Loading ...

Whether clinicians are accurately diagnosing thyroid disease was at issue for Chinese researchers who demonstrated that adding subgroup differences according to age, sex, or race when testing for thyroid disease reduced by half the number of persons eligible for L-thyroxine, a treatment for hypothyroidism.

It is the first study to examine the effect of combined age, sex, and race on the diagnosis of thyroid diseases, the authors wrote. The results were published in the Annals of Internal Medicine.

“Use of current reference intervals may result in the overdiagnosis or underdiagnosis of thyroid diseases, leading to subsequent overtreatment or delayed treatment and creating potential health risks and unnecessary healthcare burdens,” the study authors Qihang Li, MD, and colleagues wrote.

Li is an endocrinologist at the Shandong First Medical University in Jinan, China.

They challenged what they called a “one-size-fits-all” approach to defining thyroid function reference intervals. In their cross-sectional analysis, the investigators applied age-, sex-, and race-specific factors to the reference intervals used in two population datasets with available thyroid function testing results. The first was anyone aged 20 years or older in the National Health and Nutrition Examination Survey (NHANES; N = 8308; women = 4235), supplemented by a Chinese database of routine health checkups from 49 hospitals in 10 provinces for persons aged 18 years or older (N = 314,302).

Criteria for thyroid disease used by the investigators was based on two sets of reference intervals of thyroid function indicators. The first were the current reference intervals: Thyroid-stimulating hormone (TSH), 0.45-4.5 mIU/L; total thyroxine (TT4), 57.92-169.90 nmol/L (4.5-13.2 μg/dL). The other reference intervals were specific to age, sex, and race. 

In the NHANES set, the 97.5th percentile of TSH increased with age. Meanwhile, total triiodothyronine (TT3) levels declined with age as TT4 levels remained stable across different ages. Higher TT4 levels were found in women, and White individuals had higher TSH levels. Subclinical hypothyroidism varied from 2.4% for ages 20-29 years to 5.9% for ages 70 years or older, when measured with current reference intervals.

Nearly half (48.5%) of those diagnosed as having subclinical hypothyroidism using current reference intervals were found not to have the diagnosis when subtyped by age-, sex-, and race-specific reference intervals. This was especially true for female and White study individuals.

When subtyped, 31.2% persons with subclinical hyperthyroidism were found to have normal thyroid function, especially women, Black individuals, and Hispanic individuals. When compared with the findings from US participants, many of the results in Chinese participants were similar, according to the study’s authors.

Those with thyroid peroxidase antibody positivity were excluded from the database, resulting in a reduction in the occurrence of subclinical hypothyroidism and subclinical hyperthyroidism, especially in patients older than 60 years.

“We expect that our findings will help decision makers establish more accurate reference intervals for thyroid diseases and facilitate development of consensus about how to define and manage those diseases,” concluded Li and colleagues.

A previous “investigation of L-thyroxine prescription appropriateness found 31% aligned with American Thyroid Association guidelines, while 54% of new L-thyroxine prescriptions were considered suboptimal, as thyroid function results were unconfirmed or normal,” James V. Hennessey, MD, wrote in an editorial accompanying Li and colleagues’ study. Hennessey is an endocrinologist at Beth Israel Deaconess Medical Center in Boston and an associate professor of medicine at Harvard University in Cambridge, Massachusetts.

Describing what appears to be a growing body of literature on misdiagnosis in thyroid disease, Hennessey also cited a previous study that used NHANES data to show the efficacy of stratifying reference thresholds for thyroid function tests. In that study, Martin I. Surks and Joseph G. Hollowell described the effect of thyroid autoimmunity and aging on expected TSH values.

“When stratified by age, they noted the 97.5th percentile of TSH in those considered thyroid disease risk free was ‘normal’ up to 7.49 mIU/L for those older than 80 years,” wrote Hennessey.

Another study Hennessey cited found that the results of thyroid function testing within an age-adjusted laboratory reference range were not associated with fluctuations in quality of life, mood, or cognitive function in community-dwelling older men. Further, there was no change in these outcomes during 5-8 years of follow-up and without intervention.

“These observations indicate that minor ‘elevations’ of TSH do not document that thyroid dysfunction is the cause of nonspecific symptoms,” Hennessey wrote.

Hennessey referred to Li and colleagues’ study as an “enhancement” for improving diagnostic accuracy in thyroid disease, and thus patient outcomes.

“Unnecessary L-thyroxine replacement leaves quality of life diminished and symptoms unabated, and some patients seek alternative thyroid solutions to their nonthyroidal symptoms,” Hennessey wrote. “Unnecessary therapy for subclinical hypothyroidism also results in the expense for prescriptions, laboratory testing, and follow-up care. It is also associated with iatrogenic thyrotoxicosis, especially in older women.”

This study was supported by grants from the National Key Research and Development Program of China (2017YFC1309800) and the National Natural Science Foundation (82130025). Disclosure forms for the study authors and editorial writer Hennessey are available with the articles online.