Research Blog

November 22, 2022

Thyroid Biomarkers: Total T4

Optimal Takeaways

The thyroid gland regulates metabolism and affects just about every cell in the body. The main hormone produced by the thyroid is thyroxine (T4), a minimally active form that must be converted to T3 to exert its actions. Measurement of total T4 includes the majority which is bound to protein, and the free form which is a better indicator of thyroid status. Low T4 is associated with overt hypothyroidism, iodine insufficiency, decreased energy expenditure, weight gain, and increased cholesterol. Elevated T4 is associated with overt hyperthyroidism, thyroid cancer, increased energy expenditure, decreased cholesterol, and pregnancy.

Conventional Lab Range: 4.50 – 12.00 ug/dL (57.92 – 154.44 nmol/L)

Optimal Dx’s Optimal Range: 6.00 – 11.90 ug/dL (77.22 – 153.15 nmol/L)

Low total T4 is associated with hypothyroidism, Hashimoto thyroiditis, iodine insufficiency, thyroidectomy, thyroid agenesis, pituitary insufficiency, hypothalamic failure, myxedema, cirrhosis, renal failure, Cushing syndrome, TSH receptor defects, and certain medications including anabolic steroids, androgens, lithium, propranolol, phenytoin, and anti-thyroid drugs (Pagana 2021). Cognitive dysfunction is also a primary symptom of hypothyroidism (Ettleson 2020). Metabolically, thyroid insufficiency is associated with decreased energy expenditure, weight gain, and increased cholesterol levels (Mullur 2014).

High total T4 is associated with hyperthyroidism, acute thyroiditis, thyroid cancer, toxic goiter, congenital hyperproteinemia, elevated thyroid binding globulin, hepatitis, pregnancy, and certain medications including estrogen, oral contraceptives, clofibrate, heroin, and methadone (Pagana 2021). Metabolically, excess thyroid hormone contributes to increased energy expenditure, weight loss, and decreased cholesterol (Mullur 2014). Exposure to organophosphate pesticides (Fortenberry 2012), and phthalates (Choi 2020) may increase total T4.


Thyroxine (T4), also known as thyroxine or tetraiodothyronine, is the main hormone secreted by the thyroid gland. It contains four atoms of iodine and represents 90% of the total thyroid hormone released. Approximately 99% of T4 in circulation is considered inactive as it is bound to proteins including thyroid binding globulin, albumin, and transthyretin (prealbumin). Total T4 measurement reflects both bound and free T4, with free T4 best reflecting thyroid status. Hormone replacement therapy and pregnancy can increase thyroid binding globulin (TBG) and falsely elevate total T4 suggesting that hyperthyroidism is present when it is not. A reduction in TBG, e.g., hypoproteinemia, may falsely decrease total T4 even though hypothyroidism is not present (Pagana 2021).

Approximately one third of circulating T4 is converted peripherally to active T3, while one third is normally converted to reverse T3. Reverse T3 is inactive though some can be converted to active T3 (Peeters 2017). Total T4 will be elevated in overt hyperthyroidism but can be within conventional range in subclinical hyperthyroidism despite a low TSH. Total T4 will be decreased in overt hypothyroidism but may be within conventional range with an elevated TSH in subclinical hypothyroidism (IOM 2003).

Thyroid hormone production and levels are regulated by TSH from the pituitary and TRH from the hypothalamus, as well as by nutritional signals such as leptin and appetite-regulating peptides. Thyroid hormone directly affects metabolism of carbohydrates, protein, and lipids; influences energy expenditure and storage; maintains basal metabolic rate; and controls appetite and food intake. Thyroid hormone also modulates insulin sensitivity and gluconeogenesis in the liver and has direct actions in the brain, fat tissue, skeletal muscle, and pancreas. Excess thyroid hormone contributes to increased resting metabolic rate, weight loss, decreased cholesterol, increased lipolysis, and increased gluconeogenesis. Insufficiency of thyroid hormone is associated with decreased resting energy expenditure, increased weight, increased cholesterol, decreased lipolysis, and reduced gluconeogenesis. (Mullur 2014).

Thyroid hormones influence several cardiac functions as well, including heart rate, output, and vascular resistance, and thyroid abnormalities are often observed in congestive heart failure, cardiac ischemia, and associated oxidative stress (Moura 2016).

Administration of exogenous T4 can resolve hypothyroidism and its related cognitive symptoms including impaired memory and concentration, altered perceptual and executive function, and changes in language and psychomotor function. However, for those whose symptoms do not resolve, a combination of T4 and T3 may be indicated (Ettleson 2020).

While production of thyroid hormone relies on sufficient iodine, the deiodinase conversion of T4 to T3 relies on sufficient selenium. An increase in free T4 and a decrease in free T3 may be observed with selenium insufficiency (Kobayashi 2021).

It is important to evaluate micronutrient status in general when assessing thyroid function, including zinc, copper, iron, molybdenum, and vitamin A. Insufficiency of any these nutrients, as well as iodine and selenium, may impair thyroid metabolism (O’Kane 2018). The conditionally essential amino acid tyrosine is also required for thyroid hormone synthesis.

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Choi, Sohyeon et al. “Thyroxine-binding globulin, peripheral deiodinase activity, and thyroid autoantibody status in association of phthalates and phenolic compounds with thyroid hormones in adult population.” Environment international vol. 140 (2020): 105783. doi:10.1016/j.envint.2020.105783

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Fortenberry, Gamola Z et al. “Association between urinary 3, 5, 6-trichloro-2-pyridinol, a metabolite of chlorpyrifos and chlorpyrifos-methyl, and serum T4 and TSH in NHANES 1999-2002.” The Science of the total environment vol. 424 (2012): 351-5. doi:10.1016/j.scitotenv.2012.02.039

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Kobayashi, Ryohei, et al. "Thyroid function in patients with selenium deficiency exhibits high free T4 to T3 ratio." Clinical Pediatric Endocrinology 30.1 (2021): 19-26.

Moura Neto, Arnaldo, and Denise Engelbrecht Zantut-Wittmann. “Abnormalities of Thyroid Hormone Metabolism during Systemic Illness: The Low T3 Syndrome in Different Clinical Settings.” International journal of endocrinology vol. 2016 (2016): 2157583. doi:10.1155/2016/2157583

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Tag(s): Biomarkers

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