title: Two brothers with skewed thiopurine metabolism in ulcerative colitis treated successfully with allopurinol and mercaptopurine dose reduction.
abstract: Thiopurine therapy effectively maintains remission in inflammatory bowel disease. However, many patients are unable to achieve optimum benefits from azathioprine or 6-mercaptopurine because of undesirable metabolism related to high thiopurine methyltransferase (TPMT) activity characterized by hepatic transaminitis secondary to increased 6-methylmercaptopurine (6-MMP) production and reduced levels of therapeutic 6-thioguanine nucleotide (6-TGN). Allopurinol can optimize this skewed metabolism. We discuss two brothers who were both diagnosed with ulcerative colitis (UC). Their disease remained active despite oral and topical mesalamines. Steroids followed by 6-mercaptopurine (MP) were unsuccessfully introduced for both patients and both were found to have high 6-MMP and low 6-TGN levels, despite normal TMPT enzyme activity, accompanied by transaminitis. Allopurinol was introduced in combination with MP dose reduction. For both brothers addition of allopurinol was associated with successful remission and optimized MP metabolites. These siblings with active UC illustrate that skewed thiopurine metabolism may occur despite normal TPMT enzyme activity and can lead to adverse events in the absence of disease control. We confirm previous data showing that addition of allopurinol can reverse this skewed metabolism, and reduce both hepatotoxicity and disease activity, but we now also introduce the concept of a family history of preferential MP metabolism as a clue to effective management for other family members.
authors.affiliation: Inflammatory Bowel Disease Center, University of Chicago, Chicago, IL, USA. frankhoentjen@gmail.com
authors.forename: Frank
authors.initials: F
authors.lastname: Hoentjen
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Hanauer
authors.forename: Nanne K
authors.initials: NK
authors.lastname: de Boer
authors.forename: David T
authors.initials: DT
authors.lastname: Rubin
mesh_terms: D000493:Allopurinol / Q000627:therapeutic use*; D000963:Antimetabolites / Q000627:therapeutic use; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006150:Guanine Nucleotides / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000201:enzymology; D008297:Male; D015122:Mercaptopurine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use*; D008780:Methyltransferases / Q000378:metabolism; D013256:Steroids / Q000627:therapeutic use; D013873:Thionucleotides / Q000378:metabolism*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000963:Antimetabolites; D006150:Guanine Nucleotides; D013256:Steroids; D013873:Thionucleotides; C003964:6-thioguanylic acid; D000493:Allopurinol; C010240:6-methylthiopurine; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase