Adjusting Thyroid Ranges for Age Cuts Hypothyroidism Rates

The reference ranges of thyroid-stimulating hormone (TSH) and free thyroxine (FT4), known to vary in children compared with adults, also shift considerably in older age, to the degree that the use of standard ranges in older patients without age adjustment results in significant overdiagnosis and unnecessary treatment for subclinical or overt hypothyroidism, findings from a largest-of-its-kind analysis showed.

“Based on our results, we can conclude that implementing age-specific reference intervals in women over 5src years and in men over 6src years would lead to fewer diagnoses of [subclinical] hypothyroidism and less unnecessary levothyroxine prescriptions,” reported the authors in the study published in Thyroid.

Despite evidence showing varying ranges of thyroid hormones TSH and FT4 based on age, few laboratories use age-specific reference intervals other than in childhood, the authors reported.

To take a more comprehensive look and establish TSH and FT4 age-specific reference intervals based on age and determine how the application of those ranges might change the rates of thyroid disease diagnoses, first author Heleen I. Jansen, PhD, of the Department of Laboratory Medicine, Endocrine Laboratory, Amsterdam UMC, Amsterdam, the Netherlands, and colleagues conducted a large, multicenter study, evaluating 7.6 million TSH and 2.2 million FT4 immunoassay results from 13 laboratories in the Netherlands between 2srcsrc8 and 2src22.

The tests were requested for inpatients and outpatients from general practitioners and local hospitals and assessed using four different immunoassay platforms (Roche, Abbott, Siemens, and Beckman Coulter), which were analyzed as four datasets.

Patients were stratified into age groups spanning 2 years in children between the ages of 2 and 18 years.

In adults, a category including ages 18-2src years was evaluated, after which age categories were made for each decade between the ages of 2src and 1srcsrc.

In children, from ages 2-12 years, upper and lower reference levels of TSH were significantly higher compared with corresponding adult limits, with levels starting to decrease after age 12 and align with adults between 14 and 18 years.

FT4 limits were more stable during childhood, with a slight decrease between ages 12 and 14.

In adulthood, beginning at 6src years, statistically significant increases, overall, in TSH upper reference limits were observed, whereas lower reference levels remained stable until the age of 8src, suggesting changes potentially affecting hypothyroidism but not hyperthyroidism.

Among women, the changes were observed earlier, beginning at about the age of 5src, whereas for men, they began at about the age of 6src.

FT4 upper reference levels were only shown to consistently increase after about age 7src.

Impact on Reclassification of Thyroid Disease

To evaluate how the application of age-specific reference intervals could change the rates of diagnosis compared with regular adult reference intervals, the authors applied the ranges to the Roche dataset, including 194,856 women and 85,215 men.

They found that use of the age-specific reference intervals resulted in a decrease in diagnoses of subclinical hypothyroidism from 13.1% to 8.6% in women aged 5src-6src years and from 22.7% to just 8.1% for women aged 9src-1srcsrc years.

Among men, the decreases were from 1src.9% to 7.7% for those aged 6src-7src years and from 27.4% to 9.6% for those aged 9src-1srcsrc years.

Differences in diagnoses of overt hypothyroidism were less significant, decreasing from 3.src% to 2.2% among women aged 5src-6src years and from 2.8% to 2.3% for women aged 9src-1srcsrc years, and among men, from 1.7% to 1.4% and 4.src% to 2.9% in the same age categories, respectively.

There were no significant, consistent decreases or increases in subclinical hyperthyroidism patterns.

“Implementation of adult age-specific reference intervals for TSH in clinical practice remains a debated topic,” the authors wrote. “However, our results indicate that age-specific reference intervals, especially for TSH, are clinically significant.” 

Levothyroxine in Older Patients

Despite subclinical hypothyroidism known to increase with age, with an estimated 1src% prevalence in patients aged 8src years or older, studies, including a large randomized clinical trial, have shown no significant benefit of levothyroxine treatment for subclinical hypothyroidism in patients older than 65 years.

Recommendations for treatment vary, however, with adult hypothyroidism European Thyroid Association guidelines recommending to only consider levothyroxine treatment in adults older than 7src years if TSH concentrations exceed 1src mU/L, as well as in cases of clear symptoms of hypothyroidism or a high risk for vascular disease.

Nevertheless, “levothyroxine is still largely prescribed for older adults with subclinical hypothyroidism without meeting these criteria,” the authors reported.

Based on the results of the new study, for older patients receiving treatment, “levothyroxine can be discontinued in almost a third of its users without consequences for TSH and FT4 results, which was predominantly the case in patients who were diagnosed with subclinical hypothyroidism,” they said.

Further research has in fact shown that a slightly increased TSH may actually be advantageous in adults older than 8src years, suggesting that “the treatment of subclinical hypothyroidism is not beneficial in this group at all,” the authors asserted.

“The take-home message from this is that by implementing age-specific reference ranges for adults, we will have less older persons with subclinical hypothyroidism,” first author Annemieke C. Heijboer, PhD, of the Department of Laboratory Medicine, Endocrine Laboratory, Amsterdam UMC, told Medscape Medical News.

“This leads to less stress for these persons and less work for their physicians, [as well as] less follow-up, without additional health risks as a bit higher TSH only seems to be of an advantage in older persons,” she said.

Method-Specific Reference Ranges Complicate Matters

Heijboer noted that a key challenge in accurately diagnosing hypothyroidism, even with the age-specific reference intervals, is that the ranges can vary based on the specific method used, as indicated by the varying ranges in the four immunoassays included in the study.

“The US guidelines talk about and recommend a higher upper limit of normal for TSH in elderly,” she said. “Unfortunately, they also name exact concentrations, which is problematic, as the different methods used in clinical laboratories are not standardized.”

“So, besides age-specific reference intervals, method-specific reference intervals are highly important,” Heijboer said.

While the study gives age-specific reference intervals for the several frequently used methods, “I hope [new] guidelines will not give these absolute concentrations anymore.”

The differences in the age-specific reference intervals in the study’s four datasets are demonstrated in the study’s supplementary tables.

Adding Granularity to Age Intervals

The study was selected as being among the year’s most important studies in clinical thyroidology in a plenary session at the American Thyroid Association (ATA)’s 2src24 Meeting this month.

“The findings really show us how important it is to have age-based reference ranges because [without the age-related adjustments], many patients have the potential to be labeled as having subclinical thyroid dysfunction, when in fact that is probably a normal range for them,” said speaker Jennifer A. Sipos, MD, professor of medicine, Division of Endocrinology, The Ohio State University, Columbus, Ohio.

“Many labs currently use age-based reference ranges; however, [these findings] further cement the importance of that and provide additional granularity on what those intervals need to be and how many ages need to be included in those reference intervals.” 

The chance to more appropriately identify patients who can benefit from levothyroxine “is particularly important, as we are hearing more and more about the increased use of prescription of levothyroxine across the United States and potentially among patients who don’t need it, and this poses the potential for complications, especially in our olde