title: Association between adverse effects under azathioprine therapy and inosine triphosphate pyrophosphatase activity in patients with chronic inflammatory bowel disease.
abstract: BACKGROUND
  Inosine triphosphate pyrophosphatase (ITPA) catalyzes the pyrophosphohydrolysis of inosine triphosphate to inosine monophosphate. Recently, single-nucleotide polymorphisms in the ITPA gene, associated with decreased enzyme activity, have been reported. Some clinical studies have demonstrated that the 94C>A mutation is linked to flu-like symptoms, rash, and pancreatitis during azathioprine (AZA) therapy and to early AZA discontinuation. In this study, we investigated whether the enzyme phenotype is also related to adverse effects (AEs).
  
  
  METHODS
  Patients suffering from inflammatory bowel disease who were treated with AZA (N=160; age 43±12 years) were included. Data were categorized into quartiles according to the ITPA activity. Information about the therapeutic regimen, AEs [leucopenia, increased hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase), flu-like symptoms, and pancreatitis], cotherapy, and comorbidity was obtained from the responsible clinicians and patients by using a standardized questionnaire. ITPA activity was measured by a validated high-performance liquid chromatography procedure. In patients with decreased ITPA activity, the 94C>A and IVS2+21A>C genotypes were determined.
  
  
  RESULTS
  AEs were reported significantly more often for patients with low ITPA activity than for patients with high ITPA activity; the highest odds ratio for occurrence of AEs was found to be below a threshold of 59.9 μmol/(gHb·h) [hemoglobin (Hb)]. Decreased ITPA activities [particularly <89.2 μmol/(gHb·h)] were frequently accompanied by leucopenias, whereas very low enzyme activities [<37.3 μmol/(gHb·h)] were associated with a higher incidence of increased liver enzymes.
  
  
  CONCLUSIONS
  The results demonstrate a relationship between low ITPA activity and AEs and support the idea that the determination of ITPA phenotype might be an appropriate alternative to genotyping.
authors.affiliation: Central Institute for Clinical Chemistry and Laboratory Medicine, Department of Internal Medicine, Gastroenterology, Hepatology, and Oncology, Klinikum Stuttgart, Germany. m.shipkova@klinikum-stuttgart.de
authors.forename: Maria
authors.initials: M
authors.lastname: Shipkova
authors.forename: Jutta
authors.initials: J
authors.lastname: Franz
authors.forename: Manabu
authors.initials: M
authors.lastname: Abe
authors.forename: Corinne
authors.initials: C
authors.lastname: Klett
authors.forename: Eberhard
authors.initials: E
authors.lastname: Wieland
authors.forename: Tilo
authors.initials: T
authors.lastname: Andus
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001379:Azathioprine / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult; D000097630:Inosine Triphosphatase
chemical_list: D001379:Azathioprine; D011755:Pyrophosphatases; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase