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


We conducted a 6-year (2010–2016), retrospective chart review of 100 patients undergoing combination therapies from the 2400 hypothyroid patients receiving LT4 monotherapy in an endocrinology clinic in Pennsylvania. This study was approved by the Pinnacle Health System institutional review board. All of the patients were hypothyroid as defined by the ATA criteria, with elevated TSH and normal or subnormal FT4 at the beginning of LT4 therapy.[2]

Serum Assays

TSH was measured by a third-generation immunochemiluminescent assay having a functional detection limit of 0.01 mIU/L and a normal range of 0.3 to 5.1 mIU/L. FT4 and FT3 were measured by enzyme immunoassay. Laboratory collection was from 8:00 AM to 4:00 PM. The following are accepted normal ranges by the ATA and AACE:[2,3,32,36]

  • Euthyroid (TSH level within normal range, 0.35–5.5 μIU/mL)

  • Hypothyroid (TSH level >5.5 μIU/mL and FT4 level <0.56 μIU/mL)

  • Hyperthyroid (TSH level <0.01 μIU/mL and FT4 level >1.64 μIU/mL)

  • FT3 (normal range 2.5–4 μIU/mL)

  • 25-hydroxyvitamin D (25[OH]D; normal range >30 ng/mL)

  • Vitamin B12 (normal range >240 pg/mL)

  • Hemoglobin (Hb; normal range 12–17 g/dL)

Data Collection

Data were collected for clinical signs and symptoms of hypothyroidism (eg, fatigue, poor memory, depressed mood, amenorrhea, dry skin, cold intolerance, weight gain, myxedema coma) and hyperthyroidism (eg, palpitations, tremor, arrhythmia, anxiety) using a standard baseline "Hypothyroid Office Note" as an objective clinical measure (Appendix, http://links.lww.com/SMJ/A93). The laboratory tests included TSH, FT4, and FT3 while undergoing LT4 monotherapy (baseline) and combination therapy, either synthetic or natural. Monotherapy doses were started and titrated to physiological thyroid levels as recommended by ATA guidelines and maximizing control of hypothyroid symptoms. Levels before initiation of FT3 therapies served as baseline for our comparison. Levels of 25[OH]D, vitamin B12, and Hb also were collected on LT4 and combination therapy.

In 2015, the patients were contacted via telephone by the primary author in a blinded fashion. Patients were questioned about their symptoms via the Medical Outcomes Study Short Form-20 questionnaire (SF-20). This 20-question survey developed by the RAND Corporation has been shown to be effective in the evaluation of daily symptoms of hypothyroidism. The patients also were questioned about their opinions of "feeling better" on combination therapy versus monotherapy.

Study Population

Patients were started on a combination therapy if they complained of hypothyroid signs and symptoms despite optimal trials of LT4 monotherapy for at least 1 year, to achieve optimal normal TSH levels, preferably <2.5 μIU/mL based on recent evidence,[37] and if they continued to have low normal FT3 (2.5–3 μIU/mL). Then natural or synthetic therapy was chosen based on physician and patient preferences. Some patients were switched from one combination therapy to the other, depending upon thyroid levels and the patient's signs and symptoms. The starting dose of LT3 was 5 μg in conjunction with an appropriate decrease of 12.5 μg in LT4 to achieve the standard physiological circulating FT4:FT3 ratio of nearly 14:1.[38] LT3 was titrated with the maximum 12.5 μg dosage to achieve physiologic and therapeutic FT3 levels along with symptom relief. None of the patients were treated with LT3 alone.

The starting dose for DTE, with a known FT4:FT3 ratio of 4:1,[39,40] was 15 mg and was titrated to obtain physiologic and therapeutic TSH, FT4, and FT3 levels along with symptom relief. Individual endocrinologists chose the smaller dosage when switching from LT4 to DTE and to prevent adverse effects of hyperthyroidism. All of the patients receiving either therapy were studied every 3 to 6 months to achieve therapeutic thyroid levels.

Exclusion Criteria

The exclusion criteria were as follows: having other cofactors that mimicked symptoms of hypothyroidism, including low Hb, 25[OH]D deficiency, vitamin B12 deficiency, and depression; having long-standing psychiatric disorders or fibromyalgia because those can mask some of the hypothyroid symptoms (eg, fatigue, arthralgia, depression, cognitive slowing); and having a primary care physician instead of an endocrinologist studying them because those patients were not monitored per our protocol (and to prevent physician bias).


The primary outcomes of the study were whether combination therapy was effective in improving clinical signs and symptoms of hypothyroidism as documented in the clinic note; improvement in hypothyroidism symptoms via the SF-20 questionnaire; and adverse effects of clinical or biochemical hyperthyroidism, as measured by TSH, FT4, and FT3.

Statistical Analyses

Proportions were computed for all of the categorical variables. We reported continuous variables as means and medians and categorical variables as proportions. The Student t test was used to analyze between-group differences and the paired t test was used to conduct the before and after treatment comparisons. The χ2 and Fisher exact tests were used for categorical variable comparisons. P < 0.05 was considered significant. All of the statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).