Diagnostically Confusing Complications of Diphenylhydantoin Therapy

Abstract

Diphenylhydantoin (DPH) is responsible for a variety of hematologic, reticuloendothelial, and metabolic complications that are diagnostically confusing. The metabolism of DOH is briefly reviewed. Megaloblastic anemia, with leukopenia and thrombocytopenia, results from competitive inhibition of folic acid by hydantoins and barbiturates; these drugs presumably cause decreased folic acid utilization. The megaloblastic anemia is readily reversible with small doses of folic acid, even with continuation of the anticonvulsant. Leukopenia, including fatal agranulocytosis, pancytopenia, thrombocytopenia, and red cell aplasia may also occur with DPH. Reticuloendothelial reactions mimicking malignant lymphomas, infectious mononucleosis, and hepatitis are reviewed. A hypersensitivity mechanism is considered likely, since dermatitis, fever, and eosinophilia are closely associated with this reaction. Histologically, the lymph nodes may closely resemble reticulum cell sarcoma. A low serum protein-bound iodine due to competition for the binding sites of thyroxin-binding globulin by DPH occurs in the presence of normal thyroid function and may lead to a misdiagnosis of hypothyroidism. This competition does not occur with other anticonvulsant drugs. Depressed adrenal cortical function and diminished response of the pituitary-hypothalamic axis to stress occurs with DPH administration. The depressed function is not clinically significant but it may lead to misdiagnoses of adrenal cortical insufficiency or panhypopituitarism.