GROSS ANATOMY
Thyroid gland lies in front of trachea, just below the larynx and is the largest gland and butterfly shaped. The gland is bilobed with central isthmus and weighs 10-20g in adult. Behind thyroid gland there are 4 parathyroid glands.
MICROANATOMY
Thyroid gland consists of thousands of follicles filled with colloid inside and cuboidal epithelial follicular cells called thyrocytes. Colloid is composed of thyroglobulin. The interfollicular stroma contains C cells (parafollicular cells) which secrete calcitonin involved in calcium homeostasis. The primary function of thyroid is to synthesize and secrete thyroid hormones.
BIOLOGICAL ACTION
Under normal circumstances 10 nmol of tri-iodothyronine (T3) and 110 nmol of thyroxine (T4) are formed per day. The actions of thyroid hormone are exerted through modulation of gene expression. Thyroid hormones promote differentiation and growth; they are essential for normal fetal and neonatal development. Thyroid hormones increases mitochondrial oxidative phosphorylation, increase calorigenesis and oxygen consumption in tissue, except brain. They stimulate protein synthesis, gluconeogenesis, liver glycogenolysis, enhance carbohydrate absorption from GI, lipolysis and accelerate insulin degradation.
Hypothyroidism cause the increase in plasma cholesterol, CK-MM, TBG, creatinine, decreased sodium. T3 also stimulate urea cycle enzyme (CPS) so that urea is excreted rather than ammonia.
SYNTHESIS, STORAGE AND RELEASE
Synthesis of T4 and T3 occurs on thyroglobulin (Tg), a glycoprotein of molecular weight 660 kDa with 5000 amino acids, 115 tyrosine residues. Thyroglobulin is synthesized by the thyrocytes and exported to be stored within the colloid of follicular lumen. Other enzyme TPO is also synthesized in thyrocytes and present in apical membrane and involved in oxidation of Iodide to Iodine using NADP+ and H2O2. Use of radioactive iodine uptake (RIU) method has helped in elucidation of the pathway of synthesis of thyroid hormones. About 70% of iodide is present as MIT and DIT in Tg and 30% as in T3 and T4.
Trapping of iodide:
Iodide from plasma is actively transported by sodium-iodine symporter (2Na+ and 1I- are symported inside cell) situated in basal membrane of thyrocytes. This is an ATP dependent process since iodide is taken against concentration gradient. This is also a rate limiting step in thyroid hormone synthesis. In the apical membrane a anion transporter or iodide transporter protein pendrin mediates iodide efflux into colloid. Pertechnetate (which is used for radioactive imaging of gland since it inhibits the pump for iodine but itself gets transported inside), Perchlorate, thiocyanates (found in certain foods) competitively inhibit iodide pump but are not taken up. The ratio of iodide in thyroid to in serum (T:S) is about 25:1 in normal iodine diet. Small amount of iodide also enters by diffusion so any extra iodide not incorporated in MIT, DIT (about <10%) leaves by this mechanism.
Oxidation of iodide to iodine by thyroid peroxidase:
Oxidation of iodide only occurs in thyroid gland. This occurs in the luminal side of apical membrane and requires heme containing TPO and H2O2, which is generated by calcium dependent flavoprotein enzyme system situated at apical membrane. Antithyroid drugs like propylthiouracil, thiourea, methimazole, carbimazole inhibits the oxidation of iodide by TPO.
Iodination or Organification:
This occurs in tyrosyl residues present in Tg. MID and DIT are formed through the action of TPO. At first 3rd position of tyrosine is iodinated followed by 5th position. Free tyrosine can also be iodinated but it will not be incorporated into protein since there is no tRNA for iodotyrosine.
Coupling of iodine into tyrosyl residue on thyroglobulin:
This is also catalyzed by TPO and produces T3 (Tri-iodotyrosine) and T4 (Tetra-iodotyrosine) that remain linked to Tg. Here DIT + DIT forms T4 and MIT + DIT forms T3. Iodinated Tg is stored in follicular lumen. When iodine supply is limited proportion of T3 in Tg is increased.
Internalization of Tg and release of T4 and T3:
Thyroglobulin is internalized by pinocytosis and appears as colloid droplets that fuse with lysosome and undergo proteolytic degradation to release T3 and T4. Some uncoupled MIT and DIT are again deiodinated to Iodide and Tyrosine which are recycled. While in thyrocytes some amount of T4 is converted to T3 by deiodinase D1 and D2. Release into circulation occurs by fusion of endocytic vesicle containing thyroid hormones with plasma membrane.
Iodide released by deiodinase (of MIT, DIT) in thyroid cell constitute the important pool within thyroid in contrast to iodide that enters the blood.
TSH stimulates each of the above process by cAMP mediated Ca++/PI pathway by binding to cell surface G-protein coupled receptor. Prolonged TSH action cause hypertrophy and increase vascularity of thyroid gland leading to thyroid enlargement (Goiter).
Thyroid gland lies in front of trachea, just below the larynx and is the largest gland and butterfly shaped. The gland is bilobed with central isthmus and weighs 10-20g in adult. Behind thyroid gland there are 4 parathyroid glands.
MICROANATOMY
Thyroid gland consists of thousands of follicles filled with colloid inside and cuboidal epithelial follicular cells called thyrocytes. Colloid is composed of thyroglobulin. The interfollicular stroma contains C cells (parafollicular cells) which secrete calcitonin involved in calcium homeostasis. The primary function of thyroid is to synthesize and secrete thyroid hormones.
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| Fig. Hypothalamus Pituitary Axis |
 |
| Fig. a) Location of thyroid gland b) Histological structure of Thryoid follicle (Source: Bishop's Clinical chemistry, 6th edition) |
BIOLOGICAL ACTION
Under normal circumstances 10 nmol of tri-iodothyronine (T3) and 110 nmol of thyroxine (T4) are formed per day. The actions of thyroid hormone are exerted through modulation of gene expression. Thyroid hormones promote differentiation and growth; they are essential for normal fetal and neonatal development. Thyroid hormones increases mitochondrial oxidative phosphorylation, increase calorigenesis and oxygen consumption in tissue, except brain. They stimulate protein synthesis, gluconeogenesis, liver glycogenolysis, enhance carbohydrate absorption from GI, lipolysis and accelerate insulin degradation.
Hypothyroidism cause the increase in plasma cholesterol, CK-MM, TBG, creatinine, decreased sodium. T3 also stimulate urea cycle enzyme (CPS) so that urea is excreted rather than ammonia.
SYNTHESIS, STORAGE AND RELEASE
Synthesis of T4 and T3 occurs on thyroglobulin (Tg), a glycoprotein of molecular weight 660 kDa with 5000 amino acids, 115 tyrosine residues. Thyroglobulin is synthesized by the thyrocytes and exported to be stored within the colloid of follicular lumen. Other enzyme TPO is also synthesized in thyrocytes and present in apical membrane and involved in oxidation of Iodide to Iodine using NADP+ and H2O2. Use of radioactive iodine uptake (RIU) method has helped in elucidation of the pathway of synthesis of thyroid hormones. About 70% of iodide is present as MIT and DIT in Tg and 30% as in T3 and T4.
Trapping of iodide:
Iodide from plasma is actively transported by sodium-iodine symporter (2Na+ and 1I- are symported inside cell) situated in basal membrane of thyrocytes. This is an ATP dependent process since iodide is taken against concentration gradient. This is also a rate limiting step in thyroid hormone synthesis. In the apical membrane a anion transporter or iodide transporter protein pendrin mediates iodide efflux into colloid. Pertechnetate (which is used for radioactive imaging of gland since it inhibits the pump for iodine but itself gets transported inside), Perchlorate, thiocyanates (found in certain foods) competitively inhibit iodide pump but are not taken up. The ratio of iodide in thyroid to in serum (T:S) is about 25:1 in normal iodine diet. Small amount of iodide also enters by diffusion so any extra iodide not incorporated in MIT, DIT (about <10%) leaves by this mechanism.
Oxidation of iodide to iodine by thyroid peroxidase:
Oxidation of iodide only occurs in thyroid gland. This occurs in the luminal side of apical membrane and requires heme containing TPO and H2O2, which is generated by calcium dependent flavoprotein enzyme system situated at apical membrane. Antithyroid drugs like propylthiouracil, thiourea, methimazole, carbimazole inhibits the oxidation of iodide by TPO.
Iodination or Organification:
This occurs in tyrosyl residues present in Tg. MID and DIT are formed through the action of TPO. At first 3rd position of tyrosine is iodinated followed by 5th position. Free tyrosine can also be iodinated but it will not be incorporated into protein since there is no tRNA for iodotyrosine.
 |
| Fig. Structure of Thyroid hormones (Source: Tietz Textbook of clinical chemistry, 4th Edition) |
This is also catalyzed by TPO and produces T3 (Tri-iodotyrosine) and T4 (Tetra-iodotyrosine) that remain linked to Tg. Here DIT + DIT forms T4 and MIT + DIT forms T3. Iodinated Tg is stored in follicular lumen. When iodine supply is limited proportion of T3 in Tg is increased.
Internalization of Tg and release of T4 and T3:
Thyroglobulin is internalized by pinocytosis and appears as colloid droplets that fuse with lysosome and undergo proteolytic degradation to release T3 and T4. Some uncoupled MIT and DIT are again deiodinated to Iodide and Tyrosine which are recycled. While in thyrocytes some amount of T4 is converted to T3 by deiodinase D1 and D2. Release into circulation occurs by fusion of endocytic vesicle containing thyroid hormones with plasma membrane.
Iodide released by deiodinase (of MIT, DIT) in thyroid cell constitute the important pool within thyroid in contrast to iodide that enters the blood.
TSH stimulates each of the above process by cAMP mediated Ca++/PI pathway by binding to cell surface G-protein coupled receptor. Prolonged TSH action cause hypertrophy and increase vascularity of thyroid gland leading to thyroid enlargement (Goiter).
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