Endocrine Thyroid VP 2024.pdf

Cellular Biology & Homeostasis ENDOCRINE - THYROID VP 2023 Clara Camargo, DVM 1. Locate the thyroid glands and briefly describe the macro and microanatomy of it 2. Understand the synthesis/secretion, regulation, transport and metabolic clearance of thyroid hormones 3. Describe the effects of the thy...

Cellular Biology & Homeostasis ENDOCRINE - THYROID VP 2023 Clara Camargo, DVM 1. Locate the thyroid glands and briefly describe the macro and microanatomy of it 2. Understand the synthesis/secretion, regulation, transport and metabolic clearance of thyroid hormones 3. Describe the effects of the thyroid hormones on target tissues 4. Understand the symptoms of the main pathologies related to the thyroid hormones (hyperthyroidism, hypothyroidism and goiter) TERMINOLOGY Adenohypophysis Metabolic rate Albumin MIT (Monoiodotyrosine) Calcitonin Parafollicular cells (C-cells) Colloid T3 (Triiodothyronine) Cotransporter (symporter) T4 (Thyroxine) Deiodination Thyroglobulin DIT (Diiodotyrosine) Thyroid follicle Endocrinopathy Thyroid follicle lumen Endocytosis Thyroid Peroxidase Hormone clearance Thyrotropes Hypothalamus TRH Iodide TSH Iodine Tyrosine Lysosomes THYROID GLANDS - ANATOMY In most mammals, the thyroid glands are located caudal to the trachea at the level of the first or second tracheal ring CHEMICAL STRUCTURE OF THYROID HORMONES AMINES (Recall)  Derived from the amino acid tyrosine  Catecholamines (hydrophilic)  T3 and T4 thyroid hormones = hydrophobic Blood transport  Catecholamines circulate unbound in the blood  Thyroid hormones  Thyroxine-binding globulin (TBG) and albumin  produced by the liver  Half-life depends on the hormone  Thyroxine = 7-10 days  Epinephrine = 1 minute  Catecholamines bind to cell membrane receptors  Thyroid hormones bind to nuclear receptors THYROID GLAND Thyroid tissue consists of numerous sac-like structures called thyroid follicles that vary in size Follicular cells are arranged in a circular pattern  A single layer of epithelium  Synthesize the thyroid hormones THYROID GLAND - Colloid The follicles are filled with colloid  Colloid: viscous protein rich liquid (rich in thyroglobulin = glycoprotein)  The main storage of the thyroid hormones (active) Within the lumen created by glandular cells This form of storage allows mammals to withstand periods of iodine deprivation without an immediate effect on the production of thyroid hormones. THYROID GLAND – C-cells Parafollicular cells or C-cells are located outside the follicles  Secrete calcitonin  One of the hormones that regulate calcium metabolism THYROID GLAND THYROID HORMONE SYNTHESIS (Thyrotropes) THYROID HORMONE SYNTHESIS 2 molecules of importance:  TYROSINE  IODINE (I2) TYROSINE is part of a large protein called thyroglobulin (glycoprotein)  Thyroglobulin (TG) is synthesized within the follicle epithelial cell and secreted into the colloid  Contains a large number of tyrosine amino acid residues  Tyrosine is the major substrate that combines with iodine to form thyroid hormones THYROID HORMONE SYNTHESIS Iodine (I2) comes from the diet  It gets converted to IODIDE (I-) in the intestinal tract and it is transported to the thyroid follicle cells Thyroid follicle cells trap the iodide (I-) via an active transport process (Na+/I- cotransporter) sodium provides the driving force to bring iodide I- into the cell Intracellular [iodide] is 25 – 200 x higher than outside of the cel THYROID HORMONE SYNTHESIS In the thyroid follicle lumen, the Thyroid Peroxidase (enzyme!) will facilitate the synthesis of thyroid hormones in 2 steps: 1. Organification: Oxidation of iodide to iodine (I⁻→ I²) + Tyrosine iodination  Tyrosine iodination (Iodine combine to the tyrosine amino acid on thyroglobulin protein)  Tyrosyl ring can accommodate 2 iodine molecules  If 1 molecule attaches = MONOIODOTYROSINE (MIT)  If 2 molecules attach = DIIODOTYROSINE (DIT) THYROID HORMONE SYNTHESIS 2. Coupling (fusion) of two of these iodinated tyrosines  1 DIT + 1 DIT = T4 or Tetraiodothyronine or Thyronine or Thyroxine  4 iodine molecules  1 MIT + 1 DIT = T3 or Triiodothyronine  3 iodine molecules THYROID HORMONE Storage and Secretion  T3 and T4 remain attached to thyroglobulin molecule and stored in the colloid until secretion Unique type of storage (allows the thyroid to store a large reserve of the hormone)  T4 is the major hormone produced by the follicular cells Only small amounts of T3 are produced by the thyroid gland Major source of T3 is peripheral deiodination of T4 in target tissues (enzyme dependent - deiodinases) FYI Depending on the position of iodine, reverse T3 can be formed  Inactive form of the hormone  Produced in peripheral tissues during disease states THYROID HORMONE SECRETION Secretion process: Endocytosis of iodinated thyroglobulin from the follicle lumen into the follicle epithelial cell Lysosomes fuse to thyroglobulin vesicle → enzymes cleave T3 and T4 T3 & T4 are released and freely pass through the thyroid follicle cell membrane (lipophilic) into the blood stream THYROID HORMONE TRANSPORT Thyroid hormones are transported in plasma attached to proteins Thyroxine-binding globulin (TBG) Albumin (both synthesized in the liver)  A small amount of hormone is free in the circulation Free T4 and T3 are available to diffuse into the target cells Once free T4 has entered the target cell, most of it will be converted to T3  By iodothyronine deiodinases in the cytosol THYROID HORMONE TRANSPORT The equilibrium between free and bound hormone in the blood plasma is easily shifted because of physiological or pharmacological situations Such as the increase in estrogen concentrations that occurs during pregnancy Adjustments to maintain a normal amount of free hormone occur rapidly with:  A decline in the rate of metabolism or  Stimulation of thyroid hormone production through the release of thyroid-stimulating hormone (TSH) Reference values of free T4 and T3 will vary for different species HORMONE CLEARANCE The rate of the removal of the hormone from the blood can be measured It is called the METABOLIC CLEARANCE RATE The metabolic clearance rate interferes with hormone concentrations MCR = RATE OF THE DISAPPEARANCE OF HORMONE FROM PLASMA CONCENTRATION OF HORMONE HORMONE CLEARANCE T4 and T3 Hormones are “cleared” from the plasma in several ways  Conjugation formation of sulfates and glucuronides mainly in liver and kidneys  Deiodination metabolic breakdown by the tissues, mainly in:  liver  skeletal muscle  kidneys A decreased metabolic clearance rate can cause an excessively high concentration of thyroid hormones in the blood  Ex: liver disease  Excretion by the liver into the bile (than in the feces)  Excretion by the kidney into the urine ACTIONS OF THYROID HORMONES Thyroid hormones are the primary factors for the control of cellular metabolism o Bind to nuclear receptors and initiate the transcription of mRNA (protein synthesis!) o Are important for the normal metabolic activity of all tissues Physiological actions are not precisely determined o Most of the knowledge comes from the research with the diseases (hypo or hyperthyroidism) ACTIONS OF THYROID HORMONES  Increase quantity of mitochodria its activity o Increase the rate of ATP synthesis o Could be due to increased activity of the cells  Increase the basal metabolic rate of cells o BMR = is the minimal rate of energy expenditure per unit time at rest  T3 regulates the activity and gene experssion of Na+/K+ ATPase o Calorigenic: ↑ O2 consumption of tissues ↑ heat production o Weight loss in hyper, weight gain in hypothyroidism Metabolic rate o Cellular enzymes increase the activity in response to thyroid hormones Thyroid hormones ACTIONS OF THYROID HORMONES  Carbohydrate Metabolism o Increase absorption of intestinal glucose o Facilitate the movement of glucose into fat and muscle tissues  Lipids Metabolism o Increase lipolysis → enhance mobilization of fat, increasing FFAs available for β-oxidation o Thyroid stimulation decreases plasma cholesterol and liver fat  Increase cellular uptake and degradation of LDL, increase cholesterol secretion in the bile → Hypothyroid individuals can present hyperlipidemia and fatty liver ACTION OF THYROID HORMONES  Growth & development are influenced by thyroid hormones o TH permit maturation of the nervous system (CNS) during embryogenesis  If inadequate thyroid hormones: reduced mental abilities, lethargic o Work in conjunction with Growth Hormone (GH) The National Geographic Images  Increase blood flow and cardiac output o Possibly through interactions with catecholamines Health 24  Increase Heart rate o Direct effect on the excitability of the heart Balance me beautiful ACTION OF THYROID HORMONES  GI effects o Increase appetite and food intake o Increase GI motility Hyperthyroidism can cause diarrhea (hypermotility) Chinook salmon larval stages  Thyroid hormone induced metamorphosis in amphibians and fish larvae Lumen- Boundless Biology REGULATION OF THYROID HORMONES THROUGH NEGATIVE FEEDBACK LOOP FIG. 34.6 Hypothalamopituitary-thyroid axis. + signs indicate stimulation; signs indicate inhibition. T3, Triiodothyronine; T4, thyronine; TRH, thyrotropinreleasing hormone; TSH, thyroid-stimulating hormone. From Hedge GA, Colby HD, Goodman RL. Clinical Endocrine Physiology. Philadelphia: Saunders; 1987 PATHOLOGIES ASSOCIATED WITH THE THYROID HYPERTHYROIDISM Most common endocrinopathy of cats  Main cause is hyperplasia or tumors of Symptoms related to hypermetabolism the thyroid gland (thyroid adenoma)  weight loss  typically affects middle age to older cats  increased appetite (polyphagia)  is characterized by autonomous growth of  increased thirst and urination thyroid follicles (abnormality in the signal transduction of the thyroid cell) (polydipsia and polyuria)  Vomiting, diarrhea  shedding and unkempt appearance  Hyperactivity, tachycardia Animal endocrine clinic PATHOLOGIES ASSOCIATED WITH THE THYROID HYPOTHYROIDISM More common in dogs  Primary causes (strong breed disposition):  lymphocytic thyroiditis (inflammation)  congenital thyroid dysgenesis (inherited defects in DogsAholic.com the hypothalamic-pituitary-thyroid axis)  T4 transport defects  Goitrogens, iodine deficiency  autoimmune thyroiditis  Secondary causes:  pituitary tumors  radiation therapy  glucocorticoids Symptoms related to hypometabolism:  lethargy and obesity (most common)  dull hair and truncal or tail alopecia, retention of puppy hair  reproductive disorders  constipation PATHOLOGIES ASSOCIATED WITH THE THYROID IODINE DEFICIENCY IN CATTLE, SHEEP, GOATS - Goiter Iodine deficiency may be due to:  Inadequate dietary intake of iodine (i.e., Iodine deficiency typically results in enlargement of the thyroid glands (goiter). iodine deficient soils) or  Consumption of feeds containing Large firm, non-fluctuant, swelling of the compounds that either interfere with ventral neck in an otherwise healthy animal is iodine uptake by the thyroid gland or with likely to be goiter. normal synthesis of thyroid hormones (goitrogens) Goitrogens – brassicas, white clover pastures DIAGNOSIS  Total T4 and T3  Free T4 and T3 Why do we need to understand: Chemical structure of the hormones Synthesis and regulation How do they travel in the blood circulation  T3 suppression test Signal transduction  Reverse T3 Hormone clearance  Antibodies (T3 and T4, thyroglobulin)  TRH and TSH  Genetic test (TPO gene mutation)  Drugs affecting the thyroid hormones…