TPMT in the treatment of Crohn's disease with azathioprine

Azathioprine induced profound myelosuppression linked to TPMT deficiency has now been documented in many patient groups, including those with Crohn's disease. At the start of azathioprine or mercaptopurine therapy, measurement of TPMT activity has a role in identifying the 1 in 300 patients who are at risk of severe myelosuppression when treated with standard thiopurine dosages. During the initial months of azathioprine therapy a knowledge of TPMT status warns of early bone marrow toxicity. In patients established on azathioprine these is no clear evidence to suggest that TPMT is predictive of clinical response or drug toxicity, indicating a role for TPMT in the prediction of early events rather than long term control. In patients with Crohn's disease on long term azathioprine therapy, it is clear that myelosuppression, particularly leucopenia, is caused by other factors in addition to variable TPMT activity and therefore monitoring of blood cell counts throughout treatment is essential.

[1]  M. Walport,et al.  Identification of thiopurine methyltransferase (TPMT) polymorphisms cannot predict myelosuppression in systemic lupus erythematosus patients taking azathioprine. , 1999, Rheumatology.

[2]  S. Sarin,et al.  Absence of hemochromatosis associated Cys282Tyr HFE gene mutation and low frequency of hemochromatosis phenotype in nonalcoholic chronic liver disease patients in India , 2004, Journal of gastroenterology and hepatology.

[3]  R. Thomas,et al.  AZATHIOPRINE AND SEVERE BONE MARROW DEPRESSION , 1986, The Lancet.

[4]  S. Burden.  Dietary treatment of irritable bowel syndrome: current evidence and guidelines for future practice. , 2001, Journal of human nutrition and dietetics : the official journal of the British Dietetic Association.

[5]  M. C. Ellis,et al.  A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis , 1996, Nature Genetics.

[6]  T. Bayless,et al.  Enhanced bioavailability of azathioprine compared to 6‐mercaptopurine therapy in inflammatory bowel disease: correlation with treatment efficacy , 2000, Alimentary pharmacology & therapeutics.

[7]  R. Weinshilboum,et al.  Pharmacogenetics of acute azathioprine toxicity: Relationship to thiopurine methyltransferase genetic polymorphism , 1989, Clinical pharmacology and therapeutics.

[8]  E. Siris.  Bisphosphonates and iritis , 1993, The Lancet.

[9]  M. Relling,et al.  Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. , 1999, Blood.

[10]  R. Weinshilboum,et al.  Thiopurine methyltransferase. Aromatic thiol substrates and inhibition by benzoic acid derivatives. , 1983, Molecular pharmacology.

[11]  R. Weinshilboum,et al.  Purine substrates for human thiopurine methyltransferase. , 1994, Biochemical pharmacology.

[12]  N. Duc,et al.  Bioactive molecules in milk and their role in health and disease: The role of transforming growth factor‐β , 2000, Immunology and cell biology.

[13]  H. McLeod,et al.  Thiopurine Methyltransferase Genotype Predicts Therapy-Limiting Severe Toxicity from Azathioprine , 1998, Annals of Internal Medicine.

[14]  S. Targan,et al.  6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. , 2002, Gastroenterology.

[15]  David A. Harris,et al.  Textbook of biochemistry with clinical correlations (4th edn) , 1998 .

[16]  J. Lilleyman,et al.  Intracellular metabolites of mercaptopurine in children with lymphoblastic leukaemia: a possible indicator of non-compliance? , 1995, British Journal of Cancer.

[17]  B. Pasternack,et al.  Treatment of Crohn's disease with 6-mercaptopurine. A long-term, randomized, double-blind study. , 1980, The New England journal of medicine.

[18]  Jennifer J. Pointon,et al.  A valine deletion of ferroportin 1: a common mutation in hemochromastosis type 4. , 2002, Blood.

[19]  R. Weinshilboum,et al.  Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide , 2001, Gut.

[20]  K. Schmiegelow,et al.  Prognostic significance of hepatotoxicity during maintenance chemotherapy for childhood acute lymphoblastic leukaemia. , 1990, British Journal of Cancer.

[21]  N. Havu.  Enterochromaffin-like cell carcinoids of gastric mucosa in rats after life-long inhibition of gastric secretion. , 1986, Digestion.

[22]  M. Relling,et al.  Polymorphism of the thiopurine S-methyltransferase gene in African-Americans. , 1999, Human molecular genetics.

[23]  P. Mortensen,et al.  Absorption and metabolism of octanoate by the rat colon in vivo: concentration dependency and influence of alternative fuels , 2002, Gut.

[24]  S. Hanada,et al.  Development of poorly differentiated adenocarcinoma and carcinoid due to long-term Helicobacter pylori colonization in Mongolian gerbils , 1999, Journal of Gastroenterology.

[25]  R. Weinshilboum,et al.  Balsalazide and azathiprine or 6-mercaptopurine: evidence for a potentially serious drug interaction. , 1999, Gastroenterology.

[26]  M McCarthy,et al.  Hepatology , 1999, Rapid Medicine.

[27]  R. Weinshilboum,et al.  Human thiopurine methyltransferase pharmacogenetics: Gene sequence polymorphisms , 1997, Clinical pharmacology and therapeutics.

[28]  J. Visakorpi,et al.  Revised criteria for diagnosis of coeliac disease. Report of Working Group of European Society of Paediatric Gastroenterology and Nutrition. , 1990, Archives of disease in childhood.

[29]  W. Evans,et al.  Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. , 1991, The Journal of pediatrics.

[30]  W. Sandborn.  Azathioprine: state of the art in inflammatory bowel disease. , 1998, Scandinavian journal of gastroenterology. Supplement.

[31]  M. Relling,et al.  Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. , 1999, Journal of the National Cancer Institute.

[32]  S. Targan,et al.  Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. , 2000, Gastroenterology.

[33]  L. Powell,et al.  Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis. , 2002, Blood.

[34]  J. Hinnie,et al.  Textbook of biochemistry with clinical correlations , 1999 .

[35]  M. Korman,et al.  Serum Gastrin in Chronic Gastritis , 1971, British medical journal.

[36]  Sandborn Wj.  Azathioprine: State of the Art in Inflammatory Bowel Disease , 1998 .

[37]  J. Lilleyman,et al.  Congenital thiopurine methyltransferase deficiency and 6-mercaptopurine toxicity during treatment for acute lymphoblastic leukaemia. , 1993, Archives of disease in childhood.

[38]  H. Waldum,et al.  Safety of proton pump inhibitors , 2000, Alimentary pharmacology & therapeutics.

[39]  M. Cazzola,et al.  Genetic hyperferritinaemia and reticuloendothelial iron overload associated with a three base pair deletion in the coding region of the ferroportin gene (SLC11A3) , 2002, British journal of haematology.

[40]  A. Pietrangelo.  The ferroportin disease , 2014, Clinical liver disease.

[41]  J. Kirby,et al.  Pancytopenia Related to Azathioprine — An Enzyme Deficiency Caused by a Common Genetic Polymorphism: A Review , 1992, Journal of the Royal Society of Medicine.

[42]  A. Weaver,et al.  Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease , 2001, Gut.

[43]  R. Weinshilboum,et al.  Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[44]  N. Haboubi,et al.  A novel approach to a patient with Crohn disease and a high stoma output: a missed opportunity? , 2004, Scandinavian journal of gastroenterology.

[45]  B. Bonaz,et al.  Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy. , 2000, Gastroenterology.

[46]  A. Pietrangelo,et al.  Non-HFE Hemochromatosis , 2005, Seminars in liver disease.

[47]  M. Murphy,et al.  Severe megaloblastic anaemia associated with abnormal azathioprine metabolism. , 1984, British journal of clinical pharmacology.

[48]  J. Aarbakke,et al.  Inhibition of human thiopurine methyltransferase by furosemide, bendroflumethiazide and trichlormethiazide , 1996, European Journal of Clinical Pharmacology.

[49]  R. Weinshilboum,et al.  Olsalazine and 6‐mercaptopurine‐related bone marrow suppression: A possible drug‐drug interaction , 1997, Clinical pharmacology and therapeutics.

[50]  R. Weinshilboum,et al.  Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine. , 1995, British journal of clinical pharmacology.

[51]  N. Mehra,et al.  Distribution of C282Y and H63D mutations in the HFE gene in healthy Asian Indians and patients with thalassaemia major. , 2003, The National medical journal of India.

[52]  J. McManus,et al.  Adverse reactions during salicylazosulfapyridine therapy and the relation with drug metabolism and acetylator phenotype. , 1973, The New England journal of medicine.

[53]  T. Bayless,et al.  Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease , 2001, Gut.

[54]  M. Worwood,et al.  Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3). , 2002, Blood.

[55]  S. Campbell,et al.  Relevance of thiopurine methyltransferase activity in inflammatory bowel disease patients maintained on low‐dose azathioprine , 2002, Alimentary pharmacology & therapeutics.

[56]  S. Falkmer,et al.  Neuroendocrine (ECL cell) differentiation of spontaneous gastric carcinomas of cotton rats (Sigmodon hispidus). , 1999, Laboratory animal science.

[57]  Y. Théorêt,et al.  6-Mercaptopurine metabolism in Crohn's disease: correlation with efficacy and toxicity. , 1996, Gut.

[58]  R. Weinshilboum,et al.  Severe 6-thioguanine-induced marrow aplasia in a child with acute lymphoblastic leukemia and inherited thiopurine methyltransferase deficiency. , 2000, Journal of pediatric hematology/oncology.

[59]  S. Moss,et al.  Acid secretion and sensitivity to gastrin in patients with duodenal ulcer: effect of eradication of Helicobacter pylori. , 1993, Gut.

[60]  Lamers,et al.  Hypergastrinaemia during long‐term omeprazole therapy: influences of vagal nerve function, gastric emptying and Helicobacter pylori infection , 1998, Alimentary pharmacology & therapeutics.

[61]  D. Dormont,et al.  Tissue distribution of bovine spongiform encephalopathy agent in primates after intravenous or oral infection , 2004, The Lancet.

[62]  R. Weinshilboum,et al.  Erratum: Olsalazine and 6-mercaptopurine-related bone marrow suppression: A possible drug-drug interaction (Clinical Pharmacology and Therapeutics (1997) 62 (464-475)) , 2000 .

[63]  J. Gummert,et al.  Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient , 1993, The Lancet.

[64]  W. Evans,et al.  Genetic Polymorphism of Thiopurine S-Methyltransferase: Molecular Mechanisms and Clinical Importance , 2000, Pharmacology.

[65]  G. Qvigstad,et al.  Neuroendocrine differentiation in gastric adenocarcinomas associated with severe hypergastrinemia and/or pernicious anemia , 2002, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[66]  R. Weinshilboum,et al.  Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia , 1990, The Lancet.

[67]  J. Ironside,et al.  Creutzfeldt-Jakob disease: implications for gastroenterology , 2002, Gut.

[68]  S. Falkmer,et al.  Clinical and histopathological tumour progression in ECL cell carcinoids (“ECLomas”) , 1999, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[69]  J. G. Cory,et al.  Purine and Pyrimidine Nucleotide Metabolism , 2002 .

[70]  V. Marathias,et al.  6-Thioguanine alters the structure and stability of duplex DNA and inhibits quadruplex DNA formation. , 1999, Nucleic acids research.