Is TPMT (Thiopurine Methyltransferase) testing mandatory for a patient with Fabry disease prior to initiating azathioprine therapy?

Is TPMT Testing Mandatory Before Azathioprine?

TPMT testing is not strictly mandatory before initiating azathioprine, but it should be strongly considered and is recommended by multiple major guidelines to prevent severe, potentially life-threatening myelosuppression in the rare patients with absent or near-absent TPMT activity.

Guideline Recommendations

The most recent high-quality guidance from the American Association for the Study of Liver Diseases (AASLD, 2020) states to "consider screening patients for absent or near-absent TPMT activity prior to initiating treatment with azathioprine" rather than making it an absolute requirement 1. This reflects a nuanced position that acknowledges both the serious risk and the rarity of complete TPMT deficiency.

The European Association for the Study of the Liver (EASL, 2015) similarly states that "if available, TPMT testing may be performed prior to initiation of azathioprine therapy," emphasizing that the benefit in terms of safety and reassurance may outweigh arguments against universal testing 1.

The British Association of Dermatologists (2011) makes the strongest case, stating that cases of severe myelosuppression "make a watertight case for routine pretreatment TPMT measurement" and that TPMT testing is becoming cost-neutral 1.

Why TPMT Testing Matters

Absent or near-absent TPMT activity occurs in only 0.3-0.5% of the population, but these patients are at extreme risk for severe bone marrow toxicity when treated with standard azathioprine doses 1. This can result in life-threatening pancytopenia, neutropenic sepsis, and death 2, 3, 4, 5.

The Toronto Consensus (2015) explicitly states that "a TPMT assay is necessary before initiation of treatment to identify patients at risk for severe dose-dependent myelosuppression" 1.

Important Limitations of TPMT Testing

TPMT testing does NOT eliminate the need for close monitoring of all patients on azathioprine 1. This is critical because:

• Most patients who develop azathioprine toxicity have normal or near-normal TPMT activity 1
• Normal TPMT activity does not preclude dose-dependent toxicities including cytopenia 1
• TPMT testing does not predict other common side effects like nausea, rash, arthralgias, pancreatitis, or hepatotoxicity 1
• Cirrhosis itself causes cytopenia more commonly than TPMT deficiency 1

Practical Approach to TPMT Testing

Two reasonable strategies exist, depending on resource availability:

Strategy 1: Universal Pre-treatment Testing (Preferred When Available)

• Provides the broadest assurance against pre-existing risk of severe toxicity 1
• Strengthens patient and physician confidence in the treatment regimen 1
• Is essentially cost-neutral and increasingly inexpensive 1
• Particularly justified in centers where TPMT testing is readily available 1

Strategy 2: Selective Testing (Minimum Acceptable)

• Test patients with pre-existing cytopenia 1
• Test patients who develop cytopenia during therapy 1
• Test patients receiving high-dose azathioprine (≥150 mg daily) 1
• This approach is endorsed by AASLD guidelines 1

Technical Considerations

TPMT enzyme assay (phenotyping) is superior to TPMT genotyping 1. Genotyping for the three most common polymorphisms detects only 80-95% of TPMT deficiency, missing approximately 10% of deficient patients 1. Genotyping should be used as a complementary test to enzyme assay, particularly for patients with borderline or absent activity 1.

Mandatory Monitoring Regardless of TPMT Status

Even with TPMT testing, close monitoring remains mandatory for all patients:

• Complete blood count monitoring is essential and cannot be replaced by TPMT testing 1, 6
• Liver function tests must be monitored regularly 6
• The low doses typically used in autoimmune hepatitis (50 mg daily) may be insufficient to cause toxicity even in some TPMT-deficient patients, but this cannot be assumed 1

Context for Fabry Disease

For a patient with Fabry disease specifically, there is no evidence that Fabry disease itself alters TPMT metabolism or increases azathioprine toxicity risk. Standard TPMT testing recommendations apply, with the same considerations as for any other patient requiring azathioprine therapy.