BACKGROUND
The standard of care for treatment of hypothyroidism is levothyroxine to return the thyroid hormone levels to the normal range. However, some patients have continued symptoms while on levothyroxine alone. Thyroxine is converted in the body to T3 (liothyroinine), the active thyroid hormone. In patients without a thyroid, such as after a total thyroidectomy, T3 levels may not be as high on levothyroxine alone as they were when the thyroid was intact. Because of this, some have tried a combination of levothyroxine and liothyronine (T4/T3 therapy) to try to treat continued symptoms on levothyroxine alone in patients with postsurgical hypothyroidism. Indeed, some patients experience improvement on this combination therapy. One concern about including liothyronine in the treatment of hypothyroidism is the possibility that T3 levels may be raised too high and affect the heart and cause problems. In this study, investigators evaluated the effects of T4/T3 therapy on heart function parameters in healthy patients that have undergone thyroidectomy for thyroid cancer.

THE FULL ARTICLE TITLE
Biondi B et al. Preliminary results of a double-blind randomized controlled trial evaluating the cardiometabolic effects of levothyroxine and liothyronine compared to levothyroxine with placebo in athyreotic low-risk thyroid cancer patients. Thyroid. 2023;33(12):1402-1413; doi: 10.1089/thy.2023.0135. PMID: 37725587.

SUMMARY OF THE STUDY
A total of 300 patients with postsurgical hypothyroidism on long-term levothyroxine therapy who had history of total thyroidectomy and radioiodine ablation for low-risk thyroid cancer were considered for this trial. Of these patients, 28 met inclusion criteria and were randomly assigned to either receive: (a) T4/T3 treatment or (b) T4/ placebo treatment. There were 14 patients in each group. A total of 50 healthy volunteers with normal thyroid function were matched for sex, age, physical activity, and lifestyle and participated as controls.

Assessments included blood pressure, heart rate, height, weight, body-mass index and waist and hip circumferences), TSH, free triiodothyronine (FT3), free thyroxine (FT4), electrocardiography (ECG), color Doppler echocardiography (echo), and questionnaires to assess symptoms and signs of hyperthyroidism (symptom rating scale). The thyroid function tests and questionnaires were performed at baseline and after 3, 6, and 12 months. ECG, echo, and the other data were assessed at baseline and after 6 and 12 months. All data were compared with the results obtained from the 50 healthy volunteers. The T3 was administered orally in liquid drops at an initial ratio of 17:1 (T4:T3) and the daily T3 or placebo dosage was divided into two doses, one in the morning and the other 12 hours later. There were no deaths and no arrhythmias, angina, heart failure, stroke, or other serious adverse events; no potential risks were detected in patients in either group. The average levothyroxine dose in the whole group of patients was 1.97 μg/kg/day (range, 1.68–2.16) to achieve a serum TSH goal between 0.3 and 2 mIU/L.

After 12 months of treatment, serum TSH, serum FT4, body weight, BMI, waist circumference, and hip circumference did not significantly differ in the T4/T3 group as compared with the T4/placebo group. However, FT3 was significantly higher in the T4/T3 group than in the T4/placebo group. The hyperthyroid symptom score was not significantly different. Regarding the color Doppler echo data, one of the diastolic cardiac markers did not differ between the volunteers and the T4/T3 group after 12 months of treatment while it was worse in the T4/ placebo group.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
This study shows that the combination T4/T3 therapy was safe in this small group of thyroid cancer patients with post-surgical hypothyroidism. Further, the patients in the T4/T3 group had the same hyperthyroid score as those in the T4/placebo group. Interestingly, the only parameter that differed between the 2 groups was an measure of heart function, where those in the T4/placebo group had a worse score than the T4/T3 group and the normal volunteers. This study suggests T4/T3 may be a treatment option in patients with postsurgical hypothyroidism. More studies are needed to determine the role and safety of combination T4/T3 treatment on patients with other causes of hypothyroidism.

— Alan P. Farwell, MD

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