Thyroid Hormone Synthesis, Secretion, Action, Receptors & Antibodies

Thyroid Hormone Synthesis, Secretion, Action, Receptors & Antibodies
Emily Brennan PGY-4, Endocrinology August 13, 2014

Objectives At the end of this lecture, you will be able to understand:
the synthesis of thyroid hormone thyroid hormone transport and activation at local tissues the regulation and feedback mechanisms of the thyroid axis the downstream action of thyroid hormone on tissues the role and value of thyroid antibodies

Recall: The Thyroid The thyroid is the largest single organ specialized for endocrine hormone production The thyroid’s function is to secrete an appropriate amount of the thyroid hormone primarily as T4 The gland is composed of closely packed, spherical units termed follicles It’s function is to secrete an appropriate amount of the thyroid hormones, primary t4), and also In target tissues, T3 interacts with nuclear T3 receptors that are in turn boudn to sepcial nuceltoide sequences in the promoter regions of genes that are positively/negatively regulated by thyroid hormone follicles, which are invested with a rich capillary network

Thyroid Hormone and Related Structures
Comprised iodinated thyronines two tyrosine molecules joined by an ether linkage Produced only by the follicular cells of the thyroid Iodine is a key structural component of thyroid hormone Structure of thyroid hormone Tyrosine- benzene ring with the ammonia group Ether linkage – link via oxygen

Thyrocyte Williams The thyroid follicular epithlium has many features in common with other secretory cells, and some that are peculiar to the thyroid From the apex of the follicualr cell, numerous microvilli extent into the colloud It is at or near this surface of the cell that iodination, exocytosis, and the initial phase of hormone secetion (i.e. colloid reception) occur The nucleus has no distinctive features The cytoplasms has extenise endoplasmic reticulum w/ microsomes The endoplasmic reticulum contains the precursor to the thyroglobuulin The carbohydrate compoent of thyroglobuin is added to this precursor in the Golgi apparatus, which is locally apically

Thyroid Hormone Synthesis
Requirements for hormone production: Sodium-Iodide Transporter (NIS) Iodine Thyroglobulin (Tg) Thyroid peroxidase (TPO) present, function, and uninhibited.

1. Trapping -- Active transport of iodide across the basement membrane into the thyroid cell
Sodium-iodide symporter (NIS) Location: basal membrane of the thyrocyte Function: actively transports iodide from the blood; maintains concentration of iodide ~30x greater than plasma Regulation: stimulated by TSH, suppressed by excess iodide Williams The thyroid follicular epithlium has many features in common with other secretory cells, and some that are peculiar to the thyroid From the apex of the follicualr cell, numerous microvilli extent into the colloud It is at or near this surface of the cell that iodination, exocytosis, and the initial phase of hormone secetion (i.e. colloid reception) occur The nucleus has no distinctive features The cytoplasms has extenise endoplasmic reticulum w/ microsomes The endoplasmic reticulum contains the precursor to the thyroglobuulin The carbohydrate compoent of thyroglobuin is added to this precursor in the Golgi apparatus, which is locally apically

1. Trapping -- Active transport of iodide across the basement membrane into the thyroid cell
Pendrin Location: apical border of the thyrocyte Function: transports iodide into the membrane-colloid interface to become substrate for thyroid hormonogenesis Mutation: Pendred syndrome (goitre and congenital deafness) Greenspans Iodide (I-) is transported across thyrocytes’ basal membrane by the NIS Membrane-bound NIS, which derives its energy from a Na+-K+-ATPase, allows the human thyroid gland to maintian a concentration of free iodide 30 to 40 times higher than that in plasma NIS action is stimulated physiologically by TSH and pathophysiologically by the TSH-receptor stimulating antibody of Graves disease Also expressed in salivary, gastric, and breast tissues, but concentrate iodide to a lesser extent, and do not organify or store iodide, and their NIS activites are not stimulated by TSH Large amounts of iodide suppress both NIS activity an the NIS gene expression, representing iodinde autoregulaiton At the thryocyte’s apical border, a second iodide transport protein, pendrin, transports iodide into the membrane-colliod interface, which is becomes a substrate for thyroid hormonogenesis Mutations in pendrin (PDS or SLC26A4) gene impairing its function cause a Pendred syndrome (goiter, and hearing loss)

Iodine Essential micronutrient consumed in food and water
Recommended intake: 150 mcg adults 200 mcg pregnant/lactating women mcg children When iodine intake is less than 50 mcg/d, a normal-sized thyroid cannot sustain adequate hormone production The concentrating ability of the thyroid creates an intrathyroid pool (8-10 mg) Dietary iodine deficiency (less than 100 mcg/d); affects about 2 billion people The thyroid gland concentrates the uses only a fraction of the iodide supplied to it for hormone synthesis, and the remainder returns to the extracellular fluid pool The active concentrating mechanism and the subsequent organification of intracellular iodine, the intrathyroidal pool of iodine is very large (8-10 mg) This iodine provides a buffer in the event of temporary dietary iodine deficiency Foods high in iodine: eggs, seafood, milk, green vegetables, beans

Thyroglobulin A large glycoprotein molecule, composed of two subunits
Structure: Includes 140 tyrosyl residues, but only four tyrosyl sites are sterically oriented for effective hormornogenesis in each molecule Role: serves in synthesis and storage of thyroid hormone Regulation: TSH regulates the expression of the thryoglobulin gene

Thyroglobulin thyroglobulin mRNA translated into RER ↓ glycosylated and transported to golgi apparatus incorporated into exocytic vesicles fused with basement membrane at apical-colloid border, Tg is iodinated Greenspans After thyroglobulin mRNA is translated in the RER, the protein is glycosylated during transport through the Golgi apparatus, where thyroglobulin dimers are incorporated into exocytic vesicles These vesicles then fuse with the cell’s apical basement membrane, from which they are released into the follicular lumen There, at the apical-colloid border, tyrosine residues in thyroglobulin are iodinated

2. Organification -- oxidation of iodide and iodination of tyrosyl residues in thyroglobulin
Thyroid Perioxase (TPO) A membrane-bound glycoprotein Function: catalyses both iodide oxidation and covalent linkage of iodine to the tyrosine residues of thyroglobulin Location: Cell-Colloid Interface Regulation: gene expression stimulated by TSH Inhibition: methimazole, carbimazole, and propylthiouracil Within the thyroid cell, at the apical-colloid interface, iodide is rapidly oxidized by locally produced hydrogen peroxidase in a reaction catalyzed by TPO The resulting active iodide intermediate is bound to tyrosyl residues in thyroglobulin The required hydrogen peroxide is probably generated by an NADPH oxidase in the presence of calcium cations, a process also stimulated by TSH

3. Coupling -- linking pairs of iodotyrosine molecules within the thyroglobulin to form T3 and T4
The coupling of iodotyrosyl resides is also catalyzed by TPO Thought to be an intramolecular process involving the oxidation of two iodotyrosyl residues brought into proximity by the tertiary and quatenary structures of thyroglobulin, and it involves a linkage and splitting to form an iodothyronine

Coupling of iodotyrosine molecules
Boron WF (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300. ISBN

4. Pinocytosis and then proteolysis of thyroglobulin with release of free iodothyronines and iodotyrosines into circulation

Proteolysis of Thyroglobulin and Thyroid Hormone Secretion
Colloid is engulfed in vesicles by pinocytosis and absorbed into the cell ↓ Lysosomes then fuse with the vesicle Releases T4 and T3 and inactive peptides The biologically active thyroid hormones T4 and T3 enter the circulation DIT and MIT are deiodinated and their iodide conserved Greenspans

5. Deiodination of iodothyroxines within the thyroid cell with conservation and reuse of liberated iodine

6. Intrathyroidal 5’-deiodination of T4 to T3
MIT and DIT formed during the synthesis of thyroid hormones are deiodindated Occurs by intrathyroidal deiodinasesfound in mitochondria and microsomes that act on the iodotyrosines MIT and DIT, but not on T3 and T4 The 5’-deiodinase that converts T4 to T3 in peripheral tissues is also found in the thyroid gland

Summary

Thyroid Hormone Transport
Both T3 and T4 are poorly soluble in water, and therefore, circulate bound to plasma proteins 0.04% T4 unbound 0.4% T3 unbound Three major transport proteins: Thyroxine-binding globulin (TBG) Transthyretin Albumin The plasma protein binding permits blood delivery of the iodothyronines, which are otherwise poorly soluble in water Creates a large circulating thyroid hormone pool with a stable 7-day plasma half-life and ensures homogenous distribution of thyroid hormone in target tissues

Thyroxine-Binding Globulin (TBG)
Liver-derived glycoprotein Each TBG molecule has a single binding site for T4 or T3 It carries about 70% of circulating thyroid hormones (high binding affinity for T4 and T3) TBG levels can decrease in major systemic illness, and due to cleavage by leukocyte proteases, and its binding affinity for the thyroid hormone can be reduced The glycosylation of TBG influences its clearance from the plasma and its behaviour In estrogen treated patients, there is an increase in the prevalence of the more acidic bands of TBG, and this is cleared more slowly from plasma. Binding of T4 and T3 ty TBG is inhibited by phenytoin, saliyltates, furosemide, fenclofenac, and mitotane

Conditions Affecting Binding of TBG
Congenital TBG deficiency, X-linked recessive; low total T4/T3, but free hormone levels are normal; euthyroid Congenital TBG excess: elevated total T4/T3, normal fT4/fT3, euthyroid Physiologic Pregnancy/estrogen – increase the sialic acid content of TBG, decrease metabolic clearance and elevated TBG levels Pathophysiologic Estrogen secreting tumours, OCP, acute hepatitis (increased siailac acid) Systemic illness – decrease TBG due to cleavage by leukocyte protease, and decrease binding affinity; lowers hormone concentrations Drugs Salicylates, high dose phenytoin, furosemide – bind to TBG, displace T4/T3

Transthyretin Formerly known as: thyroxine-binding prealbumin
Binds to 10% of circulating T4 Affinity for T4 is 10-fold greater than for T3 Expressed in the choroid plexus the major thyroid hormone-binding produced in the CSF The dissociation of T4 and T3 from transthyretin is rapid, so that transthyretin is a source of readily available T4 Conditions Affecting Binding Congenital increased affinity for transthyretin binding for T4 elevated total T4, but normal fT4 Ectopic production of transthyretin can occur w/ pancreatic and hepatic tumours causes euthyroid hyperthyroxinemia Increased affinity for transthyretin binding for T4 can occur as a heritable ondition Affected indivials have an elevated total T4, but normal free T4

Albumin Binds to T4 and T3 with a lesser affinity than TBG or transthyretin, but it has a high plasma concentration 15% of circulating T4 and T3 Rapid thyroid hormone dissociation rates from albumin make it a major source of free hormone to tissues Conditions Affecting Binding Hypoalbuminia (nephrotic syndrome, cirrhosis) is associated with a low total T4 and T3, but normal free hormone levels Familial dysalbuminemic hyperthroxiemia: AD where 25% albumin has a higher than normal T4 binding affinity  results in elevated total T4 level, but normal fT4 = euthyroid

Transport across Cell Membranes
Originally thought to be primarily passive; however, several specific thyroid hormone transport proteins have been identified: MCT8 MCT10 Organic anion transporting polypeptide 1C1 (OATP1C1) – predominantly in the brain, transports T4 preferentially In most cells, 90% of T3 is in the cytosol except the pituitary, where 50% of the T3 is in the nucleus

Metabolism of Thyroid Hormones
Most of the plasma pool of T3 (80%) is derived from: 5’-deiodination of T4 in the liver, kidney, and skeletal muscle Deiodination of the inner ring of T4 (5-deiodination) produces reverse T3 (metabolically inert) * Normal thyroid gland secretes about 100 nmol of T4 (equivalent to approx 75 mcg) and only 5 nmol of T3 daily Less than 5 nmol of metabolically inactive reverse T3 is produced *

Metabolisms of Thyroid Hormone
Three deiodinases enzymes catalyze these reactions: D1 D2 D3 permit local tissue and cellular modulation of thyroid hormone action

Deiodination D1 Location: most abundant form, found predominantly in liver, kidney, and lesser extent in thyroid gland, skeletal, and heart muscle, and other tissues Function: major converter of T4 to T3 Inhibition: PTU (not methimazole), amiodarone and iodinated radiocontrast dye Peripheral metabolism of thyroid hormone involves the sequential removal of iodine molecules converting tetraiodothyronine (T4) into a more active triiodothyronine (T3) as well as inactivating thyroid hormone prior to their excretion. In addition, thyroid hormone can undergo conjugation in the liver, which increases their solubility and facilitates their biliary excretion. The type I iodothyronine deiodinase is expressed predominantly in liver, kidney, and thyroid. It catalyzes both outer and inner ring deiodination of thyroid hormone. It is the primary site for clearance of plasma reverse triiodothyronine (rT3) and a major source of circulating T3. Type II deiodinase is expressed primarily in the human brain, anterior pituitary, and thyroid. It only has outer-ring deiodination activity and plays an important role in the local production of T3 in tissues expressing this enzyme. The type III deiodinase is located predominantly in human brain, placenta, and fetal tissues. It only has inner-ring activity and catalyzes the inactivation of T3 more effectively than that of T4, thereby regulating intracellular T3 levels.

Deiodination D2 Location: expressed in the brain and pituitary gland, where is maintains constant levels of intracellular T3 in the CNS Function: maintenance of the level of intraacellular T3 and its neuronal cellular functions D2 is very sensitive to circulating T4 Peripheral metabolism of thyroid hormone involves the sequential removal of iodine molecules converting tetraiodothyronine (T4) into a more active triiodothyronine (T3) as well as inactivating thyroid hormone prior to their excretion. In addition, thyroid hormone can undergo conjugation in the liver, which increases their solubility and facilitates their biliary excretion. The type I iodothyronine deiodinase is expressed predominantly in liver, kidney, and thyroid. It catalyzes both outer and inner ring deiodination of thyroid hormone. It is the primary site for clearance of plasma reverse triiodothyronine (rT3) and a major source of circulating T3. Type II deiodinase is expressed primarily in the human brain, anterior pituitary, and thyroid. It only has outer-ring deiodination activity and plays an important role in the local production of T3 in tissues expressing this enzyme. The type III deiodinase is located predominantly in human brain, placenta, and fetal tissues. It only has inner-ring activity and catalyzes the inactivation of T3 more effectively than that of T4, thereby regulating intracellular T3 levels.

Deiodination D3 Location: chorionic membranes of the placenta and glial cells in the CNS Function: inactivates T4 by converting it to rT3 and it inactivates T3 by converting it to 3,3’-T2 Elevated in hyperthyroidism and decreased in hypothyroidism, may help to insulate the fetus and the brain from T4 excess of deficiency Peripheral metabolism of thyroid hormone involves the sequential removal of iodine molecules converting tetraiodothyronine (T4) into a more active triiodothyronine (T3) as well as inactivating thyroid hormone prior to their excretion. In addition, thyroid hormone can undergo conjugation in the liver, which increases their solubility and facilitates their biliary excretion. The type I iodothyronine deiodinase is expressed predominantly in liver, kidney, and thyroid. It catalyzes both outer and inner ring deiodination of thyroid hormone. It is the primary site for clearance of plasma reverse triiodothyronine (rT3) and a major source of circulating T3. Type II deiodinase is expressed primarily in the human brain, anterior pituitary, and thyroid. It only has outer-ring deiodination activity and plays an important role in the local production of T3 in tissues expressing this enzyme. The type III deiodinase is located predominantly in human brain, placenta, and fetal tissues. It only has inner-ring activity and catalyzes the inactivation of T3 more effectively than that of T4, thereby regulating intracellular T3 levels.

Regulation of Thyroid Function
The thyroid participates with the hypothalamus and pituitary in the classic feedback control lopp In addition, there is an inverse realationship between the iodine lvel in the thyroid and the fractional rate o the hormone formation Such autoregulatory mechanisms stablize the rate of hormoen synthesis despite fluctations in the availability of iodine Stability in the hormone production is achieved in part because of the large intraglandular store of hormone buffers the effect of acute increases or decreases in hormone synthesis TRH (thyrotropin-releasing hormone) is expressed in the hypothalamus, the brain, the C cells of the thyroid gland, beta pancreas, myocardium, reproductive organs (prostate + testis), the spinal corde. The parvocellular region of the paravenricular nucleiu of the hypothalamus is the source of the TRH that regulates TSH. TRH travels in the axons of the neurons through the medium eminence and is released close to the hypothalamic-pit portal plexus. T3 suppresses the levelsl of the precursurs of TRH in the hypothalamus, but normal feedback regulations requies a combination of T3/T4 in the circulations, TSH the major regulator of the morphologic and functional states of the thyroid. It is a glycoprotein secreted by the thryotrophis in the anteromedial portion of the adenohypophysis. TSH is composed of an alpha-subunit and a 14 kd that is common to LH, FSH, nCG, and has a specific beta subunit synthesized by the thyrotrophs.

Thyrotropin-Releasing Hormone (TRH) Synthesized in hypothalamus (supraoptic and supraventricular nuclei) Stored in the median eminence and then transported via the pituitary portal venous system to the anterior pituitary Role: controls synthesis/release of TSH in the anterior pituitary (binds to G-protein receptor on thyrotrophs to initiate pathway to stimulate for TSH release). Pulsatile secretion, peak midnight-4am Negative Control: TRH gene expression negatively regulated by T3 and T4 T3/T4 downregulate the TRH receptors in the pituitary thyrotrophs Thyrotropin-releasing hormone Synthesized by neurons in the supraoptic and supraventricular nuclei of the hypothalamus Stored in the median eminence of the hypothalamus and then transported via the pituitary portal venous system down the pituitary stalk to the anterior pituitary, where it controls synthesis and release of TSH TRH is also found in the other portions of the hypothalamus, brain, and spinal cord TRH gene expression negatively regulated by T3 and T4 TRH binds to specific membrane receptors on TSH- and prolactin-secreting cells, stimulating TSH and prolactin release TRH-stimulated TSH secretion is pulsatile Thyroid homrones exert negative feedback on TSH production at the level of the pituitary by downregulating the number of TRH receptors on pituitary thyrotropes TRH is also found in the pancreatic islet cells, GI tract, placenta, heart, prostate, testes, and ovaries; TRH production in these peripheral tissues is not inhibited by T3 unknown role

Thyroid-Stimulating Hormone Structure: Glycoprotein composed of an alpha and beta subunit, that are noncovalently linked The alpha subunit is common to FSH and LH and hCG The beta subunit is unique to each hormone, conferring its specific binding properties and biologic activity Role: TSH controls thyroid cell growth and hormone production binding to a specific TSH G-protein receptor on the basolateral thyrocyte membrane activates a cascade responsible for promoting thyroid cell growth and hormone synthesis/release

Effects of TSH on the Thyrocyte
Changes in thyrocyte morphology induces pseudopods at the follicular cell-colloid border, accelerating thyroglobulin resorption, which increases thyroid hormone release Cell growth individual cells increase in size, vascularity, and over time, thyroid enlargement or goiter develops Iodine metabolism TSH stimulates all phases of iodide metabolism (increased uptake, transport, secretion); increased NIS expression Thyroglobulin and TPO mRNA expression Results in increased incorporation of iodide into MIT, DIT, T3 and T4

TSH Regulation Feedback
T3 concentration in the hypothalamus within the thyrotrophs cells regulates mRNA expression, TSH translation and T3/T4 release TRH - controls postranslational glycosylation and release of TSH Inhibitors of TSH somatostatin, dopamine, dopamine agonists, high dose glucocorticoids

TSH Receptor Conditions
Congenital Familial hyperthyroidism – activating mutation of TSH receptor Familial gestational hyperthyroidism – due to structural similar hCG hormone activated aberrant TSH receptor Acquired TSH receptor blocking antibodies (cause hypothyroid) Graves’ (most common) Autoantibodies bind and stimulate the TSH receptor

Iodine Autoregulation
The capacity of the thyroid gland to modify its function to the availability of iodine, independent of pituitary TSH Allows maintenance of adequate/appropriate thyroid hormone secretion is varying intake of iodine Major adaptation to low iodide intake is preferential synthesis of T3 over T4 Iodide excess inhibits many thyroidal functions including: iodide trapping thyroglobulin iodination (Wolff-Chaikoff) thyroid hormone release from the gland

Mechanism of Thyroid Hormone Action
Genomic Actions T3 interacts with its nuclear receptors to regulate gene activity T3 binds to a specific nuclear thyroid hormone receptor (TR), which in turns bind to DNA at specific sequences called thyroid hormone response elements (TREs) T3 has a 15-fold higher binding affinity for TRs than T4 There are tissue-specific preferences in expression of the various TRs (difference expression in hypothalamus vs kidney, liver, brain and heart) Nongenomic Actions Nongenomic actions mediated by T3 and T4 occur with certain enzymes Williams p. 340

Thyroid Hormone Genomic Actions
Cellular effects of thyroid hormones. Thyroid hormones (T3 and T4) enter the cell and bind to their receptors located in the nucleus. The affinity for T3 is greater than for T4. The thyroid nuclear receptors function as ligand-activated transcription factors that influence transcription from target genes. Nuclear receptors bind enhancer elements on DNA called hormone response elements to regulate transcription from genes. Binding of thyroid hormone, leads to recruitment of specific coactivators leading to gene activation and ultimately protein synthesis

Thyroid Hormone Actions
Fetal Development Iodide is found in thyroid tissue and pituitary TSH appear in the fetus at about 11 weeks The high placental content of D3 inactivates most maternal T3 and T4, and very little free hormone reaches fetal circulation After weeks, the fetus controls most of its own thyroidal secretion Brain and skeletal maturation are markedly impaired if congenital hypothyroidism is undiagnosed

Thyroid Hormone Action
Oxygen, Heat, Free Radicals Stimulates mitochondriogenesis, augmenting the cell’s oxidative capacity Increases basal metabolic rate Increases oxygen consumption and heat production by stimulation of Na-K-ATPase in all tissues

Cardiovascular System Increases the rate of depolarization and repolarization of the SA node, increasing heart rate Positive inotropic and chronotropic effects on the heart with heightened adrenergic sensitivity Lowers peripheral vascular resistance, increase intravascular volume  increased cardiac output Increases the rate of myocardial diastolic relaxation Increases the alpha receptors

Pulmonary System Maintains the ventilatory responses to hypoxia and hypocapnia in the brain stem respiratory center

Hematopoeitic Effects Increases the oxygen dissociation from hemoglobin and increases oxygen availability to the tissues Increased cellular demand for oxygen in hyperthyroidism leads to increased production of EPO and erythropoiesis

Skeletal System Stimulates bone turnover and increases bone resorption and to a lesser degree, bone formation

Gastrointestinal System Thyroid hormone promotes gut motility

Neuromuscular System In hyperthyroidism, there is increased protein turnover and loss in skeletal muscle Changes in speed of muscle contraction and relaxation, noted as hyperreflexia or delayed DTR in hypothyroidisms Fine distal hand tremor is typical in hyperthyroidism Hyperactivity and sluggishness can be striking

Reproductive System Thyroid hormone regulates the synthesis of pituitary hormones, stimulates growth hormone production, and inhibits TSH Low thyroid hormones levels can cause delayed puberty by impairing GnRH secretion

Lipids and Carbohydrate Metabolism increases hepatic gluconeogenesis and glycogenlysis, and intestinal glucose absorption ?thyroid hormone mediated decreases in insulin sensitivity  worse glycemic control Increase cholesterol synthesis and degradation (largely due to an increase in hepatic LDL receptors, accelerating LDL clearance)

Thyroid Antibodies Considered the hallmark of the autoimmune thyroid disorders Antibodies to thyroglobulin (Tg) Antibodies to thyroid peroxidase (TPO) Antibodies directed to TSH-receptor (TSHR)

TPO-Ab and Tg-Ab Polyclonal antibodies, IgG class
Develop as a secondary response to thyroid injury Not thought to cause the disease themselves (i.e. they cross the placenta and do not cause disease in fetus) Contribute to the disease mechanisms (complement fixing cytotoxicity or T cell activation) correlates well with thyroidal damage and lymphocytic infiltration These thyroid antibodies can cross the placenta, but do not pass the disease along from mother to baby Both antibodies can contribute the disease mechanisms (ie cause damange themselves) – like the TPO-Ab on the surface of a Bcell may be involved in the antigeon presentation, and activating thyroid-specific T cells to attach Others may have complement fixing cytotoxic activity The polyclonality mitigates against a primary role in disease pathogenesis, but they contribute to the disease mechanisms (how the damage is occurring)

TPO-Ab and Tg-Ab Not necessary for evaluation of thyroid function
Almost all patients with autoimmune thyroiditis are associated with Tg-Ab and TPO-Ab May be present in Graves’ as well TPO-Ab has a higher affinity and occurs in higher concentrations Tg-Ab and TPO-Ab are more common in patients with sporadic goitre, multinodular goiter, or isolated thyroid nodules and cancer than the general population Non-specific Not necessary for evaluation of thyroid function may be helpful to predict progression of subclinical hypothyroidisms These thyroid antibodies can cross the placenta, but do not pass the disease along from mother to baby Both antibodies can contribute the disease mechanisms (ie cause damange themselves) – like the TPO-Ab on the surface of a Bcell may be involved in the antigeon presentation, and activating thyroid-specific T cells to attach Others may have complement fixing cytotoxic activity The polyclonality mitigates against a primary role in disease pathogenesis, but they contribute to the disease mechanisms (how the damage is occurring)

TSHR-Ab The presence of antibodies favours an autoimmune cause for hyperthyroidism, but not sensitive or specific  interpretable only as part of the clinical scenario Testing for TSHR Ab are the test of choice; they usually are thyroid receptor stimulating antibodies (compete with TSH for binding to its specific receptor site in the cell membrane) can behave as stimulating, inhibitory or neutral Tg-Ab and TPO-Ab are also detectable in 50-90% of patients’ with Graves The thyroid gland itself is the major site of thyroid autoantibody secretion in autoimmune thyroid disease via the B cells that form part of the intrathyroidal infiltrate TBII – thryotropbin binding inhibitory immunoglobulins

From Williams

Take Home: Requirements for Thyroid Hormone Synthesis:
Sodium-Iodide Transporter (NIS) Iodine Thyroglobulin (Tg) Thyroid peroxidase (TPO) Steps for Thyroid Hormone Synthesis: Iodine trapping via the Sodium-Iodide Symporter Oxidation and organification of thyroglobulin by TPO Coupling pairs of MIT or DIT within the thyroglobulin molecule to form T3 and T4 De-iodination of MIT/DIT to conserve iodine Release of T3/T4 into circulation

Take Home: T3 and T4 are circulate bound to: thyroxine-binding globulin, transthyretinin, and albumin T4 undergoes 5’-deiodination to form T3 (the more biologically potent hormone) T3 acts on the cell nucleus to regulate gene expression and protein synthesis. Thyroid hormone has targets of action in most tissues in the body TSHR-Ab is the most specific for Graves’ disease, and is the mechanism for the disease TPO-Ab and Tg-Ab are evidence of thyroidal injury, but are nonspecific for diagnostic purposes

References Williams Textbook of Endocrinology 12th edition.
Greenspan’s Basic and Clinical Endocrinology. Endocrine Physiology. Lange. UpToDate Boron WF (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300. ISBN

Questions?

Thyroid Hormone Synthesis, Secretion, Action, Receptors & Antibodies

Similar presentations

Presentation on theme: "Thyroid Hormone Synthesis, Secretion, Action, Receptors & Antibodies"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Thyroid Hormone Synthesis, Secretion, Action, Receptors & Antibodies

Similar presentations

Presentation on theme: "Thyroid Hormone Synthesis, Secretion, Action, Receptors & Antibodies"— Presentation transcript:

Similar presentations

About project

Feedback