Thyroid Gland

The thyroid gland is located immediately below the larynx on each side of and anterior to the trachea. * The colloid contains thyroglobulin which contains the thyroid hormones. * The parafollicular cells contain calcitonin. Iodide Kinetics Average daily intake: 0. 1 mg Absorption: iodine to inorganic iodide in stomach and upper SI Transport & Metabolism: iodide (ECF) pool thyroid pool hormone (T3T4 pool) issues (liver,muscle,etc) thyroid-serum iodide ratio: 25 to 1 Clearance: kidneys Synthesis & Release – stimulated by TSH * The iodide in the ECF will enter the follicular cells (idodide trapping) through active transport (Sodium-Iodide Symport). * The iodide will then diffuse to the apical cells where it will be oxidized (catalyzed by thyroid peroxidase) to iodine to make it capable of binding directly with thyroglobulin. * Electron acceptor: hydrogen peroxide * Iodine will enter the colloid through the Iodide-Chloride symport. Within the colloid, tyrosine, which is contained in the thyroglobulin will be iodinated which will result in the formation of monoiodotyrosine (MIT) and diiodotyrosine (DIT). * MIT and DIT will undergo coupling reaction resulting in the formation of T3 and T4. * When the thyroid cells are stimulated, iodinated thyroglobulin is taken back in to the follicular cells by endocytosis. * Lysosomal enzymes then digest thyroglobulin, releasing T3 and T4 into the circulation. * Leftover MIT and DIT are deiodinated by thyroid deiodinase. The iodine released is reutilized to synthesize more thyroid hormones.

The most important regulator of the thyroid gland function and growth is the hypothalamic-pituitary thyroid releasing hormone-thyroid stimulating hormone axis. Thyrotropin releasing hormone (TRH) secreted by the hypothalamus stimulates the anterior pituitary to secrete thyroid stimulating hormone. TSH regulates the secretion of T4 and T3 of the thyroid gland; it has immediate, intermediate, and long-term actions on the thyroid epithelium IMMEDIATE: * Induction of pseudopod extension, endocytosis of colloid, formation of colloid droplets in the cytoplasm. TSH also stimulates entry of glucose into the hexose monophostphate shunt pathway, which generates NADPH that is needed for the peroxidas reaction. * Stimulates proteolysis of thyroglobulin and release of T4 and T3 INTERMEDIATE: * Occur after a delay of hours to days and involve protein synthesis and expression of numerous genes, including those encoding NIS, thyroglobulin, TPO, and megalin. LONG TERM: * Sustained TSH stimulation leads to hypertrophy and hyperplasia of follicular cells. *Regulation is under exquisite negative-feedback control: Circulating TH act on the pituitary gland to decrease TSH secretion, primarily by repressing TSH ? subunit gene expression. The pituitary gland expresses the high affinity type 2 deiodinase. Thus, small changes in free T4 in blood result in significant changes in intracellular T3. * Because the diurnal variation of TSH secretion is small, TH secretion and plasma concentrations are relatively constant. Only small nocturnal increases in secretion of TSH and release of T4 occur. * TH also feed back on hypothalamic TRH-secreting neurons.

T3 inhibits the expression of the prepro-TRH gene. * Iodide is also an important regulator. At low levels, rate of TH synthesis is directly related to the availability of the iodide. * Circulating T4 and T3 act on the pituitary gland to decrease TSH secretion; if the levels of T4 and T3 fall, TSH secretion increases. It is free T4 and T3, not the protein-bound portions that regulate pituitary TSH output. The pituitary gland is capable of deiodinating T4 to T3, and the latter acts as the final effector molecule in turning off TSH. Fig.

TSH actions on the thyroid cell. Cyclic adenosinemonophosphate (cAMP) along with calcium ions (Ca2+) and phosphoinositol products act as second messengers generated by TSH binding to its receptor. All steps in thyroid hormone production, as well as many aspects of thyroid cell metabolism and growth, are stimulated by TSH. Growth factors are important intermediaries in cell proliferation and in synthesis of some proteins such as thyroglobulin. Thyroid Autoregulation related to iodide availability involves iodide transport & organification odide excess transport/organification till maximum sudden decrease (Wolff-Chaikoff effect) ** when iodide intake exceeds 2mg/day. The intraglandular concentration of iodide reaches a level that suppresses NADPH oxidase activity and the NIS and TPO genes and thereby the mechanism of hormone biosynthesis, this phenomenon is calle Wolff-Chaikoff effect. iodide deficiency transport/organification TSH levels normal Stimuli| Inhibitors| Epinephrine (increase SNS activity, increase TH)| Iodides (inhibit NIS)| VIP| Thyroglobulin (negative feedback)| Prostaglandin| Acetylcholine|

Leptin (low food intake, high energy expenditure thru TH synthesis)| Lithium| Cold exposure (thermogenic effect, maintenance of body temp)| Fasting (prolonged starvation, low TH [BMR])| Transport and Metabolism | T4| T3| Reverse T3| Rate of Secretion| 90%| 10%| >1%| t ? | 6-7 days| 24 hours| | Free form| 0. 03%| 0. 3%| | Comment| Serves as a prohormone in peripheral tissue; undergoes monoiodoniationInactive formTetraiodothyronine| 10x more potent than T4Active formTriiodothyronine| | | Behaves like steroid hormone| Peripheral Conversion Type 1 5’ DI — rT3 T2

Type 2 5’ DI — T4 T3 (more important, 80% of T3 is formed through this process) Type 3 5 DI — T4 rT3 (reverse T3, more produced rather than the active T3) High T4 — conversion to T3 —- conversion to type 1 Low T4 — Type 2 Peripheral metabolism of thyroxine (T4) is largely by successive deiodinations. Key regulatory step: T4 T3 rT3 (deiodination) * The liver, kidneys, and skeletal muscles are the major sites of T4 degradation. * T4 increases its own degradative metabolism * Sequential deiodination steps is regularly increased in the plasma in yperthyroidism (T4 excess) and is usually decreased in hypothyroidism (T4 deficiency). 3 Types of deiodinase: * function of these enzymes depends critically on the presence of selenium at the active catalytic sites. (D1) Type 1 5′-deiodinase| rT3 is the preferred substrate yielding 3,3-T2| expressed in the thyroid gland, liver, and kidney; regulates the circulating T3 supply by augmenting T3 production and disposing of rT3 generated from excess T4. | (D2) Type 2 5′-deiodinase| T4 T3| skeletal muscle, brain, and brown fat; favors local T3 generation| Type 3 5-deiodinase| T4 rT3| brain, skin, and placenta. | 5′-monodeiodination * T3-generating activity * supplied by D1 and D2 * D1 5′-monodeiodinase activity has a lower affinity but a higher capacity for T4 than does D2. * In humans, the normal distribution of T4 products is approximately 45% T3 and 55% rT3. An increase in T4 concentration leads to a decrease in its conversion to T3. Thus, the biological effects of T4 excess or deficiency are automatically mitigated slightly by accelerated or retarded metabolic inactivation, respectively. Clinical states and factors associated with a reduced conversion of T4 to T3 & reciprocally enhanced conversion of T4 to rT3 Gestational period

* Fasting * Major medical and surgical stress * Catabolic disease * Hepatic disease * Renal failure * Thiouracil drugs * Beta-adrenergic blockers * inhibition of hepatic D1 activity appears to explain this switch * inhibition of 5′-monodeiodinase decreases the production of T3 from T4 (reducing plasma T3), and it simultaneously decreases the degradation of rT3 to 3,3′-T2 (increasing plasma rT3). Reduction of 5′-monodeiodinase activity may also result from * Decreased glucose metabolism * Increased FFA metabolism Excess secretion of cortisol * When 5′-monodeiodinase activity is reduced, sulfation of T4 and T3 increases, and the addition of sulfate greatly diminishes the biological activity of whatever T3 is produced. Transport Carrier Proteins * Secreted T4 and T3 circulate in the bloodstream almost entirely bound to proteins. * About 0. 03% of total plasma T4 and 0. 3% of total plasma T3 exist in the free state * TBG- thyroxine-binding globulin; major binding protein – 70% * Maintains large circulating reservoir of T4 Binding of plasma T4 and T3 to large proteins prevents the loss of these relatively small hormone molecules into the urine, and thereby helps conserve iodide * primary change in TBG concentration will also disturb the ratio of free to bound T4 TTR-transthyretin; 10-15% * may provide thyroid hormones to the central nervous system. TBA – albumin; much lower affinities but much higher capacities for binding T4 and T3 Clinical Correlation TBGClinical Condition Free T4 normal hyperthyroidincreased normal euthyroid normal normal hypothyroid low levated pregnancy normal * more sensitive indicator of primary hypothyroidism: increased TSH, not the decrease in circulating T4, * Total circulating T4 represents mainly bound T4′ which is not an index of activity. * Measurement of free T4 index would be a sensitive indicator of thyroid status. * The goal in replacement therapy for primary hypothyroidism: raise plasma T4 to the point where TSH returns to normal. Thyroid Receptors TR-1 — skeletal/cardiac muscle* TR-2 — does not bind T3, inhibits TR TR-1 — brain, liver, kidney^ TR-2 — pituitary, hypothalamus; Responsible for inhibiting the expression of the prepro-TRH gene in the paraventricular neurons of the hypothalamus and of the ? -subunit TSH gene in pituitary thyrotropes. * Thus negative feedback effects of thyroid hormone on both TRH and TSH secretion * most common mutations occur in this subtype; therefore there is incomplete negative thyroid hormone feedback at the hypothalamic-pituitary level. INTRACELLULAR ACTIONS OF THYROID HORMONE Mechanism of Action hormone binds with nuclear receptors gene transcription- proteins- mitochondrial enzymes – other enzymes eg.

Na-K-ATPase hormone binds with mitochondrial R oxidative phosphorylation Figure. Overall schema of thyroid hormone effects. The upper portion represents intracellular actions resulting from T3 binding to its nuclear receptor (TR), which is linked to thyroid regulatory elements (TREs) in target DNA molecules. The lower portion catalogs all the various whole body effects of thyroid hormone that sustain increased oxygen consumption and permit disposal of the excess CO2, heat, and metabolic products. Biologic effects of Thyroid Hormone cellular metabolic systemic rowth and development whole body effects -biologically, T3 is much more important than T4. WHY?? 1. T4 is bound more tightly to plasma protein than T3 (resulting to free T4 in the circulation only about 2fold higher than T3) 2. Once T4 enter the cell, the target cell converts it to T3 3. THR in the nucleus has greater affinity for T3 than T4 (so mas potent ang effect ni T3 on a molar basis) Physiological Effects 1. Stimulate BMR or calorigenesis O2 consumption (indirect calorimetry) ;amp; heat production (direct calorimetry) thyroid hormone deficiency leads to decreased BMR

Thyroid hormone increases the BMR by stimulating both the catabolic and anabolic reactions in pathways affecting fats, carbohydrates and proteins 2. Respiratory effects RR, VE, ventilatory control 3. Cardiovascular effects CO, HR, SV TPR 4. Metabolic effects protein degradation ;amp; protein synthesis glycogenolysis ;amp; gluconeogenesis (E) glycogenesis ;amp; glucose utilization (I) lipolysis ;amp; cholesterol metabolism 5. Others NS effects bone growth ;amp; remodeling interaction with SNS Physiological Effects of Tyroid hormone| Parameter| Hypothyroid| Hyperthyroid| BMR| v| ^|

Carbs metab| v gluconeogenesisv glycogenolysis| ^ gluconeogenesis^ glycogenolysis| Protein metab| v synthesisv proteolysis| ^synthesis^proteolysisMuscle wasting| Lipid synthesis| v lipogenesisvlipolysis^serum [cholesterol]| ^ lipogenesis^ lipolysisv serum [cholesterol]| Thermogenesis| v| ^| Autonomic nervous sytem| Normal level of catecholamines| ^ expression of ? -adrenoreceptor| Major Functions of Thyroid Hormones 1. Required for normal maturation of the NS in the fetus and infants Deficiency: mental retardation (cretinism) 2. Required for normal bodily growth (permissive effects to GH) Deficiency: deficient growth in children . Required for normal alertness and reflexes at all ages Deficiency: mentally and physically slow and lethargic Excess: restless, irritable, anxious, wakeful 4. Major determinant of the rate at which body produces heat during the basal metabolic stage Deficiency: low BMR, sensitivity to cold, decreased appetite Excess: High BMR, sensitivity to heat, increased appetite 5. Facilitates SNS activity by stimulating synthesis of receptors for epinephrine and norepinephrine Excess: symptoms similar to activation of SNS (eg. HR) Functional Disorder of Thyroid Gland Hyperthyroidism – result from a number of causes.

Most commonly the entire gland undergoes hyperplasia as a result of autoimmune stimulation (Grave’s Disease), in which antibodies formed against the TSH receptor bind to it and mimic TSH action. Symptoms Nervousness Heat insensitivity Sweating Weightloss Tachycardia Palpitations Muscle weakness Moist skin Increased appetite Sleeplessness Tremor Goiter Bruit over thyroid Diarrhea antibodies (TSHR-Ab) bind to the TSH receptors, which are located on the cells that produce thyroid hormone in the thyroid gland (follicular cells), and chronically stimulate them, resulting in an abnormally high production of T3 and T4 types of autoantibodies to the TSH receptor currently recognized: * TSI, Thyroid stimulating immunoglobulins: these antibodies (mainly Immunoglobulin G) act as LATS (Long Acting Thyroid Stimulants), activating the cells in a longer and slower way than the normal thyroid-stimulating hormone (TSH), leading to an elevated production of thyroid hormone. * TGI,Thyroid growth immunoglobulins: these antibodies bind directly to the TSH-receptor and have been implicated in the growth of thyroid follicles. TBII,Thyrotropin Binding-Inhibiting Immunoglobulins: these antibodies inhibit the normal union of TSH with its receptor. Some will actually act as if TSH itself is binding to its receptor, thus inducing thyroid function. Other types may not stimulate the thyroid gland, but will prevent TSI and TSH from binding to and stimulating the receptor. Hypothyroidism – in adults most often results from idiopathic atrophy of the gland, which is thought to be preceded by a chronic autoimmune inflammatory reaction. Symptoms Muscle weakness Sleepy Sluggish Poor appetite

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