Wk 4 - MC Questions - Pituitary Gland PDF

The Pituitary Gland BMS200 Dr. Melvia Agbeko, September 23 2024 ND Katlynn’s Story OUTCOMES Learning Outcomes Contrast the functional anatomy, hormone secretion, and regulation of hormone secretion in the anterior and posterior pituitary. Briefly describe the function of oxytocin...

The Pituitary Gland BMS200 Dr. Melvia Agbeko, September 23 2024 ND Katlynn’s Story OUTCOMES Learning Outcomes Contrast the functional anatomy, hormone secretion, and regulation of hormone secretion in the anterior and posterior pituitary. Briefly describe the function of oxytocin and anti-diuretic hormone Describe the pathogenesis and relate to clinical features, and complications of common functional and non-functional pituitary growth and hypopituitarism. Briefly describe the functional anatomy and basic endocrinologic principles of the hypothalamic-pituitary-gonadal axis PRE-ASSESSMENT Quick Quiz Which of the following hormones is released from the posterior pituitary? A. TSH B. ADH C. CRH D. Somatostatin Quick Quiz Prolactin is produced by which of the following cell type? A. Thyrotrope B. Gonadotrope C. Lactotrope D. Somatotrope PARTICIPATORY LEARNING Case Presentation Female patient (mid-20’s) presents with headache and some blurry vision, as well as amenorrhea and galactorrhea. Case Presentation Initial thoughts? What do you want to know/learn from this patient? Top 3-5 relevant hypotheses The Pituitary Gland  REVIEW: HPA – basic embryology The pituitary forms when two embryological regions grow towards each other and “meet” ▪ Rathke pouch – outgrowth from the stomodeum that grows upwards towards the developing hypothalamus (part of diencephalon) Forms the anterior pituitary ▪ Infundibular process – inferior outgrowth from the developing hypothalamus Forms rest of the pituitary and infundibular stalk Rarely, a cyst (Rathke cleft cyst) or a tumour (craniopharyngio ma) can develop from remnants of REVIEW: Cranial anatomy – the hypophyseal fossa Note how the pituitary is almost completely surrounded by bone (sella  REVIEW: HPA – basic functional divisions: Magnocellular neurons transport peptide hormones from the cell body (fast axonal transport) to their axon terminals in the posterior pituitary ▪ Released into the capillary plexus formed by the inferior hypophyseal artery ▪ Hormones from magnocellular neurons need to be released in adequate concentrations to impact tissues throughout the body ▪ Major hypothalamic nuclei – PVN, SON  HPA – basic functional divisions: Magnocellular neurons reside in (fairly) clearly-defined hypothalamic nuclei ▪ PVN and SON (more later) ▪ The PVN secretes mostly oxytocin, with a bit of ADH ▪ The SON secretes mostly ADH, with a little oxytocin  Posterior pituitary – secreted hormones ADH (vasopressin, AVP) and oxytocin Small, 9-amino acid peptides that have a similar sequence and structure ADH is much more important in day-to-day maintenance of homeostasis ▪ The major regulator of water content in our body ▪ Can also cause vasoconstriction Oxytocin is a key hormone in the milk letdown reflex and in the augmentation of labour Posterior Pituitary - overview Posterior Pituitary Physiology - ADH Two stimuli for release: Osmoreceptors in the hypothalamus and in the lamina terminalis detect osmolarity of the extracellular fluid ▪ This is the major stimulus for ADH release ▪ in response to decreased osmolarity 🡪 osmoreceptors shrink 🡪 stimulate magnocellular neurons in the PVN/SON 🡪 ADH release Baroreceptors (carotid sinus, aortic arch, or atria) ▪ In response to decreased BP 🡪 cells in the carotid sinus are stimulated 🡪 communication with the PVN/SON via the brainstem ▪ Can also be stimulated by decreases in blood volume – as blood volume decreases 🡪 less stretch at the atria 🡪 release of ADH  Impact of osmolarity vs BP on ADH release Normal blood/ECF osmolarity ranges from 275 – 295 mOsm As little as a 1% increase Pituitary Gland Overview 2 glands fused together Anterior- adenohypophysis endocrine epitheilial tissue Posterior- neurohypophysis neural tissue extension originating in the brain Relevant Anatomy Structure- lima-bean sized gland connected to the brain by an infundibulum Situated in the Sella Tursica (Sphenoid bone) 2 lobes- anterior and posterior Situated below both the Hypothalamus and the Optic Chiasm Secretion of hypothalamic hormones. The hormones of the posterior lobe (PL) are released into the general circulation from the endings of supraoptic and paraventricular neurons, whereas hypophysiotropic hormones are secreted into the portal hypophysial circulation from the endings of arcuate and other hypothalamic neurons. AL, anterior lobe; MB, mamillary bodies; OC, optic chiasm. Citation: Chapter 17 Hypothalamic Regulation of Hormonal Functions, Barrett KE, Barman SM, Brooks HL, Yuan JJ. Ganong's Review of Medical Physiology, 26e; 2019. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=2525&sectionid=204292033 Accessed: August 29, 2023 Copyright © 2023 McGraw-Hill Education. All rights reserved Relevant Anatomy Vascular connection between Hypothalamus and Anterior Pituitary Neural connection between Hypothalamus and Posterior Pituitary Hypothalamic nuclei project axons into the posterior pituitary Supraoptic Paraventricular Innervation- Sympathetic/Parasympathetic Vascular Supply Hypophyseal portal system concentrated neurohormones are secreted into a capillary network and affect target organs through the blood supply Significance: smaller amounts can be secreted and have a potent effect Human hypothalamus, with a superimposed diagrammatic representation of the portal hypophysial vessels. Citation: Chapter 17 Hypothalamic Regulation of Hormonal Functions, Barrett KE, Barman SM, Brooks HL, Yuan JJ. Ganong's Review of Medical Physiology, 26e; 2019. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=2525&sectionid=204292033 Accessed: August 29, 2023 Copyright © 2023 McGraw-Hill Education. All rights reserved Histology Embryonic origins Posterior Pituitary Evagination of the Third Ventricle Anterior Pituitary Rathke pouch- evagination of the roof of the pharynx Diagrammatic outline of the formation of the pituitary (left) and the various parts of the organ in the adult (right). Citation: Chapter 18 The Pituitary Gland, Barrett KE, Barman SM, Brooks HL, Yuan JJ. Ganong's Review of Medical Physiology, 26e; 2019. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=2525&sectionid=204292155 Accessed: August 29, 2023 Copyright © 2023 McGraw-Hill Education. All rights reserved Regulation of Hormone Secretion: Anterior Pituitary Secretes 6 hormones Prolactin, TSH, GH, FSH, LH, ACTH Secretion is controlled by hypophysiotropic hormones Anterior pituitary hormones. In women, FSH and LH act in sequence on the ovary to produce growth of the ovarian follicle, ovulation, and formation and maintenance of the corpus luteum. Prolactin stimulates lactation. In men, FSH and LH control the functions of the testes. ACTH, adrenocorticotropic hormone; β-LPH, β-lipotropin; FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone. Citation: Chapter 17 Hypothalamic Regulation of Hormonal Functions, Barrett KE, Barman SM, Brooks HL, Yuan JJ. Ganong's Review of Medical Physiology, 26e; 2019. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=2525&sectionid=204292033 Accessed: August 29, 2023 Copyright © 2023 McGraw-Hill Education. All rights reserved Regulation of Hormone Secretion: Posterior Pituitary Stores and releases 2 hormones ADH (Vasopressin)- water balance Oxytocin- milk ejection and uterine contractions Oxytocin Released by posterior pituitary 2 primary functions Milk ejection: triggers milk ejections from mammary glands during chest feeding Uterine contractions: helps during childbirth to support labour and delivery Role in social bonding between individuals Oxytocin - Physiology Most well-known physiologic roles: ▪ Important stimulant of uterine contraction during childbirth ▪ Milk ejection from breast tissue in someone who is lactating Both roles involve contraction of smooth muscle ▪ Receptor activation 🡪 Gq-mediated increases in cytosolic calcium and activation of smooth muscle myosin (see next slide) ▪ Calcium excites smooth muscle using different molecular mechanisms than in skeletal or cardiac muscle  Regulation of contraction in smooth muscle To be discussed in more depth during our vascular physiology classes  Oxytocin Physiology Kind of unique endocrine regulation ▪ Stimulators – sensory stimulation of breast tissue (milk ejection) or pressure/thinning of the cervix ▪ Most of our other pituitary hormones respond to central signals or negative feedback  Oxytocin Physiology Oxytocin does not exert its effect on uterine tissue until it is time for parturition (too early 🡪 premature labour) ▪ The uterus increases gap junctions and oxytocin receptors at the end of pregnancy Steadily increasing levels of estrogen 🡪 more oxytocin receptors prostaglandin levels within the uterus also rise later in pregnancy (regulation poorly-understood) – prostaglandins also aid uterine contraction ▪ like the uterus is slowly being “primed” until secretion of oxytocin is enough to bring about the positive feedback cycle of uterine contraction and cervical thinning/dilation Oxytocin Physiology The regulation of oxytocin secretion is complex and knowledge is still developing… however: ▪ Most of the time, significant secretion of oxytocin during pregnancy is inhibited by input from other brain regions Neurotransmitters of interest include GABA, NO, endogenous opioids ▪ This inhibition is lifted near the end of pregnancy, when estrogen levels rise and progesterone levels begin to decline ▪ Other factors that inhibit oxytocin secretion: “stressors” – fear, pain, loud noise fever ADH- Anti-diuretic Hormone AKA Vasopressin Released by posterior pituitary Primary function Water regulation- acts on kidneys to increase water reabsorption results in decreased urine production—> prevents dehydration water balance maintenance—> blood osmolarity maintained Summary of ADH Physiology Release is stimulated by: ▪ increased ECF osmolarity – most powerful stimulator, detected by osmoreceptors near the hypothalamus in the lamina terminalis ▪ decreased blood pressure/volume – weaker stimulus, detected at arterial baroreceptors and venous baroreceptors (venous found in great vessels, atrial walls) ADH has two major effects: ▪ V1 receptor activation in vascular smooth muscle 🡪 vasoconstriction and increased BP ▪ V2 receptor activation in the kidney 🡪 increased water reabsorption 🡪 increased extracellular fluid volume (and decreased osmolarity) and more concentrated (and lower volume) urine Pituitary Tumours Why are pituitary adenomas so common? ▪ They are all monoclonal, so likely a mutation confers a growth advantage ▪ Some have activating mutations in Gs-proteins (1/3) ▪ Some seem to over-express or over-activate growth factor signaling (FGF or EGF) ▪ Loss of negative feedback inhibition (increased hypothalamic releasing hormone) may play a role… …but really, no one has a clear answer Rare familial syndromes (to cover with NPLEX review course) such as multiple endocrine neoplasia (MEN) involve loss of tumour suppressor genes Pituitary Tumours - Overview Adenoma Hormones Clinical Findings, Notes Cell type Lactotroph PRL Hypogonadism, galactorrhea, mass effects Most common adenoma, and cause of hyperprolactinemia Gonadotroph FSH, LH, beta- Silent – minority secrete FSH or LH subunits Can result in ovarian hyperstimulation or hypogonadism, mass effects can occur Second most common adenoma Somatotroph GH Acromegaly/gigantism, mass effects Corticotroph ACTH Cushing’s disease, mass effects – some are silent Mixed GH and PRL cell PRL, GH Hypogonadism, galactorrhea, acromegaly, mass effects Several subtypes – together are 4th most common Thyrotroph TSH Thyrotoxicosis Quite uncommon  Mass Effects – Pituitary Tumours As a pituitary grows in the sella the following can occur: ▪ Hypopituitarism – compression of functional anterior pituitary tissue Exception – often results in excessive function of lactotrophs – why? Impingement and loss of normal pituitary function are usually early manifestations of expansion The posterior pituitary stalk can also be compressed 🡪 diabetes insipidus ▪ Bitemporal hemianopsia – as it elevates the dura and “crushes” the lateral optic nerves Scotomas, blindness, and loss of red perception can also occur – everyone with a pituitary tumour needs a thorough eye exam Ophthalmoplegia and facial numbness can also occur as the cavernous sinus is impacted (CN III, CN IV, CN VI) ▪ Headaches are common, and they don’t correlate well to the size of the tumour  FYI – contents of the cavernous sinus Lot of important stuff in there… https://commons.wikimedia.org/wiki/ Selected adenomas Lactotroph adenomas are the most common cause of hyperprolactinemia with high levels of PRL ▪ See next slide for causes of hyperprolactinemia (FYI) ▪ Many (more common) causes of modest increases in PRL Presentation: amenorrhea, galactorrhea, loss of libido, and infertility ▪ Why amenorrhea & infertility? PRL inhibits GnRH secretion and directly impairs gonadal steroid production In men, can lead to low testosterone levels, loss of fertility, and loss of libido (galactorrhea is uncommon) Disorders of the Posterior Pituitary (FYI) No known disorders of oxytocin secretion (either too much or too little) Loss of ADH action (head trauma, dysfunctional V2 receptors) 🡪 diabetes insipidus ▪ Loss of large volumes of extremely dilute urine ▪ Urine loss can be as great as 20 L/day, and patients are extremely thirsty with serious hypotension if fluid is not replaced ▪ Can be treated by intranasal inhalation of desmopressin Alcohol ingestion decreases ADH secretion Nausea and infection can cause excessive ADH release – known as the syndrome of inappropriate ADH secretion (siADH) ▪ Patients do not have excessive blood volume or pressure since other physiologic mechanisms compensate ▪ Usually presents as modest hyponatremia Case Reflection Given this information, what is missing? The patient presents with headache, blurry vision, amenorrhea, and galactorrhea, knowing the function of the pituitary gland secretions, which of these problems can be readily explained by an over production or under production of these hormones? Which ones are left unexplained? Case Reflection Headache, Blurry vision, Amenorrhea, Galactorrhea, Knowing the function of the pituitary gland secretions, which of these problems can be readily explained by an over production or under production of these hormones? Which ones are left unexplained? Pituitary Growth Disorders Functional Disorders Definition-result from hormone-secreting tumours eg adenoma (can be micro or macro) Can lead to overproduction of hormones causing concerns like GH- Giantism (children) and Acromegaly (adults) PRL- Prolactinoma (most common ~50%) Clinical presentation and Complications Symptoms from mass effects include headache; visual loss through compression of the optic chiasm (classically a bitemporal hemianopia); and diplopia, ptosis, ophthalmoplegia, and decreased facial sensation from cranial nerve compression laterally. Pituitary stalk compression from the tumour may also result in mild hyperprolactinemia. Symptoms of hypopituitarism or hormonal excess may be present as well (see below). Non-Functional Tumours and Hypopituitarism Definition- do not secrete hormones- about 1/3 Can lead to hypopituitarism- insufficient hormone production As a result, can affect other hormones resulting in various symptoms ACTH- adrenal insufficiency- fatigue, weight loss, LBP TSH- hypothyroidism symptoms FSH and LH- sexual dysfunction and infertility Hyperpituitarism Increased hormone production Hypopituitarism Low levels of pituitary hormones These disorders may be genetic, congenital, traumatic (pituitary surgery, cranial irradiation, head injury), neoplastic (large pituitary adenoma, parasellar mass, craniopharyngioma, metastases, meningioma), infiltrative (hemochromatosis, lymphocytic hypophysitis, sarcoidosis, histiocytosis X), vascular (pituitary apoplexy, postpartum necrosis, sickle cell disease), or infectious (tuberculous, fungal, parasitic). Hypopituitarism- Clinical features Each hormone deficiency is associated with specific findings: GH: growth disorders in children; increased intraabdominal fat, reduced lean body mass, hyperlipidemia, reduced bone mineral density, decreased stamina, and social isolation in adults FSH/LH: menstrual disorders and infertility in women, hypogonadism in men ACTH: features of hypocortisolism without mineralocorticoid deficiency TSH: growth retardation in children; features of hypothyroidism in children and adults PRL: failure to lactate postpartum Sequential: GH>FSH>LH>TSH>ACTH. Diagram of pituitary axes. Hypothalamic hormones regulate anterior pituitary tropic hormones that, in turn, determine target gland secretion. Peripheral hormones feedback to regulate hypothalamic and pituitary hormones. ACTH, adrenocorticotropin hormone; CRH, corticotropin-releasing hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone–releasing hormone; GnRH, gonadotropin-releasing hormone; IGF, insulin-like growth factor; LH, luteinizing hormone; PRL, prolactin; SRIF, somatostatin, somatotropin release–inhibiting factor; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone. Citation: Chapter 171 Disorders of the Anterior Pituitary and Hypothalamus, Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison's Manual of Medicine, 20e; 2020. Available at: https://login.ccnm.idm.oclc.org/ Accessed: August 29, 2023 Copyright © 2023 McGraw-Hill Education. All rights reserved HPG axis HPG axis POST ASSESSMENT  Quick Quiz If a patient presents with reduced bone mineral density, increased abdominal fat and decreased stamina with some possible depression, following a recent head injury – which of the following would be reasonable mechanisms to explain this presentation? A. Increased prolactin secretion secondary to prolactinoma B. Trauma to the somatotrophs of the anterior pituitary resulting in hypopituitarism C. TSH-secreting adenoma resulting in suppression of TRH and subsequent hypopituitarism D. Side effect of starting a new antidepressant resulting in hyperprolactinemia SUMMARY  Key Points The Pituitary has 2 lobes- anterior and posterior and is controlled by the Hypothalamus The Anterior pituitary is derived from endothelial tissue and secretes 6 hormones The Posterior pituitary is a neural extension of the brain and releases 2 hormones  Key Points ADH regulates water balance. Oxytocin is responsible for uterine contractions during labour and milk ejection. It also plays a role in social bonding. Causes of Hypopituitarism vary, including genetic, traumatic, congenital and neoplastic HPG axis- feedback loops and regulation  References Hypothalamic Regulation of Hormonal Functions. In: Barrett KE, Barman SM, Brooks HL, Yuan JJ. eds. Ganong's Review of Medical Physiology, 26e. McGraw Hill; 2019. Accessed August 02, 2023. “Relation to the Pituitary Gland” https://accessmedicine-mhmedical-com.ccnm.idm.oclc.org/content.aspx?bookid=2525&sectionid=204292033 The Pituitary Gland. In: Barrett KE, Barman SM, Brooks HL, Yuan JJ. eds. Ganong's Review of Medical Physiology, 26e. McGraw Hill; 2019. Accessed August 02, 2023. “Development, structure and cell types of pituitary” https://accessmedicine-mhmedical-com.ccnm.idm.oclc.org/content.aspx?bookid=2525&sectionid=204292155 Hypothalamic Regulation of Hormonal Functions. In: Barrett KE, Barman SM, Brooks HL, Yuan JJ. eds. Ganong's Review of Medical Physiology, 26e. McGraw Hill; 2019. Accessed August 02, 2023. “Control of Anterior Pituitary Secretion” https://accessmedicine-mhmedical-com.ccnm.idm.oclc.org/content.aspx?bookid=2525&sectionid=204292033 The Pituitary Gland. In: Barrett KE, Barman SM, Brooks HL, Yuan JJ. eds. Ganong's Review of Medical Physiology, 26e. McGraw Hill; 2019. Accessed August 02, 2023. “Pituitary Gonadotropins and Prolactin” https://accessmedicine-mhmedical-com.ccnm.idm.oclc.org/content.aspx?bookid=2525&sectionid=204292155 Disorders of the Anterior Pituitary and Hypothalamus. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison's Manual of Medicine, 20e. McGraw Hill; 2020. ( Entire chapter, as its pretty short) Accessed August 02, 2023. https://accessmedicine-mhmedical-com.ccnm.idm.oclc.org/content.aspx?bookid=2738&sectionid=227559595 Thyroid Pathology BMS 200 Amna Noor September 29, 2023 Brainstorm! What can trigger autoimmune thyroid disease? How does this happen? Learning Outcomes Describe the pathophysiological process involved in the formation of goiter in both hyperthyroidism and hypothyroidism. Predict the clinical features and complications of a) over-section and b) under-section of thyroid hormones. Describe the pathophysiology of hypothyroidism due to iodine deficiency. Critique theories of the pathogenesis of autoimmune thyroid diseases (Grave's and Hashimoto's), including gut-thyroid axis, infectious triggers, pregnancy and environmental pollutants. Describe the relationship between viral infections and thyroiditis. Learning Outcomes (2) Describe the pathophysiology of myxedema. Describe the pathophysiology of thyroid cancers and relate to clinical features and complications. Describe the pathogenesis, clinical features, and complications of thyroglossal duct cysts and congenital hypothyroidism. Relate the known mechanism of action of anti-thyroid medications and levothyroxine to the pathophysiology of Graves’ disease and hypothyroidism, respectively. Describe the pathogenesis of thyroid storm and toxic multinodular goiters and relate to clinical features and complications. Goiter – Enlarged Thyroid Gland Biosynthetic Defects: ▪ Reduced production of thyroid hormones. ▪ To compensate, the body increases the production of TSH which stimulates the thyroid gland to grow in size Iodine Deficiency: ▪ Thyroid gland is unable to synthesize sufficient thyroid hormones. ▪ Pituitary gland increases TSH production. Goiter – Enlarged Thyroid Gland Autoimmune Disease – Graves’ Disease: ▪ Production of thyroid-stimulating immunoglobulins. ▪ These antibodies mimic the action of TSH and bind to thyroid receptors, leading to the overproduction of thyroid hormones. Autoimmune Disease – Hashimoto’s Thyroiditis: ▪ The immune system attacks and damages the thyroid gland. ▪ As a response, the pituitary gland increases TSH production to stimulate thyroid growth and compensate for the hormone deficiency. Thyroid Nodular Disease Abnormal growth of cells in the thyroid gland, leading to the formation of nodules or lumps within the gland. Hyperplastic Nodules result from excessive growth of thyroid cells but are not cancerous. ▪ Associated with conditions like multinodular goiter (MNG). Neoplastic Nodules result due to the abnormal growth of thyroid cells that can be cancerous. ▪ Neoplastic nodules include thyroid cancers.  Thyroid Nodular Disease Multinodular Goiter (MNG): ▪ Specific presentation of thyroid nodular disease where multiple nodules, often hyperplastic, replace a significant portion of the normal thyroid tissue. ▪ MNG is more commonly seen in regions with borderline iodine deficiency, as iodine deficiency can contribute to the development of goiters. Thyroid glands are relatively common, can be palpated in 3-7% of all adults Solitary vs. Multiple; Functional vs. Non-functional Hypothyroidism Predict the clinical features and complications. ▪ Think of the functions of thyroid hormones discussed in previous classes. Hyperthyroidism Predict the clinical features and complications. ▪ Think of the functions of thyroid hormones discussed in previous classes. Hypothyroidism & Iodine Deficiency Low Iodine Diet ▪ Iodine is essential for the synthesis of T3 & T4 How would this lead to hypothyroidism? What is the impact on TSH & TRH? Hypothyroidism & Iodine Deficiency Thyroid gland increases the ratios of MIT to DIT within thyroglobulin (TG). Thyroid glands causes an increase in the proportion of secreted relative to T4. ▪ T3 is the more active form of thyroid hormone, so this shift may be a way to maximize the effects of the limited hormone production. Low T3 & T4 🡪 Increased TRH 🡪 Increased TSH secretion & Goiter. Cretinism: mental and physical developmental delays due to the lack of thyroid hormones during critical periods of growth. Reference Cooper DS, Ladenson PW. The Thyroid Gland. In: Gardner DG, Shoback D. eds. Greenspan's Basic & Clinical Endocrinology, 10e. McGraw Hill; 2017. Accessed July 10, 2023. https://accessmedicinIe-mhmedical-com.ccnm.idm.oclc.org/content.aspx?bookid=2178&sectionid=1 66248172 ▪ Goiter & Thyroid Nodular Disease ▪ Disorders of Thyroid Function – Clinical Box 20-1 & 20-2 ▪ Iodine Metabolism ▪ Dietary Iodine Deficiency & Inherited Disorders Group Activity (50 minutes) Critique the theories of pathogenesis of autoimmune thyroid diseases (Grave's and Hashimoto's), including gut-thyroid axis, infectious triggers, pregnancy and environmental pollutants. Groups of 6-8: Have one scribe and one presenter 5-minute presentations (25 minutes) References To Use Knezevic J, Starchl C, Tmava Berisha A, Amrein K. Thyroid-Gut-Axis: How Does the Microbiota Influence Thyroid Function? Nutrients. 2020 Jun 12;12(6):1769. doi: 10.3390/nu12061769. Ferrari SM, Fallahi P, Antonelli A, Benvenga S. Environmental Issues in Thyroid Diseases. Front Endocrinol (Lausanne). 2017 Mar 20;8:50. doi: 10.3389/fendo.2017.00050. (this article includes both viral triggers as well as environmental pollutants) Galofre JC, Davies TF. Autoimmune thyroid disease in pregnancy: a review. J Womens Health (Larchmt). 2009 Nov;18(11):1847-56. doi: 10.1089/jwh.2008.1234. Can use additional references but note them down. Subacute Thyroiditis de Quervain’s thyroiditis, granulomatous thyroiditis, or viral thyroiditis. ▪ Viruses: mumps, coxsackie, influenza, adenoviruses, and echoviruses, SARS- CoV-2 ▪ Symptoms can mimic pharyngitis; peak incidence is at 30 - 50 years; women affected 3x more Subacute Thyroiditis In the early stages of subacute thyroiditis, the thyroid gland exhibits a patchy inflammatory infiltrate. Disruption of the normal structure of thyroid follicles (formation of multinucleated giant cells) Follicular changes can progress to the formation of granulomas and fibrosis. Return to normal. Subacute Thyroiditis Reference Jameson J, Mandel SJ, Weetman AP. Hyperthyroidism and Other Causes of Thyrotoxicosis. In: Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J. eds. Harrison's Principles of Internal Medicine, 21e. McGraw Hill; 2022. Accessed July 10, 2023. https://accessmedicine-mhmedical-com.ccnm.idm.oclc.org/conte nt.aspx?bookid=3095&sectionid=265439975 “Subacute thyroiditis” Myxedema Myxedema is a complication of hypothyroidism and is characterized by altered mental status, hypothermia, etc. Impacts several organ systems Myxedema & Cardiac Manifestations Loss of diastolic hypertension as a compensatory mechanism against peripheral vasoconstriction and low blood pressure. The loss of this protective mechanism contributes to the hypotension seen in myxedema coma. Common Symptoms: hypotension, arrhythmias, heart block, decreased myocardial contractility, reduced cardiac output Myxedema & Neurological Manifestations Myxedema coma typically follows a slow and gradual progression. Initial Symptoms: Lethargy, depression, disorientation, decreased deep tendon reflexes, psychosis, slow mentation, paranoia, poor recall Rare presentation: Status epilepticus Myxedema & Respiratory Manifestations Hypoventilation due to impaired ventilatory response Respiratory depression due to reduced hypercapnic response Obstructive sleep apnea due to swelling of tongue and vocal cords Reduced tidal volume due to pleural effusion and/or ascites Myxedema & GI Manifestations Abdominal pain Nausea & vomiting Ileus – partial or complete lack of intestinal movement Anorexia Constipation Ascites Poor medication absorption Risk of GI bleeding Myxedema & Other Manifestations Renal & Electrolyte: ▪ Hyponatremia, impaired sodium excretion, increased urine osmolality, bladder atony Hematology: ▪ Increased risk of bleeding, decreased blood clotting factors ▪ Reversible with T4 therapy Reference Elshimy G, Chippa V, Correa R. Myxedema. StatPearls Publishing; 2023. Accessed on July 10, 2023. https://www.ncbi.nlm.nih.gov/books/NBK545193/ “Introduction” and “Pathophysiology” Thyroid Cancer Originates from the follicular epithelium of the thyroid gland Differentiated: Papillary Thyroid Cancer (PTC) & Follicular Thyroid Cancer (FTC) 🡪 better prognosis Undifferentiated: Anaplastic Thyroid Cancer (ATC) Overdiagnosis due to dormant cancers, increased imaging Thyroid Cancer - Radiation Early research discovered that exposure to external radiation could increase the likelihood of developing thyroid cancer. External radiation was found to have the potential to cause chromosomal breaks within the DNA of thyroid cells. Children appear to be more vulnerable to the harmful effects of radiation than adults.  Thyroid Cancer – TSH & Growth Factors Differentiated thyroid cancers express TSH receptors. Higher serum TSH levels, even within the normal range, are associated with an increased risk of thyroid cancer in patients with thyroid nodules. T4 suppression: By prescribing thyroid hormone replacement therapy (typically synthetic T4), healthcare providers aim to suppress the production of TSH by the pituitary gland. Residual expression of TSH receptors on thyroid cancer cells allows for TSH-stimulated uptake of radioactive iodine therapy, specifically using iodine-131 (131I). ▪ Radioactive iodine therapy  Thyroid Cancer - Genetics Monoclonal origin; RET/PTC and PAX8-PPARγ1 rearrangements Some thyroid nodules have activating mutations of the TSH receptor and the GSα subunit. PTCs show activation of the RET-RAS-BRAF signalling pathway. RAS mutations, which stimulate the MAPK signalling cascade, are found in around 20-30% of thyroid neoplasms. Other genetic alterations (CTNNB1, P53, and TERT promoter mutations) play roles in the development of thyroid cancers, especially ATCs. Specific mutations, such as BRAF V600E mutations, may have implications for treatment choices. Inherited mutations in the RET gene cause medullary thyroid cancer (MTC) associated with Multiple Endocrine Neoplasia type 2. Papillary Thyroid Cancer PTC accounts for 80-85% of well-differentiated thyroid cancers. Tendency to spread via the lymphatic system but can also metastasize through the bloodstream, particularly to the bone and lungs. Prognosis in PTC depends on factors such as the volume of metastatic disease. Follicular Thyroid Cancer The incidence of FTC varies significantly in different parts of the world, being more common in regions with iodine deficiency. Diagnosing FTC can be challenging. Angioinvasive FTC is considered more aggressive. Prognosis varies by metastases, age, tumor size, vascular invasion Reference Jameson J, Mandel SJ, Weetman AP. Thyroid Nodular Disease and Thyroid Cancer. In: Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J. eds. Harrison's Principles of Internal Medicine, 21e. McGraw Hill; 2022. Accessed August 15, 2023. https://accessmedicine-mhmedical-com.ccnm.idm.oclc.org/conte nt.aspx?bookid=3095&sectionid=265440050 “Thyroid Cancer” – brief review excluding treatment Congenital Hypothyroidism Incidence: 1 in 2000 to 4000 newborns; neonatal screening Neonatal hypothyroidism may be transient, especially when the cause is related to factors like the presence of TSH-R blocking antibodies in the mother or the use of antithyroid drugs during pregnancy. However, permanent hypothyroidism is more common and occurs in the majority of affected newborns. Causes: Gland dysgenesis, inborn errors, TSH-R antibody mediated Mutations: Central Hypothyroidism, gland dysgenesis, abnormal TH synthesis Transplacental TH support Congenital Hypothyroidism Clinical features: prolonged jaundice, feeding problems, hypotonia, enlarged tongue, delayed bone maturation, and umbilical hernia. Importantly, permanent neurologic damage results if treatment is delayed. Typical features of adult hypothyroidism may also be present. Other congenital malformations, especially cardiac, are four times more common in congenital hypothyroidism. Thyroglossal Duct Cyst The thyroid gland begins its development in the third week of gestation from the primitive pharynx; specific point known as the foramen cecum, located on the tongue. Thyroid gland descends towards its final location in the neck. During this descent, it moves anteriorly, coming into close proximity to the developing hyoid bone. The thyroglossal duct is a narrow, tubular structure that remains as a remnant of the thyroid's descent. In approximately 50% of individuals, the distal part of the thyroglossal duct differentiates into the pyramidal lobe of the thyroid gland. In typical development, the thyroglossal duct naturally undergoes involution. However, it can persist into postnatal life and collect secretions from the surrounding tissue, leading to inflammation and the formation of a thyroglossal duct cyst. Thyroglossal Duct Cyst Thyroglossal duct cysts typically present as mobile midline neck masses near the hyoid bone. They often are asymptomatic. However, they can present as an abscess or intermittently draining sinus. The mass will elevate with tongue protrusion or swallowing. References Jameson J, Mandel SJ, Weetman AP. Hypothyroidism. In: Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J. eds. Harrison's Principles of Internal Medicine, 21e. McGraw Hill; 2022. Accessed July 10, 2023. https://accessmedicine-mhmedical-com.ccnm.idm.oclc.org/content.a spx?bookid=3095&sectionid=263546550 ▪ “Congenital Hypothyroidism” excluding diagnosis and treatment. Amos J, Shermetaro C. Thyroglossal duct cyst. StatPearls Publishing; 2023. Accessed on July 10, 2023. https://www.ncbi.nlm.nih.gov/books/NBK519057/ ▪ “Etiology”, “History and Physical” Propylthiouracil - Hyperthyroidism Anti-thyroid drug PTU inhibits the activity of an enzyme called thyroid peroxidase, which is crucial in thyroid hormone synthesis. ▪ Thyroid peroxidase normally facilitates the conversion of iodide ions into iodine molecules and incorporates these iodine molecules into amino acids called tyrosine. It inhibits the conversion of T4 to T3 outside the thyroid gland. Graves’ Disease connection? Methimazole – Hyperthyroidism Anti-thyroid drug Inhibits the activity of thyroid peroxidase. Interfere with the coupling of iodotyrosine residues. Inhibits the oxidation of iodide ions and iodotyrosyl groups. Depletion of thyroglobulin. Methimazole can reduce the levels of certain immune molecules like intracellular adhesion molecule 1, soluble interleukin 2, and anti- thyrotropin receptor antibodies. No impact on existing endogenous or exogenous TH levels Graves’ Disease Levothyroxine - Hypothyroidism Synthetic thyroid hormone medication; T4 Oral: absorbed primarily from the jejunum and upper ileum The bioavailability of tablets, compared to an equal dose of oral levothyroxine solution, is approximately 93%. Influenced by fasting (increased absorption) and reduced in the presence of food and malabsorption syndromes. Dietary fiber can also reduce its bioavailability. Binds to plasma proteins, including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin Thyroid hormones are mainly excreted by the kidneys, with a smaller portion excreted in the stool. Urinary excretion of thyroid hormones may decrease with age. References Amisha F, Rehman A. Propylthiouracil (PTU). StatPearls Publishing; 2023. Accessed on July 10, 2023. https://www.ncbi.nlm.nih.gov/books/NBK549828/ ▪ “Mechanism of action” Eghtedari B, Correa R. Levothyroxine. StatPearls Publishing; 2023. Accessed on July 10, 2023. https://www.ncbi.nlm.nih.gov/books/NBK539808/ ▪ “Mechanism of action” Singh G, Correa R. Methimazole. StatPearls Publishing; 2023. Accessed on July 10, 2023. https://www.ncbi.nlm.nih.gov/books/NBK545223/ ▪ “Mechanism of action” Thyroid Storm Presentation of hyperthyroidism Thyroid storm is estimated to account for approximately 1% to 2% of all hospital admissions related to hyperthyroidism. In the United States, the reported incidence of thyroid storm ranges from 0.57 to 0.76 cases per 100,000 people per year in the general population. In hospitalized patients, the incidence is higher, ranging from 4.8 to 5.6 cases per 100,000 people per year. Average age is 42 to 43 years; male-to-female ratio the is 1:3 Thyroid Storm Related to the rapid increase in thyroid hormone levels rather than the absolute hormone level itself. Patients with thyrotoxicosis may have an increased response to catecholamines (hormones like adrenaline), which can lead to a cascade of physiological effects. During acute stress or infections, patients with hyperthyroidism might exhibit an exaggerated cellular response to thyroid hormone. Acute stress or infections can also trigger the release of cytokines and disrupt normal immune responses. Thyroid Storm Presents with a high fever, ranging from 40°C to 41.1°C accompanied by diaphoresis. CV: Tachycardia, heart failure, arrhythmia, hypotension, cardiac arrest CNS: Agitation, delirium, anxiety, psychosis, coma GI: Nausea & vomiting, diarrhea, abdominal pain, obstruction, acute hepatic failure Physical Exam: orbitopathy, goiter, hand tremors, moist and warm skin, hyperreflexia, systolic hypertension, jaundice Toxic Multinodular Goiter Multiple nodules in the thyroid gland, some of which become overactive and produce excessive TH. Nodules operate independently and produce TH. ▪ The exact molecular basis for this autonomy in toxic MNG remains unknown. Clinical Features: Subclinical hyperthyroidism, elderly age, CV symptoms, neurological symptoms, iodine exposure The level of TSH in the blood is typically low; uncombined T4 levels may be normal or only slightly elevated; T3 levels are often elevated to a greater degree than T4. The heterogeneous pattern of iodine uptake within the thyroid gland A 24-hour uptake of radioiodine may not be significantly increased but usually falls within the upper normal range. References Pokhrel B, Aiman W, Bhusal K. Thyroid Storm. StatPearls Publishing; 2023. Accessed July 10, 2023. https://www.ncbi.nlm.nih.gov/books/NBK448095/ ▪ “Etiology”, “Pathophysiology” and relate to “History and Physical” Jameson J, Mandel SJ, Weetman AP. Thyroid Nodular Disease and Thyroid Cancer. In: Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J. eds. Harrison's Principles of Internal Medicine, 21e. McGraw Hill; 2022. Accessed July 10, 2023. https://accessmedicine-mhmedical-com.ccnm.idm.oclc.org/content.aspx? bookid=3095&sectionid=265440050 ▪ “Toxic Multinodular Goiter” (excluding treatment) Question What is a possible consequence of intense metabolic activity in thyroid storm? A. Bradycardia B. Hypotension C. Reduced oxygen requirements D. Tachycardia-induced heart failure Question What is a possible consequence of intense metabolic activity in thyroid storm? A. Bradycardia B. Hypotension C. Reduced oxygen requirements D. Tachycardia-induced heart failure Question Which condition shares pathogenesis similarities with autoimmune thyroid diseases (AITDs) like Hashimoto's thyroiditis (HT) and Graves' disease (GD)? A. Rheumatoid arthritis B. Type 2 diabetes C. Celiac Disease (CD) D. Asthma Question Which condition shares pathogenesis similarities with autoimmune thyroid diseases (AITDs) like Hashimoto's thyroiditis (HT) and Graves' disease (GD)? A. Rheumatoid arthritis B. Type 2 diabetes C. Celiac Disease (CD) D. Asthma Summary Goiter: Biosynthetic Defects, Iodine Deficiency, Hashimoto’s, Graves’ Nodular Disease: Hyperplastic, Neoplastic, Multinodular Viruses and subacute thyroiditis: Thyrotoxic, hypothyroid, recovery Myxedema coma & manifestations in several organ systems Thyroid cancer (PTC, FTC, ATC) Congenital Hypothyroidism & Thyroglossal Duct Cyst Anti-thyroid medication (PTU & Methimazole) vs. Levothyroxine Thyroid Storm Toxic Multinodular Goiter Thyroid Physiology BMS200 Week 4 Ted Talk Learning Outcomes Discuss the embryology, functional anatomy, vasculature, and histology of the thyroid gland. Describe the synthesis of T4, T3, reverseT3, their release, transport and inhibition/metabolism Describe the absorption, uptake, distribution, and excretion of iodide Relate the significance of thyroid hormone binding in blood to free and total thyroid hormone levels and their function. Discuss the importance of the conversion of T4 to T3 and reverse T3 (rT3) in extra- thyroidal tissues by deiodinase enzymes. Learning Outcomes Describe the pathway of thyroid hormone regulation, encompassing the thyroid gland, pituitary gland, and hypothalamus. Describe diurnal variations in TSH, T3 and T4 hormones Compare the biochemical structure of TSH, LH, FSH, and HCG hormones, along with their respective receptors and receptor functions. Describe the physiologic effects and mechanisms of action of thyroid hormones (T3 and T4), including metabolic rate, protein synthesis and fat metabolism  Thyroid Embryology An Overview: One of the first fetal glands to develop during embryogenesis. Originates from the endodermal lining of the primitive pharynx The thyroid begins to develop as a pit at the base of the tongue in the midline (Foramen Cecum) Begins as a small endodermal thickening in the floor of the pharynx, near the base of the tongue. foramen cecum, between the 1st and 2nd pharyngeal pouches in the 3rd week Here is when the the thyroid diverticulum forms, which descends through the neck. The thyroid descends from the foramen cecum (at the tongue base) via  Thyroid Embryology An Overview: Thyroglossal Duct Temporary duct that connects the developing thyroid to the tongue. Normally, the duct disappears by the 10th week In some, the pyramidal lobe is an extension fo the duct but remnants of it can lead to thyroglossal duct cysts. 7% of the population has this. A Midline swelling can possibly be apparent  Thyroid Embryology By the 7th week the thyroid gland is in its final anatomical position. Anterior to the trachea and Below the larynx Consists of: Two lateral lobes Isthmus  Thyroid – basic anatomy Shaped kind of like a butterfly, the isthmus usually lies below the cricoid cartilage ▪ Right and left lobes, connected via the Isthmus ▪ In some individuals, a pyramidal lobe extends superiorly from the isthmus (remnant of the thyroglossal duct)  Thyroid – basic anatomy Arterial supply: Superior thyroid artery (branch of external carotid artery). Inferior thyroid artery (branch of subclavian artery). Some have a thyroid ima artery that supplies the isthmus Venous drainage: Superior thyroid vein. Middle thyroid vein. Inferior thyroid vein All drain into the SVC via the brachiocephalic trunk Highly vascularized!!  Thyroid anatomy & embryology Cricothyrotomy is a “famous” urgent airway procedure Locate the junction of the cricoid and the thyroid cartilage Small incision provides quick and pretty save access to the trachea The thyroid is extraordinarily vascular – if one slices indiscriminately in this area, hemorrhages happen Moore’s Clinically Oriented Anatomy, Fig. 9.29  Basic histology of the thyroid gland Capsule: The thyroid gland is enclosed by a thin fibrous capsule. This capsule serves both as a protective layer and as an anchor for the gland to nearby neck structures. The capsule is not just superficial—it sends septa (thin partitions) deep into the thyroid, dividing the gland into smaller lobules. This internal structure helps compartmentalize the tissue for efficient blood flow and hormone production. The capsule is also firmly attached to the cricoid cartilage and the upper part of the trachea The thyroid moves up and down when you swallow, a key clinical sign used during physical examination of the gland.  Basic histology of the thyroid gland Follicles: Most of the thyroid gland is made up of thyroid follicles The functional units responsible for hormone production. A follicle is a spherical structure, typically surrounded by a single layer of cuboidal epithelial cells (known as follicular cells or thyrocytes). These follicular cells are responsible for synthesizing and secreting thyroid hormones thyroxine (T4) and triiodothyronine (T3)  Basic histology of the thyroid gland Parafollicular area: Between the follicles, in the interstitial spaces, are clusters of parafollicular cells (also called C cells). These cells are responsible for producing calcitonin, a hormone that helps regulate calcium levels by inhibiting bone resorption when calcium levels are high more on this in the next section Unlike thyroid hormones, calcitonin is not directly involved in metabolic processes but plays a role in calcium homeostasis. Basic histology of the thyroid gland FIGURE 20–2 Thyroid histology. The appearance of Follicular cells contain apical the gland when it is inactive (left) and microvilli and lots of rough ER (not actively secreting (right) is shown. seen here) Note the small, punched-out “reabsorption lacunae” in the colloid next to the cells in the active gland. Gartner and Hiatt’s Atlas and Text of Histology, Fig. 11- 10  Thyroid Histology Glycoprotein and thyroglobulin Inactive: flat cells, lots of colloid Active: cells become cuboidal or columnar as they take up the colloid via “reabsorption lacunae” Fenestrated capillaries  Thyroid Hormone Synthesis Overview Main Ingredients: Tyrosine and Iodine End goal: Thyroxine (T4) High amount is produced, but it is less active Can be converted into T3 in the periphery by deiodination (removal of iodine) Triiodothyronine (T3) Very little is produced, but it is VERY active Reverse-Triiodothyronine (rT3) Produced in the periphery; small amount; activity unclear  Thyroid Hormone and Tyrosine: The Chemical Foundation Thyroid hormones (T3 and T4) are derivatives of the amino acid tyrosine. Tyrosine is an aromatic amino acid that forms the backbone of the thyroid hormones. The production of thyroid hormones involves the coupling of two tyrosine molecules that undergo a series of modifications, particularly iodination.  Iodination of Tyrosine Each tyrosine molecule has an aromatic ring structure with carbon atoms at positions 1 through 6. For thyroid hormone synthesis, iodination occurs specifically at the 3- and 5-carbon positions on the ring. Iodination refers to the process where iodine atoms are added to these carbon positions. Monoiodotyrosine (MIT): A tyrosine molecule with one iodine at the 3-carbon. Diiodotyrosine (DIT): A tyrosine molecule with two iodines, at both the 3- and 5-carbons.  Coupling of Tyrosine Molecules The thyroid hormones are formed by the coupling of these iodinated tyrosine molecules: Triiodothyronine (T3): Formed when one MIT combines with one DIT, resulting in a molecule with three iodine atoms. Thyroxine (T4): Formed when two DIT molecules combine, creating a molecule with four iodine atoms. This coupling process takes place within the colloid of the thyroid follicles.  Formation of thyroid hormone Thyroid hormone is derived from tyrosine Two tyrosine molecules “stuck” together with variable levels of iodination on the 3- and 5-carbon of aromatic ring The tyrosines are initially part of a larger protein known as thyroglobulin Thyroglobulin is a large glycoprotein that acts as a precursor and scaffold for thyroid hormone synthesis. It is a large protein, containing about 2750 amino acids, and is synthesized and secreted by follicular cells into the colloid of the thyroid follicles.  Formation of thyroid hormone Tyrosine Residues in Thyroglobulin Within the thyroglobulin protein, there are 123 tyrosine residues available. However, not all of these residues are used for hormone synthesis. Only 4-8 tyrosine residues within thyroglobulin are actually iodinated and incorporated into the final thyroid hormones (T3 and T4). These specific tyrosine residues are selectively iodinated, and the iodinated tyrosine pairs are linked together to form T3 and T4.  Conversion of Thyroglobulin to Active Hormones Synthesis and Storage: Thyroglobulin is produced in the follicular cells and secreted into the colloid, where the tyrosine residues undergo iodination and coupling to form hormone precursors. Endocytosis and Proteolysis: When thyroid hormones are needed, the thyroglobulin is taken back into the follicular cells via endocytosis. Release: Inside the follicular cells, enzymes cleave the thyroglobulin, releasing the active hormones (T3 and T4) into the bloodstream. Formation & secretion of thyroid hormone Overview: 1. Iodide absorption and transport 2. Iodide uptake by the follicular cells + thyroglobulin synthesis (not “connected”) 3. Transport of thyroglobulin and iodide into the follicle (not “connected”) 4. Iodination of tyrosine residues on thyroglobulin 5. Endocytosis of thyroglobulin (now with iodinated thyronine residues on it) 6. Lysosomal destruction of endocytosed thyoroglobulin  release of thyroid hormone into the cytosol 7. Thyroid hormone enters the circulation and is carried to peripheral tissues via transport proteins  Formation and secretion of thyroid hormone See diagram for absorption and secretion routes Take-aways: a significant proportion of the iodide in the diet is absorbed into the follicular cell from the circulation by a very high-affinity sodium- iodide symporter Iodide is mostly secreted into the urinary system, some into bile As thyroid hormone is metabolized, iodide is liberated and circulates Iodine Metabolism Absorption: Small intestine Main Storage/ Utilization: Thyroid (for thyroid hormone production) Up to 2 months supply Kidneys (excreted in urine) Secondary locations: salivary glands, gastric mucosa, placenta, ciliary body of eye, choroid plexus, mammary glands (physiological role of iodine in these tissues is unclear) Excretion: Liver metabolizes thyroid hormones and releases some iodine into bile attached to the metabolites (some is reabsorbed) 80% is excreted via kidneys  Making thyroid hormone Iodide Absorption and Transport Iodide (I−) absorption: Dietary iodide is rapidly absorbed through the gastrointestinal (GI) tract into the bloodstream. Most dietary iodide comes from sources like iodized salt, seafood, and dairy products. Once in the bloodstream, iodide is transported to the thyroid gland, where it is actively concentrated for thyroid hormone synthesis.  Making thyroid hormone Iodide Uptake by Follicular Cells: Na/I Cotransporter (NIS) Sodium/Iodide Symporter (NIS): Located on the basolateral membrane of the thyroid follicular cells (the side facing the blood). The NIS (also known as SLC5A5) is a specialized Na+/I− cotransporter responsible for actively transporting iodide from the blood into the follicular cells. The NIS moves two Na+ ions and one iodide ion (I−) simultaneously into the cell.  Mechanism of NIS Function Active transport: Iodide transport by the NIS occurs against its electrochemical gradient, meaning iodide is moved into the cell even though its concentration inside the follicular cell is already higher than in the blood. The energy for this process is provided by the sodium gradient, which is maintained by the Na+/K+ ATPasepump located on the basolateral membrane. Sodium gradient: The Na+/K+ ATPase pumps sodium ions out of the follicular cell in exchange for potassium ions. This creates a low intracellular Na+ concentration, which drives the movement of Na+ into the cell along with iodide.  Making thyroid hormone Iodide Transport Across the Apical Membrane Once inside the follicular cell, iodide needs to be transported into the lumen of the thyroid follicle (colloid), where it will be used for hormone synthesis. Apical membrane transport: Iodide is transported across the apical membrane (the side facing the follicular lumen) by the Cl−/I− exchanger, known as pendrin. Pendrin moves iodide (I−) into the follicle in exchange for chloride (Cl−) ions.  Making thyroid hormone Pendrin: The Cl−/I− Exchanger Pendrin is a protein located on the apical surface of the follicular cell, responsible for secreting iodide into the follicle lumen. Pendrin (SLC26A4) exchanges one chloride ion (Cl−) for one iodide ion (I−), allowing iodide to leave the cell and enter the colloid where it is used for thyroid hormone synthesis. Clinical relevance: Mutations in the pendrin gene (SLC26A4) can lead to a congenital disorder known as Pendred syndrome and is characterized by: Goiter (enlarged thyroid gland). Hearing loss, as pendrin is also involved in the inner ear's fluid regulation. Impaired iodide transport can lead to hypothyroidism or compensatory goiter, as the thyroid enlarges in an attempt to capture more iodide.  Pendred Syndrome Caused by mutations in the SLC26A4 gene, which encodes the pendrin protein. Symptoms include: Hearing loss, often diagnosed in childhood. Goiter, which may develop later in life as the thyroid gland struggles to trap sufficient iodide. Individuals with Pendred syndrome may have normal thyroid function or develop hypothyroidism over time due to impaired iodide transport.  Making thyroid hormone Thyroglobulin (TG) Secretion and Role Thyroglobulin (TG) is a glycoprotein synthesized by the follicular cells of the thyroid gland. It contains the tyrosyl groups (tyrosine residues) that will be iodinated to form thyroid hormones (T3 and T4). TG Secretion: TG is synthesized in the rough endoplasmic reticulum (RER) and packaged in the Golgi apparatus of the follicular cell. It is transported in secretory vesicles that carry it to the apical membrane, where it is exocytosed into the follicle lumen (colloid). TG Composition: Thyroglobulin is a large protein, making up nearly half of the total protein content of the thyroid gland. It contains 123 tyrosine residues, but only 4-8 of these will be used to form the thyroid hormones.  Making thyroid hormone Thyroid Peroxidase (TPO) and Iodination Along with TG, the secretory vesicles also carry the enzyme thyroid peroxidase (TPO), which is an integral membrane protein. TPO is anchored in the apical membrane of the follicular cell, with its catalytic domain facing the follicle lumen (colloid), where iodination occurs. TPO Function: TPO catalyzes the oxidation of iodide (I−) into iodine (I ), which is a key step in thyroid hormone synthesis. The oxidized iodine forms a highly reactive iodine radical (I ), which is essential for attaching to tyrosine residues on thyroglobulin.  Making thyroid hormone DUOX2: The Role in Oxidation The oxidation reaction carried out by TPO requires the activity of another apical membrane protein, known as DUOX2 (Dual Oxidase 2). DUOX2 generates hydrogen peroxide (H2O2), which is necessary for TPO to oxidize iodide into the iodine radical.  Making thyroid hormone Once the iodine radical is formed, it reacts with the tyrosine residues on thyroglobulin in the follicle lumen. This process is catalyzed by TPO and leads to the formation of iodinated tyrosines: Monoiodotyrosine (MIT): Tyrosine with one iodine attached. Diiodotyrosine (DIT): Tyrosine with two iodines attached. Coupling Reaction: TPO then facilitates the coupling of iodinated tyrosines: Two DIT molecules combine to form T4 (thyroxine). One MIT and one DIT combine to form T3 (triiodothyronine). As mentioned in previous slide  Making thyroid hormone Endocytosis of Iodinated Thyroglobulin Thyroglobulin has been iodinated and contains some coupled MIT and DIT residues (forming T3 and T4) remains in the colloid until the thyroid is stimulated to release hormones. Endocytosis: When stimulated by TSH (thyroid-stimulating hormone), the iodinated thyroglobulin is taken back into the follicular cell via endocytosis. This forms vesicles containing TG, which are transported into the cell for further processing.  Making thyroid hormone Lysosomal Hydrolysis of Iodinated Thyroglobulin Once inside the follicular cell, the vesicles containing iodinated thyroglobulin fuse with lysosomes. Lysosomal enzymes hydrolyze the thyroglobulin, breaking it down and releasing T3 and T4 into the cytosol. Free T3 and T4: T3 and T4 are freed from the thyroglobulin backbone While unmodified tyrosyl residues (MIT and DIT) are deiodinated and recycled within the follicular cell.  Making thyroid hormone Release of T3 and T4 into the Bloodstream After being released from thyroglobulin, T3 and T4 need to leave the follicular cell and enter the bloodstream to exert their effects on target tissues. Transport Mechanism: The exact mechanism of how T3 and T4 leave the cell is not fully understood. In the bloodstream, T3 and T4 bind to transport proteins like thyroxine-binding globulin (TBG), transthyretin, and albumin to be carried to peripheral tissues. Formation and secretion of thyroid hormone  Impact of TSH on thyroid hormone production Increased secretion of TSH from the anterior pituitary will: ▪ Increase the activity of the sodium- iodide symporter ▪ Increases the synthesis of thyroglobulin ▪ Increases the activity of thyroid peroxidase ▪ Increases endocytosis of “iodinated” thyroglobulin ▪ Increases the proteolysis of thyroglobulin ▪ Stimulates the growth of the follicular cells and gland in general  Formation and secretion of thyroid hormone Inactive Forms: MIT and DIT represent half of the iodinated tyrosines, are not secreted, and are recycled within the thyroid cells. Active Forms: T3 and T4 constitute the other half, with T4 being the predominant hormone released into the bloodstream. Metabolic Function: T3 and T4 regulate critical physiological functions, whereas rT3 serves as a regulatory metabolite in certain  Thyroid hormone transport Hydrophobic Nature of T3 and T4 T3 (triiodothyronine) and T4 (thyroxine) are hydrophobic molecules due to their structural composition This lmits their solubility in aqueous environments like blood plasma. Only a very small fraction of these hormones exists in their free (unbound) form within the bloodstream.  Thyroid hormone transport Binding to Transport Proteins: Approximately 99.98% of T4 and 99.8% of T3 in circulation are bound to plasma proteins. This high degree of binding protects the hormones from rapid metabolism and excretion, prolonging their half- lives. Less Tight Binding of T3: T3 is less tightly bound to carriers compared to T4. This results in a higher proportion of free T3 available to tissues for immediate action.  Thyroid hormone transport Half-Life: T4 has a longer half-life T3 has a shorter half-life The shorter half-life of T3 makes it more readily available for tissues that require immediate responses, even though it circulates at lower concentrations. Availability to Tissues: The free (unbound) fractions of T3 and T4 are biologically active and capable of entering target cells to exert their effects. The relatively higher availability of free T3 allows it to more quickly influence metabolic processes in various tissues.  Thyroid hormone transport Major Transport Proteins Albumin: Albumin is the most abundant protein in the blood and serves as a primary carrier for both T3 and T4. While it has a lower affinity for thyroid hormones compared to other carriers, its abundance means it plays a significant role in transporting these hormones. Transthyretin (TTR): Transthyretin is another important transport protein that binds both T3 and T4. It has a moderate affinity for these hormones and helps in stabilizing their levels in circulation.  Thyroid hormone transport Major Transport Proteins Continued: Thyroid-Binding Globulin (TBG): TBG has the highest affinity for T4 among all transport proteins, meaning it binds T4 more tightly than T3. As a result, TBG is responsible for carrying the majority of T4 in circulation, which helps maintain its stable concentration over time.  Thyroid hormone deiodination Cellular Uptake: Thyroid hormones (primarily T4 and T3) enter a wide variety of tissues throughout the body, where they exert their biological effects. While some studies suggest that thyroid hormones may enter cells via simple diffusion due to their lipophilic nature it is increasingly recognized that specific transporters may facilitate their uptake but still being characterized  Thyroid hormone deiodination Once T4 enters target tissues, it undergoes deiodination a process that removes iodine atoms to convert T4 into its more active form, T3, or its inactive form, rT3. This conversion is primarily mediated by two enzymes: Deiodinase type 1 (D1) Deiodinase type 2 (D2).  Thyroid hormone deiodination Deiodinase Type 1 (D1) D1 is predominantly found in the liver, kidneys, thyroid, and pituitary gland. Its primary role is to convert T4 into T3, although it can also produce a small amount of reverse T3 (rT3). Significance of D1: By generating T3, D1 helps maintain the physiological effects of thyroid hormones in tissues where T4 levels are higher. The presence of D1 in the liver is particularly important for the regulation of systemic thyroid hormone levels.  Thyroid hormone deiodination Deiodinase Type 2 (D2) D2 is primarily found in the brain, pituitary gland, and brown adipose tissue. It mainly converts T4 to T3, ensuring that active thyroid hormone is readily available where it is needed most. Role in the Brain: D2 plays a crucial role in local T3 production in the brain, which is important for regulating metabolism and overall brain function. Adaptive Mechanism: The expression of D2 can be influenced by various physiological conditions (e.g., caloric intake, temperature), allowing the body to adapt thyroid hormone availability to its metabolic needs.  Thyroid hormone deiodination Deiodinase Type 3 (D3) Deiodinase Type 3 (D3) is predominantly found in the brain and reproductive tissues. D3 is primarily responsible for the conversion of T4 to reverse T3 (rT3) and the inactivation of T3, playing a crucial role in regulating thyroid hormone levels. Role in rT3 Production: D3 facilitates the removal of iodine from T4, leading to the formation of rT3, which is biologically inactive. This function is particularly important in contexts where reduced metabolic activity is needed, such as during stress or illness.  Thyroid hormone deiodination Selenium as a Cofactor: All deiodinases (D1, D2, and D3) require selenium for their enzymatic activity. This is due to the presence of selenocysteine residues in their active sites, which are essential for the deiodination process. Importance of Selenium: Selenium is a vital trace mineral that plays a crucial role in thyroid hormone metabolism and overall endocrine health. A deficiency in selenium can impair the function of deiodinases, leading to altered thyroid hormone levels and potentially contributing to conditions such as hypothyroidism.  Thyroid hormone deiodination Reverse T3 (rT3) Formation rT3 is formed during the deiodination of T4, typically when one iodine atom is removed from the outer ring of T4. Although rT3 is considered an inactive metabolite, its levels can rise in certain conditions, such as fasting or illness, serving as a mechanism to downregulate metabolism. Physiological Role: rT3 competes with T3 for receptor binding but does not activate the thyroid hormone receptors, thus effectively reducing metabolic activity during times of stress or caloric restriction.  Deiodination Fluctuations Deiodinases can be influenced by variety of different factors: ▪ Age (less T3 made during fetal life) ▪ Drugs ▪ Selenium deficiency ▪ Illness (burns, trauma, advanced cancer, cirrhosis, chronic kidney disease, MI, febrile state) ▪ Diet Fasting: reduces T3 by 50% in 3-7 days (rT3 is increased) Overfeeding: increases T3 and reduced rT3 Signal transduction – thyroid hormone T4 has a much lower affinity for the thyroid hormone receptor than T3 Most T4 is also de-iodinated to T3 in TSH TSH Receptors: G-protein coupled receptor (Gs): activated phospholipase C Increased iodide binding Increases synthesis of T3 and T3 Increases secretion of thyroglobulin into colloid Increases blood flow to thyroid Can cause hypertrophy or goiter with chronic high stimulation of the TSH receptors (whether by TSH or another component)  Overview of Thyroid Hormone Regulation Stimulus for T4 Production: Thyroid Stimulating Hormone (TSH) is secreted by the anterior pituitary gland in response to Thyrotropin-Releasing Hormone (TRH) from the hypothalamus. TSH binds to receptors on the thyroid follicular cells, stimulating the synthesis and secretion of thyroxine (T4). T4 is the primary hormone produced by the thyroid and is largely responsible for regulating metabolism throughout the body. Distribution of T4: Once T4 is secreted into the bloodstream, it exists in two forms: Free T4: The unbound form, which is biologically active and able to enter cells and exert effects. Bound T4: The majority of T4 binds to plasma proteins, such as thyroid-binding globulin (TBG), transthyretin, and albumin. This binding helps regulate the availability of T4 and provides a reservoir for hormone storage.  Overview of Thyroid Hormone Regulation Equilibrium Between Free and Bound T4: There is a dynamic equilibrium between free T4 and bound T4. Changes in protein levels (such as during pregnancy or illness) can alter the amount of free T4 available, affecting physiological responses.  Feedback Mechanism Free T4 and TSH Regulation: The levels of free T4 in the bloodstream are critical for regulating TSH secretion When free T4 levels rise, they exert a negative feedback effect on the anterior pituitary gland. This feedback mechanism inhibits the secretion of TSH, thus reducing stimulation of the thyroid gland and decreasing T4 production. This ensures that hormone levels remain within a normal physiological range. Feedback by T3: T3, like free T4, also has a negative feedback effect on the pituitary gland, further inhibiting TSH secretion. This feedback mechanism is vital for maintaining the delicate balance of thyroid hormones and ensuring that metabolic processes function optimally.  Regulation of TSH TSH is similar to LH, FSH, and hCG ▪ Alpha subunit is identical, beta subunit is unique (glycoprotein tropic hormone) TSH half life is 60 minutes ▪ Degraded, excreted by kidneys Pulsatile secretion, pulses increase in amplitude, frequency at night (peaks at midnight) Degraded and excreted mostly via kidneys ▪ Pulsatile secretion with rise at TSH receptor  Gq protein… 9pm, peak at midnight and decline after So what is the intracellular signaling cascade? T4 and T3 function - overview  Thyroid Hormone Actions Function Hyperthyroidism Hypothyroidism BMR ↑ ↓ Carb metabolism ↑ GNG ↓ GNG ↑ Glycogenolysis ↓ Glycogenolysis Serum glucose normal Serum glucose normal Protein ↑ Synthesis ↓ Synthesis metabolism ↑ Proteolysis ↓ proteolysis muscle wasting present Lipid metabolism ↓ Lipogenesis ↑ lipogenesis ↑ Lipolysis ↓ Lipolysis ↓ Cholesterol ↑ Cholesterol Thermogenesis ↑ ↓ ANS ↑ expression of catecholamine Globally ↓ catecholamine signalling receptors  T4 and T3 function Calorigenic (heat-producing) actions Increase energy (oxygen) consumption in almost all tissues except for the brain (including pituitary) and adult reproductive organs Calorigenic effects: ▪ Increased fatty acid mobilization ▪ Increased activity of the sodium/potassium ATP-ase… everywhere ▪ Increased cardiac output & sympathetic nervous system effectiveness ▪ Activation of uncoupling protein in brown fat and perhaps other cells  more prominent effect in young children Calorigenic Action Increase O2 consumption in almost all tissues Increase Na+ K+ ATPase activity Increase fatty acid metabolism Increase metabolic rate May result in weight loss if intake of nutrients doesn’t match Small amounts of T3 stimulate growth, but high amounts promote catabolism Increase requirement for all vitamins Thyroid hormones are also needed for liver’s metabolism of carotene into vitamin A Other general effects: Facilitates normal menstrual cycle Allows for milk secretion Support normal skin structure  T4 and T3 function Cardiovascular impacts: ▪ Vasodilation  decreased peripheral resistance  modestly increased sodium and water reabsorption (increased blood volume) ▪ As mentioned, increased effectiveness of SNS on the heart  increased heart rate and contractility ▪ Also changes the types of proteins that are expressed in the sarcomere and the SR (more later) Neurological impacts: ▪ very, very important in early neurological development in the fetus and infant CNS, basal ganglia, special senses (cochlea) ▪ Increases arousal and activation of reticular activating system, overall neuronal “excitability” (i.e. hypothyroidism  reduced reflexes) Likely due to SNS activation  T4 and T3 function Carbohydrate metabolism ▪ Increased absorption of carbohydrates from GI, increased gluconeogenesis, increased glycogenolysis However, blood glucose tends to remain normal, likely due to increased consumption Lower circulating plasma cholesterol ▪ Increased synthesis of LDL receptors Muscle growth ▪ Hard to characterize – seems to both aid development but also lead to increased protein turnover (hyperthyroidism  muscle weakness) Skeletal growth ▪ Key for normal growth in childhood and skeletal maturity ▪ Facilitates function of growth hormone Also has impacts on skin appearance/structure, milk secretion, and the normal menstrual cycle  Impact of congenital hypothyroidism on normal development This is a graph of developmental age —that is, the age that the child appears based on height, bone radiograph, and mental function— versus chronological age. For a euthyroid child, the relationship is the straight line in red The three green curves are growth curves for a child with thyroid hormone deficiency At age 4.5 years thyroid hormone replacement therapy was initiated. Notice the “catching up” of bone and height parameters, but the lag in cognitive parameters  Other thyroxine, TSH, and TBG notables Increased metabolic rate due to hyperthyroidism  increased requirements for all vitamins TSH release is induced by cold (in infants) TSH release is inhibited by cortisol and stress ▪ Impacts on pituitary and hypothalamus TBG can be increased with elevations in estrogen (and during pregnancy) and with some medications ▪ Increases “store” of bound thyroxine, no impact on free levels TBG can be decreased by glucocorticoids, androgens, and other medications ▪ Still no impact on free levels of hormone  Critical thinking exercise… Try predicting the impact of hyper- and hypothyroidism on a patient ▪ How would the appearance possibly change? ▪ Vital signs? ▪ Physical exam features? ▪ Symptoms?