Thyroid Hormone Physiology - Student Copy(1).pptx

Thyroid Hormone Physiology Module Code: Theme 1, Lecture 4 Oliver G. Steele [email protected] Join at slido.com #2883860 Lecture in Context This lecture will build on … • Hypothala mic Pituitary Axis (HPA) • Hormonereceptor mechanism s of action … by introducing and covering … Introduction t...

Thyroid Hormone Physiology Module Code: Theme 1, Lecture 4 Oliver G. Steele [email protected] Join at slido.com #2883860 Lecture in Context This lecture will build on … • Hypothala mic Pituitary Axis (HPA) • Hormonereceptor mechanism s of action … by introducing and covering … Introduction to Endocrinolog y 2 • Thyroid Physiology You are • Hormones here! secreted by the thyroid Series of • Understanding Endocrin the impact of e the thyroid in Physiolo health and gy disease Lectures • Treatment of Intended Learning Outcomes To understand the normal physiology of the thyroid axis. 3 Outline 1. Anatomy of the Thyroid • Structure, blood supply and lymphatic drainage 2. Synthesis of Thyroid Hormones • T3 and T4 and their interactions • Site of synthesis 3. Control of Thyroid Hormone Physiology • Hypothalamic-Pituitary-Thyroid Feedback Loops Thyroid Hormone Circulation& Treatment 4. • Thyroid Pathophysiology • Hypo- and Hyperthyroidism and treatment options 4 Anatomy of the Thyroid Section 1 of 4 Thyroid Anatomy Anterior Trachea Posterior Butterfly shaped gland wrapped around the trachea, just below the larynx Larynx Parathyr oid Parathyroid located on the posterior of the thyroid gland Two lobes of the thyroid are connected by the isthmus Left lobe Isthmus Right lobe Thyroid 6 Blood Supply Superior thyroid artery is a branch of the external carotid artery Inferior thyroid artery is a branch of the thyrocervical trunk branch of the subclavian artery Superior thyroid artery Inferior thyroid artery External carotid artery Subclavian artery Thyroid ima artery is a branch of the aorta, however is not common in adults (3-10%) Thyroid ima artery 7 Veinous Drainage Superior thyroid vein drains to the internal jugular vein Middle thyroid vein drains to the internal jugular vein Superior thyroid vein Internal jugular vein Middle thyroid vein Inferior thyroid vein drains to the brachiocephalic vein (innominate vein) Inferior thyroid vein Brachioceph alic vein 8 Nerve Supply Left and right tracts of the vagus nerve innervates the thyroid Recurrent laryngeal nerve innervates the larynx Recurrent laryngeal nerve loops around the aorta and then through the thyroid Complications of thyroid surgery can include voice hoarseness, change or loss Vagus nerve Recurrent laryngeal nerve 9 Lymphatic Drainage of the Thyroid Thyroid has extensive lymphatic drainage Cancerous material in lymph nodes is often first sign of metastasis from thyroid Initial drainage is to the prelaryngeal, pretracheal and paratracheal nodes Drainage is then either to the superior deep cervical nodes or the inferior deep cervical Internal jugular vein Prelaryngeal Nodes Superior Deep Cervical Nodes Pretracheal Nodes Inferiod Deep Cervical Nodes Paratracheal Nodes 1 Cell Types of the Thyroid Follicle Follicular Cells Parafollicular (C) cells Colloid haematoxylin and eosin (H&E) stained thy 1 Cell Types of the Thyroid Follicles are the major functional and structural unit of the thyroid Follicle Follicular Cells Parafollicular (C) cells Follicular cells form the membrane around each follicle, and are responsible for the uptake of Iodide and secretion of thyroid hormones Parafollicular cells are responsible for the production of calcitonin Colloid 1 Inferior thyroid artery branches from which major artery? 1. Subclavian 2. Aorta 3. External Carotid 4. Thyroid Ima Correct Answer: Subclavian Move to reveal answer 1 Answer Slide Superior thyroid artery is a branch of the external carotid artery Inferior thyroid artery is a branch of the thyrocervical trunk branch of the subclavian artery Superior thyroid artery Inferior thyroid artery External carotid artery Subclavian artery Thyroid ima artery is a branch of the aorta, however is not common in adults (3-10%) Thyroid ima artery 1 Synthesis of Thyroid Hormones Section 2 of 4 Thyroid Hormone Synthesis Summary Blood 1. Iodide Uptake 2. Thyroglobulin Synthesis 3. Iodination 4. Iodotyrosil Coupling 5. Colloidal Storage 6. Follicular Release 7. Peripheral Conversions T4 7 Iodide Follicular Cells 1 Thyroglobulin 6 2 3 Colloid 1 4 MIT, DIT T3, T4 5 T3 Iodide uptake, Thyroglobulin and Iodination Iodide Blood 1) Uptake of Iodide TSH stimulates sodium-iodide symporters (NIS) to transport iodide from circulation into follicular cells Follicular Cell 1 Iodide 2) Thyrogobulin Synthesis Thyroglobulin is produced by the rough endoplasmic reticulum and the golgi Iodide 3) Iodination Thyroid peroxidase (TPO) oxidises iodide to iodine (I-) and binds I- to tyrosyl residues on TG TG TPO Iodide 1 I- 3 I- 2 Colloid I- I- TGI- Iodotyrosil Coupling 4) Iodotyrosil Coupling Follicular Cell TPO then catalyses the coupling of iodotyrosil residues to form monoiodotyrosil (MIT) or di-iodotyrosil (DIT) TPO Colloid IIodide Further coupling of multiple iodinated thyroglobulin molecules forms T3 and T4, again catalysed by TPO 5) Colloidal Storage Iodinated thyroglobulin molecules, then are stored in the colloid Importantly, at this stage T3 and T4 are still bound to thyroglobulin I- I- TG I- MIT + DIT Tri-iodotyrosine (T3) 1 4 DIT 4 MIT I- DIT + DIT Tetra-iodotyrosine (T4) 5 Follicular release and peripheral conversion 6) Follicular Release Colloidal vesicles are taken up into the follicular cell via pinocytosis and fuse with lysosomes containing proteolytic enzymes 7 T3 T3 & T4 Blood Follicular Cell T3 & T4 Proteolysis of iodinated thyroglobulin releases MIT, DIT, T3 and T4. Lysosome 7) Peripheral Conversion MIT & DIT are reabsorbed back into the colloid whereas T3 and T4 are released into circulation, predominantly as T4 Peripherally, T4 is then converted to T3 where it is considered active 6 MIT + DIT TPO 1 Colloid Thyroid Hormone Conversion 80% of secreted thyroid hormone is in the T4 form, however is metabolically inactive Iodothyronine deiodinases convert T4 into T3, which is metabolically active T4 has a much longer half life than T3 Even homeostatic distribution throughout the body T4 is considered a pro-hormone, requiring conversion to T3 which drives metabolic rate changes T4 T4 T4 2 T4 T4 T4 T4 T4 T3 T4 T4 Iodothyroni ne deiodinases T3 Thyroid peroxidase (TPO) is not involved in which step of thyroid hormone synthesis? 1. 2. 3. 4. Iodination Iodotyrosil coupling to form MIT & DIT Iodotyrosil coupling to form T3 & T4 Breakdown of TG, releasing T3 & T4 Correct Answer: Breakdown of TG, releasing T3 & T4 Move to reveal answer 2 Answer Slide Follicular Cell TPO 1. Iodide Uptake 2. Thyroglobulin Synthesis 3. Iodination 4. Iodotyrosil Coupling 5. Colloidal Storage 6. Follicular Release 7. Peripheral Conversions 3 Iodide Colloid II- I- TG I- MIT + DIT Tri-iodotyrosine (T3) 2 4 DIT 4 MIT I- DIT + DIT Tetra-iodotyrosine (T4) Control of Thyroid Hormone Physiology Section 3 of 4 Thyroid Hormone Circulation Carrier Protein Bound 99.9% T4 99.7% T3 Thyroid hormones are peptide hormones, yet have very poor water solubility due to the presence of iodine Transported in the blood via proteins Free 0.04% T4 0.4% T3 T4 Globulin T3 Thyroid hormones are considered inactive when bound to proteins, and only free (or unbound) T3 or T4 is active Prealbumin T4 T3 T4 Albumin T4 Inert 2 Activ e Mechanism of Action of Thyroid Hormones Thyroid hormones (T3 & T4) are actively transported across the cell membrane by membrane bound transporters Inactive T4 is then converted to T3 in tissues by deiodinases T3 is able to bind to intracellular Thyroid Receptors (TRα/TRβ) Hormone-receptor complexes act as transcription factors and promote gene expression, over hours-days 2 Thyroid hormones - Physiology Master regulator of metabolism Thyroid Oxygen Consumption - T3 increases oxygen consumption and heat production in all tissues except the brain and testes • T3 & T4 Secretion • Master regulator of metabolic rate Cardiovascular Effects - T3 promotes transcription of several ATPases, in turn driving faster heart rate • Regulation of … • Gastrointestinal Effects - T3 increases gut motility and glucose utilization 2 oxygen consumption, heat production, energy utilisation, heart rate … Thyroid stimulating hormone - Regulation Hypothalamus Releasing Hormone Pituitary (Anterior) Trophic Hormone TRH Deiodinases - Gene Transcriptio n TSH Longloop Inhibitio n Thyroid Short-loop Inhibition Target Tissue 2 T3 & T4 Thyroid hormones act through what broad mechanism of action? 1. 2. 3. 4. Transmembrane transporter G protein coupled receptor Receptor tyrosine kinases None of the above, thyroid hormones cross the membrane passively without assistance Correct Answer: Transmembrane transporter Move to reveal answer 2 Answer Slide Thyroid hormones (T3 & T4) are actively transported across the cell membrane by membrane bound transporters Inactive T4 is then converted to T3 in tissues by deiodinases T3 is able to bind to intracellular Thyroid Receptors (TRα/TRβ) Hormone-receptor complexes act as transcription factors and promote gene expression, over hours-days 2 Thyroid Pathophysiology & Associated Treatments Section 4 of 4 Disrupted thyroid physiology Hyperproduction Thyroid • Increased T3 & T4 Secretion • Elevated body temperature, sweating Hypoproduction • Decreased T3 & T4 Secretion • Decreased body temperature • Slowed heart rate • General lethargy, muscle weakness. • Elevated heart rate • Increased energy, twitchiness, trouble sleeping, hyper-alert 3 Disrupted thyroid physiology - Presentation Hypothyroidism (too little) • Weight gain • Tiredness • ‘Puffy’ swollen face Hyperthyroidism (too much) • Weight loss • Difficulty sleeping • Protruding eyes (exophthalmos) Dietary iodine imbalances, certain medications (containing iodine) and a number of autoimmune conditions can lead to hypo- and hyper-thyroidism Hypothyroidism (pre treatment) (post treatment) 3 Hyperthyroid ism Treatment Strategy Presentation and Consequences driven by metabolic imbalances Long term effects are associated with chronic metabolic changes • Hypothyroidism  Cardiovascular disease, coma, mortality • Hyperthyroidism  Atrial fibrillation, stroke, mortality T3 T3T3 T3T3 Hyperthyroi dism Treatment strategy aims to rebalance the metabolic imbalances Treatments are also dependent on balancing thyroid 3 hormone levels Hypothyroid ism Hypothyroidism Treatments Levothyroxine • Orally bioavailable • Synthetic analog of T4 • Converted to T3 by iodothyronine deiodinases naturally throughout the body • Prescribed as replacement therapy when T3/T4 levels are low Adverse Effects • Related to excessive dosage, symptoms similar to hyperthyroidism! Net Effect: Increased circulating levels of T3 and T4 throughout the body Levothyroxine Tetraiodothyronine (T4) Iodothyronine deiodinases 3 Triiodothyronine (T3) Context & Interest Hyperthyroidism Treatments Carbimazole • Orally bioavailable • Prodrug, conversion to active methimazole • Thyroid peroxidase antagonist Propylthiouracil (PTU Carbimazole Follicular Cell TPO IIodide Context & Interest Propylthiouracil (PTU)I do not need you to memorise the chemical • Orally bioavailable structure • Shorter half-life than carbimazole • Thyroid peroxidase antagonist Net Effect: Decreased T3 & T4 production through blocking TPO activity Colloid I- I- TG I- MIT + DIT Tri-iodotyrosine (T3) 3 4 DIT 4 MIT I- DIT + DIT Tetra-iodotyrosine (T4) 5 Radio-Iodine Therapy Adenoma in the thyroid can secrete thyroid hormone leading to hyperthyroidism Surgical Procedures • Thyroid lobectomy if cancer is only in one lobe • Total thyroidectomy if cancer has spread Radioiodine Therapy • Thyroid takes up the radioactive iodine selectively • Both cancerous and Thyroid lobectomy Total thyroidectomy 3 Radio-iodine, Cancer Research UK Levothyroxine, a treatment for hypothyroidism, is a synthetic analogue of which hormone? 1. T3 2. T4 3. TSH 4. TRH Correct Answer: T4 Move to reveal answer 3 Hypothyroidism Treatments Levothyroxine • Orally bioavailable • Synthetic analog of T4 • Converted to T3 by iodothyronine deiodinases naturally throughout the body • Prescribed as replacement therapy when T3/T4 levels are low Adverse Effects • Related to excessive dosage, symptoms similar to hyperthyroidism! Net Effect: Increased circulating levels of T3 and T4 throughout the body Levothyroxine Tetraiodothyronine (T4) Iodothyronine deiodinases 3 Triiodothyronine (T3) Context & Interest What you need to know • Understand blood supply, lymphatic drainage and nervous innervation of the thyroid • Appreciate the different types of cells within thyroid and their function • Know the steps involved in thyroid hormone synthesis, and how pharmacological intervention in these steps can provide therapeutic benefit • Understand the role of the thyroid hormone in normal physiology • Appreciate the relationship between disrupted thyroid 3 Suggested Further Reading Greenspan’s Basic and Clinical Endocrinology. “Chapter 7 here provides a good overview of much covered in this lecture, however goes into more depth than is needed for your exams.” Tenth Edition. Gardner & Shoback. McGraw-Hill Medical; 2018. ISBN: 978-0071622431. “Similar to above, but Chapter 13 here provides a slightly different approach if the above is not your style.” Integrated Endocrinology First Edition. Laycock & Meeran. Wiley-Blackwell; 2013. ISBN: 978-0470688120. 4 Feedback Opportunity If you have any feedback for me on this lecture, please either scan the QR code or follow the link below Questionnaire is short (~2 mins) and anonymous All feedback helps me to improve, and as a result improve the quality of your teaching. https://universityofsussex.eu.qualtrics.com/jfe/form/SV_3wVeRAhOFt bXjee Help me help you! 4