Chronic hepatitis B is a widespread viral illness with the serious sequelae of
cirrhosis and
hepatocellular carcinoma. Current
therapy with
interferon is not universally efficacious, and this has led to the evaluation of other
antiviral agents. A recent Phase II trial of the
nucleoside analogue, fluoroiodoarabinofuranosyluracil (
fialuridine,
FIAU) was halted because of the sudden development of severe multisystem toxicity characterized by
hepatic failure,
lactic acidosis, and
pancreatitis, which resulted in the deaths of five patients. We systematically evaluated pre- and post-
therapy biopsy, explant, and autopsy specimens from the 15 patients involved in this trial to define the hepatic changes of
fialuridine toxicity and to determine whether the degree of pre-existing
hepatitis contributed to the severity of toxicity. Severe hepatotoxicity from
fialuridine was characterized by
hepatomegaly with diffuse, predominantly microvesicular steatosis, hepatocellular
glycogen depletion, marked bile ductular proliferation, and
cholestasis. Ultrastructural examination revealed intracytoplasmic lipid droplets and marked mitochondrial injury. Patients in whom severe toxicity did not develop mainly showed changes caused by the underlying
chronic hepatitis B alone. There was a subtle increase in the amount of microvesicular steatosis in two of six patients with mild or no symptoms of toxicity. The microscopic and ultrastructural pattern of injury and systemic symptoms in patients with
fialuridine toxicity are consistent with severe mitochondrial and metabolic derangements. Similar hepatic pathologic findings have been reported rarely for other
antiviral nucleoside analogues, which suggests that the mechanisms of toxicity might be related.