Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism

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Impaired psychological well-being, depression or anxiety are observed in 5–10% of hypothyroid patients receiving levothyroxine, despite normal TSH levels. Such complaints might hypothetically be related to increased free T4 and decreased free T3 serum concentrations, which result in the abnormally low free T4:free T3 ratios observed in 30% of patients on levothyroxine. Evidence is mounting that levothyroxine monotherapy cannot assure a euthyroid state in all tissues simultaneously, and that normal serum TSH levels in patients receiving levothyroxine reflect pituitary euthyroidism alone. Levothyroxine plus liothyronine combination therapy is gaining in popularity; although the evidence suggests it is generally not superior to levothyroxine monotherapy, in some of the 14 published trials this combination was definitely preferred by patients and associated with improved metabolic profiles. Disappointing results with combination therapy could be related to use of inappropriate levothyroxine and liothyronine doses, resulting in abnormal serum free T4:free T3 ratios. Alternatively, its potential benefit might be confined to patients with specific genetic polymorphisms in thyroid hormone transporters and deiodinases that affect the intracellular levels of T3 available for binding to T3 receptors. Levothyroxine monotherapy remains the standard treatment for hypothyroidism. However, in selected patients, new guidelines suggest that experimental combination therapy might be considered.

Key Points

  • Impaired psychological well-being and depression or anxiety affect about 5–10% of hypothyroid patients on levothyroxine, despite normal TSH levels

  • Persistent symptoms might be explained by factors unrelated to thyroid disease, unrecognized autoimmune disease, or inability of levothyroxine to restore T3 levels in serum and all target tissues

  • Randomized clinical trials have in general not shown superiority of levothyroxine plus liothyronine combination therapy over levothyroxine monotherapy

  • Some reports suggest a preference of patients for levothyroxine plus liothyronine combination therapy over levothyroxine monotherapy, which might be associated with weight loss

  • Levothyroxine remains the standard treatment modality for hypothyroidism, but levothyroxine plus liothyronine combination treatment might be offered to selected patients as an experimental modality, according to guidelines published in 2012

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Figure 1: Correlation between serum TSH and free thyroid hormone levels in 3,875 euthyroid controls and 1,811 athyreotic patients receiving levothyroxine monotherapy.
Figure 2: Thyroid hormone production and metabolism.


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Wiersinga, W. Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism. Nat Rev Endocrinol 10, 164–174 (2014) doi:10.1038/nrendo.2013.258

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