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

When you’re prescribed azathioprine for Crohn’s disease, lupus, or after an organ transplant, you’re not just taking a pill-you’re trusting a drug that can save your life… or nearly end it. Azathioprine has been used for over 60 years. It’s cheap, effective, and widely available. But for a small group of people, it can trigger a dangerous drop in blood cells-so severe it can lead to infection, hospitalization, or death. The good news? There’s a simple test that can prevent this before it happens: TPMT testing.

What is azathioprine, and why does it carry hidden risks?

Azathioprine is an immunosuppressant. It slows down your immune system so it doesn’t attack your own body-whether that’s your intestines in ulcerative colitis, your kidneys after a transplant, or your joints in rheumatoid arthritis. It’s often chosen over expensive biologics because it costs as little as $20 a month. But here’s the catch: your body doesn’t process it the same way everyone else does.

Most people break down azathioprine safely using an enzyme called TPMT (thiopurine methyltransferase). But about 1 in 300 people have a genetic variation that makes this enzyme almost nonfunctional. For them, even a standard dose can build up to toxic levels in the bone marrow, wiping out white blood cells, red blood cells, and platelets. This is called myelosuppression. It doesn’t come with warning signs at first. You might feel fine until you get a fever, start bleeding easily, or collapse from extreme fatigue.

What is TPMT testing, and how does it work?

TPMT testing checks your genetic makeup-or your enzyme activity-to see how well your body can handle azathioprine. There are two types:

• Genotyping: A blood or saliva sample looks for specific gene mutations (like *2, *3A, *3B, *3C) that reduce TPMT function.
• Phenotyping: A blood test measures actual enzyme activity in your red blood cells.

Genotyping is more reliable because it’s not affected by recent blood transfusions or other drugs. Results usually come back in 3 to 7 days. The test tells you one of three things:

• Normal activity (homozygous wild-type): You can take the full dose-1.5 to 2.5 mg per kg of body weight daily.
• Intermediate activity (heterozygous): About 10% of people fall here. Your doctor should start you at 30-70% of the normal dose.
• Low or absent activity (homozygous variant): Less than 0.3% of people. You should NOT take azathioprine at all.

For those with low TPMT, the risk isn’t just higher-it’s catastrophic. Studies show these patients have a 90% chance of developing life-threatening pancytopenia within weeks if given a standard dose.

Why TPMT testing doesn’t catch everything

TPMT testing is powerful-but it’s not magic. A 2011 study in JAMA followed 333 patients on azathioprine. Half were tested before starting. The results? Only one patient in the entire study had the dangerous homozygous TPMT deficiency. That patient got sick. Everyone else? The rate of side effects was nearly identical between tested and untested groups.

Why? Because TPMT only explains part of the story. Other genes matter too-especially NUDT15. This gene is critical for people of Asian descent. Up to 20% of people in some Asian populations carry variants that cause severe toxicity even with normal TPMT levels. The FDA updated azathioprine labeling in 2019 to include NUDT15. Many clinics now test for both.

And then there are drug interactions. Allopurinol (used for gout) blocks the same metabolic pathway as TPMT. If you’re on both, your azathioprine toxicity risk skyrockets-even if your TPMT is normal. ACE inhibitors and certain antibiotics can also interfere. Your doctor needs to know everything you’re taking.

Even with perfect genetics, you can still get liver damage. About 7% of patients develop hepatotoxicity. That’s why blood tests don’t stop after TPMT screening. You still need regular CBCs (complete blood counts) and liver function tests every week for the first month, then every 1-3 months after that.

Real stories: What patients actually experience

One patient with Crohn’s disease in Melbourne told her doctor she’d been sick for months-nausea, fatigue, constant infections. Her TPMT test showed intermediate activity. Her dose was cut from 100 mg to 50 mg. Within two weeks, her energy returned. Her white blood cell count stabilized.

Her friend, who skipped the test, started at 100 mg too. Three weeks later, she ended up in the ER with a fever of 104°F and a white blood cell count of 0.2. She needed hospitalization, antibiotics, and a blood transfusion. Her azathioprine was stopped for good.

But not all stories end well. A Reddit user wrote: “I had normal TPMT. Still got liver failure.” That’s the truth. Genetics don’t tell the whole story. Side effects like pancreatitis, rash, and photosensitivity can still happen. That’s why monitoring isn’t optional-it’s essential.

Who should get tested-and who might skip it?

Guidelines aren’t the same everywhere. The American Gastroenterological Association says: test everyone before starting azathioprine. The European Crohn’s and Colitis Organisation says it’s “recommended,” not mandatory. Why the difference?

Cost and access play a role. In the U.S., TPMT testing runs $200-$400. Insurance usually covers it. In Australia, Medicare doesn’t currently subsidize it for azathioprine, so out-of-pocket costs apply. Many community doctors still skip it because they don’t have the infrastructure or time.

But here’s the reality: if you’re on azathioprine long-term, the cost of one hospitalization for severe myelosuppression is over $20,000. The test pays for itself.

High-risk groups include:

• People of East Asian descent (due to NUDT15 risk)
• Those with a family history of blood disorders
• Patients already on allopurinol or other interacting drugs
• Anyone with unexplained low blood counts

If you’re young, otherwise healthy, and taking azathioprine for a mild condition, your doctor might delay testing and monitor closely. But if you’re older, have other health issues, or are on long-term therapy-testing is non-negotiable.

What to do if your test shows low TPMT

If you’re homozygous for a non-functional TPMT variant, you should not take azathioprine. Period. There are safe alternatives:

• Methotrexate: Often used for autoimmune conditions. Requires folic acid and liver monitoring.
• 6-MP (mercaptopurine): A close relative of azathioprine-but still risky if TPMT is low. Avoid unless under strict supervision.
• Biologics: Like infliximab or adalimumab. More expensive ($1,500-$2,500 per dose) but safer for genetically high-risk patients.

Your doctor will pick the best alternative based on your condition, cost, and insurance. Don’t push for azathioprine if your test says no. It’s not worth the risk.

What happens if you skip testing and get sick?

If you start azathioprine without testing and develop symptoms like fever, sore throat, bruising, or extreme tiredness-stop the drug immediately and get a CBC. Don’t wait. Don’t assume it’s “just a cold.”

Early detection saves lives. If your white blood cell count drops below 1.5 x 10⁹/L, your doctor will likely stop the drug. If it’s below 1.0, you may need hospital care. Recovery can take weeks. In rare cases, bone marrow damage is permanent.

And here’s something rarely discussed: photosensitivity. Azathioprine makes your skin more sensitive to UV light. Patients have reported severe sunburns after minimal exposure. Wear sunscreen, long sleeves, and a hat-even on cloudy days.

What’s next? The future of genetic testing for drugs

TPMT testing is one of the oldest and most proven examples of pharmacogenomics. But it’s just the beginning. Labs are now offering multi-gene panels that test for TPMT, NUDT15, GST variants, and more-all in one go. Companies like OneOme and GeneSight are making these tests faster and cheaper.

In the next five years, we may see routine genetic screening before prescribing any immunosuppressant-not just azathioprine. For now, if you’re about to start this drug, ask for the test. It’s simple, safe, and could prevent a medical emergency.

Don’t wait for a crisis to learn your body’s limits. Get tested. Stay monitored. And don’t assume you’re safe just because you feel fine.