Determination of TPMT Activity and Genotype

The patient in this case study developed severe pancytopenia after 3 weeks of taking a typical immunosuppressive dose of azathioprine. Therefore, it was likely that he possessed one or two TPMT alleles associated with a low-activity phenotype. The "gold standard" for diagnosis of a low-activity phenotype is to measure TPMT enzymatic activity in red blood cells (RBCs). Activity in RBCs correlates well with activity in other tissues. However, results are often spurious when patients have had a blood transfusion within 30-60 days of measurement. The patient's activity was low, at 3.5 EU (<6.7 EU is low, 6.7-23.6 is intermediate, and >23.6 EU is normal), despite a recent blood transfusion.

Azathioprine metabolites are thought to be responsible for bone marrow suppression. Studies have shown that higher levels of one metabolite, 6-TGN, are associated with development of leukopenia.2,6 The patient's 6-TGN was 1673pmol/8 x 108RBC (normal 230400 and higher risk of leukopenia if >400). However, the utility of measuring 6-TGN is controversial since cytopenias can occur without elevated 6-TGN concentrations.

Because the patient had recently been transfused, genotyping for common TPMT SNPs was also performed. He was homozygous for TPMT* 3A, the most common low-activity polymorphic allele among Caucasians. Thus, the patient's enzymatic activity, metabolite levels, and TPMT genotype confirm that he is 1 of 300 in the population that has low TPMT activity, which was responsible for prolonged and life-threatening myelosuppresion.

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