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Histopathologic changes associated with fialuridine hepatotoxicity

D E Kleiner1, M J Gaffey, R Sallie

  • 1Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
|March 1, 1997
PubMed
Summary

The antiviral drug fialuridine (FIAU) caused severe liver damage and fatalities in a clinical trial for chronic hepatitis B. Histopathology revealed significant mitochondrial injury and metabolic derangements.

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Area of Science:

  • Hepatology
  • Virology
  • Toxicology

Background:

  • Chronic hepatitis B is a global health concern with severe outcomes like cirrhosis and liver cancer.
  • Current interferon treatments for hepatitis B have limited efficacy, prompting research into new antiviral agents.
  • Nucleoside analogues are being investigated as alternative therapies for chronic hepatitis B.

Purpose of the Study:

  • To characterize the hepatic pathology associated with fialuridine (FIAU) toxicity.
  • To investigate the role of pre-existing chronic hepatitis B in the severity of FIAU-induced toxicity.
  • To correlate clinical symptoms with histopathological findings in patients treated with FIAU.

Main Methods:

  • Systematic evaluation of liver biopsy, explant, and autopsy specimens from 15 patients in a halted Phase II FIAU trial.

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  • Histopathological examination including light and electron microscopy.
  • Correlation of pathological findings with clinical data, including pre-existing hepatitis severity and toxicity symptoms.

    • Main Results:

    • Severe FIAU hepatotoxicity presented as hepatomegaly, microvesicular steatosis, glycogen depletion, bile ductular proliferation, and cholestasis.
    • Ultrastructural analysis showed intracytoplasmic lipid droplets and significant mitochondrial injury.
    • Patients without severe toxicity primarily exhibited changes related to underlying chronic hepatitis B; minimal steatosis was noted in some mildly affected patients.

    Conclusions:

    • The liver injury pattern in fialuridine toxicity suggests severe mitochondrial and metabolic dysfunction.
    • These findings highlight potential mechanisms of toxicity shared with other nucleoside analogues.
    • The study underscores the critical need for careful toxicity monitoring in antiviral drug development.