mercaptopurine and Hypertension--Portal

Thiopurines represent an effective and widely used immunosuppressant in the therapeutic armamentarium of inflammatory bowel disease. However up to 25% of patients may be unable to continue the drug due to side effects. The incidence of hepatotoxicity associated with thiopurine use is reported between 0% and 32%. Veno-occlusive disease, peliosis hepatis, perisinusoidal fibrosis and nodular regenerative hyperplasia have all been described with thiopurines. Recent trials of 6-tioguanine, although successful in patients with allergies to azathioprine or mercaptopurine, have been compromised by increased hepatotoxicity, either veno-occlusive disease or nodular regenerative hyperplasia. We describe a report of nodular regenerative hyperplasia in a Crohn's disease patient associated with 6-mercaptopurine therapy and have reviewed the management and the literature regarding this complication. Our report strengthens the importance of further safety studies to evaluate the etiology, prevalence, risk factors and screening modalities for hepatotoxicity, in particular of nodular regenerative hyperplasia, in patients treated with thiopurines for inflammatory bowel disease.

Topics: Azathioprine; Crohn Disease; Humans; Hypertension, Portal; Immunosuppressive Agents; Liver; Male; Mercaptopurine; Middle Aged

Children with acute leukemia are at high risk of hepatitis C infection, either by immunosuppression secondary to chemotherapy or by multiple transfusions of blood products during the course of the disease. Hepatitis C virus (HCV) infection constitutes a major problem during management of acute leukemia due to resultant portal hypertension or bleeding esophageal varices. Chronic HCV infection is a major cause of liver cirrhosis and hepatocellular carcinoma in leukemic survivors. The effect of amlodipine treatment on children with acute lymphoblastic leukemia (ALL) having portal hypertension secondary to HCV infection during maintenance chemotherapy has been studied. Sixty male children (mean age 11.83 ± 1.1 years) with ALL in remission and have HCV infection were included. Diagnosis of HCV infection was confirmed by real-time PCR. Thirty patients received 5 mg amlodipine orally per day for 4 weeks and compared to another 30 patients received placebo therapy and 30 age- and sex-matched children as a control group. Amlodipine significantly reduced the elevated portal blood pressure to normal level in doses which did not interfere with mechanism of action of chemotherapy (p ≤ 0.001). Treatment with amlodipine can be used to control portal hypertension in leukemic children having HCV-induced portal hypertension. HCV in leukemics could be virtually eliminated by proper testing of the blood transfusion pool.

Topics: Administration, Oral; Amlodipine; Antineoplastic Combined Chemotherapy Protocols; Blood Pressure; Calcium Channel Blockers; Child; Cohort Studies; Heart Rate; Hepatitis C; Humans; Hypertension, Portal; Male; Mercaptopurine; Methotrexate; Portal Pressure; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vincristine

The Children's Cancer Group 1952 (CCG-1952) clinical trial studied the substitution of oral 6-thioguanine (TG) for 6-mercaptopurine (MP) and triple intrathecal therapy (ITT) for intrathecal methotrexate (IT-MTX) in the treatment of standard-risk acute lymphoblastic leukemia. After remission induction, 2027 patients were randomized to receive MP (n = 1010) or TG (n = 1017) and IT-MTX (n = 1018) or ITT (n = 1009). The results of the thiopurine comparison are as follows. The estimated 7-year event-free survival (EFS) for subjects randomized to TG was 84.1% (+/- 1.8%) and to MP was 79.0% (+/- 2.1%; P = .004 log rank), although overall survival was 91.9% (+/- 1.4%) and 91.2% (+/- 1.5%), respectively (P = .6 log rank). The TG starting dose was reduced from 60 to 50 mg/m(2) per day after recognition of hepatic veno-occlusive disease (VOD). A total of 257 patients on TG (25%) developed VOD or disproportionate thrombocytopenia and switched to MP. Once portal hypertension occurred, all subjects on TG were changed to MP. The benefit of randomization to TG over MP, as measured by EFS, was evident primarily in boys who began TG at 60 mg/m(2) (relative hazard rate [RHR] 0.65, P = .002). The toxicities of TG preclude its protracted use as given in this study. This study is registered at http://clinicaltrials.gov as NCT00002744.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Hepatic Veno-Occlusive Disease; Humans; Hypertension, Portal; Infant; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine

Thiopurine metabolism was investigated in children with acute lymphoblastic leukemia treated in the United Kingdom Medical Research Council trial ALL97. This trial compared the efficacy and toxicity of thioguanine (INN, thioguanine) versus mercaptopurine.. Consecutive children were randomized to receive thioguanine or mercaptopurine during maintenance chemotherapy. Toxicity data were collected by an adverse event-reporting system with follow-up questionnaires. Red blood cell thiopurine methyltransferase (TPMT) activity and thioguanine nucleotide concentrations were measured by standard techniques.. Of the children, 748 were randomized to thioguanine and 744 were randomized to mercaptopurine. There was no difference in the event-free survival rate between the 2 groups (80% and 81%, respectively, at 5 years). Thioguanine was associated with veno-occlusive disease (VOD) of the liver in 95 children, and persistent splenomegaly as a result of portal hypertension developed in 43 children. TPMT activity was significantly lower in the children in whom VOD developed, with a median of 13.4 U (range, 5.8-23 U) compared with 15.2 U (range, 5.3-27) in a control group of 161 leukemia patients in whom VOD did not develop (median difference, 1.8 U; 95% confidence interval, 0.9-2.7 U; P = .0001). TPMT activity in children with persistent splenomegaly was also lower than that in control subjects (median difference, 1.6 U; 95% confidence interval, 0.3-2.8 U; P = .012). There was no difference in red blood cell thioguanine nucleotide concentrations.. Thioguanine was associated with liver damage in 11% of children randomized to thioguanine without an improvement in event-free survival rate. The association of lower TPMT activity with thioguanine-related liver damage could provide a means of identifying at-risk patients.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Disease-Free Survival; Female; Hepatic Veno-Occlusive Disease; Humans; Hypertension, Portal; Infant; Infant, Newborn; Male; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Splenomegaly; Thioguanine

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

Nodular regenerative hyperplasia (NRH) has been associated with thiopurine therapy in patients with inflammatory bowel disease (IBD), but prevalence and prognosis of NRH remain unclear. This study is a cross-sectional search for NRH in IBD patients with long-term azathioprine or 6-mercaptopurine treatment.. Thirty-three IBD patients with continuous azathioprine/6-mercaptopurine treatment for at least 5 years were included. Laboratory tests, thiopurine metabolite levels, liver histology, MRI were examined for NRH and signs of portal hypertension.. NRH was not observed in this cohort of 33 patients. Nevertheless, some possibly related signs of vascular changes were found by MRI in three patients. Also, splenomegaly, which may be associated with portal hypertension, was found in one patient. No high thiopurine dose neither high metabolite levels were found in these patients.. No NRH was found in this group of IBD patients with long-term azathioprine/6-mercaptopurine treatment. Larger multicenter studies are needed to determine the prevalence of NRH in thiopurine-treated IBD patients.

Topics: Azathioprine; Chronic Disease; Cross-Sectional Studies; Humans; Hyperplasia; Hypertension, Portal; Inflammatory Bowel Diseases; Mercaptopurine; Prevalence

Topics: Adult; Allopurinol; Crohn Disease; Drug Therapy, Combination; Enzyme Inhibitors; Focal Nodular Hyperplasia; Humans; Hypertension, Portal; Immunosuppressive Agents; Male; Mercaptopurine

The possibility of developing idiopathic portal hypertension has been described with thiopurine treatment despite compromises the prognosis of these patients, the fact its true prevalence is unknown.. A cross-sectional study was conducted in a cohort of inflammatory bowel disease (IBD) patients followed at our unit, to determine the prevalence of diagnosis of idiopathic portal hypertension (IPH) and its relationship with thiopurine treatment.. At the time of the analysis, 927/1,419 patients were under treatment with thiopurine drugs (65%). A total of 4 patients with IBD type Crohn's disease with idiopathic portal hypertension probably related to the thiopurine treatment were identified (incidence of 4.3 cases per 1,000). Seventy-five percent of patients started with signs or symptoms of portal hypertension. Only one patient was asymptomatic but the diagnosis of IPH because of isolated thrombocytopenia is suspected. However, note that all patients had thrombocytopenia previously. Abdominal ultrasound with fibroscan, hepatic vein catheterization and liver biopsy were performed on all of them as part of the etiology of portal hypertension. In the abdominal ultrasound, indirect portal hypertension data were observed in all patients (as splenomegaly) cirrhosis was also ruled out. The fibroscan data showed significant liver fibrosis (F2-F3).. Idiopathic portal hypertension following thiopurine treatment in IBD patients is a rare occurrence, but it must be borne in mind in the differential diagnosis for early diagnosis, especially in patients undergoing thiopurine treatment over a long period. The presence of thrombocytopenia is often the only predictor of its development in the preclinical stage.

Topics: Adult; Aged; Azathioprine; Cross-Sectional Studies; Female; Humans; Hypertension, Portal; Idiopathic Noncirrhotic Portal Hypertension; Immunosuppressive Agents; Inflammatory Bowel Diseases; Liver Cirrhosis; Male; Mercaptopurine; Middle Aged; Pancytopenia; Splenomegaly; Treatment Outcome

Topics: Child; Crohn Disease; Humans; Hypertension, Portal; Immunosuppressive Agents; Male; Mercaptopurine

Thiopurines play a pivotal role in the management of inflammatory bowel disease. Azathioprine and mercaptopurine have been associated with a number of liver abnormalities, including hepatitis, veno-occlusive disease, nodular regenerative hyperplasia, and peliosis hepatitis. Patients treated with azathioprine and mercaptopurine have their liver chemistry tests routinely checked due to this potential for hepatotoxicity. Hepatoportal sclerosis is a cause of non-cirrhotic portal hypertension that is increasingly being recognized; its etiopathogenesis is not well defined. We present the first case report of mercaptopurine-induced hepatoportal sclerosis leading to non-cirrhotic portal hypertension in a patient with Crohn's disease. He had been treated with mercaptopurine for five years, and his liver chemistry tests were always within normal limits. This case underscores the potential serious liver adverse events that may arise silently and go undetected during treatment with mercaptopurine, and should alert clinicians as to the potential need to discontinue mercaptopurine in this setting.

Topics: Ascites; Crohn Disease; Humans; Hypertension, Portal; Immunosuppressive Agents; Intestinal Obstruction; Liver Function Tests; Male; Mercaptopurine; Portal System; Sclerosis; Young Adult

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

Thiopurine drugs, azathioprine (Imuran) and 6-mercaptopurine (6-MP), are immunomodulators that have been shown to be effective at inducing and maintaining remission in inflammatory bowel disease. Although usually well-tolerated, the occurrence of side effects, typically myelotoxicity and hepatotoxicity, is a major drawback. The side effects can be classified as dose-dependent and independent. Both cholestatic hepatitis and endothelial injury, leading to vascular congestion and nodular regenerative hyperplasia, have been described during therapy with thiopurines, which can end up with portal hypertension. These injuries are potentially mediated by different metabolites. In this article we present a case of hyperammonaemic encephalopathy during therapy with 6-MP, possibly the first recorded in the literature, which probably resulted from the combination of thiopurine-induced liver injury with portal hypertension and the presence of spontaneous portosystemic venous shunts.

Topics: Aged; Chemical and Drug Induced Liver Injury; Crohn Disease; Hepatic Encephalopathy; Humans; Hyperammonemia; Hypertension, Portal; Immunosuppressive Agents; Male; Mercaptopurine; Portal Vein

We report the cases of two renal transplant recipients suffering from idopathic portal hypertension, a condition characterised by increased portal venous pressure in the absence of both histological lesion of the liver and obstruction of the portal vein. In these two patients, perisnusoidal fibrosis, invisible by light microscopy, was demonstrated by electron microscopy; it is suggested that partial obstruction of hepatic sinusoids by perisinusoidal fibrosis could be the mechanism for increased portal venous pressure in all the patients with idiopathic portal hypertension. In these two patients, who received 6-mercaptopurine and azathioprine, perisinusoidal fibrosis might be the consequence of prolonged administration of these drugs.

Topics: Adult; Azathioprine; Humans; Hypertension, Portal; Kidney Transplantation; Liver; Male; Mercaptopurine; Microscopy, Electron; Postoperative Complications; Transplantation, Homologous

Topics: Animals; Hypertension, Portal; Liver; Lymphocytes; Mercaptopurine; Rabbits; Spleen; Time Factors

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