoumon-induced liver disease is an uncommon complication, which can, however, cause (sub-) acute liver failure.

Introduction

Oral anticoagulants, such as the coumarin derivatives phenprocoumon (Marcumar®), Warfarin sodium (Coumadin®) and Acenocoumarol (Sintrom®), are used for the treatment and prophylaxis of thrombotic disorders, prevention of thromboembolism resulting from atrial fibrillation and after prosthetic valve replacement and arterial shunt surgery. Coumarin derivatives inhibit the proper synthesis of vitamin K-dependent clotting factors by competitively inhibiting the vitamin-K epoxide reductase [1]. The most frequent adverse reaction of coumarins are bleeding complications, resulting from over-anticoagulation, drug-interactions and co-morbidity, such as intestinal ulcers and angiodysplasias. Other side effects such as coumarin-induced skin necrosis are very rare (<0.1%; [2], [3], [4]) and are thought to result from different half-lives of vitamin K-dependent pro- and anticoagulant factors and can be avoided, if oral anticoagulant therapy with coumarin derivates is initiated with overlapping heparin treatment. Only few cases of oral anticoagulant-induced liver disease have been reported world-wide [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35]. The Swiss Drug Monitoring Centres SANZ and IKS recount 10 (1.5%) oral anticoagulant related cases among 674 reports of drug-induced hepatitis between 1981 and 1995 [36]. Fatal cases have thus far only been described once [37]. We here report eight cases of phenprocoumon-induced hepatitis, three of which led to a (sub-) acute liver failure requiring orthotopic liver transplantation in two cases and causing a fatal outcome in another case. Up to now, this is the only larger case series of oral anticoagulant induced hepatotoxicity occurring at one single centre. In addition, the results of an analysis conducted by the BfArM (German Federal Institute for Drugs and Medical Devices) summarising all submitted data of suspected phenprocoumon-induced liver disease in Germany are being described.

Section snippets

Patients

This study is a retrospective analysis of patients treated at the 1st Department of Internal Medicine of the Johannes Gutenberg-University Mainz between 1992 and 2002. Case ascertainment was done by screening all liver biopsy diagnoses and by individual recall. Liver tissue for histopathological investigation was obtained by liver biopsy. The tissue was fixed in buffered formalin (4%) and embedded routinely in paraffin for light microscopy. Cases were classified as liver failure, if prothrombin

Results

7523 patients were seen during 30,366 appointments at the in- and outpatient clinic of the First Department of Internal Medicine of the University of Mainz between 1992 and 2002 due to liver disease of diverse origins. Of those patients, 0.1% (8/7523) presented with phenprocoumon-induced liver disease.

Between 1992 and 2002 altogether 29 of our patients received orthotopic liver transplantation due to acute liver failure and in two cases (7%; cases 1 and 2) phenprocoumon was the probable

Discussion

Anticoagulant induced liver disease is a rare side effect and was first described by Rentschler et al. in 1963 [30] and Kreitner et al. in 1967 [23]. Since then a total of 30 publications reporting coumarin-induced liver disease have been published [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [37]. The Swiss Drug Monitoring Centres SANZ and IKS evaluated the

Acknowledgements

The authors would like to express their gratitude to Dr Paeschke from the German Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.

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