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Test ID: TPMT3    
Thiopurine Methyltransferase Activity Profile, Erythrocytes

Useful For Suggests clinical disorders or settings where the test may be helpful

Detection of individuals with low thiopurine methyltransferase (TPMT) activity who are at risk for excessive myelosuppression or severe hematopoietic toxicity when taking thiopurine drugs

 

Detection of individuals with hyperactive TPMT activity who have therapeutic resistance to thiopurine drugs and may develop hepatotoxicity if treated with these drugs

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 azathioprine (AZA, Imuran), 6-mercaptopurine (6-MP, Purinethol), or 6-thioguanine (6-TG, Thioguanine Tabloid) may develop life-threatening myelosuppression or severe hematopoietic toxicity. The metabolic conversion of AZA, 6-MP, or 6-TG 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. Adverse effects of AZA, 6-MP, or 6-TG administration can be observed in individuals who are either homozygous or heterozygous for TPMT deficiency.

 

TPMT hyperactivity is also a known phenotype. Individuals who are hypermetabolizers have therapeutic resistance to thiopurine drugs, and therefore they cannot achieve therapeutic levels. If an individual with TPMT hyperactivity is treated with higher and higher doses of thiopurine drugs, they may develop severe hepatotoxicity. Therefore, treatment with alternative medications is recommended for hypermetabolizers.

 

As such, knowing a patient's TPMT status prior to treatment with AZA, 6-MP, or 6-TG is important for purposes of calculating drug dosages.

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.

3.00-6.66 nmol/mL/hour 6-Methylmercaptopurine (normal)

5.04-9.57 nmol/mL/hour 6-Methylmercaptopurine riboside (normal)

2.70-5.84 nmol/mL/hour 6-Methylthioguanine riboside (normal)

Interpretation Provides information to assist in interpretation of the test results

This assay is used to detect individuals with low and intermediate thiopurine methyltransferase (TPMT) activity who may be at risk for myelosuppression when exposed to standard doses of thiopurines, including azathioprine (AZA, Imuran), 6-mercaptopurine (Purinethol), or 6-thioguanine (6-TG, Thioguanine Tabloid). TPMT is the primary metabolic route for inactivation of thiopurine drugs in the bone marrow. When TPMT activity is low, it is predicted that proportionately more 6-mercaptopurine can be converted into the cytotoxic 6-thioguanine nucleotides that accumulate in the bone marrow causing excessive toxicity. This test can also detect TMPT hyperactivity. Individuals who are hypermetabolizers have therapeutic resistance to thiopurine drugs, and therefore they cannot achieve therapeutic levels. If an individual with TPMT hyperactivity is treated with higher and higher doses of thiopurine drugs, they may develop severe hepatotoxcitity.

 

The activity of TPMT is measured by 3 different substrates. Reports include the quantitative activity level of TPMT for each of 3 different substrates and an interpretation of these results. When abnormal results are detected, a detailed interpretation is given, including an overview of results and suggestion as to whether patient has TPMT deficiency or hyperactivity, as well as discussion of treatment considerations.

 

TPMT phenotype testing does not replace the need for clinical monitoring of patients treated with thiopurine drugs. Genotype for TPMT cannot be inferred from TPMT activity (phenotype). Phenotype testing should not be requested for patients currently treated with thiopurine drugs.

 

TPMT activity is measured in RBCs. If a patient has had a recent blood transfusion, within 30 to 60 days of testing, the patient's true enzyme activity may not be accurately reflected.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Falsely low results may occur as a result of inappropriate specimen handling and hemolysis.

 

Patients with acute lymphoblastic leukemia (ALL) may have lower thiopurine methyltransferase (TPMT) activities before treatment and higher activities following treatment.

Clinical Reference Recommendations for 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. Lennard L: Implementation of TPMT testing. Br J Clin Pharmacol 2013;77:704-714

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

5. Brouwer C, De Abreu R, Keiser-Garritsen J, et al: Thiopurine methyltransferase in acute lymphoblastic leukaemia: biochemical and molecular aspects. Eur J Cancer 2005;41:613-623

Special Instructions Library of PDFs including pertinent information and forms related to the test