From Pages to Practice

By Bharat Ramakrishna, M.B.B.S.

Published June 21, 2017

When a patient’s thyroid stimulating hormone or serum thyrotrophin (TSH) level is elevated and the thyroxine (T4) level is low, we often prescribe thyroid replacement therapy. But, many people have subclinical hypothyroidism, defined as an elevated TSH level and normal T4 level. Subclinical hypothyroidism has been associated with adverse cardiovascular events, including coronary artery disease and congestive cardiac failure. Many patients older than 65 experience symptoms such as lethargy, weight gain, constipation, weakness, and other symptoms that we associate with hypothyroidism. Many of those patients also have normal T4 levels but elevated TSH levels with no specific symptomatology. Could treating them with thyroid replacement therapy improve their quality of life and associated symptoms of fatigue?

In a recent study published in NEJM, Stott et al. randomized 737 older adults (median age, 74; age range 65–93) with subclinical hypothyroidism (elevated TSH levels and normal T4 levels) to receive either levothyroxine or placebo. Patients who were already receiving medications that affect thyroid function (e.g., amiodarone, levothyroxine, antithyroid drugs, and lithium) and those who had undergone thyroid surgery or ablation with radioiodine, had a recent myocardial infarction or hospitalization for major illness or surgery, or had dementia or a terminal illness were excluded.

Patients randomized to levothyroxine started on a weight-based dose that was subsequently adjusted to target a TSH level of 0.40 to 4.59 mIU per liter. Patients in the control group received placebo with computerized mock adjustments to ensure that patients and physicians remained blinded. The two primary outcomes were changes in ThyPRO Hypothyroid Symptom score and Tiredness score.

After 1 year of therapy, although the mean TSH level was significantly lower in the intervention group (3.63±2.11 mIU per liter vs. 5.48±2.48 mIU per liter in the placebo group), the mean change between groups in the Hypothyroid Symptom score or the Tiredness score did not differ. Similarly, there were no differences in any of the secondary outcomes.  The investigators did not report any significant differences in the number or severity of adverse events between the two groups, although slightly more patients in the placebo group than in the levothyroxine group had with at least one serious adverse event (103 vs. 78, P=0.049).

The following limitations of the study are worth noting: Enrollment was slower than expected, and as a result, the study was underpowered to detect significant differences in cardiovascular or mortality outcomes. In addition, patients generally had few symptoms at baseline, possibly mitigating beneficial effects in the treatment arm.

So, how should we treat older patients with subclinical hypothyroidism? Based on these data, we should not expect a large benefit from treatment with levothyroxine. Whether thyroid replacement reduces cardiovascular events remains uncertain and perhaps a question for another trial.

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Raphael Rush, MD

Raphael Rush is currently completing a fellowship in rheumatology at the University of Toronto, where he previously completed a residency in internal medicine. He holds an MD from Queen's University in Canada.


Bharat Ramakrishna, M.B.B.S.

Bharat Ramakrishna is completing his Internal Medicine Residency at Monash Health in Melbourne, Australia. His interests are in Infectious Diseases, Gastroenterology, and the Social Determinants of Disease. He plans to pursue further study in Public Health and to one day become a Clinician-Researcher.