BACKGROUND
Thyroxine (T4) is the main thyroid hormone produced by the thyroid gland. Thyroxine is converted to triiodothyronine (T3) in peripheral tissues and T3 is considered the active form for thyroid hormone action. Because of this relationship, levothyroxine (L-T4) therapy is the most common treatment option for individuals with hypothyroidism. It is identical to thyroxine, gets converted to T3 within peripheral tissues in the same way, is long-acting and is given once daily. Liothyronine (L-T3) alone is not a good replacement option in hypothyroidism even though it is the active hormone because of a shorter half-life requiring twice a day dosing and causing peaks of high levels of T3 that can lead to additional problems including osteoporosis and atrial fibrillation.

L-T4 effectively controls biochemical and clinical features of hypothyroidism in most individuals. However, it is clear that there is a subset of individuals with hypothyroidism who continue to have symptoms on L-T4 alone despite their FT4 and TSH levels in the normal range. Most often, these symptoms include not feeling well, fatigue and brain fog. Sometimes a trial of L-T4 and L-T3 combination therapy can be considered in patients with continued symptoms on L-T4 alone and may result in improvement in symptoms.

Recent studies did not identify significant long-term usage concerns with combination L-T4 and L-T3 therapy. The aim of the present study was to compare the risk of osteoporosis, atrial fibrillation, cancer risk, and mood disorders in patients treated with L-T4 alone versus L-T3 therapy (either alone or in combination with L-T4) in a large patient groups in Korea.

THE FULL ARTICLE TITLE
Yi W et al 2022 Heart failure and stroke risks in users of liothyronine with or without levothyroxine compared with levothyroxine alone: A propensity score-matched analysis. Thyroid 32:764–771. PMID: 35570696.

SUMMARY OF THE STUDY
This study included adult patients receiving thyroid hormone replacement therapy for at least 90 days. Participants were identified using a search of electronic medical records from four hospital systems in Korea. The patient group was divided by L-T3 use, where L-T3 users were defined as those taking L-T3 with or without L-T4 and further subdivided based on history of thyroid cancer. Safety outcomes included osteoporosis (with or without fractures), atrial fibrillation, heart failure, heart disease, stroke, cancer including breast cancer, anxiety disorder, and mood disorder. The study group included 1,887 L-T3 users and 30,303 L-T4–only users. Approximately 90% of the group was between 30 and 70 years of age, ~ 80% were female, and >50% had been on thyroid replacement therapy for >1 year. A total of 1,434 L-T3 users and 3,908 L-T4–only users were included in the final analysis.

Overall, L-T3 users had a 1.7-fold increased risk of heart failure and a 1.8-fold risk of stroke but a significantly decreased risk of anxiety and mood disorders. In the group of thyroid cancer patients, heart failure was the only significant adverse effect that increased in L-T3 users and was not significant in those on this therapy for <1 year.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
This study found that the use of L-T3 (alone or in combination with L-T4), compared to L-T4 alone, was associated with increased risk of heart failure and stroke, but not osteoporosis, cancer or atrial fibrillation. Additional studies focusing on only the L-T4 and L-T3 combination group are needed, as the dose to L-T3 is much lower than with L-T3 alone. However, until those studies are done, it is important to take into consideration the risk of heart failure and stroke when considering adding L-T3 for the treatment of hypothyroidism.

— Alan P. Farwell, MD

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