Thyroid Gland and Calcium Homeostasis PDF

Thyroid Gland and Calcium homeostasis Prof. Marwa Abd Elaziz Ahmed  Thyroid gland -The thyroid gland is formed of 2 lobes lying on either side of the lower aspect of the larynx and upper trachea. -It is not essential for life but it is essential for growth and for physical and...

Thyroid Gland and Calcium homeostasis Prof. Marwa Abd Elaziz Ahmed  Thyroid gland -The thyroid gland is formed of 2 lobes lying on either side of the lower aspect of the larynx and upper trachea. -It is not essential for life but it is essential for growth and for physical and mental well-being. -The functional unit of the gland is the thyroid follicle, a hollow spherical unit lined with hormone secreting cells filled with ‘thyroid colloid’ containing characteristic protein called ‘thyroglobulin’. -Between the follicles there are parafollicular cells.  Thyroid follicles Thyroid follicles Thyroglobulin Parafollicular C cells  Thyroid Glands hormones 1- Thyroid follicles produce: a-Thyroxin or tetraiodothyronine (T4). 5.0 – 11.0 ug/dL. b- Triiodothyronine (T3): 100 – 200 ng/dL 2- Calcitonin from para follicular C cells produce  Thyroxin and triiodothyronine -Thyroxine hormone (T4) constitutes about 90% of the thyroid output. -Although T3 is released in a smaller amount and persists in blood for a much shorter time than does T4. T4 appears to be the most active hormone at the cellular level.  Synthesis of T3 & T4 1) Active uptake of inorganic iodide (I-) from the plasma by an active pump. 2) Oxidation of inorganic I- to organic iodine (I2). 3) Iodination of tyrosine to iodotyrosine. 4) Coupling (condensation) of iodotyrosines to form iodothyronine (T3&T4).  Iodide pump &synthesis of thyroid h. 2-Oxidation of iodide 3-Iodination of tyrosine Thyroid follicles 4-Coupling of iodotyrosines Follicular cell Thyroglobulin  Iodine requirements -Approximately 1 mg of ingested iodine is required per week for the formation of normal amounts of thyroid hormones. Areas far from the sea, as the oases, are supplied by iodized table salt to prevent iodine deficiency.  Storage and release of thyroid hormones -The thyroid hormones formed by the thyroid follicles remain in link with the thyroglobulin molecule and stored in the colloid. -On stimulation by TSH, the thyroglobulin is broken by a protease enzyme to yield T3 and T4.  Transport Proteins In the blood stream the hormones are bound to plasma proteins almost entirely. a)Alpha globulin called ‘Thyroxine Binding Globulin’ or TBG, which transports about 50% of the hormones. b)Pre-albumincalled ‘Thyroxin Binding Prealbumin ’ or TBPA, which transports about 40%. c) Plasma albumin which carries the remaining 10%.  Functions of thyroid hormones 1) Metabolic activity: Thyroid hormones increase the basal metabolic rate, oxygen consumption, heat production, and glucose uptake by cells. -Heat production is produced by accelerating the catabolic metabolism of cells. 2) Growth and development: -Thyroid hormones stimulate physical, mental and sexual growth. a) Physical growth: -Has a permissive effect on GH & potentiate the effect of somatomedins. -Eruption & development of teeth. b) Mental growth: -Growth, development & function of CNS during fetal life & 1st few years after birth. -Myelination of nerve fibers. c) Sexual growth: -Essential for normal menestrual cycle & spermato-genesis (fertility). -Stimulates milk secretion during lactation. 3- Respiratory System: rate and depth of breathing with a consequent increase in pulmonary ventilation. 4- Gastrointestinal tract: increase: Appetite and food intake. Motility of GIT. 5- Cardiovascular system: Increase Heart rate, venous return, strength of myocardial contraction, cardiac output. Arterial blood pressure: Systolic blood pressure is elevated & diastolic blood pressure is decreased. 6 - On Blood: -Thyroid hormones  erythropoiesis with increase in RBCs. 7- Specific metabolism: a) Carbohydrate metabolism: 1. They increase the rate of carbohydrate absorption from the gastrointestinal tract. 2. Stimulate rapid uptake and utilization of glucose by the cells. 3. Enhance glycolysis, gluconeogenesis (formation of glucose) b) Protein metabolism: They are anabolic in physiological level, but their excess cause protein catabolism. c) Fat metabolism: They enhance all aspects of fat metabolism: 1. Increases the plasma free fatty acid. 2. Accelerates the oxidation of free fatty acids by the cells. 3. Depletion of the fat stores. 4. Decreases the plasma cholesterol. 8- Vitamins a- synthesis of vitamin A from carotenes in the liver. Vitamin A b-Stimulate both the utilization and clearance of all vitamins. 9- Skeletal muscle: -Normal skeletal muscle function also requires thyroid hormones. -Muscle weakness occurs both in hyper- and hypothyroidism; in the former it may result from excessive catabolism of muscle proteins.  Control of thyroid function 1.Plasma level of thyroid releasing hormone TRH and thyroid stimulating Hormone (TSH). 2.Thyroid stimulating immunoglobulin (TSI). 3.All types of stress enhance thyroid activity. 4-Age. 5.Pregnancy. 6.Antithyroid agents (Goitrogens). 7.Blood iodine level.  1.TRH and TSH -There is a negative feedback mechanism between the plasma levels of the thyroid hormones and the output of TRH and TSH. 2.Thyroid stimulating immunoglobulin (TSI) -This immunoglobulin is a form of IgG produced by lymphocytes that can binds to TSH receptors on thyroid gland. TSI mimic TSH so acts on the thyroid in a manner similar to TSH causing exessive secretion of T3 & T4 but is not affected by the level of T3 and T4 in the blood (no –ve feed back). TSI increase in all cases of Grave’s disease (hyperthyroidism).  3.Cold Environment e.g Exposure to cold environment stimulates the thyroid with consequent increase in metabolic rate and heat production to counteract the effects of low temperature.  4.Age: Although its effect is small, but there tends to be a decrease in activity with increasing age. 5-Pregnancy Thyroid activity increases during pregnancy.  6.Antithyroid agents (Goitrogens) They are compounds that interfere with thyroid hormone production and promote thyroid tissue growth (increased TSH stimulation) that leads to development of goiter. Primary goitrogens include thiocyanates which inhibit the I- uptake by the thyroid gland. So interfere with T3 and T4 synthesis.  Goitrogens usually exert their effect after prolonged use and have greater impact when iodine intakes are low.  7.Blood iodine level Normal iodide stimulate thyroid hormones. a) Iodine deficiency→T3&T4 synthesis TSH. b)Excess iodine results in: TSH secretion.  Disorders of the thyroid gland Hypofunction (hypothyroidism) -Hypothyroidism may be: 1) Primary ( in thyroid defect) 2) Secondary (occurs when the hypothalamus produces insufficient thyrotropin-releasing hormone (TRH) or the pituitary produces insufficient TSH defect in the pituitary gland). Manifestations of thyroid hypofunction vary according to the age of occurrence of the disease: 1-Cretinism: -Hypothyroidism in human infants. 2-Myxedema: -Hypothyroidism in adults.  Cretinism This condition is not usually recognized until 5-6 months after birth, as some thyroid hormones reach the infant through milk from his mother.  Manifestations of Cretinism 1. Buffy eye lids. 2. Thick lips and thick protruded tongue. 3. Yellowish skin due to carotinemia. 4. Scanty coarse hair, due to failure of formation of vitamin A in the liver from carotins. 5. Abdomen is protuberant & umbilical hernia. 6. Delayed physical growth: delayed standing, walking and dentations. 7. Delayed mental growth: the child is idiot if not treated before 6 months of age. 8. Delayed sexual growth if untreated he become sterile. 9. Low BMR and O2 consumption.  2. Myxoedema -Hypothyroidism of human adults, which is characterized by: 1)Retardation of all mental processes e.g. lack of concentration, slow thinking ,speech, and sleepiness. 2) Low BMR and O2 consumption which leads to: i- Weight gain. Ii-Increased sensitivity to cold weather. 3) Bradycardia and hypotension. 4-Skin a-becomes thicker due to the deposition of a protein substance (myxoedematus tissue). b-Skin looks pale due to the presence of iron deficiency anaemia. c- It is cold due to decreased BMR. d-It is also dry and scaly with brittle hair due to vitamin A deficiency. e- It looks yellowish due to carotinaemia. 5- Failure of sexual functions e.g menstrual disturbances in the female, mainly in the form of oligomenorrhea. 6- Increased level of cholesterol & triglycerides.  Primary and Secondary Hypothyrodism Primary Secondary hypothyrodism hypothyrodism Thyroid gland T4 & T3 Ant. Pituitary TSH Hypothalamus TRH TSH stimulation test No RESPONSE  Hyperthyroidism or Thyrotoxicosis: - due to excess thyroid hormones secretion resulting from thyroid tumor or over stimulation of the thyroid by TSH or TSI. Clinical features: 1)Excessive nervousness and irritability accompanied with insomnia and tremors. 2) Increased appetite but there is loss of weight as a result of increased catabolism of tissue proteins. 3)Low serum cholesterol level. 4)Increased BMR and O2 consumption. 5)The skin: Warm and moist. 6) Exophthalmos (protrusion of one or both eye balls) occurs in most cases of hyperthyroidism as a result of accumulation of fat, water and inflammatory cells in the retro-orbital space. 7)Tachycardia, atrial arrythmias -High systolic pressure. -Diastolic pressure is not raised due to peripheral vasodilatation. 8)Rapid muscular fatigue due to reduced ATP synthesis. 9)Sexual disturbances similar to those described in myxoedema e.g. impotence in males and menstrual disturbances in the female  Goiter -Goiter means enlargement of the thyroid gland. - It is accompanied by either hypo, or hyperfunction. -Causes: 1.Physiological: during pregnancy. 2. Pathological : Goitrogens – iodine deficiency – Gravis disease-.Nodular goiter Calcium Homeostasis  Calcium homeostasis The daily calcium requirement is about 1gm and it is increased during childhood, pregnancy and lactation. It is absorbed from the small intestine mainly by active transport. This process is regulated by the active form of vitamin-D3 (1,25 dihdroxy-cholecalciferol). Blood: Normal total plasma Ca++ of about 9-11 mg/l00ml. Serum ionized calcium level is 4.5-5.5 mg/dl. Serum phosphorus level is 4-5 mg/ dl. Some functions of calcium: 1. Formation of Bone & teeth. 2. Activation of enzymes e.g. lipase, amylase 3. It plays a role in blood clotting & hemostasis. 4. Essential for muscle contraction. 5.Release of chemical transmitters e.g acetylcholine  Control of blood Ca++ level By: 1- Parathyroid hormone. 2- Thyrocalcitonin. 3- Active vitamin D  Parathyroid Hormone The parathyroid glands are four small oval bodies located on the posterior surface of the thyroid gland. Normal values are 10 to 55 pg/ml Physiologic functions of parathormone (PTH): The overall effect of PTH is to: Raise the plasma Ca+2 level when it is low by its action on bone, kidney and small intestine. This hormone also acts to lower plasma Po- 4 level. PTH uses bone as a bank from which it withdraws Ca ++ when needed.  I- Effect on bone: PTH acts directly on bone to increase calcium and phosphate absorption by two effects: 1- Rapid Phase (Osteolysis): occurs within minutes, increase calcium permeability of the bone fluid, causing rapid removal of calcium from the bone fluid to the extracellular fluid increasing the plasma calcium levels. 2- Slow Phase: Activation of the osteoclasts or formation of new osteoclasts lead to calcium phosphate release, take several days or weeks, can continue for months II- Effect on kidneys: 1-PTH increases renal tubular reabsorption of Ca++ 2- At the same time it decreases renal tubular Po4- reabsorption. III- Effect on intestine: PTH increases both Ca++ and phosphate reabsorption from the intestine by increasing the formation of 1, 25-dihydroxycholecalciferol from vitamin D in the kidney.  Control of Parathyroid Secretion Calcium is the major regulator of PTH secretion through the negative feedback mechanism: 1- The primary stimulus for PTH secretion is decreased plasma calcium ion concentration as in pregnancy and lactation. Conversely, if calcium is high, PTH secretion is inhibited and calcium is deposited in bones. 2- Increase plasma phosphate stimulates PTH secretion.  Hypoparathyroidism Damage or removal of parathyroid glands (which may occur accidentally during thyroid surgery), results in a gradual decline in plasma calcium. Tetany: Increased neuromuscular excitability due to decrease in serum calcium ion concentration. Types of tetany: Depending to the degree of lowering of the plasma calcium there are two types; manifest and latent. In manifest tetany the plasma calcium drops below 7 mg/l00mI 1- Manifest tetany - The muscle shows tonic and clonic contractions. - Tetany of the hands. This is called carpal spasm. The hand is flexed at the wrist. The fingers are flexed at the metacarpo-phalangeal, but extended at the interphalangeal joints. The thumb is adducted into the palm. -Tetany of the feet is called pedal spasm. – Spasmodic contractions of the laryngeal muscles leads to respiratory distress and cyanosis. 2- Latent tetany In latent tetany plasma calcium is above 7 mg/l00ml and below 9 mg/l00ml. No tetanic symptoms are present, but there is a tendency for the symptoms to appear when the patient is in stress as in emotions, pregnancy and lactation. Tendency for the symptoms to appear when the patient is in stress as in emotions, pregnancy and lactation. Hyperparathyroidism: It is increased production of parathormone, which leads to increase in the calcium level in the blood up to 12-15mg/l00mI. It is mostly caused by tumor of the parathyroid gland. manifestation: 1- Hyper calcaemia: Rise of plasma calcium level causes depression of the central and peripheral nervous systems, muscle weakness, polyuria, polydipsia and cardiac arrhythmias. 2-Bone disease: multiple fractures of the weakened bones can result from slight trauma. 3- Hypercalciuria and formation of stones in the kidney.  LABORATORY TESTS 01 IMAGING 02 1.Urine analysis: RBCs 1. Abdominal ultrasounds: and crystals. bilateral renal stones. 2. Blood tests: 2. X-ray on skull, ends of long bones or small Serum Ca: ⬆ bones of hands and feet: Serum phosphorus: ⬇ ostitis fibrosa cystica. Serum parathyroid 3. CT and MRI on hormone:⬆ parathyroid to discover tumor. 65 Calcitonin Hormone  Calcitonin Calcitonin is a polypeptide hormone, secreted by the parafollicular C cells of the thyroid gland tends to decrease the calcium ion concentration in the blood. Functions of calcitonin 1- Effect on bone: lower the plasma calcium level by: - Decrease the activities of the osteoclasts (immediate). - Decrease the formation of new osteoclasts (prolonged effect). - Increase the osteoblastic activities that enhance calcium deposition in bone. 2- Effect on kidneys: decreases calcium reabsorption from kidney tubules. 3- Effect on intestine: Inhibits Ca+ absorption from intestine.  Vitamin D  The most important compound belongs to Vitamin D family is Vitamin D3 (cholecalciferol).  It is a steroid compounds that behave as hormones and play a role in the regulation of plasma calcium levels.  Sources: it is found naturally in egg yolk, animal fat and milk.  Formation:  by action of ultraviolet rays on 7-dehydrocholesterol, which normally present in the skin, not itself biologically active but undergoes hydroxylation reactions to form active hormones.  The first hydroxylation takes place in the liver, giving rise to 25-hydroxycholecalciferol  A further hydroxyl group is added in the kidney to give 1,25-dihydroxy-cholecalciferol.  Actions of Vitamin D 1. On small intestine: Its main action is to stimulate the absorption of calcium, this occurs by a direct effect on the intestinal mucosa. 2. On bone: In normo-calcaemic states lead to mineralization of bone and in children lead to normal bone development. 3. On kidney: Vitamin D increases calcium and phosphate reabsorption by the epithelial cells of the renal tubules and decreases their renal excretion.