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

Before you start azathioprine, you need to know one thing: your genes could decide whether this drug saves your life-or nearly ends it.

Azathioprine has been used for over 60 years to treat autoimmune diseases like Crohn’s disease, ulcerative colitis, lupus, and to prevent organ rejection after transplants. It’s cheap, effective, and works for years when other drugs fail. But for a small group of people, even a normal dose can crash their bone marrow, leaving them with dangerously low white blood cells, red blood cells, and platelets. This isn’t rare. It’s predictable. And it’s preventable-with a simple blood or saliva test called TPMT testing.

Why Azathioprine Can Be Dangerous

Azathioprine doesn’t work directly. Your body breaks it down into active compounds that suppress your immune system. But how fast-or slow-that happens depends on an enzyme called thiopurine methyltransferase, or TPMT. This enzyme acts like a brake. It turns the active parts of azathioprine into harmless waste so they don’t pile up in your blood.

Some people are born with genetic variants that make their TPMT enzyme weak or completely inactive. About 0.3% of the population-roughly 1 in every 300 people-has two broken copies of the gene. These people have almost no TPMT activity. If they take a standard dose of azathioprine, their bodies can’t clear the drug. Toxic levels build up fast. Within weeks, they can develop pancytopenia: a total collapse of blood cell production. Without quick treatment, this can be fatal.

Another 10% of people have one working copy and one broken copy. These people have intermediate TPMT activity. Their bodies process azathioprine slower than normal. If they get the full dose, they’re at higher risk for low blood counts, liver damage, and nausea. Most doctors don’t realize how common this is-until it’s too late.

What TPMT Testing Actually Tells You

TPMT testing isn’t about guessing. It’s about measuring your genetic blueprint. There are two types of tests: genotyping and phenotyping.

Genotyping looks at your DNA to find specific mutations-like *2, *3A, *3B, and *3C-that break the TPMT gene. This is the most common method today. It’s accurate, fast, and not affected by recent blood transfusions.

Phenotyping measures how much enzyme activity your red blood cells actually have. It sounds logical, but it’s unreliable if you’ve had a transfusion in the last few months. Your donor’s blood cells can skew the results.

The results fall into three categories:

• Normal activity (homozygous wild-type): You process azathioprine normally. Standard dose is safe.
• Intermediate activity (heterozygous): Your enzyme works at 30-60% capacity. You need a reduced dose-usually 30% to 70% of the usual amount.
• Low or absent activity (homozygous variant): You’re at extreme risk. Azathioprine should be avoided entirely.

According to the Clinical Pharmacogenetics Implementation Consortium (CPIC), patients with low TPMT activity should never take azathioprine. Instead, doctors should switch them to methotrexate or a biologic like adalimumab. For those with intermediate activity, starting at a lower dose and checking blood counts weekly for the first month cuts the risk of serious side effects by over 80%.

TPMT Testing Isn’t the Whole Story

Many people think if their TPMT test is normal, they’re safe. That’s not true.

A 2011 study published in JAMA followed 333 patients taking azathioprine. Half had TPMT testing before starting. The other half didn’t. At four months, both groups had nearly the same rate of side effects-29% versus 28%. Why? Because TPMT only explains part of the risk.

Other genes matter too. NUDT15 is a big one-especially for people of Asian descent. Up to 20% of people in some Asian populations have NUDT15 variants that cause severe toxicity at standard doses. In fact, in these groups, NUDT15 mutations are more common than TPMT problems. That’s why CPIC updated its guidelines in 2022 to include NUDT15 testing alongside TPMT.

Drug interactions also play a role. Allopurinol, a common gout medication, blocks the same metabolic pathway as azathioprine. Even if your TPMT and NUDT15 are normal, taking both drugs together can cause life-threatening bone marrow suppression. The same goes for ACE inhibitors and some antibiotics.

And then there’s hepatotoxicity. About 7.4% of patients on azathioprine develop liver damage, often without any TPMT or NUDT15 issues. That’s why doctors still check liver enzymes and blood counts every few weeks-even if your genetic test came back clean.

Cost, Access, and Real-World Use

Azathioprine costs between $20 and $50 a month. A TPMT test? $200 to $400 in the U.S. Some insurers cover it. Others don’t. Medicaid coverage is spotty. In the UK, testing is more widely available through NHS genetics services, but wait times can stretch to weeks.

Adoption varies wildly. In academic hospitals in the U.S., about half of gastroenterologists test before prescribing. In Europe, it’s closer to 80%. In community clinics and non-gastroenterology practices? Often none.

One patient in Bristol told me: “My doctor didn’t mention testing. I got sick after three weeks-my white blood cell count dropped to 1.2. I spent five days in the hospital. My friend, who got tested first, started on half the dose and never had a problem.”

That’s the gap. Testing isn’t expensive compared to hospitalization. One case of severe myelosuppression can cost over $20,000 in emergency care, transfusions, and antibiotics. Testing prevents that.

What You Should Do Before Starting Azathioprine

If you’re being prescribed azathioprine, here’s what to ask for:

1. TPMT and NUDT15 genotyping before your first dose.
2. A baseline complete blood count (CBC) and liver function test.
3. A plan for weekly CBC checks for the first month, then every 2-4 weeks.
4. A discussion about other medications you’re taking-especially allopurinol, ACE inhibitors, or antibiotics.
5. An alternative plan if your test shows low enzyme activity.

If your doctor says, “We don’t do that here,” ask for a referral to a specialist or a pharmacogenomics clinic. You have a right to know if your genes make this drug dangerous.

And if you’ve already been on azathioprine for months without testing? Get tested now. It’s not too late. Your blood counts can still be saved.

What Happens If You’re TPMT Deficient?

If your test shows you have no TPMT activity, you need a new plan. Azathioprine is off the table. Period.

Good alternatives include:

• Methotrexate: Another immunosuppressant, often used in rheumatoid arthritis and IBD. Safer for TPMT-deficient patients.
• Biologics: Like infliximab, adalimumab, or vedolizumab. More expensive-$1,500 to $2,500 per dose-but avoid bone marrow toxicity entirely.
• Ustekinumab: An IL-12/23 inhibitor with a clean safety profile for patients with genetic risks.

For patients with intermediate activity, doctors should start at 30-70% of the usual dose. A typical 70kg adult would normally get 100-175mg daily. With intermediate TPMT, that drops to 30-120mg. The goal isn’t to avoid side effects entirely-it’s to avoid life-threatening ones.

What About Nausea and Other Common Side Effects?

Nausea affects up to 28% of patients on azathioprine. But it’s not always genetic. It’s often dose-related. Many patients feel better if they take it with food or split the dose into two smaller pills. Nausea usually fades after a few weeks.

Other side effects-like sun sensitivity, hair thinning, or mild liver enzyme spikes-are common but rarely dangerous. Still, you need to report them. Photosensitivity? Wear sunscreen. Hair loss? It’s usually temporary. But if your skin turns yellow, your urine turns dark, or you’re dizzy and tired-get a blood test. Fast.

Don’t ignore symptoms because you “have normal genes.” Genetics don’t protect you from everything.

Final Thought: Testing Is Prevention, Not a Guarantee

TPMT and NUDT15 testing don’t make azathioprine safe for everyone. But they make it safe for the people who need it most. For the 1 in 300 who would otherwise die from a standard dose, it’s a lifesaver. For the 1 in 10 who could avoid hospitalization with a simple dose adjustment, it’s a no-brainer.

It’s not about over-testing. It’s about not under-testing. The science is clear. The guidelines are solid. The cost is low compared to the risk.

If you’re taking azathioprine-or about to start-ask for the test. Your blood cells will thank you.