Azathioprine and TPMT Testing: How Genetic Screening Prevents Life-Threatening Side Effects

When you're prescribed azathioprine for Crohn’s disease, lupus, or after a transplant, you’re not just getting a pill-you’re starting a treatment that could save your life. But for some people, that same pill can shut down their bone marrow, leaving them with dangerously low blood counts, infections, or even death. The difference between safety and disaster often comes down to a simple genetic test most patients never hear about: TPMT testing.

Why Azathioprine Can Be Dangerous

Azathioprine has been used for over 60 years. It’s cheap-often under $50 a month-and works well for long-term immune control. But it’s also a ticking time bomb for about 1 in 300 people. That’s because the body breaks it down using an enzyme called TPMT. If your TPMT enzyme doesn’t work right, the drug builds up in your blood and starts destroying your white blood cells, red blood cells, and platelets. This isn’t just a mild side effect. It’s called severe myelosuppression, and it can land you in the hospital-or worse.

Up to 28% of people on azathioprine have side effects. Nausea is common. But when your white blood cell count drops below 1,000, you’re at serious risk of infection. Some patients develop liver damage, pancreatitis, or skin reactions from sun exposure. The scary part? Many of these reactions happen without warning. You feel fine one week, and the next, your blood test shows you’re on the edge of collapse.

What Is TPMT Testing and Why It Matters

TPMT stands for thiopurine methyltransferase. It’s a protein your liver makes to neutralize azathioprine before it turns toxic. Everyone has a different version of the TPMT gene. Most people have two normal copies and break down the drug just fine. But about 10% of people have one broken copy (heterozygous), and 0.3% have two broken copies (homozygous). Those with two broken copies are at extreme risk.

TPMT testing checks your gene or measures your enzyme activity. It’s usually done with a blood draw or cheek swab before you even take your first pill. Results come back in a few days. If you’re homozygous deficient, doctors won’t give you azathioprine at all. They’ll switch you to methotrexate or a biologic like adalimumab. If you’re heterozygous, they’ll start you on 30-70% of the normal dose and watch your blood counts closely.

This isn’t guesswork. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has clear guidelines backed by decades of research. The American Gastroenterological Association says testing should be done before starting azathioprine. The European Crohn’s and Colitis Organisation agrees-it’s recommended, even if not mandatory. And the FDA updated azathioprine’s label in 2019 to include TPMT testing information.

The NUDT15 Factor: A Hidden Risk in Asian Populations

TPMT isn’t the whole story. Around 20% of people of East Asian descent have a different genetic variation called NUDT15 deficiency. This causes the same deadly toxicity as low TPMT-but it’s invisible to standard TPMT tests. In some Asian countries, NUDT15 variants are the main reason azathioprine causes bone marrow failure.

That’s why CPIC updated its guidelines in 2022 to include NUDT15 testing alongside TPMT. If you’re of Asian, Hispanic, or Indigenous descent, asking for both tests isn’t overcautious-it’s essential. One study found that in Korean patients, NUDT15 deficiency caused more toxicity than TPMT deficiency. Many clinics still only test for TPMT. That’s a gap. If your doctor hasn’t mentioned NUDT15, ask. It could save your life.

Testing Doesn’t Replace Blood Work-It Completes It

Too many patients think a negative TPMT test means they’re safe. It doesn’t. Even people with normal TPMT can develop liver damage, pancreatitis, or low blood counts. That’s because azathioprine’s toxicity isn’t just genetic. Drug interactions matter. Allopurinol (used for gout) can double the risk of toxicity, no matter your genes. ACE inhibitors, some antibiotics, and even high doses of folic acid can interfere.

That’s why every patient on azathioprine needs regular blood tests. CBCs (complete blood counts) every week for the first month, then every 2-4 weeks for the first six months. Liver function tests too. If your white blood cell count drops below 3,000, your dose should be lowered. If it falls below 1,500, stop the drug. No exceptions. TPMT testing tells you your starting risk. Blood tests tell you if you’re still safe.

One patient in Toronto told me: “I had normal TPMT, but my white count dropped after three months. My doctor stopped the drug just in time. If I hadn’t been getting blood work, I might have gotten sepsis.” That’s the reality. Genetics give you a head start. Monitoring keeps you alive.

What Your Doctor Should Do After Testing

If your TPMT and NUDT15 results come back normal: Start at the full dose (1.5-2.5 mg/kg/day) but get blood tests weekly for the first month.

If you’re heterozygous (intermediate enzyme activity): Start at 30-50% of the normal dose. For example, if the usual dose is 100 mg, begin with 30-50 mg. Check CBCs weekly for the first month, then every two weeks. Most people stabilize at this lower dose without side effects.

If you’re homozygous deficient (severely low enzyme): Do NOT take azathioprine. Switch to methotrexate, mycophenolate, or a biologic like infliximab. The risk of fatal pancytopenia is too high. There’s no safe dose.

And if you’re on allopurinol? Never combine it with azathioprine unless you’re under close supervision. The combination can be deadly-even if your genes are fine.

Cost, Access, and Real-World Barriers

TPMT and NUDT15 testing costs $200-$400 in the U.S. and is usually covered by private insurance. In Canada, some provinces cover it under public drug plans if you’re on an immunosuppressant for IBD or autoimmune disease. But access varies. Rural clinics often don’t order it. Community pharmacists rarely push for it. And many primary care doctors don’t know the guidelines.

That’s why patients need to speak up. If your doctor hasn’t mentioned genetic testing before prescribing azathioprine, ask: “Have you checked my TPMT and NUDT15 status?” If they say no, request a referral to a specialist or pharmacy genetics service. In Toronto, hospitals like SickKids and Mount Sinai offer pharmacogenomic clinics for this exact reason.

Some doctors argue testing isn’t worth it because the overall rate of severe reactions is low. But that’s like saying seatbelts aren’t worth wearing because most car crashes aren’t fatal. You’re not trying to prevent all side effects-you’re trying to prevent death.

What Happens If You Skip Testing?

A 2011 study followed 333 patients. Half got TPMT testing before starting azathioprine. Half didn’t. At four months, both groups had nearly the same number of side effects. That’s because most side effects aren’t genetic-they’re from drug interactions, poor monitoring, or other unknown factors.

But here’s what the study didn’t show: the one patient in the non-testing group who was homozygous deficient. He developed severe neutropenia, spent three weeks in the ICU, and nearly died. That’s the one case testing would have caught. And it’s the one case you don’t want to be.

Skipping testing doesn’t make you brave. It makes you vulnerable.

What to Do Next

If you’re about to start azathioprine:

1. Ask your doctor for TPMT and NUDT15 genetic testing before your first dose.
2. If you’re of Asian descent, insist on both tests.
3. Get a baseline CBC and liver panel before starting.
4. Set up weekly blood tests for the first month.
5. Never take allopurinol with azathioprine unless your doctor is aware and monitoring you.
6. If you develop fever, fatigue, unexplained bruising, or sore throat, get your blood checked immediately.

If you’re already on azathioprine and never had testing:

• Ask for testing now-even if you’ve been on it for years.
• Review your last three CBCs. Are your white blood cells trending down?
• Check if you’re taking any other meds that interact with azathioprine.
• If your counts are dropping, don’t wait. Talk to your doctor about switching.

Azathioprine is a powerful tool. But like any tool, it needs the right safety checks. TPMT and NUDT15 testing aren’t optional extras. They’re the foundation of safe use. You wouldn’t drive a car without checking the brakes. Don’t take a drug that can kill you without checking your genes.

If you’re managing a chronic condition with azathioprine, knowledge is your best defense. Genetic testing doesn’t guarantee safety-but it gives you a real chance to avoid disaster. Pair that with regular blood work, and you’re not just taking a drug-you’re taking control.