Effects of Long-term Combination LT4 and LT3 Therapy for Improving Hypothyroidism and Overall Quality of Life

Anam Tariq, DO; Yijin Wert, MS; Pramil Cheriyath, MD; Renu Joshi, MD


South Med J. 2018;111(6):363-369. 

In This Article


Our study is one of the few in the United States to analyze the long-term safety and effects of combination therapy. Most other studies had an average duration of 10 to 16 weeks, with a maximum of 52 weeks.

In our subset population, the symptoms of hypothyroidism improved significantly with no increase in hyperthyroidism. The abnormally low TSH and elevated FT4 and FT3 levels persisted only for a short duration because of dosage adjustments and varied among patients. We did not find any difference in levels in patients according to the etiology of hypothyroidism.

We believe one of the reasons for our success is diligent follow-up by the endocrinologists, who see a large volume of patients with hypothyroidism in central Pennsylvania. Those with abnormal laboratory values or with symptoms indicating thyrotoxicosis were counseled to stop, adjust dosages, or switch to the other combination therapy. None of the patients in either FT3 therapy group were hospitalized because of medication adverse effects, most notably, atrial fibrillations, arrhythmias, and cardiac death.

Our study has several strengths. The principal strength is the longer duration of FT3 therapy (mean 27 months, median 22 months). The second strength is the maintenance of a physiological FT4:FT3 ratio of approximately 14:1, especially with synthetic therapy, for which the therapeutic dose was 75 μg/5 μg; this is equivalent to an FT4:FT3 ratio of approximately 15:1. Although a significant number of our patients were undergoing DTE, the ratio of FT4:FT3 was approximately 4:1, and dynamic, significant adverse effects were not pronounced, perhaps because of the lower dosages prescribed. Unlike the observational study from the United Kingdom that showed some benefits from FT3 supplementation,[29] our retrospective study excluded other causes of hypothyroid-like symptoms (eg, fibromyalgia, depression, chronic pain syndrome) to mitigate any confounding results before starting combination therapy. Another important aspect of this study is the SF-20 questionnaire used for the subjective analysis. DTE and LT4/LT3 populations, 92.7% and 88.6%, respectively, claimed to have improved quality of life, as assessed by the questionnaire. A convincing argument could be made that the increased rate of patient satisfaction from combination therapy may have been because some of our patients may possess underlying genetic polymorphisms that cannot be treated with levothyroxine alone. This conception of FT3 supplementation benefiting those with polymorphisms was suggested in Wiersinga's research [41] but not thoroughly investigated.

An important criticism of combination therapy is hyperthyroidism. In our study, at least 6.7% of the 100 patients complained of palpitations and anxiety and had confirmed TSH <0.35 μIU/mL but without atrial arrhythmias. This is hard to compare with other studies, particularly because many studies have not been conducted for an equal duration. From previous meta-analyses, only two studies reported significant atrial arrhythmias.[17,42] It is important to point out that our study did not titrate LT4 to supraphysiologic levels for which thyrotoxicosis was a concern before starting any combination therapy.

Our study had several limitations. The biggest limitation of this study is the retrospective nature. There was no preintervention data to compare before the initiation of FT3 therapies, mainly because many of these patients were referrals and we were unable to obtain all of their previous records. Similarly, there is no simultaneous comparison to patients who were receiving LT4 alone. We also did not compare the SF-20 questionnaire pretherapy to see whether the benefits postcombination therapy were statistically significant; however, as documented in the Methods section, patients were asked via the telephone whether they felt better on combination therapy when compared with previous monotherapy. Many patients did emphasize "feeling better on combination therapy." In addition, depending on the time of the day when laboratory tests for FT3 and FT4 were collected, thyroid function levels could vary because of the timing of thyroid medication ingestion. Most endocrinologists understand that physiologic FT4 increases to 16% for 4 to 6 hours postmedication and there are far greater increases in FT3 levels post-LT3 ingestion. Another interesting observation is the close equalization of FT3 and FT4 on either T3 therapy. We do not have an explanation for the last observation.