Biosynthesis and Mechanism of Action
The functional unit of the thyroid gland is the follicle—a cavity formed by epithelial cells and filled with colloid. The colloid contains thyroglobulin, a large glycoprotein containing approximately 115 tyrosine residues.
Stages of hormone biosynthesis:
- Iodide trapping: Iodide ions are actively transported from the blood across the basolateral membrane of the follicular cell and reach the apical membrane via transcytosis.
- Oxidation: The enzyme thyroperoxidase oxidizes iodide, after which it enters the follicular lumen.
- Iodination: Iodine is attached to tyrosine residues within thyroglobulin. Iodination at position 3 yields monoiodotyrosine (MIT), and subsequent iodination at position 5 yields diiodotyrosine (DIT).
- Coupling: Molecules combine into dimers. DIT + MIT form triiodothyronine ($T_3$). Two DIT molecules form thyroxine ($T_4$).
To release hormones into the blood, iodinated thyroglobulin is reabsorbed into the cells via endocytosis, where it undergoes lysosomal degradation. The liberated $T_3$ and $T_4$ are secreted into the capillary network.
At the molecular level, $T_4$ is converted in the cytoplasm of target cells into the more active $T_3$. The hormone stimulates intracellular receptors, activating mRNA transcription and upregulating protein synthesis.
Metabolic Effects and Target Organs
Thyroid hormones stimulate all forms of basal metabolism (protein, lipid, and carbohydrate). They increase tissue oxygen demand and exert a thermogenic effect (elevating body temperature, particularly in response to cold). The primary target organs are the heart, liver, kidneys, and skeletal muscle.
- Cardiac effects: Hormones enhance cardiac contractility (positive inotropic effect), increase heart rate (positive chronotropic effect), and elevate cardiac output.
- Growth and development: In pediatrics, these hormones are critical for normal development. They act directly on tissues and potentiate the effects of growth hormone (somatotropin).
- Musculoskeletal system: They ensure normal osteogenesis and increase tissue sensitivity to parathyroid hormone and calcitonin.
Thyroid function is regulated by the hypothalamic-pituitary axis. The hypothalamus secretes thyrotropin-releasing hormone (TRH), which stimulates the production of thyroid-stimulating hormone (TSH) in the anterior pituitary. TSH stimulates the thyroid gland. When hormone levels are elevated, negative feedback suppresses TSH secretion (with $T_3$ exerting a stronger suppressive effect than $T_4$).
Pathologies: Hypothyroidism, Hyperthyroidism, and Goiter
Thyroid dysfunction leads to severe metabolic alterations:
- Hypofunction (Hypothyroidism): Manifests as myxedema in adults; leads to cretinism (delayed mental and physical development) in children.
- Hyperfunction (Hyperthyroidism): A classic example is Graves' disease.
Goiter (struma) refers to an enlargement of the thyroid gland. It can be toxic (accompanied by clinical hyperthyroidism) or simple (nontoxic).
The most common cause of simple goiter is dietary iodine deficiency. The pathogenesis relies on a feedback mechanism: insufficient dietary iodine impairs hormone synthesis. Decreased blood hormone levels activate the hypothalamic-pituitary axis. Upregulated TSH secretion continuously stimulates the thyroid gland, causing hypertrophy. This creates a paradox: the gland enlarges, but hormone production does not increase due to a lack of substrate (iodine).
Pharmacology: Medications for Hypothyroidism
Hormone replacement therapy for hypothyroidism involves thyroid hormone preparations, inorganic iodine, or combinations thereof.
Liothyronine (Liothyroninum) is a synthetic analog of $T_3$.
- Pharmacokinetics: 95% absorbed, rapid onset. The latent period is 4–8 hours, with peak effect at 2–3 days. The half-life is 2.5 days.
- Indications: Myxedema, cretinism, endemic and sporadic goiter, thyroid cancer, hypothyroid obesity.
- Adverse effects: Tachycardia, arrhythmias, angina pectoris, headache, suppression of TSH secretion.
- Contraindications: Thyrotoxicosis, ischemic heart disease (angina), Addison's disease, diabetes mellitus.
Levothyroxine sodium (Levothyroxinum natrium) is a synthetic analog of $T_4$. It has a slower and milder onset of action (onset in 3–4 days, peak in 10–15 days). Its primary advantage is a significantly lower arrhythmogenic potential.
Other preparations include:
- Thyreotom (Thyreotom): A combination drug (40 mcg levothyroxine + 10 mcg liothyronine).
- Thyreoidinum (Thyreoidinum): An animal-derived preparation (from slaughtered livestock glands) containing levorotatory isomers of $T_3$ and $T_4$. It acts similarly to liothyronine but is 3–5 times less potent.