TPMT (thiopurine methyltransferase)
Description:
The thiopurine drugs azathioprine, 6-mercaptopurine and thioguanine are converted in vivo by purine salvage pathways to form cytotoxic thioguanine nucleotides, which exert an immunosuppressive effect. Thiopurine methyltransferase (TPMT) catalyses the methylation of thiopurine bases and thio-nucleotides and is a major catabolic pathway for these drugs. TPMT deficiency is polymorphic in the population with 1:250 to 1:300 patients being completely deficient. If patients with complete TPMT deficiency are treated with normal doses of a thiopurine drug, there is a high risk of life-threatening bone marrow suppression. Genetic carriers of TPMT deficiency occur with a frequency of 10 to 12% in the population and have approximately 50% enzyme activity. If treated with normal thiopurine doses, TPMT carrier patients have an increased risk of side effects including nausea and neutropaenia, but will tolerate reduced dose therapy.
Testing by enzyme assay is preferred in disease backgrounds where thiopurines are used as immunosuppressants as rare TPMT mutations would not be detected by genotyping for common variants.
Please note for the following clinical indications the laboratory will perform TPMT/NUDT15 genotyping:
• Patients with acute lymphoblastic leukaemia
• Patients who have received a blood transfusion within the last 3 months as this may falsely raise TPMT enzyme activity.
• Patients on renal failure/renal transplant/dialysis. TPMT inhibitors may accumulate in the blood of patients in renal failure.
• Patients with very low Hb (Hb≤70g/L). Correlation between TPMT genotype and phenotype is poor for these patients.
Monitoring thioguanine nucleotides (TGN) on therapy is useful for confirming adherence and fine tuning dose.
Testing by enzyme assay is preferred in disease backgrounds where thiopurines are used as immunosuppressants as rare TPMT mutations would not be detected by genotyping for common variants.
Please note for the following clinical indications the laboratory will perform TPMT/NUDT15 genotyping:
• Patients with acute lymphoblastic leukaemia
• Patients who have received a blood transfusion within the last 3 months as this may falsely raise TPMT enzyme activity.
• Patients on renal failure/renal transplant/dialysis. TPMT inhibitors may accumulate in the blood of patients in renal failure.
• Patients with very low Hb (Hb≤70g/L). Correlation between TPMT genotype and phenotype is poor for these patients.
Monitoring thioguanine nucleotides (TGN) on therapy is useful for confirming adherence and fine tuning dose.
Clinical details:
**TPMT deficient <10 pmol/h/mg Hb**
Erythrocyte TPMT activity is deficient. The probability of azathioprine /mercaptopurine-induced myelosuppression is VERY HIGH. This patient should not be treated with azathioprine or 6-mercaptopurine.
**TPMT carrier 10-25 pmol/h/mg Hb**
Erythrocyte TPMT activity is in the carrier range. The probability of azathioprine / mercaptopurine-induced myelosuppression, and intolerance (especially nausea) is high at standard doses. This patient may tolerate and respond to a lower dose (dose increment to a target dose of 50% the standard dose). Monitor FBC and LFTs closely. A blood transfusion in the last 3 months may mask complete TPMT deficiency.
**TPMT normal 26-50 pmol/h/mg Hb and high >50 pmol/h/mg Hb**
Erythrocyte TPMT activity is in the normal range or elevated. A TPMT above the normal range does not indicate a need to alter dosing strategy. The probability of myelosuppression is low, but not excluded as TPMT deficiency is not the only cause. Standard doses of azathioprine /mercaptopurine are appropriate. Monitor FBC and LFT as per usual. A blood transfusion in the last 3 months may mask complete TPMT deficiency.
Erythrocyte TPMT activity is deficient. The probability of azathioprine /mercaptopurine-induced myelosuppression is VERY HIGH. This patient should not be treated with azathioprine or 6-mercaptopurine.
**TPMT carrier 10-25 pmol/h/mg Hb**
Erythrocyte TPMT activity is in the carrier range. The probability of azathioprine / mercaptopurine-induced myelosuppression, and intolerance (especially nausea) is high at standard doses. This patient may tolerate and respond to a lower dose (dose increment to a target dose of 50% the standard dose). Monitor FBC and LFTs closely. A blood transfusion in the last 3 months may mask complete TPMT deficiency.
**TPMT normal 26-50 pmol/h/mg Hb and high >50 pmol/h/mg Hb**
Erythrocyte TPMT activity is in the normal range or elevated. A TPMT above the normal range does not indicate a need to alter dosing strategy. The probability of myelosuppression is low, but not excluded as TPMT deficiency is not the only cause. Standard doses of azathioprine /mercaptopurine are appropriate. Monitor FBC and LFT as per usual. A blood transfusion in the last 3 months may mask complete TPMT deficiency.
Reference range:
TPMT deficient <10 pmol/h/mg Hb
TPMT carrier 10-25 pmol/h/mg Hb
TPMT normal 26-50 pmol/h/mg Hb
TPMT high >50 pmol/h/mg Hb
Units:
pmol/h/mg Hb
Department:
Location:
Sample type and Volume required:
4 mL blood EDTA (purple top)
Turnaround time:
4 working days
Storage and transport:
Store in fridge, (don’t freeze) send to the laboratory within 3 days/1st class post. Please can you provide a recent Hb (Haemoglobin) result on all referrals for TPMT assay. Due to delays in transit/post and insufficient sample volumes, it may not be possible to have haematology testing performed at St Thomas Hospital.
Contacts:
Purine Research Laboratory at St Thomas'
020 7188 1266
St Thomas’ Hospital
North Wing - 4th Floor
Westminster Bridge Road
London SE1 7EH
North Wing - 4th Floor
Westminster Bridge Road
London SE1 7EH
Laboratory:
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Last updated: 19/12/2022
