Age- and sex-specific values needed to avoid subclinical thyroid dysfunction misdiagnosis
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Providers should use age- and sex-specific reference ranges to diagnose subclinical hypothyroidism or hyperthyroidism, especially for older adults, according to a study published in Thyroid.
“These data clearly demonstrate the clinical relevance of using age- and sex-specific values, particularly serum thyroid-stimulating hormone levels, when diagnosing subclinical hypothyroidism,” Masanobu Yamada, MD, PhD, assistant professor in the department of internal medicine, division of endocrinology and metabolism at Gunma University Graduate School of Medicine in Japan, and colleagues wrote. “We found a high rate of overdiagnosed subclinical hypothyroidism, especially in those aged 60 years and older. Although it is a low rate, patients with subclinical hyperthyroidism were underdiagnosed, particularly in middle-aged men and women.”
Researchers analyzed health records for 22,992 adults who underwent annual checkups at Takasaki Hidaka Hospital in Japan and 515 euthyroid adults who visited Okamoto Thyroid Clinic in Japan. Of those who visited Takasaki Hidaka Hospital, 14,860 had thyroid function evaluated using a Siemens test kit from 2006 to 2013, and 8,132 had thyroid function evaluated using an Abbott test kit from 2020 to 2022. The Okamoto Thyroid Clinic used kits from Toso to analyze thyroid function from 2016 to 2019.
Subclinical hypothyroidism was defined as elevated serum TSH with normal free thyroxine, and subclinical hyperthyroidism was defined as low serum TSH with normal free T4. The researchers estimated age- and sex-specific reference ranges based on TSH and free T4 measurements and compared them with the manufacturer reference ranges for all three tests.
Using the Siemens test kit, median serum TSH was 1.5 mIU/L for women aged 30 to 39 years and gradually increased with age to 1.9 mIU/L for women aged 60 to 69 years. Men aged 30 to 39 years had a median TSH of 1.4 mIU/L with an increase with age to 1.6 mIU/L for those aged 60 to 69 years. Similar increases were observed for adults tested with the Abbott kit.
Serum free T4 levels were constant with age for women using all three test kits. Men had higher free T4 levels than women and had a gradual decrease with age when using all three kits.
Using the Abbott test kit, median serum free triiodothyronine was 3.26 pg/mL for men aged 30 to 39 years and declined to 3.11 pg/mL for men aged 60 to 69 years. Levels were higher for men compared with women of the same age. Similar findings were observed using the Toso test kit.
About half of women aged 30 to 39 years who were classified as having subclinical hypothyroidism using manufacturer reference ranges had normal thyroid function when age- and sex-specific reference ranges were used. The proportion of overdiagnosed adults increased with age, with 78% of women aged 60 to 69 years classified as having subclinical hypothyroidism being reassessed with normal thyroid function using age- and sex-specific recommendations.
Overdiagnosis was less common for younger men, with no men aged 30 to 39 years and about 5% of those aged 40 to 49 years reclassified with normal thyroid function using age- and sex-specific cutoffs. However, about 62% of men aged 60 to 69 years diagnosed with subclinical hypothyroidism using manufacturer reference ranges were reclassified as having normal thyroid function using age- and sex-specific reference ranges.
The researchers acknowledged several limitations with the study, including a lack of data on adults younger than 30 years or older than 70 years, as well as the potential that reference ranges may be influenced by ethnicity in other countries.
“Our findings should therefore be validated in future studies including other racial and ethnic groups, as the prevalence of autoimmune disease may differ according to ethnicity and the geographic location,” the researchers wrote.
Perspective
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The study by Yamada and colleagues draws attention to the potential value of using specific populations when constructing a reference range to prevent the hormone status of individuals from being miscategorized. By creating age- and sex-specific populations, the authors find a substantial percentage of healthy people that would be considered to have abnormal thyroid hormone indices based on a general reference population.
The finding that men and women of older age are the most at risk for being categorized as having subclinical hypothyroidism confirms a previous analysis of the National Health and Nutrition Examination Survey III (Surks MI, et al. J Clin Endocrinol Metab. 2007;doi:10.1210/jc.2007-1499). Other studies have suggested a lack of adverse outcomes for older patients associated with mild thyroid-stimulating hormone elevation (Gussekloo J, et al. JAMA. 2004;doi:10.1001/jama.292.21.2591) and a lack of symptom improvement with levothyroxine treatment (Stott DJ, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1603825). Therefore, the benefits of using a population-specific reference range rather than the manufacturers’ cut-offs are important to considered. Appropriate categorization could prevent patients from being exposed to excess testing and treatment, and/or misattribution of symptoms to thyroid dysfunction without identifying the actual cause.
An insightful invited commentary accompanying the article notes that many important population, physiologic, assay and statistical variables are crucial to a robust and accurate reference range (Loh TP, et al. Thyroid. 2023;doi:10.1089/thy.2023.0096). Although serum TSH measurement is an extremely valuable test for determining thyroid hormone status, Yamada and colleagues highlight these complexities and the need to strive for the most accurate thyroid assessment for all patients.
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