Test TPMT Levels Before Starting Thiopurine Drug Therapy

Thiopurine methyltransferase (TPMT) is an enzyme whose physiological function is not well understood. What is well established is that TPMT is involved in the metabolism of thiopurine drugs such as athioprine (Imuran), 6-mercaptopurine (Purinethol) and 6-thioguanine. These drugs are used to treat some cancers (especially certain leukemias), autoimmune diseases (e.g., Crohn's disease, ulcerative colitis, rheumatoid arthritis), as well as organ transplant recipients.

A small but significant portion of the population is TPMT-deficient. Low TMPT levels can result in thiopurine drugs being inadequately metabolized. This can lead to life-threatening toxicity as the un-metabolized drug accumulates in bone marrow.

If your treatment plan includes thiopurine drugs, then your doctor may want to determine how much TPMT enzyme your body produces. If you are found to be deficient in TPMT, then you are at risk for accumulating toxic levels of the drug. Your doctor can use the information from the test to decide whether to adjust the drug's dosage or choose a different treatment plan all together.

There are two ways to determine whether you have adequate TPMT activity. Both involve a blood test. The most common test measures the activity of the TPMT enzyme found in red blood cells. This test will determine if you have normal TPMT activity, a TPMT deficiency, or high TPMT activity.

The second method looks at the TPMT gene. This gene contains the genetic instructions for building the TPMT enzyme. There are several known alleles (variants of the gene) that cause the TPMT enzyme activity to be deficient. If those alleles are present in your DNA your doctor can predict that there will be a deficit in TPMT enzyme activity.

The test that directly measures TPMT enzyme activity in red blood cells is call a phenotype test. The test that looks at the TPMT gene is called a genotype test.

Both tests have their place. The TPMT phenotype test is less expensive, widely available, and accurately predicts thiopurine toxicity in most cases. However, the results may be inaccurate if the patient recently received a blood transfusion, is currently being treated with thiopurine drugs, or is taking any of several other drugs that inhibit TPMT enzyme activity (including common NSAIDS). In these situations, the genotype test may be recommended.

TPMT genotyping is a one-time test. It's results will not change over time and are not affected by variables such as medications or blood transfusions. This makes it the preferred test if the patient had a recent blood transfusion or is already on thiopurine drug therapy. However, not all the alleles that cause TPMT enzyme deficits have been identified and thus the test results sometimes inaccurately predict normal TPMT enzyme activity. In addition, some of the alleles appear almost entirely in certain ethnic groups and therefore they are not commonly tested for unless the patient is known to have that ethnic heritage. This too, occasionally leads to inaccurate results. A side benefit of TPMT genotyping is that the genetic information that results may be important to other biologic family members.

In the vast majority of cases, either testing method will provide accurate results and the decision about which to use can be made on cost and availability.

Your doctor will take many factors into account but generally speaking, if you are found to have a complete, or nearly complete, TPMT deficiency, your doctor will probably chose a non-thiopurine drug for your treatment. At the very least he or she will use a very low dose of the thiopurine drug. If you are found to have an intermediate TPMT deficiency, you will probably be started at a low dose and the dose will be slowly increased until a therapeutic dose is identified that can be adequately metabolized. If you have normal TPMT activity, you will likely be given a maintenance dose right away.

Some patients have higher than normal TPMT activity. The effect of this on thiopurine drug treatment is not yet fully understood, but it is postulated that these patients may under-respond to the drug and may benefit from a somewhat higher dose.