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 kidney transplant, you’re getting a drug that’s been saving lives since the 1960s. It’s cheap, effective, and works for years. But for a small number of people, it can turn deadly - not because of a mistake, but because of their genes.

Why Azathioprine Can Be Dangerous

Azathioprine breaks down in your body into active compounds that suppress your immune system. That’s great if you have an autoimmune disease. But if your body can’t process it properly, those compounds build up and start attacking your bone marrow. The result? A sudden, dangerous drop in white blood cells, red blood cells, and platelets - a condition called myelosuppression. In severe cases, it leads to infections so bad they land you in the ICU, or worse.

About 1 in 300 people have two broken copies of the TPMT gene. That means they produce almost no TPMT enzyme, the protein that normally breaks down azathioprine. Without it, even a standard dose can cause life-threatening toxicity. Another 1 in 10 people have one broken copy. They’re at higher risk too, though not as extreme.

And it’s not just TPMT. In Asian populations, up to 1 in 5 people carry a variant in the NUDT15 gene that does the same thing - slow down azathioprine breakdown. This is why someone from Thailand or Vietnam might react badly to a dose that’s perfectly safe for someone of European descent.

What TPMT Testing Actually Does

TPMT testing isn’t about predicting nausea or headaches. It’s about catching the rare but catastrophic risk before it happens. There are two ways to test: genotyping (looking at your DNA) or phenotyping (measuring enzyme activity in your blood). Genotyping is more reliable, especially if you’ve had a recent blood transfusion - those donated red blood cells can mess up enzyme readings.

If your test shows you’re homozygous deficient (two bad copies), doctors will almost always avoid azathioprine entirely. They’ll switch you to methotrexate, mycophenolate, or a biologic like adalimumab. No point risking your life for a $30-a-month drug when safer options exist.

If you’re heterozygous (one bad copy), your dose gets cut by 30% to 70%. A typical starting dose of 150 mg might drop to 50 mg or 75 mg. Then, your doctor checks your blood count every week for the first month. That’s not because they don’t trust the test - it’s because TPMT doesn’t explain everything.

What TPMT Testing Doesn’t Do

A lot of people think if your TPMT test is normal, you’re safe. That’s not true. In one study of 139 patients on azathioprine, only one of the 13 who had to stop the drug because of side effects had low TPMT activity. The rest had normal genes - but still got liver damage, pancreatitis, or severe nausea.

Drug interactions are a big part of that. If you’re taking allopurinol for gout, it blocks the same pathway TPMT uses. Even if your genes are perfect, this combo can still cause bone marrow failure. The same goes for ACE inhibitors and some antibiotics.

And then there’s the liver. Azathioprine can cause hepatotoxicity - liver damage - in about 7% of patients. That’s linked to high levels of a metabolite called 6-MMP. No gene test predicts this. You just need regular liver function tests.

TPMT testing doesn’t replace blood work. It just makes it smarter. Think of it like a seatbelt. It won’t prevent every crash, but it stops you from dying in the ones you can’t avoid.

The Real Cost of Skipping Testing

Azathioprine costs $20 to $50 a month. TPMT testing runs $200 to $400. At first glance, testing seems expensive. But consider this: one hospital stay for severe neutropenia can cost $20,000 or more. Add in lost work time, repeated lab tests, and the emotional toll, and the math changes.

A 2011 trial with 333 patients found that genotyping didn’t reduce the overall number of side effects. But that’s because most side effects aren’t genetic. The real win? Preventing the one case in 300 where a patient would’ve died from a standard dose. That’s the value - not in reducing common nausea, but in stopping the rare disaster.

That’s why top IBD centers in Europe test everyone. In the U.S., it’s patchy. Academic hospitals do it. Community clinics? Not so much. Insurance usually covers it, but if your doctor doesn’t order it, you won’t get tested.

What You Should Do Before Starting Azathioprine

If your doctor prescribes azathioprine, ask these three questions:

1. Have you ordered TPMT and NUDT15 genetic testing?
2. Will you check my blood count weekly for the first month?
3. Am I taking any other meds that could interact - like allopurinol or an ACE inhibitor?

Don’t wait for your doctor to bring it up. Most aren’t pharmacogenomics experts. They know azathioprine works. They might not know how dangerous it can be if your genes don’t match the dose.

Also, tell your doctor if you’re of Asian, Hispanic, or Indigenous descent. NUDT15 variants are common there. Some labs now offer combined TPMT/NUDT15 panels - ask for that.

And if you’ve already started the drug without testing? Get tested now. It’s not too late. If your results come back low, your doctor can adjust your dose or switch you - before something worse happens.

What Happens If You Ignore Testing?

One patient I spoke with - a 32-year-old with ulcerative colitis - started azathioprine at 100 mg a day. No test. Two weeks later, she had a fever, sore throat, and couldn’t get out of bed. Her white blood cell count was below 1,000. Normal is 4,000 to 11,000. She spent 11 days in the hospital on IV antibiotics. Her TPMT test later showed she was heterozygous. A 50 mg dose would’ve kept her out of the hospital.

Another man, 58, took azathioprine for years after a kidney transplant. He never had blood tests. One morning, he collapsed. He had pancytopenia - no red cells, no white cells, no platelets. He needed a transfusion and a bone marrow biopsy. His TPMT was normal. But he was on allopurinol. The combo killed his bone marrow.

These aren’t rare cases. They’re predictable.

What’s Next in Pharmacogenomics

The field is moving fast. Companies like OneOme and GeneSight now offer multi-gene panels that include TPMT, NUDT15, and even GST variants linked to liver toxicity. In the next five years, it’s likely that anyone starting azathioprine will get a full pharmacogenomic profile - not just for this drug, but for other meds too, like codeine or clopidogrel.

The FDA updated azathioprine’s label in 2019 to include NUDT15. That’s a big deal. It means drugmakers can’t ignore it anymore. But the real change will come when testing becomes automatic - ordered with the prescription, not left to chance.

For now, the message is simple: if you’re about to start azathioprine, don’t skip the test. It’s not about being perfect. It’s about avoiding the one outcome you can’t come back from.