Summary about Disease
Thiopurine methyltransferase (TPMT) deficiency is a genetic condition in which the body doesn't produce enough of the TPMT enzyme. This enzyme is crucial for breaking down thiopurine medications like azathioprine, 6-mercaptopurine, and thioguanine. These medications are commonly used to treat various conditions, including autoimmune diseases (e.g., Crohn's disease, ulcerative colitis, rheumatoid arthritis), leukemia, and to prevent organ transplant rejection. When someone with TPMT deficiency takes these drugs, the medications can build up to toxic levels in the body, leading to severe and potentially life-threatening side effects, primarily severe bone marrow suppression.
Symptoms
Symptoms of thiopurine toxicity due to TPMT deficiency usually arise after starting thiopurine medication. The most common and serious symptoms include:
Bone marrow suppression:
Leukopenia (low white blood cell count) - increases risk of infections.
Thrombocytopenia (low platelet count) - increases risk of bleeding and bruising.
Anemia (low red blood cell count) - fatigue, weakness, shortness of breath.
Other potential symptoms:
Nausea, vomiting, diarrhea
Liver problems (elevated liver enzymes)
Fatigue
Mouth sores
Causes
TPMT deficiency is caused by genetic mutations in the TPMT gene. This gene provides instructions for making the TPMT enzyme. Individuals inherit two copies of the *TPMT* gene, one from each parent.
Normal TPMT activity: Individuals with two normal TPMT genes have normal TPMT activity.
Intermediate TPMT activity: Individuals with one normal and one mutated TPMT gene have intermediate TPMT activity. They may be more sensitive to thiopurine medications and require lower doses.
Deficient TPMT activity: Individuals with two mutated TPMT genes have little to no TPMT activity and are at high risk for severe toxicity if given standard doses of thiopurine medications.
Medicine Used
The main issue with TPMT deficiency is the toxic buildup of thiopurine medications. These are the drugs that need careful management:
Azathioprine (Imuran, Azasan): An immunosuppressant used in autoimmune diseases and to prevent organ transplant rejection.
6-Mercaptopurine (6-MP, Purinethol): Used in the treatment of leukemia and some autoimmune disorders.
Thioguanine (Tabloid): Primarily used in the treatment of leukemia. The treatment for individuals with TPMT deficiency who need immunosuppression or cancer treatment involves:
Alternative medications: Using drugs that don't rely on the TPMT enzyme for metabolism.
Very low doses of thiopurines: If thiopurines are unavoidable, administering extremely low doses under close monitoring.
Is Communicable
No, TPMT deficiency is not communicable. It is a genetic condition passed down from parents to their children and cannot be spread from person to person through any infectious means.
Precautions
Genetic testing: The most important precaution is genetic testing for TPMT* gene variants before starting azathioprine, 6-mercaptopurine, or thioguanine.
Dosage adjustments: If an individual is found to have intermediate TPMT activity, the dosage of thiopurine medications should be adjusted accordingly.
Monitoring: Close monitoring of blood counts (white blood cells, red blood cells, platelets) is crucial when starting or adjusting thiopurine medication dosages, especially in individuals with intermediate TPMT activity.
Awareness: Patients should be educated about the signs and symptoms of thiopurine toxicity and instructed to report any concerning symptoms to their healthcare provider immediately.
Medical alert: It may be advisable for individuals with TPMT deficiency to wear a medical alert bracelet or carry a card indicating their condition.
How long does an outbreak last?
TPMT deficiency is not an "outbreak". It is a genetic condition that is present from birth. However, the effects of the deficiency manifest when thiopurine medications are given. The duration of symptoms related to thiopurine toxicity depends on:
How quickly the toxicity is recognized and treated.
The severity of the bone marrow suppression.
The individual's overall health. Symptoms can persist for several weeks or even months after stopping the medication, especially if severe bone marrow suppression has occurred. Supportive care (e.g., blood transfusions, antibiotics) may be required during this time.
How is it diagnosed?
TPMT deficiency is diagnosed through:
TPMT enzyme activity test: This blood test measures the level of TPMT enzyme activity in red blood cells. Low enzyme activity suggests TPMT deficiency.
TPMT genetic testing: This blood test identifies specific mutations in the TPMT gene. This test is more precise and can identify individuals with intermediate TPMT activity.
Clinical presentation: Symptoms of thiopurine toxicity (e.g., bone marrow suppression) in a patient taking azathioprine, 6-mercaptopurine, or thioguanine should raise suspicion for TPMT deficiency.
Complete Blood Count (CBC): This test is used to measure the amount of white blood cells, red blood cells, and platelets. It can help diagnose the presence of bone marrow suppression.
Timeline of Symptoms
9. Timeline of symptoms The timeline of symptoms is related to the use of thiopurine medications and varies.
Initial exposure: Individuals with TPMT deficiency typically show no symptoms until they are exposed to azathioprine, 6-mercaptopurine, or thioguanine.
Early signs (days to weeks): With standard doses, signs of toxicity, such as low blood counts (leukopenia, thrombocytopenia, anemia), may appear within days to weeks of starting the medication. Nausea, vomiting, or mouth sores may also occur.
Severe toxicity (weeks to months): If the medication is continued despite early signs, the toxicity can worsen, leading to severe bone marrow suppression, infections, bleeding, and potentially liver damage.
Important Considerations
Universal testing: There is ongoing debate about whether TPMT* testing should be performed universally before starting thiopurine medications. However, testing is strongly recommended.
Pharmacogenomics: TPMT deficiency is an example of how pharmacogenomics (the study of how genes affect a person's response to drugs) can be used to personalize treatment and prevent adverse drug reactions.
Communication: It's crucial for individuals with TPMT deficiency to inform all their healthcare providers (doctors, pharmacists, etc.) about their condition before starting any new medications.
Family screening: If a child is diagnosed with TPMT deficiency, it may be prudent to screen other family members (parents, siblings) to identify individuals who may also be affected.
Pregnancy: Genetic counseling is recommended for individuals with TPMT deficiency who are planning to have children.