Transient acute hepatotoxicity of high-dose methotrexate therapy during childhood.
Serial liver-enzyme determinations were performed on 36 children with acute lymphoblastic leukemia who were randomized to receive either conventional intrathecal methotrexate (MTX) therapy with cranial irradiation, or an investigational high-dose MTX regimen consisting of 10 courses of 33,600 mg/m2 over 24 hours, with high-dose leucovorin rescue. Both groups of patients received intermittent low-dose oral MTX during maintenance therapy. Serum transaminase elevations in the group of conventionally treated patients were infrequent and moderate in severity (less than 300 IU/liter). In the investigational group, however, the majority of patients had severe, acute increases in SGPT (greater than 300 IU/liter), with peaks up to 1000 to 2000 IU/liter. The incidence and severity of acute transaminasemia were directly proportional to the number of high-dose MTX courses received: courses 1, 2, 3, 4, 5, and 6 caused transaminase elevations in 31%, 50%, 50%, 73%, 100%, and 100% of courses, respectively, and 0%, 14%, 20%, 44%, 55%, and 92%, respectively, were over 300 IU/liter. Patients in both treatment groups developed a pattern of increasing serum alkaline phosphatase concentrations after initiation of low-dose oral MTX therapy; isoenzyme analysis indicated that this effect was osseous rather than hepatic. Serum bilirubin was rarely elevated. Transaminases returned to normal within 1 to 2 weeks after each high-dose MTX treatment, and with follow-up for as long as 7 years, no patient has developed clinical evidence of residual liver disease, after 3 years of high-dose MTX therapy and multiple other antileukemia drugs. The acute hypertransaminasemia frequently observed after high-dose MTX therapy is transient and reversible, and, in children, does not appear to result in chronic liver disease.
D000293:Adolescent; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000139:chemically induced* / Q000201:enzymology; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007278:Injections, Spinal; D007945:Leukemia, Lymphoid / Q000188:drug therapy*; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects*; D013997:Time Factors
D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin; D008727:Methotrexate