Subclinical Hypothyroidism Associated with the Use of Allopurinol? What the Results of a Large Multicenter Study Suggested

Introduction

The xanthine oxidase inhibitor allopurinol is the first-line drug for patients with hyperuricemia that is not controlled by diet. Based on previous study results, it was hypothesized that its long-term use could be associated with an increase in TSH (thyroid-stimulating hormone) levels, and thus the development of subclinical hypothyroidism. The relationship between allopurinol use and TSH concentration in the blood was investigated by a large multicenter retrospective observational study.

Study Methodology

Patients using allopurinol aged ≥ 19 years, who had at least one TSH level assessed between January 1997 and August 2020, were included in the study. Those who met ≥ 1 of the following exclusion criteria within 1 year of the initial TSH level assessment were not included:

• TSH level < 0.5 mIU/l or > 4.5 mIU/l
• Diagnosed thyroid disease including Graves' disease, pituitary tumor, Sheehan's syndrome, or post-thyroidectomy condition
• Use of antithyroid drugs or levothyroxine, or condition after radioiodine therapy

After 1 year of study registration, a total of 295,815 patients (61.21% women; average age 55 years) were divided into a case group (patients with a TSH level > 4.5 mIU/l; n = 59,307) and a control group (n = 236,508).

Findings

In patients monitored at 5 of the 7 clinical sites, long-term use of allopurinol was associated with an increase in TSH levels. The odds ratio (OR) was determined to be 1.51 (95% confidence interval [CI] 1.32–1.72). The average TSH concentration in the blood at the initial assessment was 2.49 mIU/l, and subsequently an increase up to an average value of 10.54 mIU/l was observed in the case group.

The most frequently newly diagnosed diseases during follow-up were chronic renal insufficiency, gastroesophageal reflux, ischemic heart disease, type 2 diabetes mellitus, and duodenitis, which are often associated with hypothyroidism. Additionally, in the case group, increased TSH levels were not accompanied by decreased free thyroxine (fT4) levels.

Conclusion

The use of allopurinol may be associated with the development of subclinical hypothyroidism, i.e., an increase in TSH without a decrease in fT4 levels. Therefore, TSH levels should be regularly monitored in patients using this medication. It is important to consider that subclinical hypothyroidism can be a “precursor” to overt hypothyroidism.

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Source: Choi W., Yang Y.-S., Chang D.-J. et al. Association between the use of allopurinol and risk of increased thyroid-stimulating hormone level. Sci Rep 2021; 11 (1): 20305, doi: 10.1038/s41598-021-98954-1.