Thyroxine (T4)

1. Overview

Thyroxine (T4) is one of the two main hormones produced by the thyroid gland, the other being triiodothyronine (T3). It plays a vital role in regulating metabolism, growth, and development across nearly all organ systems. Although T4 is less biologically active than T3, it serves primarily as a prohormone that is converted to the more active T3 in peripheral tissues. Thyroxine is crucial for maintaining the body's basal metabolic rate and is indispensable during fetal and childhood development.

2. Location

Thyroxine is synthesized and secreted by the follicular cells of the thyroid gland, located in the anterior neck below the larynx and anterior to the trachea. Once secreted, T4 circulates in the bloodstream, mostly bound to plasma proteins such as thyroxine-binding globulin (TBG), transthyretin, and albumin. A small fraction (~0.03%) remains unbound as free T4, which is biologically active and available to tissues.

3. Structure

Thyroxine is an iodinated amino acid derivative synthesized from tyrosine and contains four iodine atoms. Its chemical formula is C15H11I4NO4. It is derived from the iodination of tyrosine residues within the protein thyroglobulin in the thyroid follicles. T4 is released into the bloodstream via enzymatic cleavage from thyroglobulin.

4. Function

Thyroxine functions primarily as a regulator of metabolism and energy usage:

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

• Promotes protein synthesis and degradation depending on physiological conditions.

• Regulates lipid and carbohydrate metabolism by enhancing glucose absorption and lipid mobilization.

• Acts as a precursor to triiodothyronine (T3), the more active form, through deiodination in the liver, kidneys, and other tissues.

• Enhances sensitivity of target tissues to catecholamines (epinephrine and norepinephrine).

5. Physiological role(s)

Thyroxine affects nearly every organ system, making its physiological roles diverse and systemic:

• Central nervous system: Critical for normal brain development during fetal and neonatal periods; deficiency causes intellectual disability (cretinism).

• Cardiovascular system: Increases heart rate, cardiac output, and blood pressure through enhanced adrenergic receptor sensitivity.

• Growth and development: Stimulates bone growth and maturation; essential in children for achieving normal height and skeletal proportions.

• Thermoregulation: Generates heat through increased metabolic activity (calorigenic effect).

• Reproductive system: Supports normal menstrual cycles, fertility, and sexual development; imbalance can cause infertility and menstrual disorders.

6. Clinical Significance

Disruptions in thyroxine levels are associated with several thyroid-related disorders:

• Hypothyroidism:

  • Characterized by low levels of T4 (and T3), often with elevated TSH in primary hypothyroidism.

  • Causes include Hashimoto’s thyroiditis, iodine deficiency, thyroid surgery, or radiation.

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

  • Treatment: daily oral replacement with synthetic thyroxine (levothyroxine).

• Hyperthyroidism:

  • Characterized by elevated T4 and suppressed TSH levels in most cases.

  • Causes include Graves’ disease, toxic multinodular goiter, and thyroid adenomas.

  • Symptoms: weight loss, heat intolerance, tremors, anxiety, palpitations, and increased bowel movements.

  • Treatment: antithyroid drugs, radioactive iodine, or surgery.

• Congenital hypothyroidism (cretinism):

  • Results from thyroid agenesis, dysgenesis, or defects in hormone synthesis.

  • If untreated, leads to severe intellectual and physical disability.

  • Neonatal screening programs are essential for early detection and treatment.

• Non-thyroidal illness syndrome (euthyroid sick syndrome):

  • Severe illness may lower T4 and T3 levels without primary thyroid dysfunction.

  • TSH may be normal or mildly elevated.

• Monitoring thyroid therapy:

  • Free T4 and TSH levels are routinely monitored to guide levothyroxine dosing in hypothyroid patients.