CYCLOPHOSPHAMIDE-INDUCED ACUTE LIVER-FAILURE REQUIRING TRANSPLANTATION IN A PATIENT WITH GENETICALLY DEFICIENT DEBRISOQUINE METABOLISM - A CAUSAL RELATIONSHIP

Severe liver damage can occur after treatment with cyclophosphamide. T he possible linkage to genetically deficient drug metabolic capacity i s unknown. A 58-year-old woman with rheumatoid arthritis was treated w ith oral cyclophosphamide 50 mg twice daily for 2 months. Due to poor response the dose was doubled and liver failure requiring transplantat ion developed within weeks. After surgery PCR amplification using DNA from leukocytes showed that she was homozygous for the mutated allele CYP2D6B, which is predictive of the poor metaboliser phenotype for deb risoquine, occurring in 7% of Caucasians. Our patient may have accumul ated high levels of the hepatotoxic 4-hydroxylated cyclophosphamide me tabolite. Pharmacogenetic methods can help in exploring mechanisms of unexpected severe adverse effects.