TPMT and NUDT15: genes that affect azathioprine and mercaptopurine

Thiopurines work by dampening overactive immune cells or by interfering with cell division in leukaemia. In the UK, azathioprine is used in conditions such as Crohn disease, ulcerative colitis, some forms of arthritis and after organ transplants, while mercaptopurine is used in inflammatory bowel disease and in leukaemia treatment.

Because they suppress blood-cell production in the bone marrow as part of how they work, the line between a useful effect and too much effect is narrower for some people than others. TPMT and NUDT15 are two of the reasons that line shifts.

MedlinePlus Genetics describes TPMT as the enzyme that turns thiopurine drugs off by metabolising them to inactive compounds. When the gene carries low-activity variants, less of the drug is switched off. Someone with two normal copies has an expected response. Someone with one low-activity copy and one normal copy has a moderately increased risk. Someone with two low-activity copies has the highest risk.

NUDT15 acts in a related part of thiopurine handling. The NHS azathioprine guidance mentions a rare inherited condition affecting the NUDT15 gene among reasons to speak to the doctor first. Frequencies of the variants differ between ancestries, and a result is read in that light by the laboratory and clinician.

The NHS says you have a blood test before starting azathioprine to make sure it is safe for you. In practice the test may measure TPMT enzyme activity or look for gene variants, and local arrangements differ, so ask the clinic which approach it uses and how quickly results arrive.

Broadly, a normal result lets treatment proceed with routine monitoring. Reduced activity usually means the team considers a lower dose or a different medicine, and a very low result may mean thiopurines are avoided. The exact thresholds come from specialist guidance, not from patient information pages, and are not reproduced here.

• Normal activity: standard start, with regular blood tests.

• Intermediate activity: a cautious plan, often with a lower starting amount and closer monitoring.

• Very low or absent activity: usually an alternative treatment, because the risk of severe bone-marrow suppression is high.

Even a normal enzyme result does not guarantee a safe course. Infection, other medicines, liver problems and individual differences can still lower blood counts. That is why the NHS explains that regular blood tests continue during treatment to monitor the liver, kidneys and bone marrow.

Expect more frequent tests at the start and after any dose change, then less often once things are stable. Keeping appointments for these tests is one of the most useful things a person on a thiopurine can do.

NHS guidance tells people to stop azathioprine and contact a doctor or NHS 111 if they develop persistent fatigue, dizziness, vomiting or diarrhoea, a high fever with chills or breathing symptoms, unusual bleeding or bruising, unexplained lumps, confusion or weakness, or severe abdominal and back pain.

A rare serious allergic reaction needs 999: swelling of the lips, mouth or throat, severe difficulty breathing, or loss of consciousness. Long-term use raises skin-cancer risk, so the NHS advises sunscreen of at least SPF 30 and clothing that covers arms and legs.

Useful questions include whether your TPMT or NUDT15 status has been checked, how often blood tests will be needed, who to contact if a result is abnormal, and what to do about infections or planned vaccines. Your hospital team can answer the vaccine question for your own situation.

If a relative has had a severe reaction to a thiopurine, mention it, as it may prompt earlier testing.