JULIA CREIDER, PGY5ENDOCRINE & METABOLISM
Thyroid Hormone Synthesis, Secretion, Action, Receptors &
Antibodies
Objectives
At the end of this presentation, you will be able to understand: Regulation and feedback mechanisms of the
hypothalamic-pituitary-thyroid axis Synthesis of thyroid hormone Thyroid hormone secretion and transport Downstream action of thyroid hormone on tissues Role of thyroid antibodies
Hypothalamic-Pituitary-Thyroid Axis
Hypothalamic-Pituitary-Thyroid Axis
Thyrotropin-Releasing Hormone (TRH)
Location: synthesized in hypothalamus, stored in median eminence then transported via pituitary portal venous system
Function: controls synthesis/release of TSH from anterior pituitary
Negative Control: gene expression negatively regulated by T3 and T4, which also down regulate TRH receptors in pituitary
Hypothalamic-Pituitary-Thyroid Axis
Thyroid-Stimulating Hormone (TSH)
Structure: glycoprotein composed of alpha and beta subunit Beta subunit unique Alpha shared by LH, FSH,
hCG Shared subunit mediates
thyrotoxicosis – transient gestational thyrotoxicosis and hyperthyroidism associated with trophoblastic tumours
Function: controls thyroid cell growth and hormone production
TSH Regulation
Feedback T3 concentration in the hypothalamus within the
thyrotrophs cells regulates mRNA expression, TSH translation and T3/T4 release
TRH controls post-translational glycosylation and release of TSH
Inhibitors of TSH Somatostatin, dopamine, dopamine agonists, high dose
glucocorticoids
Thyroid Gland Basics
Thyroid gland is located in the neck
Function is to produce appropriate amounts of thyroid hormones
Gland is composed of closely packed, spherical units termed follicles
Thyroid Hormone Structure
Comprised of iodinated thyronines
Produced by follicular cells
Iodide is key structural component
Follicular Cell
Thyroid Hormone Synthesis
Requirements: Iodide Sodium-Iodide Transporter (NIS) Thyroglobulin (Tg) Thyroid peroxidase (TPO)
Iodide
Shellfish, kelp, dairy, some vegetablesDietary intake in North America is ~150-300
mcg daily largely due to iodinization of saltThyroid uptakes ~60-75 mcg daily
Iodine Autoregulation
Capacity of thyroid 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
Trapping – Active transport of iodide
Sodium-Iodide Symporter (NIS)
Location: basal membrane of follicular cell
Function: actively transports iodide from blood
Regulation: stimulated by TSH, suppressed by excess iodide
Trapping – Active transport of iodide
Pendrin Location: apical
membrane of follicular cell
Function: transports iodide into the membrane-colloid interface
Mutation: Pendred syndrome (goiter and congenital deafness)
Thyroglobulin
Large glycoprotein, composed of two subunits
Structure: Includes 140 tyrosyl residues, but only four tyrosyl sites are sterically orientated for effective hormonogenesis in each molecule
Role: serves in synthesis and storage of thyroid hormone
Regulation: TSH regulates the expression of the thyroglobulin gene
Thyroglobulin
Organification – Oxidation of iodide and Iodination of tyrosyl residues in thyroglobulin
Thyroid Perioxase (TPO)
Function: catalyzes both iodide oxidation and covalent linkage of iodine to the tyrosine residues of thyroglobulin
Regulation: gene expression stimulated by TSH
Inhibition: methimazole, carbimazole and propythiouracil
Coupling– Linking pairs of iodotyrosine molecules within the tyroglobulin
Pinocytosis and Proteolysis – Return of thyroglobulin into cell and release of T4/T3
Pinocytosis Colloid is
engulfed in vesicles and absorbed into cell
Proteolysis Lysosomes fuse
with vesicle Releases T4
and T3 and inactive peptides
Deiodination – Iodothyroxines within the cell to conserve and reuse iodine
MIT and DIT are deiodinated
Intrathyroidal deiodinases found in mitochondria and microsomes
Stimulation of the Thyrocyte
TSH Receptor Activated by TSH G protein-coupled
receptor Also binds
TSHR stimulating, blocking and neutral antibodies
LH hCG
Also expressed in osteoclasts, fibroblasts, adipocytes and retroorbital adipocytes and skin
Effects of TSH on the Thyrocyte
Changes 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 and vascularity
Iodine metabolism TSH stimulates all phases of iodide metabolism (uptake,
transport, secretion), increased NIS expressionThyroglobulin and TPO mRNA expression
Results in increased incorporation of iodide into MIT, DIT, T3, and T4
Summary
Thyroid Hormone Transport
Both T3 and T4 are poorly water solubleCirculate bound to plasma proteins
Three major transport proteins: Thyroxine-binding globulin (TBG) Transthyretin Albumin
Thyroxine-Binding Globulin (TBG)
Liver-derived glycoprotein
Each TBG molecule has a single binding site for T4 or T3
Carries about 70% of circulating thyroid hormones (high binding affinity for T4 and T3)
Conditions Affecting Binding of TBG
Congenital TBG deficiency, X-linked recessive – low total T4/T3 but free
hormone levels are normal and euthyroid Congenital TBG excess – elevated total T4/T3, normal fT4/fT3 and
euthyroidPhysiologic
Pregnancy/estrogen – increase acid content of TBG, decrease metabolic clearance and elevated TBG levels
Pathophysiologic Estrogen secreting tumours, OCP, acute heaptitis Systemic illness – decrease TBG due to cleavage by leukocyte
protease and decrease binding affinity, lowers hormone concentrations
Drugs Salicylates, high dose phenytoin, furosemide – bind TBG, displace
T4/T3
Transthyretin
Formerly known as: thyroxine-binding prealbumin
Binds 10% of circulating T4Affinity for T4 is 10-fold greater than for T3Expressed in the choroid plexusDissociation of T4 and T3 from transthyretin is
rapidConditions Affecting Binding
Congenital increased affinity – elevated total T4 but normal fT4
Ectopic production within pancreatic and hepatic tumours
Albumin
Binds T4 and T3 with lesser affinity, but high plasma concentration
15% of circulating T4 and T3Rapid thyroid hormone dissociation, makes it
major source of free hormone to tissuesConditions Affecting Binding
Hypoalbuminia – low total levels but normal free Familial dysalbuminemic hyperthroxiemia – higher
affinity for T4, elevated total T4 but normal free T4
Metabolism of Thyroid Hormones
Most of plasma pool of T3 (80%) is derived from: 5’-deiodination of T4
in the liver, kidney and skeletal muscle
Diodination of the inner ring of T4 (5-deiodination) produces reverse T3 (metabolically inert)
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Metabolism of Thyroid Hormones
Three deiodinases enzymes catalyze reaction: 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
Deiodination
D2 Location: expressed
in the brain and pituitary gland, where it maintains constant levels of intracellular T3 in the CNS
Function: maintenance of the level of intracellular T3 and its neuronal cellular functions
D2 is very sensitive to circulating T4
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
Transport through Cell Membranes
Originally thought to be primarily passiveSeveral specific thyroid hormone transport
proteins identified: MCT8 MCT10 Organic anion transporting polypeptide 1C1
(OATP1C1) – predominately in the brain, transports T4 preferentially
Most cells, 90% of T3 is in cytosol except pituitary, where 50% of T3 is in the nucleus
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)
Non-genomic Actions Actions mediated by T3 and T4 occur with certain
enzymes
Mechanism of Thyroid Hormone Action
Thyroid Hormone Action
Fetal Development Iodide is found in
thyroid tissue and pituitary TSH appear in the fetus at ~11 weeks
High placental content of D3 inactivates most maternal T3/T4
After 15-18 weeks, the fetus controls most of its own thyroidal secretion
Thyroid Hormone Action
Metabolism Effects Increases basal metabolic rate Increases oxygen consumption and heat production by
stimulation of Na-K-ATPase in all tissues Stimulates mitochondriogenesis, augmenting the
cell’s oxidative capacityLipids and Carbohydrate Metabolism
Increases hepatic gluconeogenesis and glycogenlysis and intestinal glucose absorption
Increase cholesterol synthesis and degradation (largely due to an increase in hepatic LDL receptors, accelerating LDL clearance)
Thyroid Hormone Action
Cardiovascular System Lowers peripheral vascular resistance Positive inotropic and chronotropic effects with
heightened adrenergic sensitivity Increased cardiac output Increases the rate of myocardial diastolic relaxation Increases the rate of depolarization and repolarization
of SA node increasing heart rate
Thyroid Hormone Action
Pulmonary System Maintains the ventilatory responses to hypoxia and
hypocapnia in the brain stem respiratory centerSkeletal System
Stimulates bone turnover and increases bone resorption
Gastrointestinal System Promotes gut motility
Hematopoeitic Effects Increased cellular demand for oxygen in
hyperthyroidism leads to increased production of EPO and erythropoiesis
Increases the oxygen dissociation from hemoglobin
Thyroid Hormone Action
Neuromuscular System Changes in speed of muscle contraction and
relaxation Fine distal hand tremor in hyperthyroidism Hyperthyroidism, there is increased protein turnover
and loss in skeletal muscleReproductive System
Regulates synthesis of pituitary hormones, stimulates GH production and inhibits TSH
Low levels can cause delayed puberty by impairing GnRH secretion
Thyroid Antibodies
Hallmark of autoimmune thyroid disorders
Antibodies to: Thyroglobulin (Tg) Thyroid peroxidase (TPO) Stimulate TSH-receptor (TSHR)
Anti-TPO and Anti-Tg
Polyclonal antibodies, IgG class Develop in response to thyroid injury No thought to be disease causing Contribute to disease mechanism
Complement fixing cytotoxicity or T cell activation Correlates well with thyroidal damage and
lymphocytic infiltration
Anti-TPO and Anti-Tg
Almost all patients with autoimmune thyroiditis are associated with anti-TPO and anti-Tg May be present in Graves as well
Anti-TPO has a higher affinity and occurs in higher concentrations
More common in patients: Sporadic goiter Multinodular goiter Isolated thyroid nodules and cancer
Not necessary for evaluation of thyroid function May be helpful to predict progression of subclinical
hypothyroidism
TSHR Antibodies
Presence favours an autoimmune cause for hyperthyroidism
Not sensitive or specific, need to interpret as part of clinical scenario
Usually are stimulating antibodies that compete with TSH for binding to its specific receptor site Can be stimulating, inhibitory or neutral
Anti-Tg and Anti-TPO are also detectable in 50-90% of patients with Graves
Take Home Messages
Requirements for thyroid hormone synthesis: Sodium-Iodide Transporter (NIS) Iodine Thyroglobulin (Tg) Thyroid peroxidase (TPO)
Steps for thyroid hormone synthesis: Iodine trapping via NIS Oxidation and organification of Tg by TPO Coupling pairs of MIT or DIT within the Tg molecule to
form T3/T4 Deiodination of MIT/DIT to conserve iodine Release of T3/T4 into circulation
Take Home Messages
T3 and T4 circulate bound to: thyroxine-binding globulin, transthyretin and albumin
T4 undergoes 5’-deiodination to form T3
T3 acts on the cell nucleus to regulate gene expression and protein synthesis
Thyroid hormone has target actions in most tissues
Take Home Messages
Tightly regulated through hypothalamic-pituitary-thyroid axis
TSH-Ab is most specific for Graves’ disease and is the mechanism for disease
Anti-TPO and Anti-Tg are evidence of thyroidal injury but are nonspecific for diagnostic purposes
References
Williams Textbook of Endocrinology 12th edition
Greenspan’s Basic and Clinical EndocrinologyEndocrine Physiology. Lange.UpToDateBoron WF (2003). Medical Physiology: A
Cellular and Molecular Approach. Elsevier/Saunders. P. 1300.
Questions