The Relationship Between Serum rT3 Concentrations, T3/T4 Ratio, and Symptoms/Quality of Life in Treated Hypothyroid Patients

Rationale: L-thyroxin (T4) substitution is the mainstay of treatment for hypothyroidism irrespective of disease origin. In a subset of patients with hypothyroidism however an inadequate peripheral T4->T3 conversion is hypostasized by some authors. This is speculated to lead to tissue level hypothyroidism and persistent symptoms even with adequate T4 replacement. As a potential pathogenetic mechanism, the inborn or acquired defect of peripheral deiodinases, decreased T3 and increased rT3 production is suggested.

Few results support this hypothesis. A decreased T3/T4 ratio has been reported in some post-surgical hypothyroid patients, while a few studies patient show increased patient satisfaction with combined T4+T3 substitution. However these differences have not been shown to be significant in large meta-analyses.

Due to the lack of convincing evidence current guidelines advocate against both routine rT3 measurement and T3 substitution. However in recent years, rT3 measurement and T3 supplementation has been steadily gaining popularity amongst some medical and functional medicine practitioners. Recent publications estimate order volume for rT3 tests in the US to be over 1 million per year. Thus, despite several decades of experience and multiple trials, the role of liothyronine (T3) substitution remains somewhat controversial.

The relationship between rT3 levels, T3/T4 ratio, quality of life and persistent symptoms of hypothyroidism in patients treated with adequate thyroxine doses has not been previously assessed.

A significant association of this nature would suggest the possibility of decreased peripheral T4->T3 conversion in some patients leading to worse treatment outcomes. A lack of relationship would further discredit the above detailed theories and could potentially help reduce the inadequate use of T3 substitution in patients.

Study population: Patients treated for hypothyroidism with no significant comorbidities are to be enrolled. Sample size calculations show adequate statistical power with over 150 participants. Based on the number of hypothyroid patients at our outpatient clinic, a sample size of 300-350 patients can reasonably be expected.

Schedule of activities: All study related procedures are performed during a single visit. These include recording of basic anthropometric data, a single draw of blood, and administration of psychological questionnaires. Laboratory tests include comprehensive thyroid function testing (TSH, T3, FT3, FT4, aTPO [anti-thyroperoxidase antibody]) with the addition of rT3 measurement. Less specific markers, associated with hypothyroidism are also assessed. These include serum cholesterol, CK (creatin-kinase), GOT/ASAT (aspartate-aminotransferase), GPT/ALAT (alanine-aminotransferase), creatinine and sodium levels. Psychological tests administered at the visit include ThyDQol, ThySRQ and the Somatosensory Amplification Scale (SASS) adding up to ~50 items including demographic variables.

Statistical analysis: Statistical methods for this study possibly include correlation analysis, linear and logistic regression.

Objectives and endpoints: Current understanding of hypothyroidism and thyroid hormone replacement imply that treatment with thyroxine doses that are sufficient to the normalize TSH lead to adequate tissue T3 levels and euthyroid state in the whole body. An association however between quality of life and rT3, levels or T3/T4 ratio could point out patients that could potentially benefit from additional T3 replacement.