BACKGROUND
Hypothyroidism, or underactive thyroid, is common and is caused by the inability of the thyroid to produce and secrete thyroxine, the main thyroid hormone. Hypothyroidism is usually treated by replacing the thyroxine that the thyroid no longer makes with levothyroxine (LT4) the synthetic form of thyroxine. While most patients feel fine with most, if not all, symptoms of hypothyroidism resolved by levothyroxine, some patients still experience hypothyroid symptoms, especially fatigue and a decrease in in thinking often referred to as “brain fog” function despite treatment restoring FT4 and TSH levels to the normal range.

While thyroxine is the main hormone produced by the thyroid, it is converted outside the thyroid to triiodothyronine, the main active hormone that is responsible for the actions of thyroid hormone on the body. Triiodothyronine is also available in pill form, known as liothyronine (LT3). Because of this, some advocate for treatment with both LT4 and LT3 for patients with persistent symptoms on L-T4 alone. Though controversial, there is data that suggests the combination LT4 and L-T3 can improve symptoms and quality of life (QoL) of patients with hypothyroidism. The authors in this trial, aimed to show the effects of combination therapy with LT4+LT3 on peripheral tissue, changes in other tissue markers and QoL in patients who underwent thyroid surgery.

THE FULL ARTICLE TITLE
Brigante G, et al. Randomized double-blind placebocontrolled trial on levothyroxine and liothyronine combination therapy in totally thyroidectomized subjects: the LEVOLIO study. Eur J Endocrinol 2024;190(1):12-22; doi: 10.1093/ejendo/lvad172. PMID: 38124252.

SUMMARY OF THE STUDY
This clinical trial enrolled 160 adults who underwent thyroid surgery removal for either benign thyroid disease or thyroid cancer and were on LT4 replacement. All patients had been on a stable dose of LT4 for at least 3 months. Patients were randomly selected to one of two groups, LT4+LT3 or LT4+placebo. The study included visits for screening, baseline measurements and at 6, 12 and 24 weeks from baseline. TSH was measured at all time points and medications were adjusted if needed to keep the TSH stable in the normal range and keep the T4/T3 ratio between 13:1 and 20:1. Weight, height, BMI, and heart rate and blood pressure were measured at all time points as well as blood samples collected for free T3 (FT3), thyroid peroxidase antibodies (TPO) and for a variety of labs that are known to respond to thyroid hormone, including total cholesterol, HDL cholesterol, triglycerides, sex hormone binding globulin (SHBG) and the bone markers osteocalcin, type I collagen and bone-specific alkaline phosphatase. In addition, patients completed a thyroid-specific quality of life questionnaire (ThyPRO QoL) at all visits and adherence to the therapy was confirmed at each visit. The primary outcome of the study was SHBG variation after 6 months of treatment, while the secondary outcomes included, change in BMI, TSH, FT4 and FT3 and the above noted labs and the results of ThyPRO QoL.

The while TSH levels were higher in the L-T4+placebo group, there were no cases of overt hypothyroidism in any group. The FT3/FT4 ratio persisted in the low range in the LT4+placebo group at the end of treatment, while the ratio increased to the normal range in the LT4+LT3 group. There were no significant differences in primary and secondary outcomes of both groups by the end of treatment time. There was also no significant difference in the ThyPRO score between the two groups.

Both groups were adherent to the allocated therapies, and no major adverse events were noted. Most patients had no preference between the 2 treatments, with only 11% of patients in the LT4+LT3 group preferring the combination treatment and a similar proportion preferring the L-T4+ placebo group.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
This study showed no significant difference between those treated with LT4 alone or LT4+LT3 regarding peripheral tissue markers of thyroid function, quality of life, and BMI. However, this study showed that LT4 therapy alone did not normalize the FT3/FT4 ratio in more than 70% of patients with hypothyroidism after thyroidectomy while a more normal ratio was seen with the LT4+LT3 combination treatment. Despite this, most patients had no preference between the 2 groups.

— Joanna Miragaya, MD

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