Successful Azathioprine Treatment with Metabolite Monitoring in a Pediatric Inflammatory Bowel Disease Patient Homozygous for TPMT
An 18 year-old male was referred to our hospital for abdominal pain and loose stool. On physical examination, he had tenderness on the lower left quadrant of the abdomen. Routine laboratory tests, including complete blood cell counts (CBC) and liver function were all within normal limits except mild anemia and an elevated erythrocyte sediment rate of 82 mm/hr (reference interval, 0-22 mm/hr).\nThe patient was diagnosed with Crohn's disease according to standard clinical, endoscopic, and histologic criteria. Oral treatment with AZA (1.8 mg/kg/day) and mesalazine (55.6 mg/kg/day) was started. Two weeks later, the absolute neutrophil count (ANC) and white blood cell count (WBC) decreased from 5140/µL to 1010/µL, and 6270/µL to 2810/µL, respectively. The AZA dosage was reduced from 1.8 to 0.9 mg/kg/day. Three weeks later, ANC and WBC continued to decline further to 190/µL and 1910/µL, respectively. The AZA was discontinued. After leukopenia was recovered, the patient was restarted on AZA (0.8 mg/kg/day) with the discontinuation of mesalazine. The patient's daily dose of AZA was cautiously increased to 1.2 mg/kg while monitoring CBC levels.\nPeripheral blood samples were taken from the patient for TPMT genotyping. After obtaining written informed consent, sequence analysis of all coding exons with their flanking intron regions of TPMT gene were performed, and we identified a homozygous variant (c.719A>G; p.Tyr240Cys), TPMT.\nSimultaneously, 6-TGN and 6-MMPN concentrations were measured by the Waters 2795 Alliance HPLC system and a Quatro Micro API tandem mass spectrometer (Waters, Manchester, UK). The thresholds indicating increased likelihood efficacy (6-TGN >235 pmole/8×108 red blood cells, RBC), increased risk of leukopenia (6-TGN >450 pmole/8×108 RBC), and increased risk for hapatotoxicity (6-MMPN >5700 pmole/8×108 RBC) were suggested., The patient's 6-TGN concentration (7206 pmole/8×108 RBC) corresponded to a higher risk of leukopenia, although the daily dose had already been reduced from 1.2 mg/kg to 0.8 mg/kg because of neutropenia. The daily dosage was readily decreased to 0.2 mg/kg, and 6-TGN declined to therapeutic levels (437 pmole/8×108 RBC). Daily AZA dose was reduced further to 0.1 mg/kg as 6-TGN concentration increased again to 745 pmole/8×108 RBC (). 6-MMPN concentrations were detected at less than the limit of quantitation. The patient's laboratory parameters, including CBC and liver function, were within normal limits during the follow-up period of 24 months.