DIAGNOSIS OF ENDOCRINE DISEASE: How reliable are free thyroid and total T3hormone assays?

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Abstract

<p class="first" id="P1">Hypothyroidism is a very common disorder worldwide, for which the usual treatment is monotherapy with levothyroxine (L-T4). However, a number of patients treated with L-T4 continue to report symptoms of hypothyroidism despite seemingly normal levels of thyroid stimulating hormone (TSH), free-T3 (FT3), and free-T4 (FT4) measured by immunoassay. This review summarizes the limitations of the immunoassays commonly used to measure thyroid hormones and emphasizes the advantages of the role of liquid chromatography-tandem mass spectrometry (LC-MSMS). Immunoassays for free thyroid hormone are affected by alterations in serum binding proteins that occur in many physiologic and disease states. Multiple studies show falsely normal values for T3, FT3, and FT4 by immunoassay that are below the reference interval when measured by (ultrafiltration) LC-MSMS, a reference method. We suggest evaluation of thyroid hormone levels by ultrafiltration LC-MSMS for patients who continue to experience hypothyroid symptoms on LT-4. This may help identify the approximately 20% subset of patients who would benefit from addition of T3 to their treatment regimen (combination therapy). </p>

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2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism

Wilmar M. Wiersinga, Leonidas Duntas, Valentin Fadeyev … (2012)

Background Data suggest symptoms of hypothyroidism persist in 5–10% of levothyroxine (L-T4)-treated hypothyroid patients with normal serum thyrotrophin (TSH). The use of L-T4 + liothyronine (L-T3) combination therapy in such patients is controversial. The ETA nominated a task force to review the topic and formulate guidelines in this area. Methods Task force members developed a list of relevant topics. Recommendations on each topic are based on a systematic literature search, discussions within the task force, and comments from the European Thyroid Association (ETA) membership at large. Results Suggested explanations for persisting symptoms include: awareness of a chronic disease, presence of associated autoimmune diseases, thyroid autoimmunity per se, and inadequacy of L-T4 treatment to restore physiological thyroxine (T4) and triiodothyronine (T3) concentrations in serum and tissues. There is insufficient evidence that L-T4 + L-T3 combination therapy is better than L-T4 monotherapy, and it is recommended that L-T4 monotherapy remains the standard treatment of hypothyroidism. L-T4 + L-T3 combination therapy might be considered as an experimental approach in compliant L-T4-treated hypothyroid patients who have persistent complaints despite serum TSH values within the reference range, provided they have previously received support to deal with the chronic nature of their disease, and associated autoimmune diseases have been excluded. Treatment should only be instituted by accredited internists/endocrinologists, and discontinued if no improvement is experienced after 3 months. It is suggested to start combination therapy in an L-T4/L-T3 dose ratio between 13:1 and 20:1 by weight (L-T4 once daily, and the daily L-T3 dose in two doses). Currently available combined preparations all have an L-T4/L-T3 dose ratio of less than 13:1, and are not recommended. Close monitoring is indicated, aiming not only to normalize serum TSH and free T4 but also normal serum free T4/free T3 ratios. Suggestions are made for further research. Conclusion L-T4 + L-T3 combination therapy should be considered solely as an experimental treatment modality. The present guidelines are offered to enhance its safety and to counter its indiscriminate use.

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Mechanisms behind the non-thyroidal illness syndrome: an update.

Maria H Warner, Geoffrey Beckett (2010)

The mechanisms behind the changes in serum triiodothyronine (T(3)), thyroxine (T(4)) and TSH that occur in the non-thyroidal illness syndrome (NTIS) are becoming clearer. Induction of a central hypothyroidism occurs due to a diminution in hypothalamic thyrotropin-releasing hormone. This can be signalled by a decrease in leptin caused by malnutrition and possibly a localised increase in hypothalamic T(3) catalyzed by altered expression of hypothalamic iodothyronine deiodinases D2 and D3. Data from D1 and D2 knockout mice suggest that these enzymes may have little contribution to the low serum T(3) found in acute illness. The decline in serum T(3) and T(4) in models of acute illness precedes the fall in hepatic D1, suggesting that much of the initial fall in these hormones may be attributable to an acute phase response giving rise to a reduction in the thyroid hormone binding capacity of plasma. When measured by reliable methods, changes in serum free T(4) and free T(3) are modest in comparison to the fall seen in total thyroid hormone. Thyroid hormone transporter expression is up-regulated in many models of the NTIS, thus if diminished tissue uptake of hormone occurs in vivo, it is likely to be the result of impaired transporter function caused by diminished intracellular ATP or plasma inhibitors of transporter action. In man, chronic illness leads to an upregulation of thyroid hormone receptor (THR) expression at least in liver and renal failure. In contrast, human and animal models of sepsis and trauma indicate that expression of THRs and their coactivators are decreased in acute illness.