Seasonal Variation and Thyroid Function Testing: Source of Misdiagnosis and Levothyroxine Over-Prescription

To the Editor:

Thyroid function tests are some of the most commonly ordered tests in the USA (1). Meanwhile, levothyroxine is also the most prescribed drug in the USA, with an estimated 23 million people who have an active prescription (2). However, studies have raised concerns about levothyroxine overuse, with some suggesting that approximately 90% of prescriptions are inappropriate because they were given to patients with mild subclinical hypothyroidism or who were euthyroid without significant changes in patterns over time or any improvement in health-related quality of life (2).

The recent publication by Yamada et al. (3) in the Journal of the Endocrine Society describes the effect of seasonal variation in thyroid function results in >7000 healthy Japanese participants and directly links that to a fraction of subclinical dysfunction diagnoses (subclinical hyperthyroidism and subclinical hypothyroidism). This study showed that thyrotropin-stimulating hormone (TSH) varies widely throughout the seasons, peaking in the winter months (January–February) with its nadir in the summer months (June–August). However, free thyroxine (Free T4) was relatively stable. These seasonal changes in healthy individuals, with TSH going up while Free T4 remains stable, are not captured by our reference intervals and may lead to false diagnoses of subclinical hypothyroidism and unnecessary prescriptions of levothyroxine to euthyroid individuals. This is clearly demonstrated in Yamada et al.’s study, in which the healthy population’s upper 97.5th percentile ranges for TSH exceeded the manufacturer-recommended limit for the months of January and February, leading to higher rates of subclinical hypothyroidism diagnoses. In addition to seasonal variability, there are other factors associated with TSH variation that may contribute to misdiagnoses, including: age, sex, time-of-day, and transient elevation during nonthyroidal illness (4).

The source of this problem lies in how we derive reference intervals in current laboratory medicine practice. Reference intervals typically do not include at least 5% of the “healthy” population’s results (2.5% at either end). This approach made sense 30 years ago when laboratory testing was not as accessible, and when these tests were mainly ordered on patients exhibiting certain clinical symptoms. However, that is no longer the case today as more thyroid tests are ordered on individuals who do not need them, significantly increasing the likelihood and number of falsely abnormal results. Another major limitation is that reference interval studies typically recruit individuals over a short period of time, which, crucially for TSH, may not include all 4 seasons. For example, Fontes et al. (5) recruited 1200 participants between March and December of 2012, missing out on the crucial months of January and February when TSH is highest. So, clinical laboratories who adopt their derived reference intervals will be over-diagnosing patients tested in January and February with subclinical hypothyroidism. Making matters worse, it is unclear from product inserts how manufacturers derive their reference intervals.

A better approach may be to move away from population-based reference intervals altogether, to using universal outcome-based treatment cutoffs or decision limits for TSH (similar to glucose, cholesterol, and vitamin D). This approach makes a lot more sense, especially considering that major recent studies have found no benefit of treatment with levothyroxine unless TSH exceeds 7.0–10 mIU/L (4). Treatment of lower levels of TSH has not been shown to provide clear benefits in randomized controlled trials, yet most patients with TSH values flagged as abnormal (based on our population-based reference intervals) are treated with levothyroxine (4). Overtreatment with levothyroxine also comes with its own risks, particularly for the elderly who are at an increased risk of harm. So, age dependent TSH goals may also be a possibility in the future (4). To address these issues, laboratory experts, like fellows of the AACC Academy, should join forces with experts from the American Thyroid Association to evaluate the evidence and make clear recommendations for adopting universal outcome-based cutoffs for TSH, so we can put an end to levothyroxine overuse.

Until then, all we can do is raise awareness about the seasonal variability of TSH and its contribution to subclinical hypothyroidism misdiagnoses. My recommendation to healthcare providers and patients testing themselves today is this: if you end up with a mildly elevated TSH result and a normal Free T4, try getting retested 2–3 months later to make sure this is not a seasonal artifact or transient increase before prescribing/taking levothyroxine unnecessarily. This recommendation is in line with the European Thyroid Association guideline for management of subclinical hypothyroidism and supported by a study in >422 000 patients showing that 62% of elevated TSH levels revert to normal spontaneously when tested at least 2 months later (4).

Author Contributions

The corresponding author takes full responsibility that all authors on this publication have met the following required criteria of eligibility for authorship: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Nobody who qualifies for authorship has been omitted from the list.

Joe El-Khoury (Conceptualization-Lead, Data curation-Lead, Formal analysis-Lead, Investigation-Lead, Writing—original draft-Lead, Writing—review & editing-Lead)

Authors’ Disclosures or Potential Conflicts of Interest

Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:

Employment or Leadership

J.M. El-Khoury, Clinical Chemistry, AACC.

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