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Thyroid Gland Parts I and II The Gentlemen's Guide Like a Sir Learning Objectives 1. 2. 3. 4. 5. 6. 7. Identify the steps in the biosynthesis, storage, and secretion of tri-iodothyronine (T3) and thyroxine (T4) and their regulation. Describe the absorption, uptake, distribution, and excretion of iodide. Explain the importance of thyroid hormone binding in blood on free and total thyroid hormone levels. Understand the significance of the conversion of T4 to T3 and reverse T3 (rT3) in extra-thyroidal tissues. Describe the physiologic effects and mechanisms of action of thyroid hormones. Explain what conditions can cause an enlargement of the thyroid gland. Understand the causes and consequences of A. B. over secretion of thyroid hormones under secretion of thyroid hormones Location of Thyroid Gland Thyroid • • • • Located in the neck over the first part of the trachea Humans-”butterfly” –two lateral lobes connect by an isthmus Nodules on thyroid=parathyroid glands (2 superior/2 inferior) Parafollicular (C cells)—major source for hormone calcitonin canine Chemistry of Thyroid Hormone • Thyroid hormones are derivatives of the amino acid tyrosine covalently bound to iodine • Iodine bound at either 3 or 4 positions on two linked tyrosines • Other iodinated molecules can be generated (example: rT3 but are inactive) • T3 and T4 are poorly soluble in water (blood) so are carried bound to proteins • Principle binding protein is thyroid-binding globulin • Other important carrier proteins are albumin and transthyrein • Carriers allow a stable pool of hormone in blood that can release free hormone to tissues (sites of action) Steps in Biosynthesis, Storage and Secretion of T3/T4 Raw materials: 1: Tyrosine-sourced from thyroglobulin in colloid thyroglobulin secreted by thyroid epithelial cells 2: Iodide (I-)-uptake from blood by thyroid epithelial cells (outer plasma membrane has a Na+/I- symporter) once in cell transported to colloid with thryoglobulin Steps in Biosynthesis, Storage and Secretion of T3/T4 1. Thyroid peroxidase adds the (iodide) I- to tyrosines on thyroglobulin (organifaction of iodide). 2. Synthesis of thyroxine (T4) or tri-iodotyrosine (T3) from two iodotryosines Remember that the hormone is still tied to the thyroglobulin ---needs to be liberated into the circulation as needed Thyroid Hormone Cycle Steps in Biosynthesis, Storage and Secretion of T3/T4 Release of T3/T4 from colloid: 1. Thyroid epithelial cells ingest iodinated thyroglobulin from apical surface (endocytosis) 2. Colloid filled endosomes fuse with lysosomes that contain hydrolytic enzymes that digest the iodinated thyroglobulin • Release of active thyroid hormone 3. Free thyroid hormone diffuses across the basolateral epithelial membrane into ECF (blood) 4. Free thyroid hormone quickly bound to carrier proteins to be transported and release at target cells. Transport of Thyroid Hormone • T3/T4 are highly bound to plasma protein carriers – – – – – Major carrier is thyroxine–binding globulin (TBG) Secondary carriers are albumin and thyroxine-binding prealbumin Approximately 99.9% of T4 bound and <0.1% is free hormone [T3]free in plasma <1% (more active than T4) Because of tight binding to plasma proteins has long half life • (T4=7 days) • Free hormone is what is captured by target cells and • exerts its biological effect before degradation Transport of T4/T3 to peripheral tissues • Increases (pregnancy) and Decreases (liver diseases) in circulating plasma • TBG levels change the amount of TBG bound hormone • However, They only transiently effect the amount of biologically active FREE hormone because the negative feedback of free hormone on TSH levels • Remember: TSH stimulates release of free hormone • Example: In pregnancy, a fall in T3 levels, causes a compensatory increase in TSH levels that in turn will increase production of free hormone in the circulation. Increased thyroid hormone shuts off TSH • But total [free hormone = T3] may be higher • Thyroxine (T4) conversion to T3 • • • • T4 is the dominant secreted/circulated form from the thyroid However: Most of the T4 secreted by thyroid is metabolized to T3 De-iodinated at the 5’ or 5 position in peripheral tissues to either T3 or rT3 (inactive) • Since T4 is primarily converted to T3 that has a higher affinity for thyroid hormone receptors --sometimes T4 is considered a prohormone for T3 • • Ratio of T4 to T3 is 5:1 in circulation Potency of T4 to T3 is 1:10 (affinity) • T4 is converted to T3 by peripheral peroxidase Mechanism of Action and of T3/T4 • • • • • • • Receptors for thyroid hormone action are INTRACELLUAR DNA-BINDING PROTEINS Function as hormone responsive transcription (HRE) factors • Mode of action is similar to steroid hormones T3 binds to short repetitive sequences of DNA called Thyroid Response Elements (TRE) TRE DNA sequence= AGGTCA Can be arranged as direct repeats, pallindromes or inverted repeats. Can be monomer (AGGTCA) homodimer (AGGTCANNNNAGGTCA) or a heterodimer (T3+ another protein in complex) with the retinoic acid receptor (RXR) another member of the nuclear receptor subfamily Heterodimer is the high affinity form and thought to be the major functional entity Mechanism of Action and of T3/T4 • Thyroid hormone receptors bind to the TRE DNA with and without T3 • Biological effects of T3 bound vs. T3 unbound receptor are dramatically different Generally: 1: Binding of receptor w/o T3 to DNA transcriptional repression results in compacted “turned off” chromatin HDA=histone deactelyase 2: Binding of T3+receptor complex transcriptional activation complex recruits different co-activators proteins – conformational changesleads to gene activation HAT=histone transacetylase Thyroid Hormone Receptors Structure Mammalian Thyroid Receptors are encoded by two genes α and β Three Functional Domains: 1. Transactivation • amino terminus---interacts with other transcription factors 2. DNA Binding • Recognition of HRE for binding 3. Ligand-Binding and dimerization • T3 lignad binding at carboxy terminus Primary gene transcript for both forms can be alternately spliced to form multiple α and β isoforms. Thyroid Receptors The different isoforms of thyroid receptor have patterns of expression that differ by tissue and developmental stage. Examples: • α1, α2 and β1 isoforms are expressed in virtually all tissues • β2 found predominantly in hypothalamus, anterior pituitary and developing ear • α1 first to be expressed in fetus and β1, β2 up-regulated in developing brain after birth • They activate several genes known to important in brain development such as myelin basic protein Regulation of Thyroid Hormone Secretion Hypothalamic-pituitary-thyroid axis • • Control of thyroid hormone secretion is a NEGATIVE FEEDBACK LOOP Binding of TSH on thyroid epithelia enhances all the processes for hormone synthesis of 1. Iodide transporter 2. Thyroid peroxidase 3. Thyroglobulin • Magnitude of the TSH signal sets the rate for endocytosis of colloid TSH Faster rates of colloid synthesis hence more hormone in circulation TSH Decrease in colloid synthesis hence less hormone in circulation COLD Exposure can increase TRH release enhanced thyroid hormone release Degradation of Thyroid Hormone These steps occur in peripheral tissues: 1. Deiodination and decarboxylation 2. Glucuronidation/Sulfonation in liver 3. Excretion into bile ducts 4. Excretion of glucuronide conjugate in urine Thyroid Hormone and Cellular Metabolic Rate Many of the effects of T3 are secondary to increased BMR • sweating and thermogenesis – heat elimination from skin • Rate and depth of breathing – need for O2 • Cardiac output – from increases in SV and HR and changes in contractile force • Improve memory and learning capacity • Most tissues – Increase in O2 consumption – Increase in heat production • Mitochondria increase in size and number • Key respiratory enzymes increase Physiological Effects of Thyroid Hormone Metabolism: • Thyroid hormone stimulates most tissues of the body resulting in an increase of basal metabolic rate • This involves: 1. Increases body temperature • O2 consumption and ATP hydrolysis 2. Stimulates fat mobilization leading to increases of [FA] in plasma • FA oxidation is also increased 3. Increases in carbohydrate metabolism • increased insulin dependent glucose entry into cells, gluconeogenesis ,glycogenolysis Growth: • Thyroid hormone synergistically combines with growth hormone to enhance grow processes Physiological Effects of Thyroid Hormone Development: • Critical for development of fetal and neonatal brain Cardiovascular: • Promotes vasodilation ---increased vascular flow in organs • Increases cardiac output, cardiac rate, and cardiac contractility CNS: • Decreased hormone sluggish mental activity • Increased hormone related to anxiety Reproduction: • Low hormone levels frequently associated with infertility (female) (male?) Thyroid and Bone • Bone cells have receptors for Thyroid hormone: • Necessary for growth and maturation of the skeleton • If thyroid hormone levels are too high • Osteoporosis and bone loss Thyroid and the Heart: T3-Responsive Genes for Important Cardiac Proteins Positive regulation-increased gene expression • Sarcoplasmic reticulum calcium adenosine triphosphatase • Myosin heavy chain α • β1-Adrenergic receptors • Guanine-nucleotide-regulatory proteins • Sodium/potassium adenosine triphosphatase • Voltage-gated potassium channels Negative regulation-decreased gene expression • T3 nuclear receptor α1 • Myosin heavy chain β • Phospholamban • Sodium/calcium exchanger • Adenylyl cyclase types V and VI Thyroid Function in Pregnancy and Fetal Development Maternal Thyroid Function in Pregnancy: Normal changes in thyroid function during pregnancy include: 1a) 2-fold increase T4 (thyroxine) binding globulin (TBG) stimulated by increases in estrogen 1b) Increased levels of TBG decrease free T4 therefore more TSH is made, in turn, increasing T3 and T4 1c) Increased amounts of thyroid hormone balance reached at 20 weeks and maintained until parturition 2. Increased demand for iodine—significant increase in pregnancy clearance of I- by kidney and siphoning of Iby fetus from maternal circulation 3. Thyroid stimulation by hCG—TSH and hCG similar enough that hCG can increase mimics TSH at gland receptor stimulates T3 release while TSH maybe suppressed (graph) Some women may develop transient hyperthryoidosis in pregnancy or if a woman has subclinical hypothryoidism the demand of fetus can precipitate hypothyroidism. Thyroid and Fetal Brain Thyroid receptors present in brain tissue before fetus is synthesizing its own hormone. • During fetal brain development thyroid hormone assists in activation of genes (HRE) involved with terminal stages of brain differentiation 1. Synaptogenesis 2. Growth of dendrites and axons 3. Myelination 4. Neuronal migration Thyroid Hormone Resistance • Mutations in β receptor gene that abolish ligand-binding • In most families transmitted as dominant trait • Clinically: • Hypothyroidism with goiter • Elevated serum [T3] and [thyroxine] and normal or elevated serum [TSH], significant number of pediatric patients show attention deficit disorder. – Activity is decreased because there is no receptor binding. Graves Disease – Most common form of hyperthyroidism – Antibodies Thyroid stimulating immunoglobulins (TSIs) form against the TSH receptor of the thyroid gland – TSI’s bind to TSH receptor and mimic action of TSH – Results in Goiter and increases thyroid hormone and decreases in TSH because of negative feedback due to increased thyroid hormone in plasma Predicted Changes in Graves 1. Increased metabolic rate 2. Heat intolerance and sweating 3. Increased appetite but weight loss 4. Palpitations and tachycardia 5. Nervousness and emotional swings 6. Muscle weakness 7. Tiredness but inability to sleep – Many patient’s develop protruding eyeballs (exopthalmos) • Degenerative changes in extraocular muscles resulting from autoimmune reaction Hypothyroidism Hashimoto’s Thyroiditis • • • • Autoimmune destruction of gland Also called Autoimmune Thyroiditis Predicted changes 1) Decreased metabolic rate 2) Cold intolerance and decreased sweating 3) Weight gain w/o increased appetite 4) Bradycardia 5) Slowness of speech, thought and movement 6) Lethargy and sleepiness Accummulation of mucoplysacchrides in interstial spaces----”puffiness” of skin myxedema Decreased Thyroid hormone increased TSH levels (may lead to compensatory goiter) Thyroid Deficiency In Fetus and Neonate Fetus has two potential sources of thyroid hormone Maternal Fetal • Fetus begins to make T3/T4 at approximately 12 weeks gestation • Substantial transfer of hormone across the placenta • placenta has a de-iodinases that converts T4 to T3 Three forms of hypothyroidism in Pregnancy: 1. Isolated Fetal Hypothyroidism 2. Isolated Maternal Hypothyroidism 3. Iodide Deficiency (combined maternal and fetal hypothyroidism) Cretinism • Severe hypothyroidism resulting stunted growth and mental retardation – Athyrotic cretinsim • thyroid aplasia or Iodine deficiency in utero – Endemic cretinism • iodine deficiency – Spasticity, deaf-mutism, motor dysfunction • Symptoms – Puffy face, short stature, protruding abdomen and swollen tongue, slow reflexes Iodide Deficiency • Combined maternal-fetal hypothyroidism • Most common cause of preventable mental retardation world-wide • Results in cretinism, mental retardation,deaf mutism and spasticity • Supplement with iodine in 1st and 2nd trimester (later will not prevent defects) • Endemic Goiter – high plasma TSH stimulates gland Hyperthyroidism in Pregnancy Gestational Hyperthyroidism • Increased risk for: • – Preeclampsia – Premature labor – Fetal or perinatal death – Low birth weight May be caused by Grave’s Disease • Auto-antibodies against TSH receptor Fetal Hypothyroidism Sporadic Congenital Hypothyroidism • Fetal gland doesn’t produce enough hormone – Normal at birth (maternal compensation) • Needs rapid diagnosis shortly after birth or risk child having permanent mental and growth retardation Maternal Hypothyroidism • Female hypothyroidism frequently associated with infertility • If pregnancy does occur there is an increased risk of fetal death and gestational hypertension • Subclinical maternal hypothyroidism – Diagnosed retrospectively – Auto-antibodies to thyroid that can cross placenta – Children with lower IQ scores Hamburger Thyrotoxicosis Rare Case A 61 yr. old woman in Canada presented to physicians with intermittent hyperthyroidism that would resolve on its own over 2-3 months. They saw rapid weight loss, increased sweating and palpitations, tremor in her hands and a heart rate of 112 beats/minute. Diagnosis was confirmed by and elevated free T4 (46 compared to 9-23) and a very low TSH. Within 2 months her symptoms disappeared on their own and her T4 returned to normal range. She did not have thyroid antibodies. The woman had 5 such episodes over an 11 year period. The physicians were left puzzled. Resolution: 1. Patient indicated she did not take herbal supplements or thyroid supplements 2. Additional questioning about her dietary habits revealed the cause. • She lived on a farm and every year a cow was slaughtered and the butcher packaged the meat for use. It was discovered that the butcher did not know that “gullet trimming” was prohibited. Hence, muscles from the larynx and thyroid were trimmed and used to make hamburger patties. The woman consumed these (her husband did not) patties and had exposure to cow thyroid gland. • 1984-85—similar cases seen in Minnesota, South Dakota and Iowa. Key Concepts • • • • • • • • How is thyroid hormone regulated ? Why is mode of action like a steroid hormone? Over secretion of thyroid hormone has what consequences? Under secretion of thyroid hormone has what consequences? What is the active form of the hormone? How does hormone reach tissues? What are the actions at tissue level? What amino acid forms the backbone of thyroid hormone? Sample Board Question Blood levels of ________would be decreased in Grave’s Disease. A. Tri-iodothyronine (T3) B. Thyroxine (T4) C. Diiodothyrosiine (DIT) D. Thyroid Stimulating Hormone (TSH) E. Iodide (I-)