Symptoms Persist Despite Normalized TSH With Levothyroxine

Nancy A Melville

October 25, 2016

Despite having normal blood levels of thyroid-stimulating hormone (TSH), many patients treated for hypothyroidism with levothyroxine (L-T4) continue to have symptoms, including fatigue as well as a higher body mass index (BMI) and a greater likelihood of antidepressant and beta-blocker use, compared with healthy controls, according to new research.

"Patients have told us this for years — they complain of having a hard time losing weight and feeling sluggish and depressed," senior author Antonio C Bianco, MD, professor of medicine at Rush University Medical Center in Chicago, Illinois, told Medscape Medical News.

"Now, for the first time, we have documentation that supports the patients' complaints, demonstrating that…[this] was not only in their minds, as some have suggested," said Dr Bianco.

Having Normal TSH Doesn't Necessarily Equate With Euthyroidism

The study, published this month in the Journal of Clinical Endocrinology and Metabolism by lead author Sarah J Peterson, PhD, also of Rush University Medical Center, and colleagues, involved cross-sectional data from the US National Health and Nutrition Examination Survey (NHANES) from 2001 to 2012, including 9981 participants who had normal serum TSH, among whom 469 were being treated with L-T4.

In matching healthy controls with the L-T4 patients by age, sex, race, and serum TSH, the results showed those in the L-T4–treatment group had approximately 10% to 15% higher total and free thyroxine (T4) levels and about 5% to 10% lower serum and total triiodothyronine (T3) levels compared with the healthy controls (all P < .0001).

And the serum T3:T4 ratios in the L-T4–treated group were approximately 15% to 20% lower than in the healthy matched controls (P < .0001).

Also, compared with the healthy controls, those in the L-T4 group had major differences in seven of 21 objective parameters, including BMI (P < .001), total cholesterol (P < .01), HDL cholesterol (P = .02). and LDL cholesterol (P = .03); and in use of beta-blockers (P < .0001), statins, and antidepressants (both P < .01).

There were also major differences in five of 31 subjective parameters, including physical activity and nutrient intake: those taking L-T4 weighed approximately 10 pounds more than healthy controls of the same height, despite consuming fewer calories (P = .05), and they were significantly less physically active.

"While we recognize that these parameters are not specific markers of hypothyroidism and we cannot determine whether they were different between the groups prior to L-T4 treatment, this does not mitigate the fact that these data present a strong challenge to the dogma that having a normal serum TSH equates with euthyroidism in L-T4 treatment," the authors state.

They looked for factors that could lead to higher serum T3:T4 ratio; on multivariate analysis, only age and female sex were significantly inversely associated with the ratio (both P < .0001).

Furthermore, a direct association between calorie intake and T3:T4 ratio was observed only in L-T4–treated participants (P = .05). No other socioeconomic, biological or nutritional factor was found to affect the serum T3:T4 ratio.

T3 Levels Are Not Normal in Those Treated With Levothyroxine

Endocrinologists have long believed that serum T3 levels are normal in hypothyroid patients treated with levothyroxine, based on evidence that L-T4 monotherapy, in doses that normalize serum TSH, should effectively convert to T3 and maintain homeostasis.

But this study adds to mounting evidence countering that belief.

"Endocrinologists have accepted and propagated the notion that blood T3 levels are 'normal' in hypothyroid patients treated with levothyroxine," Dr Bianco noted.

Yet there are "are a handful of relatively recent studies indicating this is not the case," of which "ours is the most recent one, confirming that serum T3 is lower in these patients."

They note that animal models of primary hypothyroidism in fact suggest that L-T4 monotherapy is not sufficient to normalize systemic thyroid levels or other biological parameters that depend on thyroid hormones such as serum cholesterol.

Levothyroxine is currently the most commonly prescribed treatment for hypothyroidism and was in fact reported to be the single most commonly prescribed medication in the US in 2015.

Considering the widespread use, findings on persisting symptoms have important clinical implications, Dr Bianco stressed.

"Physicians should discuss this with their patients and explain the limitations of the levothyroxine therapy instead of saying that all will be back to normal.

"This is particularly important when patients suffer from other thyroid diseases and are considering treatment that involves total thyroidectomy or utilization of radioactive iodine, both of which will lead to hypothyroidism."

The authors had no relevant financial relationships.

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J Clin Endocrinol Metab. Published online October 4, 2016. Abstract

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