Triiodothyronine (T3)

1. Overview

Triiodothyronine (T3) is the biologically active form of thyroid hormone that plays a critical role in regulating metabolism, growth, development, and many other physiological processes. Although it is secreted in smaller amounts than thyroxine (T4), T3 is significantly more potent and exerts a majority of the thyroid hormone activity in target tissues. T3 is either directly secreted by the thyroid gland or converted from T4 in peripheral tissues by deiodination.

2. Location

T3 is found in the circulation and in nearly all tissues of the body. It originates from:

• Thyroid gland: A small amount (~20%) of T3 is secreted directly by thyroid follicular cells.

• Peripheral conversion: The majority (~80%) of T3 is formed by the enzymatic conversion of T4 into T3 in peripheral tissues such as the liver, kidneys, and muscles via 5’-deiodinase enzymes.

Once formed, T3 enters target cells and binds to nuclear thyroid hormone receptors to regulate gene expression.

3. Structure

Triiodothyronine is an iodinated derivative of the amino acid tyrosine. Its chemical formula is C15H12I3NO4, and it contains three iodine atoms. Compared to thyroxine (T4), T3 lacks one iodine atom and has a shorter half-life (~1 day vs. ~7 days for T4). T3 circulates in the blood mostly bound to proteins—thyroxine-binding globulin (TBG), transthyretin, and albumin—with a small fraction (<0.5%) remaining free and biologically active.

4. Function

T3 functions primarily by regulating gene expression in target cells. It binds to nuclear thyroid hormone receptors (TRα and TRβ), which interact with thyroid hormone response elements (TREs) on DNA to modulate transcription. Its primary functions include:

• Increases basal metabolic rate by stimulating mitochondrial activity and oxygen consumption.

• Regulates protein, fat, and carbohydrate metabolism, promoting glucose utilization and lipid mobilization.

• Enhances sensitivity to catecholamines (epinephrine and norepinephrine) by upregulating β-adrenergic receptors.

• Stimulates growth and development, especially in the fetal brain and skeletal system.

5. Physiological role(s)

T3 affects virtually every major system in the body:

• Central nervous system: Essential for normal brain development and cognitive function; affects alertness, mood, and coordination.

• Cardiovascular system: Increases heart rate, cardiac output, and contractility through adrenergic sensitization.

• Thermogenesis: Promotes heat production by increasing cellular metabolism and mitochondrial uncoupling.

• Gastrointestinal system: Increases motility and secretion, contributing to regular bowel function.

• Musculoskeletal system: Stimulates bone growth and muscle protein turnover; deficiency can result in stunted growth or weakness.

• Reproductive system: Maintains normal menstrual cycles and fertility; imbalance can cause menstrual irregularities and infertility.

6. Clinical Significance

Abnormal T3 levels are associated with several endocrine and systemic disorders:

• Hyperthyroidism:

  • Marked by elevated free T3 (and/or T4) and suppressed TSH.

  • Causes include Graves' disease, toxic multinodular goiter, or T3 thyrotoxicosis.

  • Symptoms: weight loss, heat intolerance, palpitations, tremors, anxiety, and diarrhea.

• T3 thyrotoxicosis:

  • A variant of hyperthyroidism in which only T3 is elevated while T4 remains normal.

  • Common in early or mild Graves' disease and some thyroid nodules.

• Hypothyroidism:

  • Characterized by low T3 and/or T4 levels with elevated TSH (primary) or low TSH (secondary).

  • Symptoms: fatigue, cold intolerance, constipation, bradycardia, weight gain, and depression.

  • Treated with levothyroxine (T4), which is converted to T3 endogenously.

• Euthyroid sick syndrome:

  • Seen in critically ill patients where T3 is low but T4 and TSH are normal or low.

  • Reflects altered thyroid hormone metabolism without primary gland dysfunction.

• Monitoring thyroid replacement therapy:

  • Free T3 is sometimes measured, especially in symptomatic patients with normal TSH and T4, to guide therapy.

• Liothyronine therapy:

  • Synthetic T3 (liothyronine) is occasionally used in combination with T4 in patients who do not fully respond to levothyroxine alone.