Thyroid Hormones-Calcium Metabolism (Medical Physiology-ERD-313 PDF)

Medical physiology-ERD-313 LECTURE 3 Physiology: Thyroid hormones-Calcium metabolism Learning objectives: 1- List the main physiological actions of thyroid hormone 2- Describe regulation of thyroid hormone secretion 3- Identify the effect of disturbed thyroid hormone level on di...

Medical physiology-ERD-313 LECTURE 3 Physiology: Thyroid hormones-Calcium metabolism Learning objectives: 1- List the main physiological actions of thyroid hormone 2- Describe regulation of thyroid hormone secretion 3- Identify the effect of disturbed thyroid hormone level on different body functions 4- Describe the major physiological functions of parathyroid hormone 5- Identify the effect of disturbed parathyroid hormone level on different body functions 6- List the functions of vitamin D 7- Describe the physiological functions of calcitonin Thyroid gland hormones Hormones Describe regulation of T4 Calcitonin Reverse T3 thT3 Thyroxine(Tetraiodothyroni Hormone. Biologically (Triiodothyronin) ne) inactive ↓Ca++ blood Contains 3 iodine Contains 4 iodine levels Most potent (Humoral When it reaches the tissue its stimulation) Most potent majority will be converted to (For Ca++ T3 More free (less metabolism) bind pp) More binding to receptor Amount 10% 90% - - Less but has stronger action than T4 Site of Apical and basal membrane in follicular cells Parafollicular - synthesis cells C-cell 1  Medical physiology-ERD-313 The synthesis of the hormones is partially intracellular and partially extracellular. 2  Medical physiology-ERD-313 I. Thyroid Hormone Within The Circulation There are two types: 1. Unbound free: Small amount. 2- Bound: >99% is bound. - 70%-80% bound to thyroxine-binding globulin (TBG), which is synthesized by the liver. - The reminder is bound to albumin and prealbumin. II. Release Of T4 & T3 To The Tissues The release is slow because of the high affinity of the plasma binding proteins: The mechanism of the T3 action: T3 + nuclear receptor → T3-receptor complex → activation of thyroid regulating element on DNA → DNA transcription → formation of mRNA → translation of mRNA → specific protein synthesis. - III. Physiological actions of thyroid hormones. 1- Increased oxygen consumption by the cells resulting in an increase in the metabolic activity of all tissues (Calorigenic action) except adult brain, retina, lung, lymph node, gonads and anterior pituitary Mechanism increase number and activity of mitochondria, increase respiratory enzymes uncoupling oxidation phosphylation (increase heat with small increase in ATP) and Increase Na-K Atpase Due to this calorigenic action T3 & T4 increase: - Appetite and food intake with increased rate of the food digestion and absorption. - Increase rate and depth of respiration. - Increase heart rate, cardiac output, and pulse pressure (↑SBP with ↓ DBP). 2- Growth:- Help mental (myelination of nerve fibers), physical (bone, teeth, muscle & skin) and sexual growth (are essential for gonadal hormones to exert their action). BONE ARE AFFECTED MORE THAN SOFT TISSUE 3- Metabolism  Protein: increased the protein synthesis permissive function on GH but, if excess it produces catabolic reaction. 3  Medical physiology-ERD-313  Fat: i. Lipolysis and Mobilization of lipid from fatty tissues ii. Decreased cholesterol level BY increase loss in feces and excretion in bile and increase LDL receptor. N.B. hypothyroidism is increased blood cholesterol concentration (atherosclerosis).  Carbohydrate: i. They stimulate glucose uptake and utilization by the tissues, ii. They increase liver glycogenolysis and gluconeogenesis iii. They increase intestinal absorption of glucose.  Vitamins: necessary for the hepatic conversion of carotene to vitamin A N.B. The general increase in enzymes activity leads to a general increase in the body needs for vitamins: the coenzymes. 4- OTHERS CVS  Increase heart rate & stroke volume (increased contractility) which lead to raises the Cardiac out put up to 60%  Decrease peripheral resistance  increase quantities of metabolic end products from the tissues. These effects cause vasodilation in most body tissues  Mean ABP NO CHANGE Causes potentiate the effect of catecholamine in the circulation Activation of β-adrenergic receptors. Respiration Increase the rate and depth of respiration GIT 1- Increase appetite and food intake. 2- Increase of digestive juices secretion. 3- increase of G.I tract motility. Excess thyroid H secretion diarrhea. Decrease thyroid H secretion lead to constipation. 4  Medical physiology-ERD-313 CNS A) Peri-natal period: maturation of the CNS. B) Adult -hyperexcitability. - irritability. Endocrine :- Negative effect on TSH - potentiate catecholamine.- Permissive GH. IV. Regulation of Hormones secretion It is regulated by the hypothalamic-pituitary axis. 1. Thyrotropin-releasing hormone (TRH): 2. Thyroid-stimulating hormone (TSH): It‘s a glycoprotein, released from the anterior pituitary. Mechanism of action Act by CAMP Action 1- It regulates the metabolism, secretion & growth of the thyroid gland (Trophic effect). 2- Immediate release proteolysis of thyroglobulin Slow increase synthesis –Iodine trapping --- iodination ---Coupling Increase hyperplasia and hypertphy of follicular cell and vascularity V. Disorder of thyroid gland more common in women Hyperthyrodism: Causes A-THYROIDAL CAUESE  Graves disease caused by autoantibodies that mimic TSH stimulation by binding to the thyroid, inducing increased TH secretion TSI  Thyroid gland tumor mostly benign  Acute thyroiditis Exogenous T3 & T4 B-Suprthyroidal hypothalamus or pituitary tumours C-Extra thyroidal ectopic thyroid tissue MANIFESTIONS 5  Medical physiology-ERD-313 1- calorogenic Increased the metabolic rate 100% with heat intolerance (Hot sweating). Hyperphagia with loss of the body weight 2- Metabolism Increase ptn catabolism - Decreased cholesterol level - Decrease liver glucogen liver failure 3- Skin sweating warm flushed 4- Muscle atrophy weakness by increase ptn catabolism 5- SYSTEMS CNS Irritability , Fine tremors , increase tendon jerk and insomnia CVS Increased heart rate (Tachycardia palpitation). Respiration tacypnea GIT increased appetite -diarrhea. Goiter ( Enlargement of the thyroid gland). Goiter can be accompanied with : 1-Normal hormone production 2- Hypo production 3- Hyper production Exophthalmos (Characteristic sign) auto immune AB against extraocular muscle and large amount of mucopolyscharides in retro orbital muscle Investigation High T3, T4 and Low TSH → in primary hyperthyroidism High T3, T4 and High TSH → in secondary hyperthyroidism Hypothyrodism 1. Cretinism: Before puberty (since birth; congenital absence of gland or genetic defect of enzymes) Symptoms and signs appear within 6 months after birth when the mother's milk insufficient for the infant's need. They include: 1- Dwarfism (bones are more affected) + hypogonadism+ mental retardation 2- Delayed all milestones of the development (sitting, standing, walking, speaking). 3- Retention of fluid rich in protein under the skin that lead to swollen eye lids depressed nose with wide nostrils, enlarged protrusion tongue and umbilical hernia N.B. Treatment should start soon after birth 2. Myxoedema =is the hypothyroidism in adults (After puberty) A-Primary causes in the thyroid itself 6  Medical physiology-ERD-313 1- chronic thyroditis hashimoto disease autoimmune disease(antibodies against thyroglobulin ) 2- Chronic iodine deficiency ( rare ) endemic goiter, feedback ↑ TSH level that causes hypertrophy of thyroid gland 3- Drugs ant thyroidal drugs 4-Excess removal of thyroid or excess radiation B- 2nd cause in the pituitary and tertiary hypothalamus. Manifestations of hypothyrodism myxoedema: 1- Calorogenic Decrease the basal metabolic rate 40-50 % that lead to cold intolerance. Body weight increased with food intake decreased 2- Metabolism nonpitting oedema (myxedema) CHO increase glycogen in liver and muscle -Lipid atherosclerosis - vitamin increase carotene 3- Skin. Dry cold decrease hair yellow and pale 4- Muscle weaknesses fatigue 5- systems Anemia due to bone marrow depression CVS Decrease heart rate (Bradycardia) and atherosclerosis due to increase cholesterol..CNS Decreased celebration and slow thinking. Slow speech and sluggish reaction. GIT constipation Respiratory bradyapnia N.B. Laboratory findings: a. Increased level of cholesterol in plasma. b. Low T3 & T4 with high TSH in blood (Inj hypothyroidism = thyroid origin). c. Low T3 & T4 with low TSH in blood (2ry hypothyroidism (pituitary) or 3ry hypothyroidism (hypothalamic). 7  Medical physiology-ERD-313 Hormonal control of calcium metabolism Parathyroid hormone Calcitonin Vitamin D Polypeptide h secreted by chief cells of Polypeptie h Steroid hormone- parathyroid gland. secreted by the 1--Sunlight: (7- Mechanism of action of PTH: parafollicular cells dehydrocholesterol) PTH binds to membranous receptors (C cells) of the 2--Dietary intake activates adenyl cyclase and increases thyroid gland. the intracellular cAMP ↑ plasma calcium level by its action Decreased plasma 1- Intestine It Has a potent on: calcium level by its effect to increase calcium & 1- Kidney: - ↑ Ca++ & Mg ions action on phosphate absorption by: reabsorption from the DCT, CT and a. Induces the synthesis ascending loop of Henle 1- bone - of Calcium binding (hypercalcemia+ hypocalciuria) a- ↑Ca++ deposition protein (calbindin). of bone (decrease it b. Formation of - ↓ phosphate reabsorption from PCT in blood)-increase Calcium-stimulated Hypophosphatemia+ phosphaturic action activity of osteoblast ATPase. - ↑ Formation of 1, 25 vit D3 in the b- Inhibits Bone 2- Kidneys Increases Renal kidney. activates 1alphahydroxlase resorption by calcium and Phosphate inhibition of reabsorption 2- Intestine: ↑ calcium absorption osteoclasts number indirect by increasing the activation and avtivity 3- Bone - of vitamin D. In the presence of a high 2- On kidney: Ca2+ & P04-, it stimulates 3- Bone: Slow mechanism. PTH osteoblastic activity. stimulates at first the osteoblasts it stimulates secretion production of IL6 and RANKL of both Ca2+ & P04— (receptor activated NF-KB ligand), in urine that in turn stimulates osteoclasts ↓ Ca++ reabsorption In the presence of a low proliferation i.e. osteoclasts have no from DCT and ↑↑ Ca2+ & P04 promotes bone receptors for PTH ↑ bone Ca++ excretion in resorption by : resorption) ↑ plasma Ca2+ urine a. Increase PTH action. ↓ phosphate b. increase Number & reabsororption from activity of osteoclast. Rapid mechanism Osteolysis PCT) Stimulation of the Ca2+ pump It is generally 4- Immune system mechanism of the osteocytic membrane antagonistic to PTH, as Stimulate differentiation of rapid mobilization of the regards Ca2+, but with immune cells exchangeable part of bone salts ↑ plasma similar effects on P04 Ca2+. 8  Medical physiology-ERD-313 Regulation of secretion Parathyroid hormone Calcitonin Vitamin D 1. A rise in : ↓Ca+2 , ↓Mg ,or ↓1,25 plasma Ca2+ 1- low Ca++ ions D3 ↑ PTH stimulates CT 2- PTH A rise in P04— will release. 3- low decrease extracellular 2. Estrogen 1.25dihycholicalciferol 2 Ca + causing an increase All stimulate renal and prolactin in PTH secretion 1alpha hydroxylase stimulate CT Conditions that increase release. 1,25-DHCC negative the cAMP in parathyroid 3. GIT feedback on l alpha gland as B-adrenergic hormones: gastrin hydroxylase enzyme stimulation, increase and CCK limit the formation of PTH secretion. stimulate CT more 1 ,25-DHCC. release to prevent A rise in plasma Ca2+ post- pradndial inhibits PTH secretion hyperecalcemia. from the parathyroid. 1 ,25(OH)2D3 inhibits the formation of PTH and so decreases its secretion. Disorders of secretion HYPOPARTHYRODISM HYPEPARATHYRODISM Tetany It is a state of increased of Primary hyperarathyroidism :. neuromuscular excitability due to decreased Adenoma (90%) the ionized calcium in the blood (Normal calcium level 9-11 mg %). hyperplasia Familial hyperparathyroidism Causes: 1- hypoparathyroidism surgical Carcinoma (1 %) removal (injury during thyroidectomy) Secondary hyperparathyroidism: 2- decreased calcium intake or increased need as in pregnancy (compensatory) 3- decreased intestinal absorption vitamin D Occurs in all conditions deficiency as in rickets accompanied with reduced serum 4- renal failure as it decreases calcium calcium as with undernutrition, vit. reabsorption and no vitamin D activation 9  Medical physiology-ERD-313 increase phosphate retention D deficiency, renal diseases 5. -Excess oxalat or citrate (excess blood Tertiary Hyperparathyroidism: transfusion) ndependent nodule secreting 6- Alkalosis ??? (caused by hyperventilation or excessive vomiting) as it precipitates the excessive parathyroid hormone after calcium lead to decrease in the ionized a long period of secondary calcium. hyperparathyroidism. Hypomagnesmic tetany Types: Characterized by: 1- Manifest tetany:- Calcium below 7mg % Hypercalcemia (↑Ca2+), -skeletal muscles show twitches, -tonic contraction of laryngeal and Hypercalciuria. diaphragm that lead to asphyxia and Hypophosphatemia (↓PO-4), cyanosis Hyperphosphaturia -Carpopadel spasm in the hands (Obstetrician hand; flexion of wrist and metacarpo-phalangeal joints, extension of 1- Weak and fragile bone (Osteitis interphalangeal joints and adduction of fibrosa cystica) due to excessive thumb into the hand). bone resorption and increased 2- Latent tetany: Calcium between 7 – 9 mg %. osteoclastic activity accompanied by Manifestations of tetany are absent at rest. They appear when here is increased in the body need osteoblastic activity increased for calcium or exposure to stress (as in alkaline phosphatase activity in pregnancy, lactation, emotions and plasma hyperventilation) 2- Urinary tract stone. Positive Trousseau’s sign (carpal spasm): arresting (stopping) blood flow to the forearm 3- Decreased the muscle excitability for few minutes (e.g. by sphygmomanometer), causing muscle weakness and causes flexion at the wrist, thumb, and constipation. metacarpophalangeal joints. 4- CNS depressed and peripheral Positive Chvostek’s sign (facial muscle nervous system depressed. twitch): tapping the facial nerve as it emerge from the parotoid gland in front of the ear 5- Peptic ulcer is common causes contraction of facial muscles. hypercalcemia stimulates gastrin secretion Treatment:  In Attack (Manifest tetany): Intravenous injection (very slowly) of calcium gluconate.  In between attack or in latent tetany: - Oral calcium + Vit D+Acidification ionization. - Oral Dihydrotachysterol. It doesn't produce anti-bodies formation 10  Medical physiology-ERD-313 11