BIOCHEMISTRY - Textbook - Ostapchenko L. I. - 2012

Chapter 15. INTEGRATION OF METABOLIC PATHWAYS. HORMONES

15.8. Thyroid Hormones

The Thyroid Gland consists of follicles whose cavities are filled with colloid and surrounded by a single layer of cuboidal epithelial Cells (thyroid cells).

The synthesis of iodothyronines is stimulated by TSH secreted by the adenohypophysis. In turn, TSH secretion is controlled by two mechanisms: 1) hypothalamic thyrotropin-releasing hormone stimulates TSH Synthesis and Secretion; 2) THYROID Hormones directly inhibit TSH secretion via a negative feedback loop. Iodothyronines are synthesized as part of the thyroglobulin protein within thyroid cells. Thyroglobulin is a glycoprotein with a molecular mass of 660 kD containing 115 Tyrosine residues; it is synthesized in the basal region of The Cell and stored in the extracellular colloid, where tyrosine residues are iodinated to form iodothyronines.

Iodine enters the body with food and Water as I^-, is absorbed in the intestine, and enters the extracellular fluid, forming the inorganic iodide pool. From there, it is taken up by the thyroid gland, where inorganic iodine crosses the basolateral membrane of thyroid cells via Active Transport mediated by Na⁺K⁺-ATPase. Peroxidases located in the membrane oxidize inorganic iodine into an active organic form. Under the Action of Thyroid peroxidase, oxidized iodine reacts with tyrosine residues to yield monoiodotyrosines and diiodotyrosines. Monoiodotyrosine contains iodine at position 3 of the phenolic ring, whereas diiodotyrosine contains it at positions 3 and 5. Two molecules of diiodotyrosine condense to form thyroxine (T₄), while a monoiodotyrosine and a diiodotyrosine condense to form triiodothyronine (T₃). Lysosomal Enzymes hydrolyze thyroglobulin, releasing T₃, T₄, peptide fragments, and Amino Acids into the bloodstream. Under basal conditions, 80-90 µg of T₄ is secreted per day. About 30 % of T₄ is converted to T₃ via outer-ring monodeiodination of the phenolic ring, a process that occurs primarily in The Liver and Kidneys. The hormonal activity of T₃ is three times greater than that of T₄ (Fig. 15.10).

In the Blood, iodothyronines exist in both free and bound forms. Only free T₃ and T₄ exhibit hormonal activity, though their proportion is extremely small—only 0.03-0.04 % of T₄ and 0.3 % of T₃. The bulk of the hormones are bound to carrier Proteins, predominantly thyroxine-binding globulin, which accounts for 70-75 % of bound T₄ and 80 % of bound T₃. These carrier proteins act as a reservoir ensuring a steady supply of free hormones. A dynamic equilibrium exists between the total hormone content and the free hormone fraction. An increase in thyroxine-binding globulin concentration initially leads to a transient drop in free hormone levels, which then triggers an upregulation of thyroid hormone secretion, raising serum levels until the normal equilibrium of free forms is restored.

TSH receptors are located on The Plasma Membrane of thyroid cells; TSH binding stimulates the inorganic iodide transport system, ATPase activity, and the synthesis of thyroglobulin, peroxidases, and lysosomal enzymes. Alongside hypothalamo-pituitary regulation, the gland features an autoregulatory mechanism linked to the availability of inorganic iodide.

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Fig. 15.10. Structure of thyroid hormones:

A - thyroxine, B - 3,5,3'-triiodothyronine

Thyroid Hormone Receptors are intracellular. Iodothyronines regulate tissue growth, differentiation, and METABOLISM/26.html">Energy Metabolism. They are essential for normal fetal GROWTH AND DEVELOPMENT, including Brain development. T₃ action leads to an increase in mitochondrial size and enhanced enzymatic activity, which manifests as elevated oxygen consumption and increased ATP synthesis. Thyroid hormones also increase the number of β-adrenergic receptors in the myocardium, skeletal Muscles, adipose tissue, and lymphocytes. Consequently, the cardiac effects of these hormones include increased oxygen consumption, elevated Heart rate, and accelerated impulse conduction velocity.

Chronic excess of thyroid hormones in the blood and their overstimulation of target Organs leads to thyrotoxicosis, primarily caused by glandular hyperfunction (hyperthyroidism). Thyroid hyperfunction presents in two main forms: Graves' disease (DIFFUSE TOXIC GOITER) and autoimmune thyroiditis. Diffuse toxic goiter is the most common cause of thyrotoxicosis. Typical symptoms include nervousness, hyperexcitability, tremors, excessive sweating, tachycardia, Muscle weakness, and muscle atrophy. The thyroid gland is generally enlarged.

Inflammatory Diseases of the thyroid gland are a leading cause of its dysfunction. Consequently, thyroiditis ranks second among endocrine disorders in children, following Diabetes Mellitus.

In autoimmune thyroiditis, the blood of most patients contains an immunoglobulin that binds to TSH receptors in the thyroid gland, mimicking TSH action and chronically stimulating the synthesis of iodothyronines.

Hypothyroidism is a clinical syndrome resulting from insufficient thyroid hormone action on target Tissues. Primary hypothyroidism is caused by structural or secretory defects in thyrocytes, whereas secondary hypothyroidism stems from Disorders of the adenohypophysis or Hypothalamus. Peripheral hypothyroidism is most commonly caused by target tissue resistance to thyroid hormones due to genetic receptor defects. A hallmark manifestation of hypothyroidism is Myxedema (mucous edema), caused by the accumulation of glycosaminoglycans, primarily hyaluronic acid, in the Skin and subcutaneous tissue.

Hypothyroidism can also result from inadequate dietary iodine intake. Endemic goiter is prevalent among populations residing in regions with low iodine content in drinking water and soil.

Glandular hypofunction in early childhood leads to delayed physical and mental development, known as cretinism. Key symptoms of hypothyroidism include somnolence, cold intolerance, weight gain, decreased body Temperature, memory impairment, and depression.