Also known as:Thiopurine methyltransferase; TPMT RBC; TPMT Genotype; TPMT Phenotype
Formal name:Thiopurine S-methyltransferase Phenotype; Thiopurine S-methyltransferase Genotype
Related tests:Complete Blood Count, Pharmacogenetic Tests
Why Get Tested?
To detect a thiopurine methyltransferase (TPMT) deficiency and determine your risk of developing severe side effects if treated with the class of immune-suppressing thiopurine drugs that includes azathioprine, mercaptopurine, and thioguanine
When to Get Tested?
Typically, prior to thiopurine drug treatment; this is a specialized test and is not routinely ordered.
A blood sample drawn from a vein in your arm or a swab from inside your cheek (i.e., buccal swab)
Test Preparation Needed?
For measuring TPMT enzyme activity (TPMT phenotyping), the test must be performed prior to taking a thiopurine drug since it may affect results; for the genetic test (TPMT genotyping), no specific test preparation is needed.
How is it used?
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.
People who have low enzyme activity have an increased risk of side effects, and those who are severely deficient are likely to experience serious side effects such as suppression of the bone marrow. When the bone marrow is suppressed, it is unable to produce sufficient numbers of red blood cells, white blood cells, and platelets. This may result in a significant drop in blood cell counts, leading to complications such as anemia, serious infections, and/or excessive bleeding. These complications may be life-threatening.
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.
When is it ordered?
A doctor 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.
What does the test result mean?
Phenotype test for TPMT
- If someone has little to no detectable TPMT activity, they are at risk of developing severe side effects to thiopurine drugs. Usually the doctor will find an alternative drug treatment. Sometimes the doctor 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 doctor may reduce the dose of thiopurine drug given.
- If someone has normal TPMT activity, the doctor 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.
Is there anything else I should know?
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.
While the TPMT genotype test may predict risk of myelosuppression, the test should not replace complete blood count (CBC) monitoring to detect myelosuppression during treatment with thiopurine drugs. CBC monitoring is a common test and is sometimes ordered as a routine part of monitoring drug treatments, including those that affect bone marrow.
A few people may have high levels of TPMT activity. It is thought that this decreases the effectiveness of thiopurine therapy, but there is not yet consensus on how this information should be used to guide treatment.
What is being tested?
Thiopurine methyltransferase (TPMT) is an enzyme that breaks down (metabolizes) a class of drugs called thiopurines. These drugs are used to suppress the immune system and are prescribed to treat various immune-related conditions or blood disorders (e.g., leukemia). The activity level of the TPMT enzyme, or the genetics underlying the enzyme's activity, is tested before thiopurine drug therapy to make sure that individuals treated with the drugs can metabolize them.
Examples of thiopurines include azathioprine, mercaptopurine, and thioguanine. These medications are used to treat diseases such as acute lymphoblastic leukemia, inflammatory bowel disease, and autoimmune disorders. They may also be prescribed for organ transplant recipients to help delay or prevent organ rejection. If someone's TPMT activity is too low, the person may not effectively metabolize thiopurines, which can lead to severe side effects.
About one person in every 300 is severely deficient in TPMT, and about 10% of the population in the U.S. has lower than normal levels of TPMT. Individuals in both categories are at an increased risk for thiopurine drug toxicity, which can include suppression of the bone marrow (myelosuppression) and/or very reduced levels of blood cells (hematopoetic toxicity). These side effects can cause an individual to become severely ill and may even be life-threatening. These side effects can be avoided if TPMT production is tested before starting thiopurine treatment.
There are two ways to determine whether an individual is at risk of side effects from thiopurine therapy:
- TPMT activity test (phenotype)–this method tests the activity level of the enzyme thiopurine S-methyltransferase (TPMT) in a person's red blood cells. Depending on the enzyme activity level, a person may be prescribed a standard dose of the thiopurine drug, a reduced dose of the thiopurine drug, or a different drug other than a thiopurine.
- TPMT genetic test (genotype)–an alternative test to TPMT enzyme activity level is a genetic test that can identify genetic variations in the TPMT gene. This genetic test identifies individual genetic differences associated with risk for thiopurine toxicity. Each person has two copies of the TPMT gene. Most people have two copies of "wild type" TPMT that produce sufficient TPMT enzyme. Approximately 10% of people have one wild-type gene and one gene variation associated with decreased TPMT (heterozygous) and intermediate activity. Approximately one in 300 individuals have two copies of TPMT with variations resulting in little or no enzyme activity (homozygous). While numerous variations can occur in TPMT, there are five variations in particular that have been proven to be associated with TPMT deficiencies. Most genetic tests look for these five variations, although depending on the method used, more variations can be detected.
This genetic test provides information about a person's likely response to thiopurines, but it will not quantify how much TPMT enzyme is actually being made by the body. There can be significant person-to-person and ethnic variability in TPMT production, even in people with the same gene variations.
A third, different kind of test may be used after thiopurine treatment begins. A test that measures thiopurine breakdown products (thiopurine metabolites) may be used to monitor therapy and adjust doses. For more on this, see Common Questions #1.
How is the sample collected for testing?
For both genetic and enzyme activity testing, a blood sample is taken by needle from a vein in the arm. Alternatively, for the genetic test alone, a swab of cells from the inside cheek (buccal swab) may be collected.
NOTE: If undergoing medical tests makes you or someone you care for anxious, embarrassed, or even difficult to manage, you might consider reading one or more of the following articles: Coping with Test Pain, Discomfort, and Anxiety, Tips on Blood Testing, Tips to Help Children through Their Medical Tests, and Tips to Help the Elderly through Their Medical Tests.
Another article, Follow That Sample, provides a glimpse at the collection and processing of a blood sample and throat culture.
Is any test preparation needed to ensure the quality of the sample?
For the method that measures TPMT enzyme activity, taking a thiopurine drug could lead to falsely low results, so the test should be performed prior to starting therapy. For the genetic test (TPMT genotyping), no specific test preparation is needed.
- My doctor ordered a test for thiopurine metabolites. What is it and how is it related to TPMT testing?
A doctor 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 doctor 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 doctor 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.
- What are the pros and cons of TPMT phenotyping and genotyping?
The opinions of medical organizations vary on which TPMT test to recommend. You should consult with your health care provider 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 because the phenotype assay quantifies the level of TPMT enzyme activity in patients who are being treated with thiopurines for ulcerative colitis.
© 2017 American Association for Clinical Chemistry, republished from Lab Tests Online.*
Descriptions of clinical laboratory tests were originally prepared for use on Lab Tests Online, an award-winning patient education website on clinical laboratory testing. Lab Tests Online is produced by the American Association for Clinical Chemistry (AACC), a global scientific and medical professional organization dedicated to clinical laboratory science and its application to healthcare. The Lab Tests Online website is developed in collaboration with other laboratory professional societies and is funded in part through corporate sponsorships.