Risk Factors For Thiopurines

Some medications must be processed by enzymes in the body to work properly. The TPMT gene provides instructions to tell the body how to make the TPMT enzyme. The TPMT enzyme helps the body process thiopurine drugs such as azathioprine (Imuran®), mercaptopurine (Purinethol®), and thioguanine (6-TG, Tabloid® or Lanvis®). Variants in the TPMT gene may impair the body's ability to process thiopurine drugs, causing the drug to build up in the body. If a thiopurine drug builds up in the body, serious and life-threatening side effects can occur.

Thiopurine Drug Side Effects

The most serious potential side effect of thiopurine drugs is bone marrow suppression. Bone marrow suppression is a severe decrease in cells responsible for providing immunity, carrying oxygen, and those responsible for normal blood clotting. This can occur in someone who has low TPMT enzyme activity levels (impaired ability to process thiopurine drugs) and is given the standard dose.

Other side effects of thiopurine drugs include:

  • pale skin
  • feeling light-headed or short of breath
  • rapid heart rate
  • trouble concentrating
  • fever, chills, body aches, sore throat, flu-like symptoms
  • sores or white patches in the mouth, on the lips and in the throat
  • easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under the skin
  • severe pain in the upper stomach spreading to the back
  • severe nausea, vomiting, or diarrhea
  • pain or burning with urination
  • bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds
  • loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes)

Less serious side effects of thiopurine drugs may include:

  • vomiting
  • mild diarrhea
  • hair loss
  • mild itching or skin rash
  • darkened skin color

TPMT Gene Variants

There are multiple genetic variants in the TPMT gene that impact the way the body responds to thiopurine drugs. Your response to thiopurine drugs is determined by your specific combination of genetic variants in the TPMT gene, not simply by the number of variants that you have. Each combination of genetic variants in or near a gene is called a "haplotype." There can be many different combinations of variants for each gene. To distinguish one combination of variants from another, scientists sometimes use a numbering system. For example: one combination of variants within the TPMT gene may be called "star 3C", written as *3C, while another combination is known as *1.
thiopurines-risk-factors-main-1How Haplotypes Are Inherited
Since we have two copies of each gene, one from our mother and one from our father, each person will have one combination of variants (called a haplotype) from each parent. When genetic testing is performed the results are noted as two numbers (each representing the haplotype from each parent), separated by a slash. For example, someone who inherited the combination of variants from their father known as *1 and the combination known as *3C from their mother would be a *1/*3C for the gene tested. Some people have combinations of variants that are rare and have not been studied or named. Sometimes, the genetic test that is performed cannot determine a person's result with certainty.

The Impact of TPMT Gene Variants on TPMT Activity Level

Different combinations of variants in the TPMT gene can be used to predict how a person will respond to a particular drug, like azathioprine (Imuran®), mercaptopurine (Purinethol®), or thioguanine (6-TG, Tabloid® or Lanvis®). A person's predicted TPMT activity level is based on the two TPMT haplotypes they inherited from their parents. The following table summarizes the possible TPMT enzyme activity levels that are determined by variants in the TPMT gene.

Are There Other Factors That Can Affect How I Respond to Thiopurine Drugs?
Many factors affect how your body will respond to a medication. In fact only 25% of severe side effects, like bone marrow suppression, are caused by low TPMT activity levels. Non-genetic factors that affect your response to thiopurine drugs include interactions between different drugs you may be taking, interactions between drugs and your other health conditions, and interactions between drugs and your lifestyle.