Pathology of flupirtine-induced liver injury: a histological and clinical study of six cases

Virchows Arch. 2011 Jun;458(6):709-16. doi: 10.1007/s00428-011-1087-9. Epub 2011 May 18.


Drug-induced liver injury may cause impairment of liver function and is a leading cause of acute liver failure. Identification of the causative substance in patients receiving several drugs is often difficult in clinical practice. Evaluation of liver biopsies in suspected drug-induced injury is a challenging task that requires close clinico-pathological correlation. Recognizing a characteristic morphological pattern of liver injury may contribute to identification of the causative drug. Flupirtine, a non-opioid analgesic, has been reported to cause liver injury of idiosyncratic type in rare instances. We wished to characterize the histopathological features of flupirtine-induced liver injury, which have not been reported so far. Liver biopsies of five patients with severe liver injury and one explanted liver of a patient with flupirtine-induced acute liver failure that required transplantation were assessed. In addition clinical presentation and course were reviewed and clinical follow up was performed. Extensive perivenular necrosis with associated ceroid pigment-laden macrophages and a mild to moderate lymphocytic infiltrate was a common feature in all cases. Histological extent of liver necrosis corresponded well to serum amino-transferase levels. Accidental reexposure of one patient resulted in a plasma cell rich hepatitis with perivenular necrosis. This study provides evidence that flupirtine can cause substantial liver injury of hepatocellular type. Liver damage is associated with a characteristic morphological picture, the recognition of which will aid in causality assessment of drug-induced liver injury. Clinical and histological features raise the possibility of an immune-mediated toxicity.

Publication types

  • Case Reports

MeSH terms

  • Aged
  • Alanine Transaminase / blood
  • Aminopyridines / adverse effects*
  • Analgesics / adverse effects*
  • Aspartate Aminotransferases / blood
  • Biopsy
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Chemical and Drug Induced Liver Injury / pathology*
  • Female
  • Humans
  • Liver / metabolism
  • Liver / pathology
  • Lymphocytes / pathology
  • Macrophages / pathology
  • Male
  • Middle Aged


  • Aminopyridines
  • Analgesics
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • flupirtine