Thyroid Hormone Biosynthesis, Regulation, and Function (PDF)

Thyroid Hormone 123I or 131I imaging By the end of this session and through private study, you ought to be able to demonstrate understanding and apply your knowledge through:- Production of a diagrammatic outline of the TRH/TSH/T3 endocrine axis A brief summary of the basic str...

Thyroid Hormone 123I or 131I imaging By the end of this session and through private study, you ought to be able to demonstrate understanding and apply your knowledge through:- Production of a diagrammatic outline of the TRH/TSH/T3 endocrine axis A brief summary of the basic structure and function of the Thyroid gland Description of the processes of Thyroid hormone (T4, T3, rT3) biosynthesis Analysis of the effects of Thyroid hormones on BMR, growth and development A comparative description of the causes and effects of hyper- and hypothyroidism Familiarity with standard clinical treatments for thyroid-related disorders. THYROID GLAND: STRUCTURE C cells are also called parafollicular cells; secrete calcitonin, a peptide hormone; can cause medullary carcinomas thyroid epithelial cells, also called thyrocytes, are organized into spherical follicles The thyroid thus secretes 3 hormones T3 T4 and calcitonin  Thyroid Gland Products 3,5,3',5'-tetraiodothyronine (L-thyroxine/L-T4) secreted in greater amounts than 3,5,3’-triodothyronine (L-triiodothyronine/L-T3) (90% vs 10%) 1% is in the form of 3,3',5'-triiodothyronine (reverse T3, or rT3) which is inactive T3 more potent than T4 T4 converted to T3 by a “deiodinase” enzyme found in many peripheral tissues T3 binds with high affinity to T3 receptors (TRa and TRb) associated with DNA in cell nucleus ® can either activate or repress gene transcription ® regulation of mRNA synthesis and protein synthesis Also, calcitonin secreted by parafollicular cells  Deiodinases 3’ 3 5’ 5 type 1 deiodinase (low affinity, Km of 1 μM) occurs in tissues with high blood flows and rapid exchanges with plasma, supply circulating T3 for uptake by other tissues in which local T3 generation may not be sufficient. type 2 deiodinase (high affinity, Km of 1 nM) expressed by glial cells in CNS provides T3 even when free T4 falls to low levels Biosynthesis of Thyroid Hormone Apical Basal  Thyroid Hormone Synthesis in Thyrocytes Thyroglobulin (TG/TRG) is synthesized by thyroid epithelial cells and secreted into the lumen of the follicle. One TG contains 134 tyrosines. Iodide (I-), is avidly taken up from blood via a sodium-iodide symporter or "iodine trap". Iodide is transported into the colloid along with thyroglobulin. Synthesis of thyroid hormones is conducted by the enzyme thyroid peroxidase, it catalyzes 1) iodination and 2) coupling sequential reactions Thyroid epithelial cells ingest colloid (and TG+thyroid) by endocytosis Colloid-laden endosomes fuse with lysosomes, which contain enzymes that digest thyroglobluin. Free thyroid hormones diffuse out of lysosomes into blood and bind to carrier proteins (Thyroxine-binding globulin (TBG, major), transthyretin (minor, particularly important for delivery to the CNS), albumin (minor).  Thyroglobulin and Thyroid Hormones OH OH Thyroglobulin - a I very large protein I I (5500 amino acids) with 134 tyrosine residues; makes up CH2 CH2 most of thyroid HN CH CO PEPTIDE HN CH CO follicular colloid CHAIN monoiodotyrosine unit (MIT) di-iodotyrosine unit (DIT) OH OH I I I Iodination and coupling reactions upon tyrosine O O residues in thyroglobulin I I I I believed to be carried out by peroxidase enzyme CH2 CH2 H2N CH COOH H2N CH COOH tri-iodothyronine (T3) thyroxine (T4) Iodine Distribution and Turnover 400 μg of iodide is ingested and excreted daily minimum daily requirement 150 μg for adults, 90 to 120 μg for children, 200 μg for pregnant women About 70 to 80 μg of iodide is taken up daily by the thyroid gland whose total iodide content averages 7500 μg (all as iodothyronines). 70 to 80 μg (about 1% of the total) is released daily. The large ratio (100:1) of iodide stored in the form of hormone to the amount turned over daily protects the individual from the effects of iodide deficiency for many days.  The Thyroid Receptor A. Structural domains of Thyroid Receptor (TR) B. Transcriptional regulation by TR. TR functions as heterodimer with Retinoic Acid X receptor (RXR). TR-RXR bind to Thyroid Response Element (TRE) on target gene In absence of TH, TR-RXR represses gene transcription through the recruitment of a corepressor complex containing histone deacetylase (HDAC). When TH is present, the corepressor complex is released and coactivator complexes including histone acetyltransferase (HAT) activity are recruited. HAT-containing complexes increase histone acetylation to promote transcription. Retinoic acid binds to RXR  Physiological Effects of Thyroid Hormones Two primary categories of biological responses Effects on cellular differentiation and development, on the nervous system in particular Effects on metabolic pathways and use of carbohydrates, lipids and proteins These two actions are interconnected Virtually every cell in the body expresses a thyroid receptor!  Physiological Effects of Thyroid Hormones T3 and T4 promote accelerated metabolism. increase carbohydrate, fat and protein turnover, ensuring that adequate cellular energy is available to support metabolically demanding activities increase oxygen consumption and increase heat production. Help regulate basal metabolic rate and body temperature Important during development and growth. TH’s promote growth of neurones and stimulate maturation of the central nervous system Between week 11 and birth TH is essential. After birth, TH are required for correct mental development and body growth. (deficiency in childhood ® intellectual disability) Sympathomimetic (permissive) action. Increases responsiveness to catecholamines by increasing numbers of receptors.  Physiological Effects of Thyroid Hormones Cardiovascular and Respiratory effects alters the expression of ryanodine Ca2+ channels in the sarcoplasmic reticulum, promoting Ca2+ release. enhances the sensitivity (and expression) of adrenoceptors (especially b1-receptors) to stimulation by noradrenaline Effects on Basal Metabolic Rate Thyroid hormones increase the basal rate of oxygen consumption and heat production adjust heat loss through sweating, and ventilation. Changes in body temperature parallel fluctuations in thyroid hormone availability. The overall metabolic effect - accelerating the response to starvation. Effects on the Autonomic Nervous System and Catecholamine Action increasing the number of β-adrenergic receptors in heart muscle increasing the generation of intracellular second messengers, such as cAMP Effects on the Nervous System Development but also enhances wakefulness, alertness, responsiveness to various stimuli Regulation of Thyroid Hormone Secretion (1) TRH = thyrotropic releasing hormone TSH = thyroid stimulating hormone T3/T4émetabolism in peripheral tissue BMR restored Regulation of Thyroid Hormone Secretion (2) Low BMR Cold Trauma Stress TRH Sense levels of T4 and adjust TSH levels of receptors for TRH Glucocorticoids Estrogens (Anti-inflammatory prescription) Thyrocytes Gs Gq AC PLC PKA PKC Cai éiodide uptake Both, short-term and éSynthesis of peroxidase long-term (via effects éSynthesis of TG on gene transcription) éColloid uptake  Abnormalities of Thyroid Function HYPERTHYROIDISM can be caused by: RAI Scan demonstrating multiple 'hot' or toxic nodules Autoimmune disease (Graves Disease) – autoantibodies (immunoglobulins) that stimulate thyrotrophin receptors on thyroid gland follicle cells leading to continual stimulation of thyroid hormone synthesis Benign tumour of thyroid cells causing enlargement of gland and increased hormone secretion Excessive secretion of TSH from a TSH-producing tumor Goitre is associated with hypothyroidism or hyperthyroidism (i.e., secondary hyperthyroidism) HYPOTHYROIDISM can be caused by: Inflammatory/Autoimmune disease (Hashimoto Disease) – antibodies attacking specific thyroid cellular components (e.g. thyroglobulin), causing gland damage Defective hypothalamic and pituitary function causing insufficient thyrotrophin secretion for normal stimulation of thyroid gland Dietary iodine deficiency  Goitre Enlarged thyroid gland Worldwide, over 90% cases of goitre are caused by iodine deficiency The "iodide pump “ of thyroid gland is very effective. Up to 30% of ingested iodide is taken up by the thyroid. When dietary iodide intake is insufficient for normal TH production, TSH secretion increases and thyroid cells proliferate:- a normal human thyroid gland of 25 g may grow to become a 250 g goitre under such circumstances. This is hypothyroid goitre. Hypothyroidism secondary to hypothalamic or ant.pit. failure does not result in goitre. NB:- Other causes may result in hyperthyroid goitre, these include- Grave’s Disease Excess TSH production from pituitary tumour 18  Hyperthyroidism – Graves Disease highly characteristic symptom of weight loss despite an increased intake of food. increased heat production causes excessive sweating, and a greater intake of water. trouble with heart rate and function and tremor (increased rate and involuntary muscle contraction) difficulty in swallowing or breathing due to compression of the esophagus or trachea by the enlarged thyroid gland (goitre). Major clinical signs in Graves disease are exophthalmos and periorbital edema diagnosed by an elevated serum free and total T4 or T3 level Serum TSH levels are low, because the hypothalamus and the pituitary gland are inhibited by the high levels of T4 and T3. Graves disease pituitary adenoma (primary endocrine disease) (secondary endocrine disease) éTSI (thyroid stimulating immunoglobulin) êTSI êserum TSH éserum TSH  Treatment of Hyperthyroidism SURGERY Partial or complete removal of gland – especially if enlarged gland obstructs neck veins and trachea, or if malignant tumour present DRUGS (1) Thioureylene (also called thiourea or thionamide) compounds (2) Iodine-containing preparations (3) b-adrenoceptor antagonists “Thioureylene” Antithyroid Drugs Thiocarbamide group ( S – C – N ) essential for activity propylthiouracil metabolized in body to active drug carbimazole methimazole (used in (used in UK) some other countries)  Effects of Thioureylenes Orally active - inhibit thyroid hormone synthesis: (i) prevent iodination of tyrosine residues in thyroglobulin – probably by interfering with peroxidase enzyme action (ii) prevent coupling reactions of monoiodo- and di-iodotyrosines CARBIMAZOLE or METHIMAZOLE often used first; common side effect is “skin rash”, so patient then switched to.. PROPYLTHIOURACIL – additional useful action of inhibiting deiodinase enzyme that converts T4 to T3 in many tissues Hormone synthesis inhibited rapidly (within 24 hr) BUT fall in hormone levels and effects takes several weeks because… (i) gland has large pre-existing hormone stores (ii) T4 is tightly bound to binding proteins in blood plasma – leads to slow T4 metabolism in the body and slow T4 excretion from the body (in urine) When hormone levels decrease to normal range, this can often be maintained by using lower drug doses – withdraw drug completely after 1 year in some patients  Iodine-containing Preparations (1) RADIOIODINE (I131) Major method of treating hyperthyroidism Taken orally as capsules of radioactive sodium iodide (NaI) – radioiodine in blood accumulates in thyroid gland Produces g-rays and (mainly) b-particles; short range of b-particles causes localized cell damage to thyroid follicular cells Used as single administration (given to adults and children but not to pregnant mothers – could harm foetal thyroid) Radioactive half-life of about 8 days – total cytotoxic effect develops over 1 – 2 months May produce hypothyroidism if too much gland damage – if so, may need thyroid hormone replacement therapy  Iodine-containing Preparations (2) POTASSIUM IODIDE (KI) AND IODINE if the intake of iodide exceeds 2 mg/day, the intraglandular concentration of iodide reaches a level that suppresses NADPH oxidase activity and the NIS and TPO (thyroid peroxidase) genes, and thereby the mechanism of hormone biosynthesis. This autoregulatory phenomenon is known as the Wolff-Chaikoff effect. Hence, given _as mixture of KI + iodine in water (called Lugol’s solution) – iodine converted to (I ) in liver Transient inhibitory effects for up to 2 weeks – then effects decline as gland becomes “tolerant” to iodine overload Used for short-term thyroid suppression (along with other antithyroid drugs) especially for a few days before surgery to gland Used with the other antithyroid drugs for emergency treatment of “thyroid storm” – life-threatening excessive hormone levels!  b-Adrenoceptor Antagonists PROPRANOLOL (usually) No direct effect on thyroid hormone synthesis, release etc. Used to block noradrenaline overstimulation of cardiac b1-adrenoceptors [Increased sympathetic nervous system (noradrenaline) activity in hyperthyroidism can cause dangerously increased heart rate (tachycardia) and abnormal heart rhythms (dysrhythmias)] Particularly used in patients (a) awaiting gland surgery or (b) when waiting for suppression of thyroid hormone levels by thioureylenes to take effect  Treatment of Hypothyroidism Hypothyroid individuals have weight gain despite poor appetite, cold intolerance, constipation and lethargy. Synthetic (manufactured) L-THYROXINE (T4) and L-TRIIODOTHYRONINE (T3 or L- IOTHYRONINE) used as “replacement therapy” T4 – first choice, daily oral tablets, initial build-up to maximum effects takes several days because …. At start of treatment, initially absorbed T4 molecules bind reversibly to blood plasma proteins; need these binding sites to become saturated with T4 before enough accumulates as “free” hormone in the plasma to enter and have effects in body tissues T3 – i.v. injection in emergencies to treat “hypothyroid coma” due to its more rapid action than T4 Important side effect of administered thyroid hormones: Cardiac dysfunction if “replacement therapy” dose too high  The source and transport of T3 in the brain T4 enters a glial cell and is converted to T3 by the D2 deiodinase. T3 exits the cell and is transported into a neuron via MCT8. Inside the neuron, it either enters the nucleus, binding a TR, or is inactivated to T2 by D3 deiodinase. D2, D3, deiodinases; RXR, retinoid X receptor; TR, TH receptor; TRE, TH response element. ? signifies that the transport mechanism is uncertain. C.E. Schwartz & R.E. Stevenson  MCT8 mutations Monocarboxylate transporter 8 (MCT8) gene is located on the X chromosome Males:- One copy of MCT8 gene. Deleterious mutations result in Allan-Herndon-Dudley syndrome Affected males have abnormal plasma TH concentrations and neurological abnormalities. Failure to deliver TH to specific foetal brain areas irreversibly impairs CNS development (global developmental delay, central hypotonia, spastic quadriplegia, impaired gaze and hearing). Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S. Am J Hum Genet. 2004 74: 168-75 Females:- Two copies of MCT8 gene. Heterozygous mutant females have mild thyroid phenotype and no neurological defects. 50% chance of passing mutation onto a son.