Hormonal control of calcium phosphate.pptx

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1. Dr.Sarah Yousif MBBS,MSc Hormonal control of calcium & phosphate (calcium homeostasis)

2. Many of the hormones of the body control functions that, though important, are not necessarily vital for survival, Such as growth. the control of body calcium concentrations is vitally important. absence of the hormone would be catastrophic, even life threatening

3. CALCIUM young adult contains about 1100 g 99% percent of the calcium is in the skeleton(BONE). Plasma calcium, normally at a concentration of around 10 mg/ dL (5 mEq /L, 2.5 mmol /L) Calcium exists in the body fluids in two form: 1. free, soluble, ionized form ( physiologically active) 2. bound to proteins

4. Functions of Ca It is the free, ionized calcium (Ca2+) in the body fluids that is: A vital second messenger Is necessary for blood coagulation muscle contraction nerve function Metabolic co-enzyme

5. Decrease in ca : exerts excitatory effect on nerve and muscle cells The result is hypocalcemic tetany (extensive spasms of skeletal muscle, involving especially the muscles of the extremities and the larynx). Laryngospasm can become so severe that the airway is obstructed and fatal asphyxia is produced. Ca2+ also plays an important role in blood clotting but fatal tetany would occur before compromising the clotting reaction

6. Factors the effect the level of ca Because the extent of Ca2+ binding by plasma proteins is proportional to the plasma protein level, it is important to know the plasma protein level when evaluating the total plasma calcium Other electrolytes and pH also affect the free Ca2+ level. example, symptoms of tetany appear at higher total calcium levels if the patient hyperventilates, thereby increasing plasma pH . Plasma proteins are more ionized when the pH is high, providing more protein anions to bind with Ca2+.

7. Extracellular Ca concentration normally remains within a narrow homeostatic range. Large deviations in either direction can disrupt neurological and muscular activity, For example, a low plasma Ca concentration increases the excitability of neuronal and muscle. high plasma Ca concentration causes cardiac arrhythmias and depresses neuromuscular excitability via effects on membrane potential

8. Phosphate homeostasis Phosphate homeostasis is likewise critical to normal body function, particularly given its inclusion in adenosine triphosphate (ATP) Cyclic adenosine monophosphate ( cAMP ) 2,3-diphosphoglycerate its role as a biologic buffer, its role as modifier of proteins, thereby altering their functions. (Phosphorylation and dephosphorylating of proteins )

9. Total body phosphorus is 500–800 g 85–90% of which is in the skeleton. Total plasma phosphorus is about 12 mg/ dL , 1. with two-thirds of this total in organic compounds 2. The remaining inorganic phosphorus (Pi)

10. Many of the systems that regulate calcium homeostasis also contribute to that of phosphate,

11. Pi in the plasma is filtered in the glomeruli, and 85–90% of the filtered Pi is reabsorbed. Active transport in the proximal tubule accounts for most of the reabsorption and involves is powerfully inhibited by PTH. Pi is absorbed in the duodenum and small intestine increase by 1,25-dihydroxycholecalciferol

12. Effector Sites for Ca Homeostasis Ca homeostasis depends on the interplay among: bone Kidneys gastrointestinal tract. with changes in calcium mobilization, excretion, or uptake

13. 1. Bone Approximately 99% of total-body calcium is contained in bone. the movement of Ca into and out of bone is critical in controlling the plasma Ca concentration.

14. Bone is a connective tissue made up of several cell types surrounded by a collagen matrix called osteoid , upon which are deposited minerals, particularly the crystals of calcium, phosphate, and hydroxyl ions known as hydroxyapatite . In some instances, bones have central marrow cavities where blood cells form. Approximately one-third of a bone , by weight, is osteoid , and two-thirds is mineral (the bone cells contribute negligible weight). 1. Bone

15. The three types of bone cells involved in bone formation and breakdown are : osteoblasts , osteocytes , and osteoclasts osteoblasts are the bone-forming cells. They secrete collagen to form a surrounding matrix, which then becomes calcified, a process called mineralization. Once surrounded by calcified matrix, the osteoblasts are called 2. osteocytes.

16. Figure : Cross section through a small portion of bone. The light tan area is mineralized osteoid. The osteocytes have long processes that extend through small canals and connect with each other and to osteoblasts via tight junctions.

17. 3. Osteoclasts are large, multinucleated cells that break down (resorb) previously formed bone by secreting hydrogen ions , which dissolve the crystals , and hydrolytic enzymes , which digest the osteoid

18. Structure of a typical long bone before (left) and after (right) epiphyseal closure.

19. Throughout life, bone is constantly remodeled by the osteoblasts (and osteocytes) and osteoclasts working together . Osteoclasts resorb old bone, and then osteoblasts move into the area and lay down new matrix, which becomes mineralized. This process depends in part on the stresses that gravity and muscle tension impose on the bones , stimulating osteoblastic activity

20. Many hormones, and a variety of autocrine or paracrine growth factors produced locally in the bone also play a role.

21. Summary of Major Hormonal Influences on Bone Mass Hormones That Favor Bone Formation and Increased Bone Mass - Insulin -Growth hormone -Insulin-like growth factor 1 (IGF-1) -Estrogen -Testosterone -Calcitonin Hormones That Favor Increased Bone Resorption and Decreased Bone Mass - Parathyroid hormone (chronic elevations) -Cortisol -Thyroid hormone T3

22. 2. Kidneys The kidneys filter the blood and eliminate soluble wastes. The control of Ca excretion is exerted mainly on reabsorption. Reabsorption decreases when plasma Ca concentration increases, and it increases when plasma Ca decreases.

23. 2. Kidneys Plasma Ca2+ is filtered in the kidneys, but 98–99% of the filtered Ca2+ is reabsorbed. About 60% of the reabsorption occurs in the proximal tubules and the remainder in the ascending limb of the loop of Henle. Distal tubular reabsorption is regulated by PTH.

24. 3. Gastrointestinal Tract The absorption of such solutes as Na1 and K1 from the gastrointestinal tract into the blood is normally about 100%. In contrast, a considerable amount of ingested Ca is not absorbed from the small intestine and leaves the body along with the feces.

25. 3. Gastrointestinal Tract The active transport system that achieves Ca absorption from the small intestine is under hormonal control . Thus, large regulated increases or decreases can occur in the amount of Ca absorbed from the diet. Hormonal control of this absorptive process is the major means for regulating total-body-calcium balance,

26. Hormonal Controls of ca (three hormones) The two major hormones that regulate plasma Ca concentration are parathyroid hormone 1,25-dihydroxyvitamin D. A third hormone, calcitonin , plays a limited role

27. A. Parathyroid Hormone ( PTH ) bone, kidneys, and the gastrointestinal tract are subject, directly or indirectly, to control by this hormone parathyroid hormone a protein which is produced by the parathyroid glands These endocrine glands are in the neck, embedded in the posterior surface of the thyroid gland, but are distinct from it

28. Figure : The parathyroid glands. There are usually four parathyroid glands embedded in the posterior surface of the thyroid gland.

29. SYNTHESIS &METABOLISM OF PTH It is synthesized as part of a larger molecule ( preproPTH ) then processed till packaged in secretory granules The normal plasma level of intact PTH is 10–55 pg / mL. The half-life of PTH is approximately 10 min, cleaved by the Kupffer cells in the liver and then cleared by the kidneys.

30. REGULATION OF SECRETION (PTH) Parathyroid hormone production is controlled by the extracellular Ca concentration acting directly on the Ca2+ sensing receptor on cell membrane of the gland cell. Activation Ca2+ sensing receptor, ( CaSR ) is G-protein coupled receptor, In the parathyroid, activation of this receptors inhibits PTH secretion. In this way, when the plasma Ca2+ level is high, PTH secretion is inhibited and Ca2+ is deposited in the bones.

31. So Decreased plasma Ca concentration stimulates parathyroid hormone secretion, Increased plasma Ca concentration inhibit parathyroid secretion

32. Action of Parathyroid hormone It directly increases the resorption of bone by osteoclasts, which causes calcium (and phosphate) ions to move from bone into extracellular fluid. It directly stimulates the formation of 1,25-dihydroxyvitamin D, which then increases intestinal absorption of calcium (and phosphate) ions. Thus, the effect of parathyroid hormone on the intestines is indirect

33. Action of Parathyroid hormone It directly increases Ca reabsorption in the kidneys, thereby decreasing urinary Ca excretion. for phosphate It directly decreases the reabsorption of phosphate ions in the kidneys, thereby increasing its excretion in the urine.

34. B. 1,25-Dihydroxyvitamin D The term vitamin D denotes a group of closely related compounds. Vitamin D3 ( cholecalciferol ) is formed by the action of ultraviolet radiation from sunlight on a cholesterol derivative (7 dehydrocholesterol) in skin. Vitamin D2 ( ergocalciferol ) is derived from plants. Both can be found in vitamin pills and enriched foods and are collectively called vitamin D.

35. Because of clothing, climate, and other factors, people are often dependent upon dietary vitamin D. .Regardless of source, vitamin D is metabolized by the addition of hydroxyl groups, - first in the liver by the enzyme 25-hydroxylase - and then in certain kidney cells by 1-hydroxylase

36. The end result of these changes is 1,25-dihydroxyvitamin D (abbreviated 1,25-(OH)2D ), the active hormonal form of vitamin D

37. Action of 1,25-(OH)2D The major action of 1,25-(OH)2D is to stimulate the intestinal absorption of Ca . Thus, the major consequence of vitamin D deficiency is decreased intestinal Ca absorption, resulting in decreased plasma Ca

38. The blood concentration of 1,25-(OH)2D is subject to physiological control. The major control point is the second hydroxylation step that occurs primarily in the kidneys by the action of 1 hydroxylase : 1. Which is stimulated by parathyroid hormone. 2. Also 1α-hydroxylase, is regulated in a feedback manner by plasma Ca2+ and PO43+ increase of Ca2+ and PO43+ lead to 1,25 dihydroxycholecalciferol and opposite is true

39. C. Calcitonin Calcitonin is a peptide hormone secreted by cells called Para follicular cells that are within the thyroid gland but are distinct from the thyroid follicles. Its secretion is stimulated by an increased plasma Ca concentration,

40. Mechanism of action Receptors for calcitonin are found in bones and the kidneys Calcitonin lowers circulating calcium and phosphate levels. 1. mainly by inhibiting osteoclasts, thereby reducing bone resorption. 2. increases Ca2+ excretion in the urine.

41. Unlike parathyroid hormone and 1,25-(OH)2D, calcitonin appears to play no role in the normal day-to-day regulation of plasma Ca in humans. It may be a factor in decreasing bone resorption when the plasma Ca concentration is very high.

42. Metabolic Bone Diseases Various diseases reflect abnormalities in the metabolism of bone.

43. 1. Rickets and osteomalacia Rickets (in children) osteomalacia (in adults) Are conditions in which mineralization of bone matrix is deficient , causing the bones to be soft and easily fractured. In addition, a child suffering from rickets is typically severely bowlegged due to weight bearing on the weakened developing leg bones. A major cause of rickets and osteomalacia is deficiency of vitamin D

44. 2. Osteoporosis osteoporosis , both matrix and minerals are lost as a result of an imbalance between bone resorption and bone formation. The resulting decrease in bone mass and strength leads to an increased incidence of fractures.

45. Causes of Osteoporosis: Can occur in people who are immobilized (“disuse osteoporosis”) In people who have an excessive plasma concentration of a hormone that favors bone resorption in people who have deficient plasma concentration of a hormone that favors bone formation

46. Hormones That Favor Bone Formation and Increased Bone Mass -Insulin -Growth hormone -Insulin-like growth factor 1 (IGF-1) -Estrogen -Testosterone -Calcitonin Hormones That Favor Increased Bone Resorption and Decreased Bone Mass - Parathyroid hormone (chronic elevations) -Cortisol -Thyroid hormone T3

47. It is most commonly seen, however, with aging. Everyone loses bone as he or she ages but osteoporosis is more common in elderly women than in men for several reasons .: Women have a smaller bone mass to begin with, and the loss that occurs with aging occurs more rapidly particularly after menopause removes the bone-promoting influence of estrogen Con: causes of Osteoporosis

48. 3. Hypercalcemia cause of hypercalcemia 1. Common cause of hypercalcemia is primary hyperparathyroidism : This is usually caused by a benign tumor (known as an adenoma) of one of the four parathyroid glands. These tumors are composed of abnormal cells that are not adequately suppressed by extracellular Ca . Primary hyperparathyroidism is most effectively treated by surgical removal of the parathyroid tumor

49. 2. Certain types of cancer can lead to ( humoral hypercalcemia of malignancy ) : The cause of the hypercalcemia is often the release of a molecule that is structurally similar to PTH, called PTH-related peptide ( PTHrp ), that has effects similar to those of PTH.

50. This peptide is produced by certain types of cancerous cells (e.g., some breast-cancer cells, kidney, ovary, and skin) However PTH release from the normal parathyroid glands is decreased due to the hypercalcemia caused by PTHrp released from the cancer cells. T the most effective treatment of humoral hypercalcemia of malignancy is to treat the cancer that is releasing PTHrp . In addition, drugs such as bisphosphonates that decrease bone resorption can also provide effective treatment

51. 3 . Excessive ingestion of vitamin D can lead to hypercalcemia, as may happen in some individuals who consume vitamin D supplements far in excess of what is required.

52. Symptoms hypercalcemia symptoms primarily from its effects on excitable tissues. Among these symptoms are tiredness and lethargy with muscle weakness, as well as nausea and vomiting (due to effects on the GI tract).

53. 4. Hypocalcemia Causes: Hypocalcemia can result from a loss of parathyroid gland function ( primary hypoparathyroidism ). One cause of this is the removal of parathyroid glands, which may occur when a person with thyroid disease has his or her thyroid gland surgically removed.

54. Because the concentration of PTH is low, 1,25-(OH)2D production from the kidney is also decreased. Decreases in both hormones lead to decreases (in bone resorption, kidney Ca reabsorption, and intestinal Ca absorption .)

55. Causes of hypocalcemia 2. Resistance to the effects of PTH in target tissue (hypo responsiveness) : can also lead to the symptoms of hypoparathyroidism, even though in such cases PTH concentrations in the blood tend to be elevated. This condition is called pseudohypoparathyroidism

56. 3. secondary hyperparathyroidism : Failure to absorb vitamin D from the gastrointestinal tract, or decreased kidney 1,25-(OH)2D production, which can occur in kidney disease, can lead to secondary hyperparathyroidism. Decreased plasma Ca that results from decreased intestinal absorption of Ca results in stimulation of the parathyroid glands..

57. Although the increased concentration of parathyroid hormone does act to restore plasma Ca toward normal, it does so at the expense of significant loss of Ca from bone and the acceleration of metabolic bone disease

58. The symptoms of hypocalcemia It increases the excitability of nerves and muscles, which can lead to: 1. CNS effects (seizures) 2. Muscle spasms ( hypocalcemic tetany ) 3. Neuronal excitability.

59. Long term treatment of hypoparathyroidism involves : giving calcium salts and 1,25-(OH)2D or vitamin D.