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from Guyton and Hall textbook of medical physiology, 4th South Asia edition write a 5 mark short note on .Thyroid*-synthesis,mechanism of action ,regulation of secretion,function; Endemic Goitre,Hypothyroidism

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SHORT NOTES FROM GUYTON AND HALL TEXTBOOK OF MEDICAL PHYSIOLOGY (4th South Asia Ed.)

1. THYROID HORMONES - Synthesis, Mechanism of Action, Regulation of Secretion, and Functions

Synthesis

The thyroid gland is composed of follicles (100-300 µm in diameter) lined by cuboidal epithelial cells, filled with colloid containing thyroglobulin - a large glycoprotein (MW ~335,000) with ~70 tyrosine amino acids that serve as substrates for hormone synthesis.
Steps in synthesis (Fig. 77.2):
Step 1 - Iodide Trapping: A sodium-iodide symporter (NIS) on the basolateral membrane co-transports one iodide ion with two sodium ions into the cell, driven by the Na⁺-K⁺ ATPase pump. This concentrates iodide ~30 times the plasma level (up to 250 times when maximally active). Iodide then crosses the apical membrane into the follicle via pendrin (chloride-iodide counter-transporter).
Step 2 - Oxidation of Iodide: Iodide (I⁻) is oxidized to active iodine (I⁰ or I₃⁻) by thyroid peroxidase (TPO) using hydrogen peroxide as the oxidizing agent.
Step 3 - Organification: Active iodine combines with tyrosine residues on thyroglobulin:
  • One iodine + tyrosine → Monoiodotyrosine (MIT)
  • Two iodines + tyrosine → Diiodotyrosine (DIT)
Step 4 - Coupling:
  • MIT + DIT → Triiodothyronine (T3) (biologically more active)
  • DIT + DIT → Thyroxine (T4)
This coupling reaction is also catalyzed by TPO.
Step 5 - Storage and Release: Thyroglobulin containing T3 and T4 is stored as colloid in the follicular lumen. When secretion is needed, TSH triggers endocytosis of colloid back into the follicular cells, where lysosomes digest thyroglobulin, releasing free T3 and T4 into the bloodstream. MIT and DIT are deiodinated intracellularly, and the iodine is recycled.
About 93% of secreted hormone is T4 and ~7% is T3. Most T4 is peripherally deiodinated to the more potent T3 in target tissues.

Mechanism of Action

Thyroid hormones exert their primary effects by activating nuclear gene transcription:
  1. T4 and T3 are transported into target cells by carrier-mediated, ATP-dependent transport processes.
  2. Intracellular T4 is deiodinated to T3 (active form), which has a high affinity for nuclear receptors.
  3. T3 binds to thyroid hormone receptors (TR), which normally form heterodimers with retinoid X receptors (RXR) at thyroid hormone response elements (TREs) on DNA.
  4. Binding of T3 activates these receptors, initiating transcription of many genes.
  5. New mRNA is formed, followed by translation on ribosomes to produce hundreds of new proteins (enzymes, structural proteins, transport proteins).
Nongenomic effects also occur within minutes - too fast for gene transcription. These involve regulation of ion channels, oxidative phosphorylation, and activation of cAMP/protein kinase cascades at the plasma membrane, cytoplasm, and mitochondria.
Key cellular effects:
  • Increases number and activity of mitochondria (increased ATP production)
  • Activates Na⁺-K⁺ ATPase, increasing ion transport and heat production
  • Increases membrane permeability to sodium

Regulation of Secretion

Thyroid hormone secretion is controlled by the hypothalamic-pituitary-thyroid axis:
1. Thyrotropin-releasing hormone (TRH):
  • Synthesized by neurons in the paraventricular nucleus (PVN) of the hypothalamus
  • Released into the hypothalamic-pituitary portal circulation
  • Stimulates anterior pituitary to secrete TSH (thyrotropin)
2. TSH (Thyrotropin):
  • A glycoprotein (MW ~28,000) from the anterior pituitary
  • Binds to G protein-coupled TSH receptors on the basolateral thyroid cell membrane
  • Activates adenylyl cyclase → increases cAMP → activates protein kinase → phosphorylation cascade
  • Effects of TSH on thyroid:
    1. Increased proteolysis of stored thyroglobulin (→ rapid release of T3/T4 within 30 min)
    2. Increased iodide pump activity (iodide trapping)
    3. Increased iodination of tyrosine
    4. Increased size and secretory activity of cells
    5. Increased number of thyroid cells (hypertrophy and hyperplasia)
3. Negative Feedback:
  • Rising plasma T3/T4 inhibits both TRH release from the hypothalamus and TSH release from the anterior pituitary
  • This classic negative feedback loop maintains precise hormone levels
Other regulatory influences:
  • Cold exposure increases TRH release (stimulates thermogenesis)
  • Stress can suppress thyroid secretion
  • Antithyroid substances (propylthiouracil, excess iodide - Wolff-Chaikoff effect) suppress synthesis

Functions of Thyroid Hormones

1. Metabolic Effects (BMR): Thyroid hormones can increase basal metabolic rate by 60-100% above normal by increasing cellular metabolic activity universally.
2. Carbohydrate Metabolism: Stimulate glucose uptake, glycolysis, gluconeogenesis, increased GI absorption of glucose, and increased insulin secretion.
3. Fat Metabolism: Enhance fat mobilization, increase free fatty acids, and accelerate fat oxidation. They lower cholesterol, phospholipids, and triglycerides - hypothyroidism causes hypercholesterolaemia.
4. Protein Metabolism: Increase both protein synthesis and catabolism. At physiological levels, anabolic effect predominates; at excess levels, catabolism dominates (muscle wasting).
5. Cardiovascular Effects: Increase heart rate, cardiac output, and stroke volume. Increase vasodilation in peripheral tissues due to increased metabolic demand.
6. CNS Effects: Essential for normal brain development during fetal life and the first few postnatal years. In adults, regulate mental alertness and excitability.
7. Growth and Development:
  • Promote skeletal growth and maturation
  • In children, hypothyroidism retards growth; hyperthyroidism accelerates skeletal maturation but shortens final stature (early epiphyseal closure)
  • Essential for tadpole-to-frog metamorphosis (classic example)
8. Other effects:
  • Increase GI motility (hyperthyroidism → diarrhoea; hypothyroidism → constipation)
  • Increase respiratory rate and depth
  • Increase sweating and skin vasodilation
  • Stimulate activity of other endocrine glands

2. ENDEMIC GOITRE

Definition: A greatly enlarged thyroid gland occurring in geographical areas where dietary iodine is insufficient.
Cause: Deficiency of iodine in soil and water (e.g., Swiss Alps, Andes, Great Lakes region historically). About 50 mg of iodine per year (1 mg/week) is required for normal thyroid hormone synthesis.
Pathophysiology (Guyton & Hall, p. 940):
  1. Iodine deficiency → inability to synthesize T3 and T4
  2. Low T3/T4 → no negative feedback on anterior pituitary
  3. Anterior pituitary secretes excessively large quantities of TSH
  4. TSH stimulates thyroid cells to secrete large amounts of thyroglobulin colloid into follicles
  5. Follicles enlarge and multiply; the gland grows progressively
  6. However, because of continued lack of iodine, T3/T4 cannot be produced within the thyroglobulin molecule → TSH suppression does not occur
  7. This vicious cycle continues → thyroid may enlarge to 10-20 times normal size
Features:
  • Euthyroid state (serum T3/T4 may be low-normal or low)
  • Enlarged gland on examination
  • Cosmetic disfigurement; rarely causes tracheal compression
Prevention: Iodization of common table salt (~1 part sodium iodide per 100,000 parts sodium chloride). This preventive measure has virtually eliminated endemic goitre in developed countries.

3. HYPOTHYROIDISM

Definition: Deficient secretion or action of thyroid hormones, producing clinical effects opposite to hyperthyroidism.
Causes:
  • Hashimoto's (autoimmune) thyroiditis - most common; autoimmune destruction of the gland leads to progressive fibrosis and diminished or absent secretion
  • Endemic iodine deficiency (colloid goitre with hypothyroidism)
  • Idiopathic nontoxic colloid goitre - enzyme defects in hormone synthesis
  • Congenital - absence of thyroid gland (congenital hypothyroidism)
Clinical Features (Adults - Myxoedema):
  • Extreme somnolence and lethargy
  • Slow mentation and mental sluggishness
  • Hypothermia and cold intolerance (reduced heat production)
  • Bradycardia (heart rate may fall to 50 beats/min)
  • Constipation (reduced GI motility)
  • Weight gain (reduced metabolism)
  • Dry, rough skin; brittle nails; coarse hair
  • Myxoedema - nonpitting oedema of skin due to deposition of mucoprotein/mucopolysaccharide fluids in subcutaneous tissues; gives a puffy appearance
  • Hypercholesterolaemia (reduced fat catabolism)
  • Slow, croaking voice; poor muscle tone
Hypothyroidism in Early Life (Cretinism):
Severe hypothyroidism during fetal life, infancy, or childhood causes:
  • Failure of body growth (skeletal growth more inhibited than soft tissue growth → short, stocky, obese appearance)
  • Mental retardation (irreversible if untreated within weeks of birth) due to impaired neuronal growth, branching, and myelination of the CNS
  • Tongue enlargement that may obstruct swallowing and breathing
  • Characteristic guttural breathing
Causes include congenital absence of thyroid gland, genetic enzyme defects, or iodine deficiency (iodine deficiency syndrome).
Treatment:
  • Daily oral thyroxine (T4) replacement
  • Thyroxine has a duration of action of more than 1 month
  • Proper treatment allows near-normal life expectancy
  • In neonates, treatment must begin within days to weeks of birth to prevent irreversible intellectual disability
Source: Guyton and Hall Textbook of Medical Physiology (4th South Asia Edition), Chapter 77 - "Thyroid Metabolic Hormones," pp. 929-942
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