1. Assist prof. of Medical Physiology

3. Site: 4 glands on the posterior aspect of the thyroid gland. Size and Weight Each measures 3-5 mm in diameter Combined weight of the 4 glands about 120 mg.

5. Functions: Secrete ‘parathormone PTH’ (84 aa). PTH is essential for life Have essential role in the regulation of Ca2 + metabolism in the body

6. Histology: Parathyroid glands are formed of columns of; a)Chief cells : More numerous and secrete PTH. b)O xyphil cells: Appear in the gland at 10 th year of life. Represent inactive chief cells.

9. The main function of PTH is to keep a normal plasma Ca 2+ level (9-11 mg%). –Parathormone increase the blood Ca 2+ level. –Maintains a constant ratio between plasma Ca 2+ & PO4, Ca x PO4 = K (constant). (solubility product) Ca 2+ and PO 4 - are inversely related. PTH tend to raise lowered blood Ca by ;

12.  Serum calcium  Parathormone  Ca ++ absorption  Ca ++ reabsorption  bone resorption  Ca ++ - - PTGs

13. 1. On the kidney –On the ALH and distal CT Increase reabsorption of Ca2+ Increase PO4 excretion. –On the proximal CT Increase the reabsorption of Mg Activate vitamin D to (1,25 dihydroxycholecalciferol)

15. 2. On the small intestine 1. Increase the absorption of: Ca2 + Mediated by active vitamin D (1,25 dihydroxy cholecalciferol) 2. Increase the absorption of: PO4 and Mg.

16. 3. On Bone –Increase the number and activity of osteoclasts (bone destroying cells). –Results in resorption of bone, release of Ca 2+ into the blood and hypercalcemia. 4. On breast –Decrease Ca 2+ secretion in milk.

18. Through cell membrane receptor: 1. Activation of adenyl cyclase enzyme & –increase the intracellular cAMP. 2. Increase intracellular Ca2+. Ca2+ –Acts as a second messenger or –Modulate adenyl cyclase response.

21. a) Plasma Ca level: It the main regulator of PTH secretion. ↓ Plasma Ca level → ↑ PTH secretion b) Plasma Mg level: as Ca c) Plasma PO4 level: opposite to Ca d) Nervous factors: β-adrenergic receptors agonists as isoproterenol→↑ PTH secretion

22. Epinephrine and isoproterenol stimulate PTH secretion –through β-adrenergic receptors identified on chief cells. Some Patients with pheochromocytoma Show hypercalcemia

24. Excess PTH Secretion Decreased PTH Secretion Hyperparathyroidism Hypoparathyroidism

25. Causes –Deficient parathyroid activity is uncommon –Most cases result from: 1) Accidental removal of the parathyroid glands or 2) Damage of their blood supply during thyroidectomy.

27. Characterized by: –Hypocalcaemia –Increase neuro-muscular excitability (tetany) Mechanism: Decrease plasma Ca 2+ ions < 9 mg/dl –Increase the excitability of Nervous system due to ↑ neuronal membrane permeability to Na + –Hyperexcitable nerve fibres, spontaneously initiate nerve impulses to peripheral sk ms –thus eliciting tetanic contraction.

28. Manifested by ↑ed neuromuscular excitability due to ↓ plasma ionized Ca 2+ Causes : a) Hypoparathyroidism. b) Alkalaemia, decrease the solubility product of Ca 2+ & PO 4 and leads to reduced ionized Ca 2+. precipitation of CaPO 4 ;

29. Causes : c) Decreased Ca 2+ absorption from the intestine: –1. Low calcium intake. –2. Excess intake of antiacids (peptic ulcer) lead to Ca 2+ precipitation and decreased absorption. –3. Steatorrhea (fatty diarrhea), where Ca 2+ is lost in stools.

30. These depend on the degree of ↓ed blood Ca 2+ level: 1. Manifest tetany : –Blood Ca 2+ level is below 7 mg% (N 9-11 mg%). –Muscular spasms in the hands and feet (Carpo-pedal spasm). 2. Latent tetany : –Blood Ca 2+ level is at 7-9 mg%, –Muscle spasms only occur when the patient is exposed to stress.

31. blood Ca 2+ level is below 7 mg% (N. 9-11 mg%). ‘Carpo-pedal spasm’. The hands (Carpal spasm), –1) Flexion of: Wrists and Metacarpo-phalangeal joints, –2) Extension of the inter-phalangeal joints and –3) Adduction of the thumb.

32. Carpal spasm

33. The feet (pedal spasm), –Dorsiflexion of the ankle –Planterflexion of the toes Occasionally, –Few patients, children, may have generalized convulsions. –Infants with tetany show spasm in the laryngeal ms leading to: a difficulty in breathing (laryngismus stridulus).

34. Blood Ca 2+ level is at 7-9 mg%, –Ms spasms only occur when the patient is exposed to stress. –The patient have widespread: tingling feelings and sensations of heat & flushing (parasthesia).

35. Provokative tests: tests used to demonstrate the neuro-muscular hyper- excitability in latent tetany: a) Chvostek’s test: –Tapping over the facial nerve in front of the ear –Produce twitching of the ipsilateral (same side) facial ms, especially those of the upper lip.

36. Chvostek’s test Chvostek’s test

37. Provokative tests: b) Trousseau’s test: Inflating the sphygmomanometer cuff round the upper arm to a pressure above the systolic BP for 2 minutes. –Leads to Carpal spasm: Explanation –Ischaemia increase the excitability of the nerve trunks and increase the effect of hypocalcaemia.

39. Provokative tests: c) Erb’s sign: Stimulation of motor nerve by a subthreshold galvanic current –Induce muscle contraction.

41. 1. IV injection of Ca 2+ gluconate during ms spasm. –stops immediately the tetanic spasms. 2. Calcium level is then maintained by: –giving vitamin D and administration of oral calcium. 3. Acidifying salts as ammonium chloride –help Ca 2+ absorption as they increase the ionization of Ca 2+.

42. 4. In hypoparathyroidism: Repeated administration of parathormone leads to –formation of antihormone which antagonizes its action. A synthetic steroid ‘dihydrotachysterol (or AT 10)’ –Has similar effects as parathormone and vitamin D, –Not produce antihormone.

44. Def., Excess production of parathormone Cause: –usually due to parathyroid tumor Effect –Leads to hypercalcaemia (blood Ca 2+ level may exceed 20 mg%).

46. Manifestations 1. Bone resorption due to: –Increased osteoclastic activity with mobilization of Ca 2+ from bones (decalcification). –In severe cases the affected bones show formation of fibrous masses and cysts (osteitis fibrosa cystic). –Increased bone fragility leads to spontaneous fractures.

48. Manifestations 2. The high Ca 2+ levels in the kidney filtrate lead to: –Precipitation of Ca 2+ compounds and the formation of calculi. –Renal failure eventually develops. 3. Polyuria, due to: –a) Osmotic diuresis by excess excretion of Ca 2+ and PO4 in urine. High filtration of Ca 2+ exceeds the effect of parathormone on Ca 2+ reabsorption. –b) Renal damage due to the frequent formation of calculi.

50. Manifestations 4. Hypotonia of muscles, and muscle weakness. 5. Vomiting, constipation and intestinal pain. 6. Severe cases show: –Cardiac irregularities –Mental confusion, even coma.

51. Treatment of hyperparathyroidism: –Surgical removal of the parathyroid tumor –is the only line of treatment.

52. 1. Neoplasms with secondary deposits in bones. 2. Neoplasms secreting parathormone-like substance. 3. Excessive intake of vitamin D.

55. 1.Participates in numerous enzymatic reactions. 2.Vital component in the mechanism of hormone secretion and a mediator of hormonal effects. 3.Involved in neurotransmission, in muscle contraction, and in blood clotting. 4.Major cation in the crystalline structure of bone and teeth.

56. Total Body Calcium (1000 g (1 Kg)) Less than 1% In ECF (900 mg) More than 99% In bone and teeth (910 g) After the 3 rd decade of life, bone resorption exceeds bone accretion (i.e. formation), and there a slow but progressive loss of bone occurs which is greater in women than in men.

57. Plasma Ca + concentration Plasma Ca + concentration = 9 -11 mg/dl Nondiffusable(40%)Diffusible(60%) Bound to albumin Ionized Ca+ (50%) (Active form) Complexed Ca+ such as CaHCO3 (10%)

60. Daily recommendations: Minimum daily requirement for Ca 2+ is 400 mg for adults Greater amounts are needed in childhood, pregnancy and lactation. However, the intestine has a remarkable facility for adapting to a low Ca diet by increasing the proportion of the absorbed dietary Ca 2+.

61. Absorption: Site: from all parts of the small intestine. The greatest absorbing capacity is in the duodenum Mechanism: 1. In duodenum by active transport mechanism controlled by vitamin D (such action of vit. D is facilitated by parathromone) 2.In jejunum and ileum Ca 2+ absorption takes place by passive or facilitated diffusion

62. Factors affecting Ca + absorption Factors that ↓ Ca + absorption 1.Vitamin D deficiency 2.Renal failure 3.Intestinal malabsorption 4.Phytic acid, phosphates or steroids 5.Excess unabsorbed fatty acids in the intestine 6.Advancing age Factors that ↑ Ca + absorption 1.Parathormone 2.Growth hormone not in the absence of vitamin D.

63. Kidney : Filtered amount : About 9 gm Ca 2+ daily into the GFR. Site of reabsorption: Most of filtered Ca is reabsorbed by the tubules Urinary excretion : About 80-400 (150 mg/day) Factors affecting: 1.↑ed in hyperparathyroidism 2.↓ed hypoparathyroidism, sodium diuretics, calcitonin and excess corticosteroids

65. 1.Integral component of all glycolytic compounds as G-1-P 2.Part of structure of high energy transfer compounds such as ATP and creatine phosphate 3.Part of cofactors such as NAD and NADH 4.Part of lipids such as phosphatidyl choline 5.Modifier of numerous enzymes and an important component of bones.

66. Plasma PO4 - concentration Plasma PO4 - concentration = 2.5 -4.5 mg/dl Nondiffusable (12 %) Diffusible(88%) Bound to proteins

67. Dietary PO4 - : Since phosphorus is present in all animal and plant cells, dietary deficiency never occurs in man. Phosphate depletion may occur as a result of: 1.Renal tubular disorders. 2.Excessive intake of aluminium hydroxide, an antacid which binds phosphorus in the gut.

68. Intestinal Absorption: Percentage : % of phosphate absorbed from the diet is relatively constant Linearly related to the intake over a wide range Adaptive bowel regulation is of minor importance

69. Renal Absorption: Major mechanism for preserving phosphate balance. 90% of the filtered phosphorus is reabsorbed in the tubule. This ratio varies from 70- 100%, to compensate for large swings in dietary intake

70. Other hormones that affect bone and calcium metabolism

72. Osteoblasts –Primary cells concerned with synthesis of new bone. –Produce bone osteoid which will subsequently undergo calcification. Osteocytes –Mature bone cells which are less active than osteoblasts. Osteoclasts –Multinucleated cells derived from macrophages which function to resorb bone.

73. Def: Is a continuous process throughout life, even after epiphyseal fusion and cessation of linear bone growth. Remodeling consists of bone formation and bone resorption.

75. PTH and Calcitonin are the major Ca 2+ regulating hormones, A number of hormones have an important influence on bone and mineral metabolism, These include: 1) Vitamin D 2) Estrogens and androgens 3) Glucocorticoids 4) Thyroid hormones 5) Growth hormone

77. Protein hormone (32 a.a) Secreted by the parafollicular cells or C-cells of the thyroid gland. Its plasma concentration (10- 100 pg/ml)

78. Synthesis: As protein hormones: –it is as pre-prohormone which is transformed into prohormone and stored in secretory granules. There is species variation in calcitonin Fish & animal calcitonin are active in human.

80. Stimuli for Release 1. Rise in serum Ca 2+ (The major stimulus), e.g. –Acute rise of serum Ca 2+ as little as 1 mg% (increases 2-10 times). –Ca 2+ increase intracellular cAMP→ stimulate calcitonin release. 2. Ingestion of food stimulates calcitonin secretion. –Mediated by several GIT hormones –The most potent of which is gastrin.

81. Although its physiological role in human is uncertain, calcitonin is important regulator of plasma Ca 2+ in lower animals that live in aquatic environment high in Ca 2+.

82. The major effect of calcitonin administration to produce a rapid fall in plasma Ca 2+ Young growing animals are more affected than adults, (have more stable skeleton &, only a minimal response is seen). Through acting on bones, kidney and intestine

84. 1) Bones: Inhibit osteolysis by osteocytes Reduce bone resorption by osteoclasts. Decrease Ca 2+ mobilization from bone to blood ( inhibits Ca 2+ permeability of bone cells).

85. 2. A physiological antagonist to parathormone with respect to Ca 2+, but has the same effect of parathormone on PO4. –decreases plasma PO4 level, and has no effect on plasma magnesium level.

86. 4. Increase urinary excretion of Ca 2+ and PO4. 5. Decrease Ca 2+ absorption from the intestine.

89. Active Vitamin D is a steroid hormone having both dietary and endogenous precursors. Vitamin D2 (ergocalciferol) –is formed in plants from ergosterol Vitamin D3 (cholecalciferol) –is formed by ultraviolet rays from precursor 7- dehydrocholesterol in skin.

92. Biological effects of vitamin D: 1.Intestine (is the principal target) 2.Bone 3.Kidney 4.Immune system. 1) On the intestine –Stimulates both Ca2+ and phosphorus absorption. 2) On Bone (the second major target of vitamin D). –Provides Ca2+ and phosphate to initiate the crystallization of bone osteoid.

94. 3) On the kidney –Vitamin D increase renal tubular reabsorption of both Ca2+ and phosphate. 4) On the immune system has important regulatory effects. –Promotes differentiation of monocyte precursors to monocytes and macrophages. –Bone resorbing osteoclasts arise from this differentiation pathway. –Affects both T and B lymphocytes, inhibiting IL-2 production and other effector functions.

96. Gonadal steroids are involved in: –Pubertal growth spurt –Closure of the epiphyses. During childhood and puberty, –Gonadal steroids favor bone formation over resorption.

98. In the adult female –Estrogens protect the skeleton from osteoporosis or decreased bone mass by: a) Inhibiting PTH mediated bone resorption. –Estrogen receptors have been detected in osteoblasts, and –Osteoblasts release factors that inhibit osteoclastic resorption. b) Reduce bone-resorbing cytokines such as IL-1 & IL-6 in bone.

99. c) Increase serum parathormone, –due to the hypocalaemic effect of the inhibition of bone resorption. –It also facilitates parathormone action at the kidney with greater phosphate excretion, calcium absorption and vitamin D3 activation.

100. Androgens protect men from osteoporosis, as evidenced by: –Excessive bone loss in hypogonadal conditions such as: Klinefelter’s syndrome (47, XXY), and following castration (removal of testicles).

101. At physiological levels –glucocorticoids are necessary for skeletal growth. Prolonged excess glucocorticoids, have deleterious effects on Ca 2+ homeostasis: –a) decrease renal tubular Ca2+ absorption. –b) interfere with intestinal Ca2+ absorption.

102. Excess glucocorticoids c) Increase parathormone secretion through: –Direct effect on parathyroid, –Secondary hyperparathyroidism due to low Ca2+ level. d) They inhibit osteoblastic bone formation. e) They suppress gonadal estrogen and testosterone production

103. The thyroid hormones are important for the development and growth of the skeleton in infancy and childhood. Hypothyroidism : –Show retarded bone age, as indicated by: delayed ossification of the cartilaginous bone growth centres. Hyperthyroidism –Causes increased bone resorption.

104. It has striking effects on bone growth –Through somatomedin or IGF-1 ( mitogenic for chondrocytes and osteoblasts). Growth hormone also –increase intestinal Ca2+ absorption by a vitamin D-dependent mechanism, –increase renal tubular phosphate reabsorption.

105. Thanks