Z Gastroenterol 2015; 53 - A3_22
DOI: 10.1055/s-0034-1397143

Phenprocoumon-induced liver injury

BK Straub 1, V Dries 2, HU Kasper 3, E Schömig 4, U Drebber 3, C Langner 5, HP Dienes 6, P Schirmacher 1
  • 1Ruprecht-Karls-University Heidelberg, Institute of Pathology, University Clinic, Heidelberg, Germany
  • 2synlab MVZ Pathologie Mannheim GmbH, Institute of Pathology, Mannheim, Germany
  • 3University of Cologne, Institute of Pathology, Cologne, Germany
  • 4University of Cologne, Institute of Pharmacology, Cologne, Germany
  • 5Medical University of Graz, Institute of Pathology, Graz, Austria
  • 6University Vienna, Institute of Clinical Pathology, Vienna, Germany

Introduction: Phenprocoumon (Marcumar®), a derivative of 4-hydroxycoumarin with similarity to warfarin, is the most frequently used oral anticoagulant drug in continental europe. Apart from bleeding disorders, other adverse reactions are rare due to its mechanism of action. In the last years, hepatotoxicity has been observed and several case reports have been published. Yet, so far, no systematic analyses of this potentially life-threatening complication have been performed.

Material & Methods: We analysed the clinical presentation and the liver histology of 53 patients with hepatic disease of unknown origin, who were on medication with phenprocoumon.

Results: In 38 cases, the data were highly suggestive of phenprocoumon-induced liver injury, 6 cases were doubtful due to intake of several drugs described to potentially cause similar histologic findings and 9 cases could be ruled out with high probability. Histologically, in all 38 positive cases, acute or subacute hepatitis with a uniform picture of centrolobular/zone 3 necrosis with bridging necrosis was found which lead to the diagnosis. The clinical presentation of these patients ranged from elevated aminotransferases alone up to severe liver disease and acute liver failure in five patients (representing 13% of cases). Hepatic disease occurred in general 4 to 9 months after the first application of phenprocoumon, yet in 4 patients who were reexposed with phenprocoumon, relapse occurred earlier, i.e. after 1 to 6 weeks following renewed phenprocoumon-therapy. Four patients needed liver transplantation, complete recovery was eventually seen in all other patients after drug omission.

Summary: Phenprocoumon-induced liver injury is a potentially life-threatening adverse reaction with characteristic histology (centrolobular/zone 3 necroses), occurring after a latency of 4 – 9 months following onset of therapy so that often phenprocoumon is frequently not the suspected cause of the liver injury. The mechanism of action is most likely an idiosyncratic hepatic injury; yet, the mode of action is so far unknown, e.g. polymorphisms for the CYP2C9 gene have been only found in 1 (heterozygous) of 7 cases. In case of phenprocoumon-induced liver injury, complete omission of the drug is mandatory to prevent progression of liver injury, and reexposure should be strictly avoided as relapse will occur faster and more severe.

Corresponding author: Straub, Beate K.

E-Mail: beate.straub@med.uni-heidelberg.de