Thyroid Physiology Updated (1).pdf

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 ab...

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 the thyroglossal duct. By the 7th week, the thyroid reaches its final position in front of the trachea.  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 Development of Thyroid Lobes Thyroid develops into two lateral lobes connected by an isthmus.  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) microvilli and lots of rough ER (not and actively secreting (right) is seen here) shown. 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 conditions. Tiny amount is RT3  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 the responding cell 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 TSH receptor Gq Pulsatile secretion with protein… rise at 9pm, peak at midnight and decline after So what is the intracellular signaling cascade? T4 and T3 function - overview  Thyroid Hormone Actions Difficult to clarify the Function Hyperthyroid Hypothyroid molecular basis of thyroid physiology thus far Increased decreased BMR – Some of the biggest clues about thyroid Carb é GNG é Glycogenolysis ê GNG ê Glycogenolysis physiology are obtained metabolism Serum glucose Serum glucose by observing people normal normal who have a hyper- or Protein é Synthesis ê Synthesis hypofunctioning gland metabolism é Proteolysis ê proteolysis muscle wasting – In general, T3 tends to: present Increase basal Lipid é Lipogenesis ê lipogenesis metabolic rate metabolism é Lipolysis ê Lipolysis Greatly aid in normal ê Cholesterol Cholesterol increased growth and development Thermo- increased decreased genesis ANS Increased expression Globally reduced of catecholamine catecholamine receptors signalling  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?