thioguanine-anhydrous and Liver-Diseases

The mean prevalence of azathioprine (AZA) or 6-mercaptopurine (MP)-induced liver injury in patients with inflammatory bowel disease was approximately 3%, and the mean annual drug-induced liver disorder rate was only 1.4%. However, this low figure calculated from retrospective studies contrasts with a much higher incidence (>10%) reported by a prospective study. Thiopurine-induced hepatotoxicity can be grouped into three syndromes: hypersensitivity, idiosyncratic cholestatic reaction, and endothelial cell injury (with resultant raised portal pressures, veno-occlusive disease, or peliosis hepatis). A small percentage of patients present with a slight elevation of liver tests (LTs) that do not have clinical implications and LTs return to normal values during the follow-up, indicating that it is not always necessary to adjust the dose of the immunomodulator. However, when abnormalities in LTs are more marked, the dose of AZA/MP may be reduced 50%, with posterior clinical and analytical controls. With this strategy, LTs frequently normalize spontaneously, and the initial AZA/MP dose may be cautiously prescribed again. Thiopurines may induce an unusual severe cholestatic jaundice that may not regress but even progress despite thiopurine withdrawal. Therefore, these drugs should be completely withdrawn, and not only tapered, in those patients presenting clinically significant jaundice. Despite a lack of evidence that monitoring of LTs is necessary in patients receiving AZA/MP, routinely performed laboratory controls including LTs seem recommendable. However, the optimal monitoring schedule remains to be established. As long-term hepatotoxicity seems to be an unpredictable and potentially severe adverse drug reaction of 6-thioguanine, this drug should not be administered outside a clinical trial setting. (Am J Gastroenterol 2007;102:1518-527).

Topics: Antimetabolites, Antineoplastic; Azathioprine; Chemical and Drug Induced Liver Injury; Global Health; Humans; Inflammatory Bowel Diseases; Liver Diseases; Mercaptopurine; Practice Guidelines as Topic; Prevalence; Thioguanine

Topics: Adolescent; Adult; Aged; Azathioprine; Female; Humans; Hyperplasia; Inflammatory Bowel Diseases; Liver Diseases; Male; Mercaptopurine; Middle Aged; Thioguanine; Young Adult

The United Kingdom (UK) acute lymphoblastic leukaemia (ALL) 97/99 clinical trial compared 6-mercaptopurine (6MP) with 6-thioguanine (6TG) as maintenance therapy for childhood ALL. Review of interim results has led to discontinuation of the 6TG arm.. We report six children with ALL, who presented with splenomegaly after a median (range) treatment duration of 12 (6-22) months. All these children were treated in the 6TG-arm.. The median (range) age at presentation was 6.6 (3.2-11.5) years. There were five boys. The presenting features were splenomegaly in all and hepatomegaly in four. AST was abnormal in one (80 IU/l, normal range 10-50). Abdominal sonography showed an altered texture of the liver parenchyma and confirmed splenomegaly. Microscopy showed findings within the spectrum of occlusive venopathy and nodular regenerative hyperplasia (NRH). After a median (range) follow-up of 23 (4-36) months splenomegaly and thrombocytopenia, suggestive of progressive portal hypertension, continue to worsen in all children.. 6TG is associated with chronic hepatic toxicity and progressive portal hypertension on follow-up. Microscopy showed NRH in all patients with features in keeping with an intrahepatic occlusive venopathy and variable parenchymal atrophy and loss.

Topics: Antimetabolites, Antineoplastic; Biopsy; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Chronic Disease; Disease Progression; Female; Follow-Up Studies; Humans; Liver Diseases; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Thioguanine; Ultrasonography

Topics: Azathioprine; Biopsy; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Tolerance; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Liver; Liver Diseases; Mercaptopurine; Thioguanine

Three children developed acute veno-occlusive disease of the liver following combination chemotherapy for acute myelocytic leukemia. The clinical presentation was similar in all three, with acute onset of hepatomegaly and thrombocytopenia in the absence of significant transaminasemia or icterus. In all three patients, radionuclide imaging with technetium-99m sulfur colloid showed hepatosplenomegaly, decreased liver uptake, and increased splenic activity. The results of liver biopsy established the diagnosis, revealing marked centrilobular congestion with hemorrhage into the spaces of Disse, atrophy of central hepatic cords, and edema of the walls of the central and sublobular veins. Each patient showed marked improvement following temporary cessation of chemotherapy. The diagnosis of veno-occlusive disease is suggested by the triad of: (1) clinical signs and symptoms; (2) scintigraphic findings; and (3) temporal relationship to chemotherapy.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Budd-Chiari Syndrome; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Daunorubicin; Drug Therapy, Combination; Female; Hepatic Veins; Humans; Leukemia, Myeloid, Acute; Liver Diseases; Male; Radionuclide Imaging; Thioguanine

Lesions of hepatic veno-occlusive disease were found in the needle biopsy specimen of one patient suffering from chronic granulocytic leukaemia and in the liver at necropsy of a second patient suffering from acute myeloid leukaemia. The treatment included administration of 6-thioguanine which was the only relevant compound used in the first patient and which was combined with cytosine arabinoside in the second patient.

Topics: Adult; Chemical and Drug Induced Liver Injury; Constriction, Pathologic; Female; Hepatic Veins; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Liver; Liver Diseases; Male; Thioguanine; Vascular Diseases