Thiopurine methyltransferase (TPMT)

The tests for thiopurine methyltransferase (TPMT) enzyme activity or its underlying genetics are measured in people who are about to start treatment with a thiopurine drug. One or the other of these tests is used to identify individuals at risk of developing severe side effects from thiopurine therapy, such as suppression of the bone marrow that leads to reduced numbers of red blood cells, white blood cells and platelets.

Thiopurines such as azathioprine, mercaptopurine, and thioguanine are drugs that are prescribed for diseases such as acute lymphoblastic leukemia (ALL), inflammatory bowel disease, and autoimmune disorders. They may also be prescribed for organ transplant recipients to help prevent organ rejection.

A healthcare practitioner will typically order a TPMT enzyme activity test or genetic test before starting a person on thiopurine drug treatment. Occasionally, a TPMT genotype test may be ordered when a person treated with a thiopurine drug experiences side effects, such as a decreased WBC count.

Phenotype test for TPMT

• If someone has little to no detectable TPMT activity, that person is at risk of developing severe side effects to thiopurine drugs. Usually the health care practitioner will find an alternative drug treatment. Sometimes the healthcare practitioner may prescribe a very small dose of the thiopurine.
• Low to intermediate TPMT activity also puts individuals at increased risk for toxicity. In this case, the healthcare practitioner may reduce the dose of thiopurine drug given.
• If someone has normal TPMT activity, the health care practitioner can treat the person with a standard dose of a thiopurine drug.

Genotype test for TPMT

• A genetic test to detect genetic variations in the TPMT gene will help determine TPMT activity and risk for side effects from low TPMT activity.
• Individuals with two “wild type” copies of the TPMT gene produce sufficient TPMT and have little risk of thiopurine toxicity. Most people fall into this category and can be treated with a standard dose.
• People who have one normal gene and one gene variation associated with decreased TPMT (heterozygous) may produce an intermediate amount of TPMT. Approximately 30-60% of people who are heterozygous have severe side effects from standard doses of thiopurines. They will likely require reduced doses of the drug but may need to be given an alternative drug.
• People with two copies of a variant TPMT gene (homozygous) and who produce little to no TPMT have 100% likelihood of developing severe bone marrow toxicity (myelosuppression) when treated with conventional doses of thiopurines. They will likely be given an alternative drug.
• The genetic test usually detects the most common variants associated with TPMT deficiency. It is possible for a person to have a rare variant not detected by this test, who may subsequently experience serious side effects from treatment with a thiopurine drug.

Though the TPMT test is used to predict risk of bone marrow toxicity, complete blood counts (CBCs) should also be done at regular intervals to detect bone marrow toxicity during treatment with thiopurine drugs. The CBC is a common blood test that measures the number of red blood cells, white blood cells and platelets. It is often used to monitor drug treatments that are known to affect the bone marrow.

TPMT enzyme activity is measured in red blood cells, so if you have recently received a transfusion of blood, the results of this test may be inaccurate.

Besides your genetic makeup, there may be other reasons for increased risk of bone marrow toxicity (myelosuppression) from treatment with thiopurine drugs. Interactions between certain drugs can also inhibit TPMT enzyme activity. These drugs include naproxen, ibuprofen, ketoprofen, furosemide, sulfasalazine, mesalamine, olsalazine, mefenamic acid, thiazide diuretics, and benzoic acid inhibitors. TPMT inhibitors may contribute to falsely low results; people should not take these drugs for at least 48 hours prior to TPMT testing.

A few people may have high levels of TPMT activity. It is thought that this decreases the effectiveness of thiopurine therapy, and these people may be treated with an alternative drug.

A health practitioner may order a blood test for thiopurine metabolites to monitor drug therapy. Measuring the metabolites is another way to ensure that toxic levels do not build up in the blood. Prior to administering the first dose, a healthcare practitioner may test a person’s TPMT enzyme activity or genotype to help determine risk of side effects as described in other sections of this article. The healthcare practitioner can adjust the prescribed dose according to those results. After therapy begins, the level of metabolites can be measured and monitored, with subsequent doses adjusted as necessary to avoid toxicity.

The opinions of medical organizations vary on which TPMT test to recommend. You should consult with your healthcare practitioner about which one best fits your individual situation. For example:

• The U.S. Food and Drug Administration (FDA) and prescribing information for azathioprine and mercaptopurine recommend either TPMT genotyping or phenotyping prior to thiopurine treatment.
• The American College of Gastroenterology prefers TPMT phenotyping for people who are being treated with thiopurines for inflammatory bowel disease because the phenotype test measures the level of TPMT enzyme activity.