Characteristic histopathology of phenprocoumon-induced liver injury: correlation with clinical presentation and outcome

Phenprocoumon (PPC) was for a long time one of the most frequently used oral anticoagulant drugs in continental Europe and is still used for certain indications. We retrospectively analysed clinical presentation and liver histology of 29 PPC-patients with hepatic disease of unknown origin and validated the data in a second independent prospective cohort of 36 cases. According to causality assessment score (CIOMS), overall 50 cases were highly suggestive of PPC-induced hepatitis (PIH), 5 cases were doubtful and 10 cases could be ruled out with highest probability. Histologically, acute or subacute hepatitis with characteristic centrilobular and/or bridging necrosis was present and only minimal inflammatory infiltrate mainly consisting of ceroid-laden macrophages. The clinical presentation ranged from elevated aminotransferases in the absence of clinical symptoms to acute liver failure in 9 patients (18%) necessitating liver transplantation. Complete recovery after drug cessation was seen in 41 patients. Hepatic disease occurred 4 to 9 months after initiation of PPC treatment in 46 PIH cases and 1 to 6 weeks after reexposure in 5 PIH cases, so PPC was often not considered causative and liver biopsy was critical in supporting the diagnosis, as autoimmune hepatitis and other causes of TA elevations could be excluded. PIH-patients were significantly more often female (70% versus 49%) and of younger age (60.1 versus 71.9 years) when compared to non-hepatic PPC adverse reactions in the literature. PIH is a potentially life-threatening adverse reaction with characteristic histology, clinical presentation and course, suspicious of idiosyncratic metabolic injury. Our data suggest liver transaminase controls 3-4 months after PPC treatment start. Complete omission of PPC prevents progression of liver injury, as reexposure appears faster and more severe.