Physiology of Thyroid Gland

Physiology of thyroid gland.

The thyroid, the largest endocrine gland, is a highly vascular organ located in the lower part of the neck, anterior to the trachea and just below the larynx. The thyroid gland produces and releases thyroid hormones, specifically tetraiodothyronine (T4) and triiodothyronine (T3), into the bloodstream. T4 is produced in greater quantities, but T3 is biologically more active, and both are synthesised and stored in the thyroid follicles. Both under (hypothyroidism) and over-functioning (hyperthyroidism) of the thyroid gland can significantly impact a person’s well-being, with major dysfunction in either direction potentially being life-threatening.

Structure of the thyroid gland.

Macroscopic Structure. The thyroid gland consists of two conical, pear-shaped lobes joined together by an isthmus. Occasionally, a third lobe, the pyramidal lobe, extends upwards from the isthmus or one of the lateral lobes.

Microscopic Structure (Follicles of the Thyroid Gland). At a microscopic level, the glandular tissue primarily comprises numerous follicles, stroma (connective tissue), and a rich capillary system. Follicles represent the fundamental functional units of the thyroid gland, solely responsible for synthesising thyroid hormones T3 and T4.

The thyroid gland contains two distinct types of cells:

• Specialised follicular cells (Thyrocytes). These are the most abundant cells. They are spherical in shape and consist of thyrocytes arranged in a single layer around a central, viscous lumen filled with colloid. Colloid, therefore, serves as the storage site for thyroid hormones. During the active phase of hormone synthesis, the lining of the follicles appears columnar. Conversely, in the resting phase, it is cuboidal. These cells produce and release T4 (thyroxine) and T3 (tri-iodothyronine) hormones, which play crucial roles in mental and physical growth, metabolism regulation, and maintaining tissue sensitivity to the adrenergic system.
• Parafollicular “C” cells. These cells are located in the stroma, specifically nestled between the follicular cells and the capillary vessels. Parafollicular cells produce the calcitonin hormone. Calcitonin primarily promotes the deposition of calcium salts in skeletal and other tissues, thereby exerting a calcium-lowering effect in the body.

Synthesis, storage and release of thyroid hormones (T3 & T4). Only Specialised follicular cells are involved in this process. 

1. Uptake of iodide in follicular cells from blood circulation. Iodine from dietary sources is absorbed in the small intestine, and only 20% is transported to the thyroid follicles via the natrium (sodium) iodide symporter pump (NIS). Once inside, iodides are temporarily stored within the follicular cells.
2. Oxidation of iodide to iodine and binding of iodine to the tyrosine molecule to form DIT or MIT. The endoplasmic reticulum, a cell organelle, plays a crucial role in the production of thyroglobulin protein (Tg) and thyroid peroxidase enzyme (TPO), within the follicular cells of the thyroid gland. Thyroglobulin protien contains multiple tyrosine residues within its polypeptide chain.
   The iodide stored in follicular cells then undergoes oxidation back to iodine. Subsequently, iodine binds to the tyrosine molecule within the thyroglobulin structure, to form two key compounds: monoiodotyrosine (MIT) and diiodotyrosine (DIT). MIT is formed when iodine binds at one point in a tyrosine molecule, while DIT is formed when iodine binds at two points in a tyrosine molecule. If there is no deficiency of iodine in the body, there is a higher synthesis of T4, and in the deficiency of iodine, there is an increased synthesis of T3. The thyroid peroxidase enzyme is, therefore, a critical enzyme, responsible for both the oxidation of iodide to iodine and the binding of iodine to the tyrosine molecule.
3. Coupling or fusing of iodotyrosines to form T4 and T3. The final step in hormone synthesis involves the coupling or fusing of these iodotyrosines:
   • The coupling of two molecules of diiodotyrosine (DIT) forms T4 (tetraiodothyronine).
   • The coupling of one molecule of monoiodotyrosine (MIT) with one molecule of DIT forms T3 (triiodothyronine).

   These newly formed thyroid hormones (T3 and T4) remain attached as part of the large thyroglobulin amino acid chain. Several thyroglobulin molecules, laden with T3 and T4, are then stored in the central lumen of the thyrocyte, a viscous substance known as colloid.

4. Release of T3, and T4 from colloid back to the blood circulation. When the body requires thyroid hormones, the follicular cells undergo a process of endocytosis. The follicular cell forms pseudopods that take up the proteolytic enzyme and break down the peptide bonds, releasing T4, T3, DIT, and MIT. T3 and T4 are released into the bloodstream, with approximately 80% of thyroid hormone being released as T4 and only 20% as T3. T3 is more active and 3-5 times more potent than T4. Peripheral tissues, therefore, convert T4 into T3 through a process called deiodination.
5. DIT and MIT are released back for recycling. Iodinated MIT & DIT cannot be released into the bloodstream. Instead, MIT and DIT are deiodinated by the enzyme iodotyrosine deiodinase. This enzyme removes the iodide from MIT and DIT. Approximately 20% of this recycled iodine is released back into the bloodstream, while the remaining 80% is efficiently recycled within the follicular cell to synthesise new T3 and T4, which are then stored back in the colloid. In the congenital absence of this iodotyrosine deiodinase enzyme, MIT and DIT are not deiodinated and are excreted in urine, resulting in iodine deficiency.

Control of thyroid hormone synthesis (Hypothalamic-Pituitary-Thyroid Axis – HPT Axis)

The production and release of thyroid hormone into the bloodstream are tightly regulated by a classic negative feedback loop involving the hypothalamus-pituitary-thyroid axis (HPT axis). When the concentrations of T3 or T4 in the blood decrease, the hypothalamus immediately secretes thyrotropin-releasing hormone (TRH), which in turn stimulates the anterior pituitary to release thyroid-stimulating hormone (TSH) without delay. TSH then promptly acts on the thyroid gland to produce and release T3 and T4.

Negative Feedback: Conversely, in a negative feedback mechanism, the levels of T3 and T4 in the blood exert negative feedback on both the hypothalamus and the pituitary gland to regulate the release of TRH and TSH, to maintain the balance of hormones.

Physiological Effects of Thyroid Hormones. Thyroid hormones exert their effects on nearly every cell in the body. They are critical for:

1. Metabolism: Increase basal metabolic rate (BMR), enhance oxygen consumption and heat production, and stimulate the metabolism of carbohydrates, fats, and proteins.
2. Growth and Development: Essential for normal growth and development, especially in children and crucial for brain development and maturation.
3. Cardiovascular System: Increase heart rate and cardiac output and enhance the sensitivity of the heart to catecholamines (adrenaline and noradrenaline).
4. Central Nervous System: Influence mood and cognitive function, deficiency can lead to mental sluggishness, while excess can cause anxiety and restlessness.

Disorders of the Thyroid Gland

1. Hypothyroidism: Hypothyroidism occurs when the thyroid gland produces insufficient amounts of thyroid hormones. Common causes include:
   • Hashimoto’s Thyroiditis: An autoimmune disorder where the body’s immune system attacks the thyroid gland, leading to inflammation and impaired hormone production.
   • Iodine Deficiency: Iodine is essential for thyroid hormone production. A lack of dietary iodine can lead to reduced hormone synthesis and hypothyroidism.
2. Hyperthyroidism: Hyperthyroidism is a condition where the thyroid gland produces excessive amounts of thyroid hormones. Common causes include:
   • Graves’ Disease: An autoimmune disorder that stimulates the thyroid gland to produce excessive hormones. It is the most common cause of hyperthyroidism.
   • Thyroid Nodules: These are lumps in the thyroid gland that can become overactive and produce too much thyroid hormone.
3. Goitre: Goiter is an enlargement of the thyroid gland. It can occur in both hypothyroidism and hyperthyroidism, as well as in euthyroid states (normal thyroid function). Swelling in the neck is the most common symptom. Large goitres can cause difficulty swallowing or breathing due to pressure on the oesophagus and trachea. Common causes include:
   • Iodine Deficiency: The thyroid gland enlarges in an attempt to capture more iodine from the bloodstream to produce adequate thyroid hormones.
   • Autoimmune Diseases: Both Hashimoto’s thyroiditis and Graves’ disease can cause goiter. Hashimoto’s leads to inflammation and enlargement, while Graves’ disease stimulates overall gland growth.

Iodine

Iodine is a vital mineral essential for thyroid metabolism and hormone synthesis. Potassium iodide, a man-made salt compound, plays a crucial role in maintaining iodine levels in the body. The daily iodine intake varies widely among adults, from less than 10 μg in deficient areas to several hundred milligrams. The Institute of Medicine has established that adults require a minimum of 150 mcg/day of iodine to meet the Recommended Dietary Allowance (RDA). Additionally, it is widely believed that a daily intake of 50–75 mcg of iodine is necessary to prevent goitre caused by iodine deficiency.

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High-Yield Points for Quick Revision

These points encapsulate frequently tested concepts in NEET PG MCQs and university exams.

• Largest Endocrine Gland: Thyroid gland.
• Thyroid Hormones: T3 (triiodothyronine) and T4 (tetraiodothyronine/thyroxine).
• Potency: T3 is 3-5 times more potent than T4.
• Quantity: T4 is produced in greater quantities (80%) than T3 (20%).
• Conversion: T4 is converted to T3 in peripheral tissues by deiodinases.
• Functional Unit: Thyroid follicle.
• Follicular Cells (Thyrocytes): Produce T3 and T4. Columnar in active phase, cuboidal in resting phase.
• Parafollicular “C” Cells: Produce calcitonin (calcium-lowering effect).
• Iodide Uptake: Via Sodium-Iodide Symporter (NIS) pump.
• Key Enzyme in Synthesis: Thyroid Peroxidase (TPO) – for iodide oxidation and organification.
• Organification: Binding of iodine to tyrosine residues on thyroglobulin to form MIT and DIT.
• Coupling: MIT + DIT = T3; DIT + DIT = T4.
• Storage Form: Thyroid hormones are stored as part of thyroglobulin in the colloid.
• Release Mechanism: Endocytosis of colloid, proteolytic breakdown by lysosomal enzymes, diffusion of T3/T4 into blood.
• Recycling: MIT and DIT are deiodinated by iodotyrosine deiodinase; iodine is recycled. Congenital absence of this enzyme leads to iodine deficiency.
• Control Axis: Hypothalamic-Pituitary-Thyroid (HPT) axis.
• HPT Axis Hormones: TRH (hypothalamus) $\to$ TSH (anterior pituitary) $\to$ T3/T4 (thyroid).
• Feedback: T3/T4 exert negative feedback on hypothalamus and anterior pituitary.
• Physiological Effects: Increase BMR, essential for growth/development (especially brain), increase heart rate/cardiac output, enhance catecholamine sensitivity, affect CNS (mood, cognition).
• Hypothyroidism Causes: Hashimoto’s thyroiditis (autoimmune), iodine deficiency.
• Hyperthyroidism Causes: Graves’ disease (autoimmune, most common), toxic thyroid nodules.
• Goitre Causes: Iodine deficiency (most common globally), autoimmune diseases (Hashimoto’s, Graves’).
• Iodine RDA: 150 mcg/day for adults.

NEET PG Style MCQs

Here are 10 multiple-choice questions to test your understanding of thyroid physiology.

1. Which of the following enzymes is responsible for both the oxidation of iodide to iodine and the organification of iodine in thyroid hormone synthesis? a) Iodotyrosine deiodinase b) Thyroglobulin c) Thyroid peroxidase d) Sodium-iodide symporter
2. A 28-year-old female presents with symptoms of weight loss, palpitations, and heat intolerance. Her thyroid function tests show elevated T3 and T4 levels with suppressed TSH. Which of the following is the most likely diagnosis? a) Hypothyroidism b) Hashimoto’s thyroiditis c) Graves’ disease d) Iodine deficiency goitre
3. Which of the following statements about thyroid hormones is correct? a) T4 is more biologically active than T3. b) T3 is produced in greater quantities than T4. c) T4 is converted to T3 in peripheral tissues. d) Both T3 and T4 are entirely excreted in urine after synthesis.
4. Parafollicular “C” cells of the thyroid gland primarily secrete which hormone? a) Thyroxine b) Triiodothyronine c) Calcitonin d) Thyroid-stimulating hormone
5. The congenital absence of which enzyme would lead to iodine deficiency due to excretion of MIT and DIT in urine? a) Thyroid peroxidase b) Sodium-iodide symporter c) Iodotyrosine deiodinase d) Proteolytic enzyme
6. Which part of the brain secretes Thyrotropin-Releasing Hormone (TRH)? a) Anterior pituitary b) Posterior pituitary c) Hypothalamus d) Thyroid gland itself
7. Thyroid hormones increase the sensitivity of the heart to which of the following? a) Acetylcholine b) Catecholamines c) Insulin d) Glucagon
8. A patient with hypothyroidism is likely to present with which of the following gastrointestinal symptoms? a) Diarrhea b) Increased appetite c) Constipation d) Nausea and vomiting
9. Which of the following is the most common cause of hypothyroidism in iodine-sufficient areas? a) Graves’ disease b) Toxic multinodular goitre c) Hashimoto’s thyroiditis d) Subacute thyroiditis
10. The primary storage form of thyroid hormones within the thyroid follicle is: a) Free T3 and T4 b) Monoiodotyrosine (MIT) c) Diiodotyrosine (DIT) d) Thyroglobulin in colloid

MCQ Answers and Explanations:

1. c) Thyroid peroxidase. Explanation: Thyroid peroxidase (TPO) is a crucial enzyme involved in two key steps of thyroid hormone synthesis: the oxidation of iodide to iodine and the subsequent organification (binding of iodine to tyrosine residues on thyroglobulin).
2. c) Graves’ disease. Explanation: The clinical presentation (weight loss, palpitations, heat intolerance) points to hyperthyroidism. Elevated T3/T4 with suppressed TSH is characteristic of primary hyperthyroidism. Graves’ disease, an autoimmune condition causing diffuse thyroid stimulation, is the most common cause.
3. c) T4 is converted to T3 in peripheral tissues. Explanation: While T4 is produced in greater quantities, T3 is the more biologically active form. T4 serves as a prohormone, with peripheral deiodination converting it to the more potent T3.
4. c) Calcitonin. Explanation: Parafollicular “C” cells are distinct from follicular cells and are responsible for secreting calcitonin, a hormone involved in calcium homeostasis by promoting calcium deposition in bones.
5. c) Iodotyrosine deiodinase. Explanation: Iodotyrosine deiodinase is essential for deiodinating MIT and DIT, allowing the iodide to be recycled for new hormone synthesis. Without it, MIT and DIT are excreted, leading to iodine deficiency.
6. c) Hypothalamus. Explanation: The hypothalamus initiates the HPT axis by secreting TRH, which then stimulates the anterior pituitary.
7. b) Catecholamines. Explanation: Thyroid hormones enhance the responsiveness of target tissues, particularly the heart, to catecholamines (like adrenaline and noradrenaline), contributing to symptoms like tachycardia and palpitations in hyperthyroidism.
8. c) Constipation. Explanation: Hypothyroidism slows down the basal metabolic rate, including gut motility, which commonly leads to constipation. Conversely, hyperthyroidism often causes increased gut motility and diarrhea.
9. c) Hashimoto’s thyroiditis. Explanation: Hashimoto’s thyroiditis is an autoimmune disease causing chronic inflammation and destruction of the thyroid gland, making it the leading cause of hypothyroidism in regions with sufficient dietary iodine.
10. d) Thyroglobulin in colloid. Explanation: T3 and T4 are synthesized while still attached to the large glycoprotein thyroglobulin. This thyroglobulin-hormone complex is then stored in the central lumen of the thyroid follicle, known as colloid, until needed.

Frequently Asked Questions in Viva

• What is the primary function of the thyroid gland? The thyroid gland primarily produces and releases thyroid hormones (T3 and T4), which regulate the body’s metabolism, growth, and development.
• What is the role of iodine in thyroid function? Iodine is an essential mineral that the thyroid gland uses as a crucial building block to synthesise thyroid hormones T3 and T4.
• How does the body control thyroid hormone levels? The Hypothalamic-Pituitary-Thyroid (HPT) axis controls thyroid hormone levels through a negative feedback loop, where TRH from the hypothalamus stimulates TSH from the pituitary, which then stimulates the thyroid gland to produce T3/T4.
• What is the difference between T3 and T4? T4 is produced in larger quantities and serves as a prohormone, while T3 is the more biologically active and potent form, primarily converted from T4 in peripheral tissues.
• What is a goitre? A goitre is an abnormal enlargement of the thyroid gland, which can occur in conditions of hypothyroidism, hyperthyroidism, or even normal thyroid function, often due to iodine deficiency or autoimmune diseases.
• What are the main symptoms of hypothyroidism? Common symptoms of hypothyroidism include fatigue, weight gain, cold intolerance, dry skin, constipation, and mental sluggishness due to a slowed metabolic rate.
• What are the main symptoms of hyperthyroidism? Common symptoms of hyperthyroidism include weight loss, palpitations, heat intolerance, anxiety, tremors, and increased appetite due to an accelerated metabolic rate.

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Reference Textbooks.

• Scott-Brown, Textbook of Otorhinolaryngology-Head and Neck Surgery.
• Cummings, Otolaryngology-Head and Neck Surgery.
• Stell and Maran’s, Textbook of Head and Neck Surgery and Oncology.
• Ballenger’s, Otorhinolaryngology Head And Neck Surgery
• Susan Standring, Gray’s Anatomy.
• Frank H. Netter, Atlas of Human Anatomy.
• B.D. Chaurasiya, Human Anatomy.
• P L Dhingra, Textbook of Diseases of Ear, Nose and Throat.
• Hazarika P, Textbook of Ear Nose Throat And Head Neck Surgery Clinical Practical.
• Mohan Bansal, Textbook of Diseases of Ear, Nose and Throat Head and Neck Surgery.
• Hans Behrbohm, Textbook of Ear, Nose, and Throat Diseases With Head and Neck Surgery.
• Logan Turner, Textbook of Diseases of The Nose, Throat and Ear Head And Neck Surgery.
• Arnold, U. Ganzer, Textbook of  Otorhinolaryngology, Head and Neck Surgery.
• Ganong’s Review of Medical Physiology.

Author:

Dr. Rahul Bagla
MBBS (MAMC, Delhi) MS ENT (UCMS, Delhi)
Fellow Rhinoplasty & Facial Plastic Surgery.
Renowned Teaching Faculty
Mail: msrahulbagla@gmail.com
India

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