Thiopurine Methyltransferase (TPMT), Erythrocytes
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Thiopurine methyltransferase (TPMT) deficiency is a condition in which patients treated with standard doses of the immunosuppressant azathioprine (AZA, Imuran) or the antineoplastic drug 6-mercaptopurine (6-MP, Purinethol) may develop life-threatening myelosuppression or severe hematopoietic toxicity. The metabolic conversion of AZA or 6-MP to purine nucleotides and the subsequent incorporation of these nucleotides into DNA play an important role in both the therapeutic efficacy and the toxicity of these drugs. A competitive catabolic route for the metabolism of thiopurines is catalyzed by the TPMT enzyme, which inactivates them by thiomethylation. A balance must be established between these competing metabolic pathways so that: 1) sufficient amounts of drug are converted to the nucleotide to act as an antimetabolite and 2) the antimetabolite levels do not become so high as to cause potentially lethal bone marrow suppression.
TPMT deficiency is an autosomal recessive condition with an incidence of approximately 1 in 300 individuals homozygous for deleterious mutations in the TPMT gene; about 10% of the population are heterozygous carriers of TPMT mutations. The incidence of individuals who are homozygous or heterozygous carriers of TPMT mutations varies by population. Adverse effects of AZA or 6-MP administration can be observed in individuals who are either homozygous or heterozygous for TPMT deficiency. As such, knowing a patient's TPMT status prior to treatment with AZA or 6-MP is important for purposes of calculating drug dosages.
Detection of individuals with low thiopurine methyltransferase activity who are at risk for excessive myelosuppression or severe hematopoietic toxicity when taking azathioprine (Imuran) or 6-mercaptopurine (Purinethol)
Expected values for individuals in the carrier range for thiopurine methyltransferase (TPMT) deficiency are between 6.0 and 10.0 U/mL RBC.
Expected values for individuals homozygous for deleterious mutations in the TPMT gene (deficient TPMT) are < or =5.9 U/mL RBC.
Results between 10.1 and 14.9 U/mL RBC represents probable low normal.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
There is partial overlap for the distribution of thiopurine methyltransferase activities observed between patients with normal and heterozygous genotypes; thus, results that fall within the low-normal range can occur because of assay variability or biological variation.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
> or =15.0 U/mL RBC (normal)
10.1-14.9 U/mL RBC (low normal)
6.0-10.0 U/mL RBC (carrier)
0.0-5.9 U/mL RBC (deficient)
Reference values apply to all ages.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Relling MV, Gardner EE, Sandborn WJ, et al: Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2011;89(3):387-391
2. Sandborn WJ: Pharmacogenomics and IBD: TPMT and thiopurines. Inflamm Bowel Dis 2004;10:Suppl 1 S35-S37
3. Schedel J, Godde A, Schutz E, et al: Impact of thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations in patients with chronic inflammatory diseases. Ann N Y Acad Sci 2006;1069:477-491
4. Zhou S: Clinical pharmacogenomics of thiopurine S-methyltransferase. Curr Clin Pharmacol 2006;1:119-128