Total Thyroxine

Thyroid hormone T4, or thyroxine, is a vital player in regulating metabolism, growth, and energy balance within the human body. Produced by the thyroid gland, T4 serves as a precursor to the more active hormone T3; its presence plays a crucial role in maintaining overall health and well-being. 

Its levels are tightly controlled by the hypothalamic-pituitary-thyroid axis, with deviations often indicating underlying thyroid dysfunction. Understanding T4 levels, both total and free, is essential for assessing thyroid function and diagnosing various thyroid disorders. 

This article explores the significance of T4, its testing methods, interpretation of results, clinical implications, and lifestyle strategies to support optimal T4 levels, offering valuable insights into maintaining thyroid health and overall wellness.

Introduction to Thyroxine, the Thyroid Hormone T4

What is T4?

T4, or thyroxine, is a thyroid hormone synthesized by the thyroid gland primarily in response to stimulation by thyroid-stimulating hormone (TSH) from the pituitary gland. It serves as a precursor to the more metabolically active hormone T3 and is primarily produced in the form of thyroxine-bound protein.

Thyroid hormone consists of the thyroglobulin molecule with a specific number of iodine atoms attached: T4 contains 4 iodine atoms, while T3 contains 3 iodine atoms in a specific placement. 

T4 is converted to T3 by the deiodinase family of enzymes.  Type 1 deiodinase enzymes are highly active in the liver and kidneys; type 2 deiodinase enzymes are active in muscle and in the glial cells of the brain.  A third type of deiodinase enzyme converts T4 to reverse T3, the inactive form of T3.  

As a prohormone, T4 plays a critical role in regulating metabolism, growth, and energy balance in the body. Through its conversion to T3 it influences almost every organ system, including the cardiovascular, nervous, and reproductive systems. T4 levels are tightly regulated to ensure the body's metabolic processes function optimally, with deviations from normal levels often indicating thyroid dysfunction.

What is Free T4?

Free T4 refers to the fraction of thyroxine hormone that is not bound to carrier proteins and is therefore biologically active, or available for peripheral conversion to T3. 

Unlike total T4, which includes both bound and free forms, free T4 represents the amount of hormone available for conversion to the biologically active form of thyroid hormone, T3.

Bound T4 acts as a storage form of T4, and becomes available for conversion to T3 as soon as it’s liberated from its carrier protein in the bloodstream.  

The three most common carrier proteins for thyroid hormone in the bloodstream are thyroxine binding protein, transthyretin, and albumin.  [12.]

Production and Regulation of T4

Synthesis of T4 in the Thyroid Gland

T4 synthesis in the thyroid gland begins with the uptake of iodine from the bloodstream by follicular cells. These cells actively transport iodine across their membranes and then oxidize it to produce iodine atoms, which are incorporated into tyrosine residues within the thyroglobulin protein. 

The enzyme thyroid peroxidase catalyzes the coupling of iodinated tyrosine residues within thyroglobulin, forming T4 and smaller amounts of T3. Thyroglobulin-containing colloid is then endocytosed into follicular cells, where it undergoes proteolysis to release T4 and T3 into the bloodstream. 

Approximately 90% of the thyroid hormone produced in the thyroid gland is T4, and only 10% of what is produced is the active form of thyroid hormone, T3.  Most T3 in the body is converted peripherally in the tissues from available, or free, T4 as needed for cellular metabolism.

Regulation of T4 Production by the Hypothalamic-Pituitary-Thyroid Axis

The hypothalamic-pituitary-thyroid (HPT) axis tightly regulates T4 production to maintain thyroid hormone homeostasis. The hypothalamus releases thyrotropin-releasing hormone (TRH), which stimulates the anterior pituitary gland to secrete thyroid-stimulating hormone (TSH). 

TSH acts on the thyroid gland to promote the synthesis and release of T4 and T3. The negative feedback loop ensures that circulating levels of T4 and T3 inhibit TRH and TSH secretion when they are elevated, thereby preventing excessive thyroid hormone production. Conversely, decreased levels of T4 and T3 stimulate TRH and TSH secretion, promoting thyroid hormone synthesis and release. 

This intricate feedback mechanism helps maintain stable levels of thyroid hormones in the body, ensuring proper metabolic function.

Testing T4 Levels

Overview of T4 Testing Methods

T4 testing methods primarily involve blood tests to measure the levels of total T4 (bound and unbound) or free T4 (unbound). 

Total T4 testing measures the total amount of T4 in the blood, including both the protein-bound and free forms. This test provides an overall assessment of thyroid function but may be influenced by changes in protein levels or binding capacity. 

Free T4 testing, on the other hand, specifically measures the unbound, biologically available form of T4. 

T4 testing is commonly performed as part of thyroid function tests, along with TSH and T3 measurements, to evaluate thyroid health and diagnose conditions such as hypothyroidism or hyperthyroidism. These tests are usually conducted using a blood sample obtained from a vein in the arm, and fasting is not typically required.

What is the Free T4 Blood Test?

The T4 free blood test measures the concentration of unbound thyroxine hormone, or T4, in the bloodstream. It provides valuable information about thyroid function and can help diagnose various thyroid disorders, including hypothyroidism and hyperthyroidism. 

T4 Blood Test Procedure

The T4 blood test measures the levels of thyroxine, or T4, in the bloodstream. It requires a blood sample drawn from a vein, typically in the arm.  It is often performed alongside other thyroid function tests like TSH and T3 to provide a comprehensive evaluation of thyroid health.

The American Thyroid Association recommends running thyroid blood tests before taking thyroid medication.  [7.]

Some lab companies offer a blood spot version of this test, which can be done at home.  The sample is then mailed into the lab.

TSH with Reflex to FT4

TSH with reflex to FT4 testing is a comprehensive approach that not only measures TSH levels but also assesses the level of free thyroxine (FT4), one of the thyroid hormones.  This reflex testing is triggered when TSH levels fall outside the normal range, prompting further evaluation of thyroid function. 

Specifically, if TSH levels are either too low or too high, the test will do an additional assessment of free, or bioavailable, T4 levels in the body.  [1.]  Reference ranges may differ by labs, but typical levels for a TSH reflex to T4 test are 

TSH <0.450

or

TSH >4.5

‍

This reflex test provides additional immediate assessment of excessive or decreased thyroid function, aiding in the diagnosis of hyper- or hypothyroidism.  

Interpretation of T4 Test Results

Normal T4 Levels

It's essential to note that reference ranges can vary slightly between different laboratories. 

Normal T4 reference ranges may also fluctuate depending on factors such as age, sex, and individual health conditions. In infants and children, T4 levels tend to be higher than in adults due to rapid growth and development.  Due to increased demand for thyroid hormone in pregnancy, T4 levels may also need to be adjusted in pregnancy.  

Typical reference ranges for total thyroxine (TT4) are generally:  [6., 17.]

• In newborns up to age 14 days: 11.8-22.6 mcg/dL (152-292 nmol/L)
• In babies and older children: 6.4-13.3 mcg/dL (83-172 nmol/L)
• In adults: 5.4-11.5 mcg/dL (57-148 nmol/L)

Typical reference ranges for free thyroxine (FT4) are generally: 

• In children/adolescents: 0.8-2 ng/dL (10-26 pmol/L)
• In adults: 0.7-1.8 ng/dL (9-23 pmol/L)
• In pregnant patients: 0.5-1 ng/dL (6.5-13 pmol/L)

It is important to note that often, T4 levels will remain within normal range the longest in the setting of thyroid dysfunction, as T3 and TSH levels adjust to maintain an appropriate thyroid response.  Therefore, it is not uncommon to see normal T4 levels in the setting of hypothyroidism.  [5., 18.]

Normal Range for Free T4 in Women

Reference ranges for T4 are given above; however, it is important to note that T4 levels in women may trend higher than those in men.  [5.]  One potential cause of this is the naturally higher levels of estrogen, which causes an increase in thyroid binding proteins and a subsequent increase in total T4.  [5.]  

Additionally, demands on thyroid function increase in pregnancy, with an increased requirement for thyroxine.  For that reason free T4 values should be monitored throughout pregnancy to avoid subclinical hypothyroidism.  [15.]

Normal T3 and T4 Levels with Low TSH

Normal T3 and T4 levels while TSH is low could indicate a condition known as hyperthyroidism. In this scenario, the thyroid gland is overactive, producing excessive amounts of the thyroid hormones T4 and T3. 

This situation may lead to symptoms such as weight loss, rapid heartbeat, anxiety, and heat intolerance. Further evaluation by a healthcare provider is essential to determine the underlying cause and appropriate management.

Clinical Significance of Abnormal T4 Levels

Causes of Abnormally Low T4 Levels:

Hypothyroidism: Underactive thyroid gland due to autoimmune thyroiditis (Hashimoto's thyroiditis), thyroid surgery, radioactive iodine therapy, endocrine disorders or other potential causes.

Central Hypothyroidism: Dysfunction of the hypothalamus or pituitary gland leading to decreased TSH production, resulting in reduced thyroid hormone synthesis.

Iodine Deficiency: Inadequate dietary intake of iodine, essential for thyroid hormone synthesis, leading to decreased T4 production.

Medications: Certain drugs including lithium, amiodarone, or anti-thyroid medications, can interfere with thyroid hormone synthesis and/or thyroid binding proteins and reduce T4 levels.

Thyroiditis: Inflammation of the thyroid gland, including subacute thyroiditis, postpartum thyroiditis, or silent thyroiditis, can temporarily lower T4 levels.

Congenital Hypothyroidism: a rare genetic disorder present at birth, it’s characterized by impaired thyroid hormone production or synthesis.

Pituitary or Hypothalamic Dysfunction: Tumors, trauma, or radiation affecting the pituitary or hypothalamus can disrupt TSH secretion, leading to low T4 levels.

Causes of Abnormally High T4 Levels:

Hyperthyroidism: an overactive thyroid gland commonly caused by Graves' disease, toxic multinodular goiter, or toxic adenoma, leading to excess T4 production.

Thyroid Hormone Resistance: Genetic condition characterized by reduced tissue responsiveness to thyroid hormones, resulting in compensatory elevated T4 levels.

Thyroid Hormone Replacement Therapy: Excessive doses of thyroid hormone replacement medication (levothyroxine) can lead to supraphysiological T4 levels.

Thyroiditis: Inflammation of the thyroid gland, such as Hashimoto's thyroiditis or acute thyroiditis, can cause transient increases in T4 levels due to hormone release from damaged thyroid follicles.

Thyroid Hormone Overdose: Intentional or accidental ingestion of large doses of thyroid hormone supplements can result in elevated T4 levels.

‍Pregnancy: During pregnancy, estrogen-induced increases in thyroid-binding globulin (TBG) can lead to higher total T4 levels; free T4 often remains within the normal range.

TSH-Secreting Pituitary Adenoma: Rare pituitary tumor that autonomously produces TSH, leading to unregulated thyroid hormone synthesis and elevated T4 levels.

Natural Strategies to Address Thyroid Health

Nutrition for Thyroid Health

Selenium-rich Foods: increase consumption of selenium-rich foods like Brazil nuts, eggs, and sunflower seeds, as selenium plays a role in thyroid hormone metabolism.

Iodine-rich Foods: incorporate a serving of iodine-rich foods such as seaweed, fish, and shellfish as iodine is essential for thyroid hormone synthesis.

Zinc-rich Foods: consume foods high in zinc, such as oysters, beef, and pumpkin seeds, as zinc helps regulate thyroid function.  [BETSY]

Goitrogen Foods: limit consumption of raw cruciferous vegetables such as broccoli, cabbage, and cauliflower, as they contain compounds that can interfere with thyroid hormone synthesis when consumed in large amounts.  It is generally recommended to wash and cook these foods to reduce their goitrogenic tendency.

Avoid Processed Foods: minimize intake of processed and refined foods, including packaged snacks, sugary beverages, and foods high in artificial additives and preservatives, as they can contribute to inflammation and disrupt thyroid function.  [19.]

Lifestyle Adjustments for Thyroid Health

Stress reduction: manage stress levels through techniques like meditation, yoga, or deep breathing exercises, as stress can impact thyroid hormone levels. [8.]

Get enough sleep: ensure adequate sleep hygiene and aim for sufficient restorative sleep each night, as sleep deprivation can affect thyroid function.  [13., 14.]

‍Exercise: engage in regular physical activity, including both aerobic and strength-training exercises, to support overall metabolic health.  [4.]

Herbal and Supplement Support for Thyroid Health

Herbal adaptogens: consider supplementing with adaptogenic herbs like ashwagandha and rhodiola, which may help support thyroid function and reduce stress.  [9., 16.]  

Vitamin D: low vitamin D has been associated with hypothyroidism and with autoimmune thyroiditis.  Individuals with hypothyroidism may benefit from having vitamin D levels assessed, and supplementing appropriately if low.  [2., 11.]

Consult with a healthcare professional before starting any new supplements, as individual needs may vary, and certain supplements may interact with medications or underlying health conditions.