mercaptopurine and Esophageal-and-Gastric-Varices

6-Thioguanine (TG) was recently studied to determine whether TG in maintenance therapy achieves better event free survival than 6-mercaptopurine (MP) for standard risk acute lymphoblastic leukemia (ALL) on the clinical trial, CCG-1952 (5/1996-1/2000). Veno-occlusive disease was previously recognized as a complication of TG on CCG-1952. We report a newly recognized pediatric complication of TG: splenomegaly and portal hypertension (PH) developing during maintenance or after completion of therapy.. Twelve patients (3-10 years) had been randomized to receive a targeted dose of 50 mg/m(2)/day of TG during maintenance phases. Actual TG dose ranged from 25 to 77 mg/m(2)/day (median 34 mg/m(2)/day).. The initial patient, a boy who had marked thrombocytopenia and intermittent splenomegaly during maintenance therapy, was evaluated for persistent pancytopenia and progressive splenomegaly 3 months after completion of therapy. Dilated splenic vein and collaterals consistent with PH were documented by MRI/MRA. Esophagogastroduodenoscopy found esophageal varices. Liver biopsy showed periportal fibrosis and marked dilatation of veins and venules. Of the other 12 patients, 9 patients studied had abnormal MRI/MRAs with evidence of varices in 4. Eight patients had splenomegaly on physical examination. Liver biopsies in a girl after 3.3 courses of TG and a boy after 4.6 courses of TG showed periportal fibrosis and dilatation of venules and sinusoids and minimal focal fatty changes. Subsequent MRI/MRAs have been stable or improved.. The evaluations of these 12 patients suggest that treatment with TG causes injury to the liver leading to PH and that thrombocytopenia and splenomegaly are clinical hallmarks of this toxicity.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Child; Child, Preschool; Esophageal and Gastric Varices; Female; Humans; Hypertension, Portal; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Male; Mercaptopurine; Pancytopenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Splenomegaly; Thioguanine; Thrombocytopenia

Immunomodulator therapy with thiopurine analogues azathioprine or 6-mercaptopurine is commonly prescribed for the treatment of organ transplantation, inflammatory bowel disease, autoimmune diseases and malignancies. Hepatotoxicity due to thiopurine analogues usually presents as an increase in serum transaminase levels. Toxicity is usually not severe, and a dose reduction is effective in most patients. Nodular regenerative hyperplasia (NRH) is a very rare but potentially severe complication of thiopurine-containing therapy. NRH is often asymptomatic, neither biochemical nor molecular markers are indicative for NRH. The suspicion rises when there are clinical symptoms of portal hypertension or increases in transaminases levels orthrombocytopenia. Liver biopsy is essential for definitive diagnosis. This is a case report of a 40-year-old male patient with Crohn's disease who developed increased serum levels of liver enzymes and thrombocytopenia following the administration of thiopurine. Although treatment with thiopurine was discontinued, he has further progressed and presented with acute variceal bleeding due to portal hypertension. The diagnosis of nodular regenerative hyperplasia was proven by a liver biopsy. In conclusion, NRH is a very rare but potentially severe complication of thiopurine-containing immunosuppressive therapy for IBD.

Topics: Adult; Chemical and Drug Induced Liver Injury; Crohn Disease; Disease Progression; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Hyperplasia; Hypertension, Portal; Immunosuppressive Agents; Male; Mercaptopurine; Thrombocytopenia

Topics: Antimetabolites; Biopsy; Chemical and Drug Induced Liver Injury; Child; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Hypersplenism; Hypertension, Portal; Leukemia, Lymphoid; Liver; Liver Diseases; Mercaptopurine