mercaptopurine and Liver-Diseases

Hepatic involvement is often encountered in gastrointestinal (GI) diseases, in part because of the close anatomic and physiologic relations between the liver and GI tract. Drainage of the mesenteric blood supply to the portal vein permits absorbed and/or translocated nutrients, toxins, bacterial elements, cytokines, and immunocytes to gain hepatic access. Liver problems in digestive disorders may range from nonspecific hepatocellular enzyme elevations to significant pathologic processes that may progress to end-stage liver disease. Hepatobiliary manifestations of primary GI diseases in childhood and adolescence are not uncommon and include several well-described associations, such as sclerosing cholangitis with inflammatory bowel disease. Liver damage may also result from the effects of drugs used to treat GI diseases, for example, the hepatotoxicity of immunomodulatory therapies. This review highlights the important features of the hepatic and biliary abnormalities associated with 3 common pediatric GI conditions: inflammatory bowel disease, celiac disease, and cystic fibrosis.

Topics: Adolescent; Antibodies, Monoclonal; Azathioprine; Celiac Disease; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cholagogues and Choleretics; Cholangitis, Sclerosing; Cystic Fibrosis; Humans; Infant; Inflammatory Bowel Diseases; Infliximab; Liver Diseases; Liver Function Tests; Mercaptopurine; Methotrexate; Tumor Necrosis Factor-alpha; Ursodeoxycholic Acid

Immunomodulator therapy with the thiopurine analogues azathioprine or 6-mercaptopurine is commonly prescribed for the treatment of inflammatory bowel disease (IBD). Drug adverse effects and the lack of efficacy, however, commonly require withdrawal of therapy. Allopurinol, a xanthine oxidase inhibitor, was recently evaluated in its role in modifying thiopurine metabolism and improving drug efficacy in IBD.. This article reviews the role and safety of allopurinol co-therapy in the setting of thiopurine hepatotoxicity and/or non-responsiveness in IBD.. Published articles on thiopurines in the treatment of IBD were examined.. The addition of low dose allopurinol to dose-reduced thiopurine analogue seems safe but careful monitoring for adverse effects and profiling of thiopurine metabolites is essential. There is evidence of improved immunomodulator efficacy and reduced hepatotoxicity clinically but further confirmatory studies are required before more definitive treatment recommendations can be given.

Topics: Allopurinol; Azathioprine; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Enzyme Inhibitors; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Liver Diseases; Mercaptopurine

It is anticipated that unraveling the human genome will have a direct impact on the management of specific diseases. Variations or mutations in genes involved in drug metabolism or disease pathophysiology in gastroenterology and hepatology are expected to have effect on response to therapy. The spectrum of diseases is vast. Thus, we focus this review on clinical pharmacogenetics of inflammatory bowel disease, Helicobacter pylori infections, gastroesophageal reflux disease, irritable bowel syndrome, liver transplantation, and colon cancer. Although only a few genotyping tests are used regularly in clinical practice, we anticipate that in the future there will be more routine use of many of the tests described in this review.

Topics: Antineoplastic Agents; Azathioprine; Biotransformation; Colorectal Neoplasms; Gastrointestinal Agents; Gastrointestinal Diseases; Genetic Predisposition to Disease; Genotype; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Irritable Bowel Syndrome; Liver Diseases; Liver Transplantation; Mercaptopurine; Patient Selection; Pharmacogenetics; Phenotype; Polymorphism, Genetic; Treatment Outcome

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: Azathioprine; B-Lymphocytes; Chronic Disease; Denmark; Drug Evaluation; Female; Glucocorticoids; Hepatitis; Humans; Immunity, Cellular; Immunosuppressive Agents; Liver Cirrhosis; Liver Diseases; Male; Mercaptopurine; Placebos; T-Lymphocytes

Topics: Acute Disease; Age Factors; Alcoholism; Azathioprine; Chemical and Drug Induced Liver Injury; Chronic Disease; Cortisone; Diet Therapy; Exchange Transfusion, Whole Blood; Halothane; Hepatic Encephalopathy; Hepatitis; Hepatitis A; Hepatitis B; Hepatitis B Antigens; Hospitalization; Humans; Liver Diseases; Liver Function Tests; Malabsorption Syndromes; Mercaptopurine; Prednisone; Prognosis; Pruritus

Topics: Adrenal Cortex Hormones; Antimetabolites; Chronic Disease; Female; Humans; Liver Diseases; Lupus Erythematosus, Systemic; Male; Mercaptopurine; Neutrophils

Topics: Adrenal Cortex Hormones; Azathioprine; Chronic Disease; Diagnosis, Differential; False Positive Reactions; Hepatitis; Hepatitis A; Humans; Liver; Liver Cirrhosis; Liver Diseases; Liver Function Tests; Mercaptopurine

Topics: Acute Disease; Glucocorticoids; Hepatitis; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis; Liver Diseases; Mercaptopurine; Prednisolone; Prednisone

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

Juvenile xanthogranuloma (JXG), one of the most common forms of Langerhans-dendritic cell proliferation in young children, usually presents as spontaneously regressing cutaneous lesions. JXG with systemic (extracutaneous) involvement is a rare histiocytic disorder in which significant morbidity and death may occur. The systemic type, especially combined with multiple central nervous system lesions in young children, has a very poor prognosis. The patient described here presented with disseminated disease including lungs, liver, kidneys, ribs, scalp, and central nervous system. The patient was treated with multiagent chemotherapy based on the Langerhans cell histiocytosis II treatment protocol. The regimen used included an additional intrathecal therapy with methotrexate and prednisolone to control central nervous system lesions. The patient was treated for 28 months and has been in remission for almost 5 years.

Topics: Central Nervous System Diseases; Combined Modality Therapy; Craniotomy; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Infant; Injections, Spinal; Liver Diseases; Lung Diseases; Mercaptopurine; Methotrexate; Paresis; Prednisolone; Skin Diseases; Vinblastine; Xanthogranuloma, Juvenile

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

The incidence of thiopurine-induced hepatotoxicity in patients with inflammatory bowel disease varies in different studies.. To assess the rate of thiopurine-induced liver toxicity in patients with inflammatory bowel disease; to determine the predictive factors and to characterize its clinical course and management.. A cohort of 161 patients was prospectively followed for a median of 271 days. Hepatotoxicity was established when alanine transaminase or alkaline phosphatase plasma levels were greater than twice the upper normal limit.. Abnormal liver function was detected in 21 patients (13%; 95% CI: 7-18). Hepatotoxicity occurred in 16 patients (10%; 95% CI: 6-16) after a median of 85 days. In five cases, treatment was withdrawn due to hepatotoxicity. Use of corticosteroids was associated with hepatotoxicity (OR: 4.94; 95% CI: 1.01-23.98) with antitumour necrosis factor concomitant therapy showing a protective role (OR: 0.3; 95% CI: 0.1-3.1). gamma-Glutamyl transferase plasma levels at the onset of hepatotoxicity showed the best predictive value for treatment withdrawal (area under the receiver operating characteristic curve: 0.95).. The incidence of hepatotoxicity in inflammatory bowel disease patients receiving thiopurines is relevant, mainly in patients co-treated with corticosteroids. gamma-Glutamyl transferase plasma level is a useful biomarker in therapy withdrawal prediction.

Topics: Adolescent; Adult; Aged; Azathioprine; Biomarkers; Chemical and Drug Induced Liver Injury; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Liver; Liver Diseases; Liver Function Tests; Male; Mercaptopurine; Middle Aged; Prospective Studies; Risk Factors

A 26-year-old man, diagnosed with acute myelogenous leukemia had multiple inflammatory pseudotumors (IPT) in the liver. The patient presented complete remission after remission induction therapy, and then showed right upper quadrant discomfort and intermittent fever. An ultrasonography disclosed multiple hypoechoic nodules in the liver. A biopsy of the nodules showed focal liver cell necrosis with scant inflammatory cells, compatible with IPT. After several courses of chemotherapy, the nodules in the liver increased. The second liver biopsy of the nodule showed fibrosis. Multiple IPTs in the liver should be distinguished from abscess and metastatic nodules.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Cytarabine; Daunorubicin; Diagnosis, Differential; Granuloma, Plasma Cell; Humans; Leukemia, Myeloid, Acute; Liver Abscess; Liver Diseases; Liver Neoplasms; Magnetic Resonance Imaging; Male; Mercaptopurine; Prednisolone; Tomography, X-Ray Computed

In a population-based study of 115 children with non-B-cell acute lymphoblastic leukaemia, we analysed the relation of the degree of leukopenia and risk of relapse to the degree of hepatotoxicity (as measured by serum aminotransferase (AT] during oral methotrexate (MTX) and 6-mercaptopurine (6MP) maintenance chemotherapy (MT). Hepatotoxicity was calculated as a mean of all AT-measurements (mATMT). Lack of hepatotoxicity was defined as a mATMT less than or equal to 40 IUl-1. A highly significant correlation was demonstrated between the mean AT during the first, second, and third year of MT (r greater than 0.70, P less than 0.00001). mATMT was not related to the mean WBC during MT (r = -0.03, P = 0.36), but was related to the rise in WBC following cessation of therapy (r = 0.24, P = 0.06). Patients with recurrent disease had significantly lower mATMT than patients staying in remission (P = 0.03 for both over-all and haematological relapse risk). Patients with a mATMT greater than 40IUl-1 had a lower risk of relapse than patients with a mATMT less than or equal to 40IUl-1 (4.5 year CCR: 0.70 and 0.50, P = 0.06; and 4.5 year haematological remission: 0.83 and 0.63, P = 0.03). The favourable outcome for patients with hepatoxicity could be demonstrated for all risk groups.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Female; Humans; Liver Diseases; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Transaminases

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Chemical and Drug Induced Liver Injury; Dexamethasone; Humans; Liver; Liver Diseases; Male; Mercaptopurine; Methotrexate; Prednisone

Antibody binding to living Chang liver cell was measured in sera from 71 patients with various chronic liver diseases using 125I-labelled protein A binding assay. The level of antibody binding to Chang liver cell was significantly elevated in sera from patients with chronic active hepatitis (CAH), chronic persistent hepatitis (CPH) and liver cirrhosis as compared to those from healthy donors, but not in sera from patients with fatty liver. There was no detectable antibody binding to HeLa cells in those sera. The antibody binding to Chang liver cell was blocked by a human liver specific protein (LSP) preparation. The levels of antibody binding to Chang liver cell were significantly higher in patients with CAH than patients with CPH. On the other hand, the level of antibody binding to Chang liver cell was significantly decreased in sera from patients with CAH after a treatment with prednisolone (PSL) for 2 months and a subsequent combined administration of 6MP and a maintenance dose of PSL for 1 month. These results suggest that antibodies to Chang liver cell are closely correlated with the activity of chronic liver disease and that PSL and 6MP treatment can reduce the level of the antibodies.

Topics: Antibodies; Antigen-Antibody Reactions; Cell Line; Chronic Disease; Humans; Immunoassay; Liver; Liver Diseases; Membrane Proteins; Mercaptopurine; Prednisolone; Proteins; Staphylococcal Protein A

Serial liver function tests and percutaneous liver biopsies were performed on 21 children receiving treatment for acute lymphoblastic leukaemia (ALL). The patients received continuing chemotherapy either with daily 6-mercaptopurine and weekly methotrexate or with five-day pulses of these drugs every three weeks. Liver function tests were transiently abnormal in the majority of children, but the abnormalities bore no relationship to the histology of the liver biopsy. Mild inflammatory and fatty changes were commonly seen, and early portal fibrosis was found in three out of 16 patients biopsied at between 108-130 weeks on treatment. There was no correlation between treatment regime and results of biopsy. Three patients showed possible progression of abnormalities on repeat biopsy. The risk of development of portal fibrosis appears low after 2-3 years of continuing chemotherapy, but examination of liver histology may be indicated if more prolonged therapy is contemplated.

Topics: Adolescent; Antineoplastic Agents; Biopsy; Chemical and Drug Induced Liver Injury; Child; Humans; Leukemia, Lymphoid; Liver Diseases; Liver Function Tests; Mercaptopurine; Methotrexate

A 3 months old girl presented with significant enlargement of liver, spleen and lymphnodes, with moderate anemia, thrombopenia and leucocytosis. In the differential count there was a shift to the left and an increase of monocyte-like cells (35%). Differential diagnosis included leucemoid reaction, infectious mononucleosis, myelo-proliferative disorder with a missing C chromosome and chronic myeloid leucemia. Clinical symptoms, cytochemistry and caryotype of bone marrow cells suggested infantile chronic myeloic leucemia and normal ALP index and possibly normal HbF. Treatment with 6-mercaptopurine was followed by partial remission. The therapeutic consequences of exact differential diagnosis are discussed.

Topics: Anemia; Chromosome Aberrations; Chromosome Disorders; Diagnosis, Differential; Humans; In Vitro Techniques; Infant; Infectious Mononucleosis; Leukemia, Myeloid; Leukocytosis; Liver Diseases; Lymphatic Diseases; Mercaptopurine; Myeloproliferative Disorders; Splenic Diseases; Thrombocytopenia

Eleven adults with refractory leukemia treated with a combination of 6-mercaptopurine and Adriamycin developed hepatic dysfunction manifested by elevations of serum total bilirubin, alkaline phosphatase, and glutamic oxaloacetic transaminase. Liver tissue obtained at necropsy showed intrahepatic cholestasis (eight cases), hepatocellular necrosis (ten cases), leukemic infiltration (two cases), and fatty change (nine cases). Neither this frequency nor severity of hepatocellular destruction has hitherto been associated with 6-mercaptopurine at the dose levels used in this study, nor has Adriamycin previously been found to be hepatotoxic. It is postulated that Adriamycin potentiated the hepatotoxicity of 6-mercaptopurine in these patients.

Topics: Adult; Chemical and Drug Induced Liver Injury; Doxorubicin; Drug Synergism; Drug Therapy, Combination; Humans; Hyperbilirubinemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Liver Diseases; Mercaptopurine

Topics: Animals; Azathioprine; Graft Rejection; Hepatitis A; Humans; Immune Adherence Reaction; Kinetics; Liver Cirrhosis; Liver Diseases; Liver Transplantation; Mercaptopurine; Sheep; Sulfur Isotopes

Topics: Chronic Disease; Hepatitis; Hepatitis B Antigens; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Liver Cirrhosis; Liver Diseases; Lymphocyte Activation; Mercaptopurine; Prednisolone

Topics: Azathioprine; Binding Sites, Antibody; Carbon Isotopes; Chromatography, Ion Exchange; Humans; Imidazoles; Immune Adherence Reaction; Intestinal Absorption; Liver Diseases; Lymphocytes; Mass Spectrometry; Mercaptopurine; Sulfates; Sulfur Isotopes; Uric Acid

Topics: Azathioprine; Female; Humans; Liver Cirrhosis; Liver Diseases; Lupus Erythematosus, Systemic; Menopause; Mercaptopurine; Middle Aged

Topics: Adolescent; Biopsy; Blood Protein Disorders; Child; Chronic Disease; Cortisone; Female; gamma-Globulins; Hepatitis; Hepatomegaly; Humans; Liver; Liver Diseases; Liver Function Tests; Liver Regeneration; Male; Mercaptopurine; Microscopy, Electron; Prednisone; Prognosis; Serum Albumin; Splenomegaly

Topics: Adolescent; Adult; Aged; Alkaline Phosphatase; Aspartate Aminotransferases; Bacteroides; Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Enterococcus faecalis; Female; Humans; Hyperbilirubinemia; Jaundice; Liver; Liver Diseases; Liver Function Tests; Male; Mercaptopurine; Postoperative Complications; Pseudomonas; Sepsis; Staphylococcus; Streptococcus; Tetracycline; Transfusion Reaction

Topics: Adult; Angiotensin II; Animals; Bile Duct Neoplasms; Biliary Tract Diseases; Blood Pressure; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Chloramphenicol; Endopeptidases; Erythromycin; Female; Gout; Hepatitis; Humans; Hypertension; Liver; Liver Cirrhosis; Liver Diseases; Liver Function Tests; Liver Neoplasms; Male; Mercaptopurine; Middle Aged; Nephrotic Syndrome; Rats

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

Topics: Chronic Disease; Humans; Liver Diseases; Mercaptopurine

Topics: Deoxyribonucleases; DNA; Hepatectomy; Histocytochemistry; Liver; Liver Diseases; Liver Regeneration; Mercaptopurine; Nucleotides; Pharmacology; Rats; Research; RNA; Sulfhydryl Compounds

Topics: Child; Diagnosis; Hepatomegaly; Humans; Infant; Leukemia; Leukocyte Disorders; Leukocytosis; Liver Diseases; Lymphadenitis; Mercaptopurine; Prednisolone; Prednisone; Splenomegaly

Topics: Disease; Humans; Intestinal Diseases; Intestine, Small; Intestines; Liver Diseases; Mercaptopurine