Thyroxine (T4) and triiodothyronine (T3) are important hormones produced by the thyroid gland that are essential for brain and physical development in infants and for metabolic activity in adults.¹ Thyroid hormones help the brain, heart, liver, muscles, and other organs function properly.²  If unregulated, thyroid hormone imbalances can lead to life-threatening conditions such as myxedema coma (dangerously low thyroid hormones) and thyroid storm (excessive thyroid hormone concentration). Health care professionals should know how to monitor these hormones to prevent emergencies and improve outcomes.

Thyroid Hormone Function and Production

The thyroid gland, located in the anterior neck, consists of two types of cells: follicular cells, which produce T3 and T4, and parafollicular cells, which produce and secrete thyrocalcitonin (also called calcitonin).³

The thyroid takes iodine, found in our diet, combines it with an amino acid, tyrosine, and converts it into T3 (containing three iodine atoms) and T4 (containing four iodine atoms). T4 is produced solely by the thyroid gland. About 80% of T3 is formed by the removal of one iodine atom from T4, a process called deiodination. This occurs primarily in the liver and kidney, but T3 is also produced in some, if not all tissues.¹

Factors that inhibit the conversion of T4 to T3 include stress, starvation, beta-blockers, amiodarone, corticosteroids, iodinated contrast media, and propylthiouracil (PTU).³ Cold temperatures may increase the conversion.³ The thyroid gland synthesizes and stores mass quantities of T3 and T4 within the protein thyroglobulin.¹

T3 and T4 production is regulated by thyroid stimulating hormone (TSH) secreted by the pituitary gland, which is in turn regulated by thyrotropin-releasing hormone (TRH) secreted by the hypothalamus.² This process works as a negative feedback loop. When levels of T3 and T4 decrease below normal, the pituitary gland produces TSH, stimulating the thyroid gland to produce more hormones and raise the blood levels. Once the levels rise, the pituitary then decreases TSH production.

The thyroid hormones are released into the bloodstream and transported throughout the body. Most are bound to plasma proteins, while a smaller portion circulates as free hormones that enter cells and trigger metabolism.³ More than 99.95% of T4 and 99.5% of T3 in serum are bound to serum proteins such as thyroxine-binding globulin (TBG), transthyretin (TTR), albumin, and lipoproteins.¹

For T4, approximately 75% is bound to TBG, 10 % to TTR, 12% to albumin, and 3% to lipoproteins. A minimal amount, about 0.02%, of T4 in the serum is free, or unbound.

For T3, approximately 80% is bound to TBG, 5% to TTR, and 15% to albumin and lipoproteins.¹ About 0.5% of T3 in the serum is free.

It is the free T3 and T4 concentrations in the blood that are responsible for biologic activity.¹ The binding proteins maintain serum free T3 and T4 within tight limits yet ensure that these hormones are accessible as needed to the tissues, therefore acting as both storage and buffer systems. For example, if the thyroid stops secreting hormones, the hormones stored in the serum will help delay the onset of hypothyroidism.¹ T3 and T4 are rapidly released from binding proteins and can become available almost instantly. Conversely, the binding proteins also protect tissues from sudden increases in thyroid secretion or extrathyroidal T3 production.¹

What role do these hormones play in measuring thyroid function?

Evaluation of Thyroid Hormone Function

Thyroid function is assessed by one or more of the following tests¹:

• Serum TSH concentration: As stated earlier, there is a relationship between serum free T4 and TSH concentrations in that very small changes in serum free T4 stimulate very large changes in TSH. A high TSH level indicates poor thyroid gland function or hypothyroidism. If the thyroid is not making enough hormone, the pituitary keeps making and releasing TSH into the blood. A low TSH typically indicates an overactive thyroid that is producing too much thyroid hormone, or hyperthyroidism.¹ The pituitary then ceases production and release of TSH into the blood. Normal ranges vary among laboratories; however, a typical range is 0.4 to 5.0 mlU/L.


• Serum Total T4 concentration: This measures both bound and unbound (free) T4. A high serum T4 may indicate hyperthyroidism while a low level may indicate hypothyroidism. However, a high or low level may not indicate a problem. For example, if the patient is pregnant or taking oral contraceptives, levels will be higher. Critical illness, corticosteroids and medicine that treat asthma, arthritis, and other health problems, can lower T4 levels. These medications may change the amount of binding proteins and therefore may not correctly reflect T4 levels.¹ Normal ranges will vary among laboratories; however, a typical range is 4.6 to 11.2 mcg/dL (60 to 145 mmol/L).¹


• Serum Total T3 concentration: A high T3 level may help confirm a diagnosis of hyperthyroidism if the T4 level is normal. The normal range is more variable among laboratories than total T4; the typical range is 75 to 195 ng/dL (1.1 to 3 nmol/L).¹  


• Serum Free T4 concentration: This measures T4 unbound to proteins; a low free T4 will indicate hypothyroidism, while a high free T4 will indicate hyperthyroidism.¹ This test may provide a better indication of T4 levels since it is not affected by binding proteins.


• T3 resin uptake (T3RU): an indirect measure of serum thyroid hormone binding capacity.


• Free T4 index (FT4I): is derived from T4 and T3RU and indicates how much free T4 is present compared to bound T4. FT4I can help determine if a high T4 level is due to abnormal amounts of TBG.

*Consult your institution’s normal laboratory ranges.

Screening for Thyroid Hormone Dysfunction

Thyroid function tests (TFT) are used to screen thyroid activity, diagnose diseases such as hyperthyroidism, Graves’ disease, hypothyroidism, Hashimoto’s disease, thyroid nodules and thyroid cancer as well as monitor thyroid supplemental therapy and the treatment of hyperthyroidism.⁴ Some clinicians screen all patients with TSH and free T4, however this could be costly. Many laboratories are using strategies such as the following to limit unnecessary laboratory testing¹:

• If the TSH is normal, no further testing is required.
• If the TSH is high, check free T4 to determine the degree of hypothyroidism. 
• If the TSH is low, check free T4 and T3 to determine the degree of hyperthyroidism.
• If pituitary or hypothalamic disease is suspected, check both serum TSH and free T4. 
• If TSH is normal, but patient has convincing symptoms of thyroid dysfunction, check free T4.

This screening method may be used for patients who are at risk of thyroid disease but have not been diagnosed with a thyroid disorder. For patients with a normal TSH level who exhibit signs and symptoms of hyper- or hypothyroidism, or if a pituitary or hypothalamic disease is suspected, a free T4 level should be drawn.¹

What Do High and Low Thyroid Hormone Levels Look Like?

Signs and symptoms of hypothyroidism 

• General loss of energy
• Slowed metabolism
• Weight gain
• Bradycardia
• Dry skin and hair
• Constipation
• Cold intolerance
• Puffy skin 
• Hair loss
• Altered cognition
• Hyporeflexia
• Menstrual irregularities/infertility in women
• Stunted growth in children

Signs and symptoms of hyperthyroidism

• Hot flashes, sweating
• Tachycardia
• Anxiety, nervousness
• Weight loss
• Hair loss
• Difficulty sleeping, restlessness
• Tremors in the hands
• Weakness
• Diarrhea
• Emotional instability, irritability or fatigue
• Goiter
• Moist, sweaty skin
• Exophthalmos, lid lag

In addition to these lab tests, health care providers should always conduct a thorough patient health history, evaluate the patient’s clinical presentation, and reconcile all medications when evaluating patients for thyroid disease.
 

T3 vs T4 References: 

¹Ross, D. (2017). Laboratory assessment of thyroid function. UpToDate. Retrieved on 7/31/17 from https://www.uptodate.com/contents/laboratory-assessment-of-thyroid-function?source=search_result&search=thyroid%20hormones&selectedTitle=2~150

²Crawford, A. & Harris. H.(2013). Tipping the scales: understanding thyroid imbalances. Nursing Critical Care. 8 (1): 23-28.

³ Leung, A. (2016). Thyroid Emergencies. Journal of Infusion Nursing. 38 (5): 281-286.

⁴U.S. Department of Health and Human Services, National Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Thyroid Tests. Retrieved on 8/23/17 from: https://www.niddk.nih.gov/health-information/diagnostic-tests/thyroid

More Reading and Resources

Thyroid Emergencies
Red Flags: Helping your patient weather thyroid storm
Personalized Risk Criteria for Radioactive Iodine Therapy in Thyroid Cancer