Calcium homeostasis

Calcium homeostasis

1. Calcium homeostasis Presented by: Sumantha Sarathi Acharjee (1 st Prof. Mbbs)

2. Contents: Introduction Distribution of calcium Biochemical functions Daily requirement and sources of calcium Calcium homeostasis Parathyroid hormone Calcitriol Calcitonin Disease states Hypercalcemia Hypocalcemia

3. Introduction Calcium is the most abundant mineral in the body. Calcium contribute to the physiology and biochemistry of organisms. They play an important role in signal transduction, in contraction of muscles and in fertilization. The total content of calcium in an adult man is about 1 to 1.5 kg. As much as 99% of it is present in the bones and teeth. The rest 1% is present in extracellular fluid(mainly blood). Plasma calcium levels are tightly regulated in mammals(including humans) with bone as the major storage site. Parathyroid hormone, calcitriol and other factors regulate plasma calcium levels.

4. In bones: 99% of body calcium is present in bones. Bone is composed of a tough organic matrix that is greatly strengthened by deposits of calcium salts. Average compact bone contains by weight about 30 percent matrix and 70 percent salts. Newly formed bone may have a considerably higher percentage of matrix in relation to salts. The crystalline salts deposited in the organic matrix of bone are composed principally of calcium and phosphate. Major crystaline salt is calcium hydroxyapatite{Ca 10 (PO 4 ) 6 (OH) 2 ] Distribution of calcium

5. Plasma calcium: Most of the blood Ca is present in the plasma since the blood cells contain very little of it. The normal concentration of plasma or serum Ca is 9-11 mg/dl (4.5-5.5 mEq/l). 50% ionized form = 5mg/dl 40% protein bound = 4-5mg/dl 10% complexed with = 1mg/dl citrate, phosphate

6. C alcium in cells: Intracellular Ca 2+ concentration= 2mEq/l Calcium influx into the cell is by Na + / Ca 2+ exchange mechanism. This mechanism is rapid but has low affinity for calcium. Entry of Ca 2+ into mitochondria is by a calcium uniport system. But calcium exit by a Na + -Ca 2+ system which in turn is dependent on the Na + -H + ATPase pump.

7. Biochemical Functions Development of bones and teeth : Calcium alongwith phosphate is required for the formation(hydroxyapatite) and physical strength of skeletal tissue. Bones are in dynamic state and serve as reservoir of calcium. Muscle contraction: Ca 2+ interacts with troponin C to trigger muscle contraction. Calcium also activates ATPase, increases the interaction between actin and myosin. Blood coagulation: Several reactions in cascade of blood clotting process are dependent on Ca 2+ (factor IV). Figure: Biochemical functions of Calcium

8. Nerve transmission: Ca 2+ is necessary for the transmission of nerve impulse. Membrane integrity and permeability: Ca 2+ influences the membrane structure and transport of water and several ions across it. Activation of enzymes: Ca 2+ is needed for the direct activation of enzymes such as lipase(pancreatic), ATPase and succinate dehydrogenase. Calmodulin mediated action of Ca 2+ : Calmodulin is a calcium binding regulatory protein. Ca-calmodulin complex activates certain enzymes e.g., adenylate cyclase, Ca 2+ dependent protein kinases, myosin kinase, phospholipase C, glycogen synthase. Figure: Mechanism of action of calcium mediated calmodulin

9. Calcium as intracellular messenger : Certain hormones exert their action through the mediation Ca 2+ (instead of cAMP). Calcium is regarded as a second messenger for such hormonal action e.g. epinephrine in liver glycogenolysis. Calcium serves as a third messenger for some hormones e.g. antidiuretic hormone(ADH) acts through cAMP), and then Ca 2+ .

10. Release of hormones: The release of certain hormones(insulin, PTH, calcitonin) from the endocrine glands is facilitated by Ca 2+ . Secretory processes: Ca 2+ regulates microfilament and microtubule mediated processes such as endocytosis, exocytosis and cell motility. Contact inhibition: Calcium is believed to be involved in cell to cell contact and adhesion of cells in a tissue. The cell to cell communication may also require Ca 2+ . Action on heart: Ca 2+ acts on myocardium and prolongs systole.

11. Calcium homeostasis Calcium homeostasis  refers to the maintenance of a constant concentration of   calcium ions   in the  extracellular fluid . It includes all of the processes that contribute to maintaining calcium at its “set point.” Because plasma [Ca 2+ ] rapidly  equilibrates   with the extracellular fluid, ECF [Ca 2+ ] is kept constant by keeping the plasma [Ca 2+ ] constant. 

12. Factors regulating plasma Calcium level The major Hormones that regulate plasma calcium level are: Parathyroid hormone Calcitriol Calcitonin Figure: Overview of calcium homeostasis

13. Principle organ systems for Calcium homeostasis: Intestine Bone Kidney Figure: Organs of calcium homeostasis

14. Parathyroid hormone(PTH) Parathyroid hormone (PTH) is secreted by two pairs of parathyroid glands that are closely associated with thyroid glands. Parathyroid hormone (mol. wt. 95,000) is a single chain polypeptide, containing 84 amino acids.

15. Synthesis of PTH: PTH is originally synthesized as preproPTH which is degraded to proPTH and, finally, to active PTH. The rate of formation (by degradation of proPTH) and the secretion of PTH are promoted by low Ca 2+ concentration. Thus, the release of PTH from parathyroid glands is under the negative feedback regulation of serum Ca 2+ Figure: Structure of preproparathyroid hormone

16. Control of Parathyroid Secretion by Calcium Ion Concentration: Even the slightest decrease in calcium ion concentration in the extracellular fluid causes the parathyroid glands to increase their rate of secretion within minutes. Changes in extracellular calcium ion concentration are detected by a calcium-sensing receptor(CaSR). Figure: Effects of parathyroid hormone

17. Mechanism of action of PTH : PTH binds to a membrane receptor protein on the target cell and activates adenylate cyclase to liberate cAMP. This, in turn, promotes the phosphorylation of proteins (by kinases) which, finally brings about the biological actions. PTH has 3 independent tissues-bone, kidneys and intestine-to exert its action. The prime function of PTH is to elevate serum calcium level. Figure: Mechanism of action of PTH

18. Action of PTH on Bones: In the bone, PTH causes demineralization or decalcification. The number of osteoclasts are also increased . Osteoclasts release lactate into surrounding medium which solubilizes calcium. PTH also causes secretion of collagenase from osteoclasts. This causes loss of matrix and bone resorption.

19. Action of PTH on intestine: Parathyroid stimulates 1-hydroxylation of 25-hydroxycholecalciferol in kidney to produce calcitriol. This indirectly increases calcium absorption from intestine. Figure: Organs of calcium homeostasis

20. Action of PTH on kidney: In kidney, PTH causes decreased renal excretion of calcium and increased excretion of phosphates. The action is mainly through increase in reabsorption of calcium from kidney tubules. Figure: Action of PTH on kidney

21. Calcitriol The physiologically active form of vitamin D is a hormone, namely calcitriol or 1,25-dihydroxycholecalciferol (1,25 DHCC).

22. Action of calcitriol: Calcitriol induces the synthesis of a specific calcium binding protein, Calbindin , in the intestinal cells. This protein increases the intestinal absorption of calcium as well as phosphate. Thus blood Ca level is increased by calcitriol (the active vitamin D). Furthermore, calcitriol stimulates calcium uptake by osteoblasts of bone and promotes calcification or mineralization (deposition of calcium phosphate) and remodeling Figure: Action of calcitriol

23. Figure: Action of calcitriol on intestine

24. Calcitonin Calcitonin is a peptide containing 32 amino acids. It is secreted by parafollicular cells of thyroid gland. The action of CT on calcium metabolism is antagonistic to that of PTH. Thus calcitonin promotes calcification by increasing the activity of osteoblasts. Further, calcitonin decreases bone resorption and increases the excretion of Ca into urine. CT, therefore, has a decreasing influence on blood calcium.

25. Disease states The blood Ca level is maintained within a narrow range by the homeostatic control, most predominantly by PTH. Hence abnormalities in Ca metabolism are mainly associated with alterations in PTH

26. HYPERCALCEMIA Elevation in serum Ca level (normal 9-11 mg/dl) is hypercalcemia. Hypercalcemia is associated with hyperparathyroidism caused by increased activity of parathyroid glands. Decrease in serum phosphate (due to increased

27. CAUSES OF HYPERCALCEMIA: Overactive parathyroid glands (hyperparathyroidism):  This most common cause of hypercalcemia Cancer:  Lung cancer and breast cancer, as well as some blood cancers(multiple myeloma). Metastatic carcinoma of bones Other diseases:  Certain diseases, such as tuberculosis, sarcoidosis, Paget’s disease Hereditary factors: Familial hypocalciuric hypercalcemia. Thyrotoxicosis and Addison’s disease Severe dehydration:  A common cause of mild or transient hypercalcemia Medications:  Certain drugs — such as lithium, used to treat bipolar disorder Supplements:   Milk alkali syndrome:- Taking supplements of calcium. Excess vitamin A and vitamin D Figure: Hyperparthyroidism

28. Symptoms of hypercalcemia: Anorexia, nausea, vomiting Polyuria and polydipsia Confusion, depression, psychosis Renal stones Ectopic calcification and pancreatitis Blood alkaline phosphatase is increased

29. HYPOCALCEMIA Hypocalcemia is a more serious and life threatening condition. lt is characterized by a fall in the serum Ca to below 7 mg/dl, causing tetany. The symptoms of tetany include neuromuscular irritability, spasms and convulsions. Figure: Carpopedal spasm in Tetany

30. CAUSES OF HYPOCALCEMIA: Deficiency of Vitamin D: Decreased exposure to sunlight Melabsorption, dietary deficiency Hepatic diseases Decreased renal synthesis of calcitriol Deficiency of parathyroid Hypoparathyroidism(primary, secondary) Increased calcitonin Medullary carcinoma of thyroid Deficiency of calcium Intestinal melabsorption Alkalosis decreasing ionized calcium Deficiency of magnesium Increase in posphorus level Renal failure Hypoalbuminemia

31. Symptoms of hypocalcemia: Muscle cramps Paresthesia, especially in fingers Neuromuscular irritability, muscle twitchings Tetany(Chvostek’s sign, Trousseau’s sign) Seizures Bradycardia Prolonged QT interval Figure: Chvostek’s sign Figure: Trousseau’s sign

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