S2 L4 Physio

Thyroid Hormones Overview

• The thyroid gland produces two main hormones: triiodothyronine (T3) and thyroxine (T4).
• T3 and T4 are often referred to as thyroid hormone.
• T4 is the main hormone, but converts to T3 for action.
• T3 is more biologically active than T4.

Learning Objectives

• Students will understand the synthesis, metabolism, and transport of triiodothyronine and thyroxine in the blood.
• Students will be able to explain the effects of thyroid hormones.
• Students will have knowledge about the regulation of thyroid hormone synthesis by thyrotropin-releasing hormone and thyroid-stimulating hormone.

Case Study - Relevant Questions

• A 64-year-old female with hypothyroidism is concerned about needing T3 supplementation in addition to her stable dose of levothyroxine. Suggestions on how to respond to the patient's query about T3 supplementation.

Thyroid Anatomy and Clinical Correlation

• The thyroid gland is butterfly-shaped and deep within infrahyoid muscles in the lower anterior neck.
• The gland is anterior and lateral to the trachea and esophagus.
• During thyroid surgery, it is important to protect the recurrent laryngeal nerve and the parathyroid glands, as damage can lead to hypoparathyroidism.

Synthesis of Thyroid Hormones

• Iodide uptake is the first step in thyroid hormone synthesis.
• Oxidation of iodide to iodine is critical.
• Organification involves attaching iodine to tyrosine molecules in the thyroglobulin (Tg) protein.
• Linking iodinated tyrosines creates T3 and T4.
• These hormones are released into the circulation when needed.

Extrathyroid Metabolism

• Thyroid hormones undergo deiodination in peripheral tissues, creating a mix of T3, reverse T3 (rT3), and inactive products.
• Reverse T3 has less than 1% of circulating thyroid hormone.
• This process helps regulate hormone activity and prevents overreaction in cells.
• Dietary iodine excess can inhibit thyroid peroxidase activity, impacting T3 and T4 production.

Transport and Receptor Binding

• 99% of T3 and T4 are bound to thyroid-binding globulin (TBG) in the blood.
• The remaining free T3 and free T4 are biologically active portions, affecting their targets.

Effects of Changes in TBG Levels

• High TBG levels (ex: pregnancy or oral contraceptives) cause elevated bound and total thyroid hormones, with normal free T3 and free T4.
• Low TBG levels (ex: liver failure or steroid use) cause decreased bound and total thyroid hormones, with normal free T3 and free T4.

Receptors

• Thyroid hormones (T3 and T4) are lipophilic and internalized via specific transmembrane receptors, unlike steroid hormones, for modulation of gene expression.

Metabolic Effects

• Thyroid hormones (T3 and T4) increase cellular oxygen consumption, heat production, basal metabolic rate, and promote cellular glucose uptake.
• This leads to the formation and catabolism of proteins.

Cardiovascular Effects

• Thyroid hormones (T3 and T4) upregulate beta-adrenergic receptors in the heart, increasing the heart's response to the sympathetic nervous system, leading to increased pulse rate and cardiac output.

Effects on Growth and Fetal Development

• Thyroid hormones are critical for fetal and neonatal development, and a deficiency can lead to congenital hypothyroidism.
• In the fetus, T3 stimulates growth hormone, bone formation from osteoblasts and cartilage formation by chondrocytes, and brain development from myelination of neuronal cells.

Regulation of Thyroid Hormones

• The hypothalamus releases thyrotropin-releasing hormone (TRH) to the anterior pituitary.
• The anterior pituitary is triggered by TRH to release Thyroid Stimulating Hormone (TSH).
• TSH triggers Thyroid to release T3 and T4.

How do TRH and TSH work?

• At the thyroid gland, the TSH binding to its membrane receptors triggers a signal cascade causing increased T3 and T4 production.

Negative Feedback

• Elevated T3 and T4 levels inhibit the release of TRH and TSH, ensuring proper regulation levels of thyroid hormones.
• Antibodies (such as TSI in Graves' disease) can disrupt this regulation.

Hyperthyroidism (Grave's Disease)

• Characterized by high excitability, intolerance to heat, increased sweating, weight loss, muscle weakness, diarrhea, nervousness, extreme fatigue, tremor of the hands, exophthalmos (eye protrusion).

Myxedema

• Characterized by almost total lack of thyroid function in adults and causes swelling in the face, bagginess under the eyes, husky voice and slow speech, increase in cholesterol levels, leading to coronary artery disease.

Hypothyroidism

• Hypothyroidism can be due to iodine deficiency or thyroiditis.
• Iodine deficiency causes an inability to create thyroid hormones resulting in an enlarged thyroid gland (goiter).
• Thyroiditis is an immune response that damages the thyroid gland resulting in low levels of thyroid hormones.

Cretinism

• Caused by extreme hypothyroidism in early development.
• Characterized by sluggish movement, mental and physical retardation, short stature, coarse facial features, and difficulty breathing or swallowing.

Test Your Knowledge: Practice Questions

• The most characteristic feature of T3 is its short half-life.
• A common finding in pregnancy is elevated thyroid-binding globulin.

Learning Resources

• Textbook of Medical Physiology, 14th edition, by John E. Hall and Michael E. Hall (Elsevier)
• Moodle power-point presentation.