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Azathioprine and diffuse alveolar haemorrhage: the pharmacogenetics of thiopurine methyltransferase

¹ Depts of Pharmaceutical Sciences, ⁴ Medicine, ⁵ Laboratory Medicine and Pathobiology, ⁶ Pediatrics (Genetics), and ⁷ Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ² Dept of Medicine, McMaster University, and ³ Centre for Evaluation of Medicines, St. Joseph's Healthcare, Hamilton, ON, Canada.

CORRESPONDENCE: N. K. J. Adhikari, Dept of Critical Care Medicine, Room D1.08, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada. Fax: 1 4164804999. E-mail: neill.adhikari{at}sunnybrook.ca

Keywords: Azathioprine, diffuse alveolar haemorrhage, myelotoxicty, pharmacogenetics, polymorphism, thiopurine methyltransferase

Received: March 6, 2007
Accepted July 6, 2007

Current guidelines support the use of corticosteroids and azathioprine as one possible treatment strategy for idiopathic pulmonary fibrosis (IPF). However, some patients with genetic polymorphisms of thiopurine methyltransferase (TPMT) are at risk of severe azathioprine myelotoxicity.

The current authors present the case of an 85-yr-old Caucasian male with IPF who developed diffuse alveolar haemorrhage as a complication of azathioprine-induced myelosuppression.

Leukocyte genetic TPMT testing revealed that the patient had homozygous polymorphisms associated with the absence of TPMT activity and severe azathioprine-induced myelotoxicity.

Thiopurine methyltransferase deficiency should be considered in patients who develop leukopenia early in treatment with azathiopurine, or who present with severe marrow suppression at usual doses. For centres with equipped laboratories, a dosing suggestion is provided based on thiopurine methyltransferase testing. Even with screening strategies, frequent monitoring of complete blood count and liver biochemistry should remain the mainstay of surveillance for azathioprine toxicity.