Hepatic ultrastructure in leukemic children treated with methotrexate and 6-mercaptopurine

Methotrexate (MTX) and 6-mercaptopurine (6MP), the two drugs most commonly used for maintenance treatment of childhood leukemia, are both potent hepatotoxins. In order to assess MTX-6MP-induced damage, we obtained biopsies from 11 children with acute lymphocytic leukemia (ALL) for light microscopic and transmission electron microscopic study. Prednisone, vincristine, and L-asparaginase were used for induction of remission in all patients. Although light microscopic findings were minimal, we found significant ultrastructural abnormalities in all patients. Changes included nuclear abnormalities, disruption of rough and smooth endoplasmic reticulum, a variety of mitochondrial changes, steatosis, fibrosis, and changes in peroxisomes and lysosomes. These abnormalities could not have been predicted from liver function tests or histopathology. Three of the eleven patients studied had also received cyclophosphamide and cytosine arabinoside during maintenance therapy. The ultrastructural abnormalities in this group were not distinguishable from those observed in the group that did not receive these additional chemotherapeutic agents. The long-term clinical significance of these findings is not known.