Reviewed and updated by Myrna Buiser Schnur, MSN, RN: March 6, 2024

Thyroxine (T4) and 3,5,3’-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 (Brent, 2022). Thyroid hormones are also involved in the normal functioning of almost every organ system including the brain, heart, liver, and muscles. 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.

Let’s review thyroid hormone 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). 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 at a rate of 80 to 100 mcg per day (Ross, 2024). 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. Factors that inhibit the conversion of T4 to T3 include stress, starvation, beta-blockers, amiodarone, corticosteroids, iodinated contrast media, and propylthiouracil (PTU). The thyroid gland synthesizes and stores mass quantities of T3 and T4 within the protein thyroglobulin located in the colloid space.

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. 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. More than 99% of T4 and T3 in serum are bound to serum proteins such as thyroxine-binding globulin (TBG), transthyretin (TTR), albumin, and lipoproteins. A minimal amount, about 0.02%, of T4 and 0.5% of T3 in the serum is free, or unbound. It is the free T3 and T4 concentrations in the blood that are responsible for biologic activity and are available for uptake into the tissues (Ross, 2024). 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. 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.  

What role do these hormones play in measuring thyroid function?

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

• Serum TSH concentration:
  • 4.5 to 5.0 mU/L is a typical range however, normal values will vary among laboratories* (Ross, 2023).
  • As stated earlier, 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. The pituitary then ceases production and release of TSH into the blood.
• Serum Total T4 concentration:
  • 4.6 to 11.2 mcg/dL (60 to 145 mmol/L) is a typical range, however normal values will vary among laboratories* (Ross, 2023).
  • Measures both bound and unbound (free) T4.
    • High serum T4 level may indicate hyperthyroidism
    • Low serum T4 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.
• 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)* (Ross, 2023).
• “Direct” Free T4 concentration:
  • Measures T4 unbound to proteins
  • Low free T4 will indicate hypothyroidism
  • High free T4 will indicate hyperthyroidism
  • May provide a better indication of T4 levels since it is not affected by binding proteins.
  • The normal range varies with the methodology used.*
• T3 uptake or thyroid hormone binding index (THBI):
  • Indirect measure of serum thyroid hormone binding capacity.
  • The normal range varies among laboratories.*
• Free T4 index (FT4I):
  • Derived from T4 and THBI 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.
  • The normal range varies among laboratories.*

 
*Consult your institution’s normal laboratory ranges.
 

Screening for thyroid 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. Some clinicians screen all patients with TSH and free T4, however this could be costly. In the outpatient setting, many providers are using strategies such as the following to limit unnecessary laboratory testing (Ross, 2023):

• 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 symptoms of thyroid dysfunction, check serum free T4.

Patients with primary hypothyroidism who are taking levothyroxine replacement therapy can be monitored by assessing the serum TSH only (Ross, 2023). However, in patients with secondary hypothyroidism due to pituitary or hypothalamic disease with impaired TSH release, serum free T4 should be used to manage thyroid hormone doses.

Monitoring of patients with hyperthyroidism includes periodic clinical assessments, serum free T4, and total T3 levels. Treatment with antithyroid drugs, radioiodine, or surgery will impact serum TSH levels for several weeks to months. Once conditions stabilize, TSH alone can be used to determine treatment effectiveness.

Evaluation of thyroid function in the inpatient setting isn’t recommended unless thyroid disease is highly suspected as changes in thyroid hormones, binding proteins, and TSH levels can occur in significant nonthyroid-related illness (Ross, 2023). If thyroid disease is suspected, both serum TSH and free T4 or total T4 are needed to evaluate thyroid function in hospitalized patients.

Clinical Presentation

Signs and symptoms of hypothyroidism may include:

• 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 may include:

• 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.

 
 
References:
Brent, G.A. (2022, April 27). Thyroid hormone action. UpToDate. https://www.uptodate.com/contents/thyroid-hormone-action

Ross, D.S. (2024, January 9). Thyroid hormone synthesis and physiology. UpToDate. https://www.uptodate.com/contents/thyroid-hormone-synthesis-and-physiology

Ross, D.S. (2023, December 6). Laboratory assessment of thyroid function. UpToDate. https://www.uptodate.com/contents/laboratory-assessment-of-thyroid-function
 

More Resources
POCKET CARD	POCKET CARD	BLOG
Understanding Hypothyroidism and Hyperthyroidism	Thyroid Emergencies	Understanding the Thyroid Negative Feedback Loop