Individualized Therapy for Hypothyroidism: Is T4 Enough for Everyone?

• Published in: The journal of clinical endocrinology and metabolism Vol. 105; no. 9; pp. e3090 - e3104
• Main Authors: Ettleson, Matthew D, Bianco, Antonio C
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.09.2020
• Subjects: Care and treatment; Cholesterol; Clinical trials; Cognition; Drug Resistance - drug effects; Drug Therapy, Combination; Hormone Replacement Therapy - methods; Hormone Replacement Therapy - standards; Humans; Hypothyroidism; Hypothyroidism - blood; Hypothyroidism - drug therapy; Hypothyroidism - epidemiology; Lipid metabolism; Metabolism; Online Only; Patient satisfaction; Physiological aspects; Practice Patterns, Physicians' - standards; Practice Patterns, Physicians' - statistics & numerical data; Practice Patterns, Physicians' - trends; Precision Medicine - methods; Precision Medicine - trends; Thyroid; Thyroid Function Tests; Thyroid gland; Thyroid-stimulating hormone; Thyrotropin; Thyrotropin - blood; Thyroxine; Thyroxine - administration & dosage; Treatment Failure; Triiodothyronine; Triiodothyronine - administration & dosage; patient satisfaction; combination therapy; levothyroxine; desiccated thyroid extract; hypothyroidism
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgaa430

Abstract Context It is well recognized that some hypothyroid patients on levothyroxine (LT4) remain symptomatic, but why patients are susceptible to this condition, why symptoms persist, and what is the role of combination therapy with LT4 and liothyronine (LT3), are questions that remain unclear. Here we explore evidence of abnormal thyroid hormone (TH) metabolism in LT4-treated patients, and offer a rationale for why some patients perceive LT4 therapy as a failure. Evidence Acquisition This review is based on a collection of primary and review literature gathered from a PubMed search of “hypothyroidism,” “levothyroxine,” “liothyronine,” and “desiccated thyroid extract,” among other keywords. PubMed searches were supplemented by Google Scholar and the authors’ prior knowledge of the subject. Evidence Synthesis In most LT4-treated patients, normalization of serum thyrotropin levels results in decreased serum T3/T4 ratio, with relatively lower serum T3 levels; in at least 15% of the cases, serum T3 levels are below normal. These changes can lead to a reduction in TH action, which would explain the slower rate of metabolism and elevated serum cholesterol levels. A small percentage of patients might also experience persistent symptoms of hypothyroidism, with impaired cognition and tiredness. We propose that such patients carry a key clinical factor, for example, specific genetic and/or immunologic makeup, that is well compensated while the thyroid function is normal but might become apparent when compounded with relatively lower serum T3 levels. Conclusions After excluding other explanations, physicians should openly discuss and consider therapy with LT4 and LT3 with those hypothyroid patients who have persistent symptoms or metabolic abnormalities despite normalization of serum thyrotropin level. New clinical trials focused on symptomatic patients, genetic makeup, and comorbidities, with the statistical power to identify differences between monotherapy and combination therapy, are needed.