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Thiopurine S-methyltransferase deficiency

Synonym(s) -
Prevalence -
Inheritance -
Age of onset -
  • E79.8
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Disease definition

Thiopurine S-methyltransferase (TPMT) deficiency is a metabolic anomaly that increases the risk of adverse drug effects in patients treated with thiopurine drugs, especially hematopoietic toxicity.


TPMT deficiency is not rare. It has a prevalence of around 1/300. The prevalence of variant TPMT alleles varies considerably among ethnic groups.

Clinical description

Thiopurine drugs may induce various adverse effects in patients with TPMT deficiency, in particular myelosuppression (leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia). Myelosuppression manifests as fatigue, dizziness, pallor especially at the lips and nail beds, tachycardia, fever, chills, signs of infection, diarrhea, rash, easy bruising, epistaxis or gingival bleeding, hematuria, hematochezia or hematemesis, and petechiae.


Thiopurine S-methyltransferase (TPMT) is an enzyme that catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine and 6-thioguanine, two cytotoxic agents, and azathioprine, an immunosuppressant, and thus reduces the transformation of these drugs into cytotoxic thioguanine nucleotides (TGNs), which are incorporated into DNA and/or RNA. TPMT deficiency results in increased conversion of parent thiopurine drugs into toxic TGNs. TPMT deficiency is caused by mutations of the TPMT gene. Heterozygous individuals have intermediate TPMT enzymatic activity, homozygous individuals have very low or absent enzymatic activity.

Diagnostic methods

Diagnosis is based on measurement of erythrocyte TPMT activity and on genotyping for the detection of TPMT gene mutations. In patients who have received blood transfusion, it has been suggested that TPMT activity should be measured at least 120 days after the transfusion in order to avoid interference from the donor blood. Negative genotyping results do not exclude low or absent TPMT activity since there may be rare mutations present not screened. Screening for TPMT deficiency is recommended in the pre-assessment of patients who need thiopurine drug therapy.

Differential diagnosis

Myelotoxicity as a side effect of thiopurine drugs may also occur in the absence of TPMT deficiency. Furthermore, other reported side effects of thiopurine drugs, e.g., hepatoxicity, pancreatitis are not necessarily associated with deficient TPMT activity.

Genetic counseling

Transmission is autosomal co-dominant.

Management and treatment

Homozygous TPMT deficient patients screened prior to starting thiopurine drugs are usually not treated with thiopurine drugs. If treatment has already started and the patient presents with myelotoxicity, this must be managed supportively and thiopurine drug treatment withdrawn. Heterozygous / low TPMT activity patients are often started on a reduced dose, which then may be adjusted depending on the clinical efficacy and toxicity of the treatment. Thiopurine metabolites (6-thioguanine nucleotides (6TGN) and 6-methytlmercaptopurine nucleotides (6MMPN)) are increasingly monitored in TPMT heterozygotes to allow titration of the dose or in patients on thiopurine drugs presenting with toxicity symptoms.


Withdrawal of the thiopurine drug allows recovery of the myelotoxicity in many patients. However, if overwhelming infection occurs for example, the toxicity may be fatal. Furthermore, in some cases, irreversible bone marrow suppression may occur.

Expert reviewer(s)

  • Dr Nicola BARLOW

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