From the Guidelines
Thiopurine Methyltransferase (TPMT) elevation is not typically caused by external factors, but rather by genetic variations that affect the enzyme's activity.
Causes of TPMT Elevation
- Genetic polymorphisms: TPMT enzyme activity is controlled by >25 genetic polymorphisms, but the most common 4 alleles are found in 80-95% of tested persons 1.
- Normal TPMT activity: The usual dose of azathioprine is 2-2.5 mg/kg daily and for mercaptopurine 1-1.25 mg/kg daily for patients with normal TPMT activity 1.
Important Considerations
- Low or absent TPMT enzyme activity can lead to severe bone marrow toxicity due to the excess production of drug-derived TGN metabolites 1.
- Patients with heterozygous TPMT deficiency are at increased risk of discontinuing thiopurines due to adverse effects, and may require dose reduction 1.
- Genetic variation in NUDT15 has also been described in association with myelosuppression, particularly in East Asian patients 1.
Clinical Implications
- Pretreatment testing of TPMT activity is recommended to identify patients with low or absent TPMT activity who are at risk for severe myelosuppression 1.
- TPMT measurement in all patients starting thiopurine therapy is cost-effective, and can help guide dosing and minimize adverse effects 1.
From the Research
Causes of Thiopurine Methyltransferase (TPMT) Elevation
- TPMT activity can be elevated in uremic patients before hemodialysis, and this elevation is reduced after hemodialysis, suggesting that uremic factors can activate TPMT 2.
- Azathioprine treatment can induce an increase in TPMT activity, which may be related to enzyme induction 2.
- The age of red blood cells can influence TPMT activity, with younger erythrocytes having higher TPMT activity, which may lead to elevated TPMT activity after bone marrow depression or in cases of activated erythropoiesis 3.
- There is no direct evidence to suggest that genetic polymorphisms alone cause TPMT elevation, but rather that they can result in diminished TPMT activity 4, 5, 6.
- Other factors, such as drug interactions, may also influence TPMT activity, but the evidence is limited to suggesting that TPMT may be the target for clinically significant drug interactions 4.
Factors Influencing TPMT Activity
- Uremic factors can activate TPMT, leading to elevated activity in uremic patients before hemodialysis 2.
- Azathioprine treatment can induce an increase in TPMT activity 2.
- The age of red blood cells can influence TPMT activity, with younger erythrocytes having higher TPMT activity 3.
- Genetic polymorphisms can result in diminished TPMT activity, rather than elevation 4, 5, 6.