Treating Subclinical Hypothyroidism Is of Little Benefit

Nancy A. Melville

October 02, 2018

Treatment of subclinical hypothyroidism with levothyroxine, though commonly practiced, is not associated with improvements in quality of life or thyroid-related symptoms, according to a new meta-analysis.

The review underscores that "most patients with subclinical hypothyroidism do not require levothyroxine treatment," first author Martin Feller, MD, MSc, of the Department of General Internal Medicine, Bern University Hospital, at the University of Bern, Switzerland, told Medscape Medical News.

"Although current guidelines are at first sight cautious with treatment recommendations, more than 90% of persons with subclinical hypothyroidism and a thyrotropin level of less than 10 mIU/L would actually qualify for treatment," Feller and colleagues note in their article published online October 2 in JAMA.

"However, results of this meta-analysis are not consistent with these guideline recommendations," they say.

Feller said people are often treated because of nonspecific symptoms that are potentially attributable to hypothyroidism, such as fatigue, but these can turn out to be unrelated.  

"These findings do not support the routine use of thyroid hormone therapy in adults with subclinical hypothyroidism," he and his colleagues conclude.

Findings of Meta-Analysis

The meta-analysis included 21 randomized controlled trials involving 2192 adults with subclinical hypothyroidism treated primarily with the standard thyroid hormone replacement therapy levothyroxine.

With the duration of interventions ranging from 3 to 18 months, mean thyrotropin (or thyroid-stimulating hormone, TSH) levels were more likely to be lowered to normal reference ranges with treatment compared with placebo (range, 0.5–3.7 mIU/L vs 4.6–14.7 mIU/L).

Treatment was not associated, however, with benefit over placebo in terms of improvements in general quality of life (n = 796; standardized mean difference [SMD], −0.11) or thyroid-related symptoms (n = 858; SMD, 0.01) in the studies.

The trials included in the meta-analysis ranged in size from 20 to 737 participants, with mean ages ranging from 32 to 74 years. The percentage of women in the studies ranged from 46% to 100%, and patients' mean baseline thyrotropin values ranged from 4.4 to 12.8 mIU/L.

The largest of the trials in the analysis, published in the New England Journal of Medicine (2017;376:2534-2544), as reported by Medscape Medical News, was a multicentre study involving 737 adults a mean age of 74.4 years who had persisting subclinical hypothyroidism (thyrotropin level, 4.60–19.99 mIU/L; free thyroxine level within the reference range), which is particularly common in older individuals.

Participants were randomized to placebo or levothyroxine at a starting dose of 50 μg daily, or 25 μg if body weight was < 50 kg or the patient had coronary heart disease, with dose adjustment according to thyrotropin level.

After 1 year, there were no differences between the groups in mean change in hypothyroid symptoms or tiredness scores.

There were also no beneficial effects of levothyroxine in secondary outcomes and no significant differences between men and women.

Guidelines Acknowledge Little Evidence of Treatment Benefit

The American Thyroid Association/American College of Clinical Endocrinology guidelines (Endocr Pract. 2012;18:988-1028) indicate that "treatment based on individual factors for patients with TSH [thyrotropin] levels between 4.5 and 10 mIU/L should be considered particularly if patients have symptoms suggestive of hypothyroidism."

And the European Thyroid Association guidelines from 2013 indicate that "in patients aged under 70 years, a serum TSH of less than 10 mIU/L and with symptoms suggestive of hypothyroidism, a trial of L-thyroxine replacement therapy should be considered."

But Feller notes that the guidelines also recognize the lack of consensus on the issue of treatment.

"Both guidelines are cautious in that they acknowledge the limited evidence that supports their recommendations," he said.

"However, people usually qualify for treatment because of symptoms that are potentially attributable to hypothyroidism such as fatigue, depressed mood, or overweight."

"The problem is that these symptoms are nonspecific, frequent, even among healthy individuals, and most often unrelated to subclinical hypothyroidism," he explained.

Adequately Powered Trials to Fine-Tune Treatment Recommendations

In addition to treatment for subclinical hypothyroidism possibly being ineffective, the approach can have risks, with one study showing that more than 20% of people with subclinical hypothyroidism (and up to 40% of those older than age 65) who were treated with levothyroxine had decreased thyrotropin levels, with specific risks including new-onset atrial fibrillation and fractures (Eur J Endocrinol. 2017;177:R199-R217).

Feller noted that thyrotropin levels around the 10 mIU/L level may warrant treatment; however, more research is needed to fine-tune recommendations.

"Patients with thyrotropin levels above 10 mIU/L may be candidates for treatment, but as a researcher, I would like this to be confirmed in adequately powered randomized clinical trials."

Author Terry Quinn reported being an investigator of a trial included in the review funded by the European Union and an investigator on a trial in which the study drug was provided by Merck. Author David Stott reported a research grant from the European Union. Coauthor Nicolas Rodondi has received funding from the Swiss National Science Foundation.

JAMA. Published online October 2, 2018. Abstract

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