1. Calcium Homeostasis Ihab Samy Lecturer of Surgical Oncology National Cancer Institute Cairo University 2010 Ihab Samy Lecturer of Surgical Oncology National Cancer Institute Cairo University 2010

2. Facts About Calcium Date of Discovery: 1808 Discoverer: Sir Humphrey Davy Name Origin: From the latin word calcis (lime) Uses: life forms for bones and shells Obtained From: chalk, limestone, marble. 3.5% of crust

3. Physiological importance of Calcium Calcium salts in bone provide structural integrity of the skeleton Calcium ions in extracellular and cellular fluids is essential to normal function of a host of biochemical processes Neuoromuscular excitability Blood coagulation Hormonal secretion Enzymatic regulation Calcium salts in bone provide structural integrity of the skeleton Calcium ions in extracellular and cellular fluids is essential to normal function of a host of biochemical processes Neuoromuscular excitability Blood coagulation Hormonal secretion Enzymatic regulation

4. Calcium Homeostasis 99% of body calcium is in the skeleton 0.9 % intracellular 0.1% extracellular 45% bound to plasma proteins mainly albumin 45% in ionized form (the physiologically active form) 10% complexed with anions (citrate, sulfate, phosphate) Corrected calcium = (4-serum albumin) X 0.8 + measured serum calcium 99% of body calcium is in the skeleton 0.9 % intracellular 0.1% extracellular 45% bound to plasma proteins mainly albumin 45% in ionized form (the physiologically active form) 10% complexed with anions (citrate, sulfate, phosphate) Corrected calcium = (4-serum albumin) X 0.8 + measured serum calcium

5. Calcium Regulation Parathormone (PTH) 4 parathyroid glands Release of PTH (chief cells) in response to drop in serum calcium Magnesium needed to activate PTH release Effects on bone, kidney and indirectly on intestines Activates osteoclasts/osteoblasts leading to bone resorption and release of calcium and phosphorous Promotes reabsorption of calcium and excretion of phosphorous in the kidney Activates vitamin D Parathormone (PTH) 4 parathyroid glands Release of PTH (chief cells) in response to drop in serum calcium Magnesium needed to activate PTH release Effects on bone, kidney and indirectly on intestines Activates osteoclasts/osteoblasts leading to bone resorption and release of calcium and phosphorous Promotes reabsorption of calcium and excretion of phosphorous in the kidney Activates vitamin D

8. Calcium Regulation Vitamin D 2 sources Skin and Diet. 25 (OH) Vitamin D Storage form of Vitamin D. Liver. 1,25 (OH) Vitamin D Active form of Vitamin D. Activated by PTH and hypophosphatemia through 1- alpha hydroxylase enzyme in the kidney. Vitamin D 2 sources Skin and Diet. 25 (OH) Vitamin D Storage form of Vitamin D. Liver. 1,25 (OH) Vitamin D Active form of Vitamin D. Activated by PTH and hypophosphatemia through 1- alpha hydroxylase enzyme in the kidney.

10. Calcium Regulation PTH secretion responds to small alterations in plasma Ca 2+ within seconds. A unique calcium receptor within the parathyroid chief cell membrane senses changes in the extracellular fluid concentration of Ca 2+. This is a typical G-protein coupled receptor that activates phospholipase C and inhibits adenylate cyclase  increase in intracellular Ca 2+ via generation of inositol phosphates and decrease in cAMP which prevents exocytosis of PTH from secretory granules. PTH secretion responds to small alterations in plasma Ca 2+ within seconds. A unique calcium receptor within the parathyroid chief cell membrane senses changes in the extracellular fluid concentration of Ca 2+. This is a typical G-protein coupled receptor that activates phospholipase C and inhibits adenylate cyclase  increase in intracellular Ca 2+ via generation of inositol phosphates and decrease in cAMP which prevents exocytosis of PTH from secretory granules.

11. Calcium regulates PTH secretion

12. Calcium Regulation When Ca 2+ falls, cAMP rises and PTH is secreted. 1,25-(OH) 2 -D inhibits PTH gene expression, providing another level of feedback control of PTH. Despite close connection between Ca 2+ and PO 4, no direct control of PTH is exerted by phosphate levels.

13. Calcium Homeostasis Calcitonin Little role in calcium homeostasis. Secreted by parafollicular C cells of thyroid. Neural cell origin Medullary Hyperplasia/Cancer Most sporadic case MEN IIA or IIB 15 % cases Calcitonin Little role in calcium homeostasis. Secreted by parafollicular C cells of thyroid. Neural cell origin Medullary Hyperplasia/Cancer Most sporadic case MEN IIA or IIB 15 % cases

14. Parathyroid“C” Cells PTHCalcitonin Bone Kidney Intestine Bone Kidney [Ca ++ ] Stimulate Inhibit In plasma Calcium Homeostasis

15. Maximum secretion of PTH occurs at plasma Ca 2+ below 3.5 mg/dL. At Ca 2+ above 5.5 mg/dL, PTH secretion is maximally inhibited.

16. Hypercalcemia Symptoms and Signs Only 20 % people with hypercalcemia exhibit signs and symptoms “Calcium Stones, fragile bones, abdominal groans, psychic moans and fatigue overtones” Symptoms and Signs Only 20 % people with hypercalcemia exhibit signs and symptoms “Calcium Stones, fragile bones, abdominal groans, psychic moans and fatigue overtones”

18. Etiologies of Hypercalcemia Increased GI Absorption Milk-alkali syndrome Elevated calcitriol Vitamin D excess Excessive dietary intake Granuomatous diseases Elevated PTH Hypophosphatemia Increased Loss From Bone Increased net bone resorption Elevated PTH Hyperparathyroidism Malignancy Osteolytic metastases PTHrP secreting tumor Increased bone turnover Paget’s disease of bone Hyperthyroidism Increased GI Absorption Milk-alkali syndrome Elevated calcitriol Vitamin D excess Excessive dietary intake Granuomatous diseases Elevated PTH Hypophosphatemia Increased Loss From Bone Increased net bone resorption Elevated PTH Hyperparathyroidism Malignancy Osteolytic metastases PTHrP secreting tumor Increased bone turnover Paget’s disease of bone Hyperthyroidism Decreased Bone Mineralization Elevated PTH Aluminum toxicity Decreased Urinary Excretion Thiazide diuretics Elevated calcitriol Elevated PTH

19. Familial Hypocalciuric Hypercalcemia (FHH) Genetic, autosomal dominant Mimics primary hyperparathyroidism PTH slightly high, however inappropriate for level of calcium Mutation in parathyroid calcium sensor Higher setpoint Low urinary calcium/creatinine <0.01 No end organ damage No treatment required Genetic, autosomal dominant Mimics primary hyperparathyroidism PTH slightly high, however inappropriate for level of calcium Mutation in parathyroid calcium sensor Higher setpoint Low urinary calcium/creatinine <0.01 No end organ damage No treatment required

20. Etiologies of Hypocalcemia Decreased GI Absorption Poor dietary intake of calcium Impaired absorption of calcium Vitamin D deficiency Poor dietary intake of vitamin D Malabsorption syndromes Decreased conversion of vit. D to calcitriol Liver failure Renal failure Low PTH Hyperphosphatemia Decreased Bone Resorption/Increased Mineralization Low PTH (aka hypoparathyroidism) PTH resistance (aka pseudohypoparathyroidism) Vitamin D deficiency / low calcitriol Hungry bones syndrome Osteoblastic metastases Decreased GI Absorption Poor dietary intake of calcium Impaired absorption of calcium Vitamin D deficiency Poor dietary intake of vitamin D Malabsorption syndromes Decreased conversion of vit. D to calcitriol Liver failure Renal failure Low PTH Hyperphosphatemia Decreased Bone Resorption/Increased Mineralization Low PTH (aka hypoparathyroidism) PTH resistance (aka pseudohypoparathyroidism) Vitamin D deficiency / low calcitriol Hungry bones syndrome Osteoblastic metastases Increased Urinary Excretion Low PTH s/p thyroidectomy s/p I 131 treatment Autoimmune hypoparathyroidism PTH resistance Vitamin D deficiency / low calcitriol

21. Hypocalcemia PTH Resistance Pseudohypoparathyroidism Congenital defect Absent metacarpal, short stature, round face, mental disability Target organ unresponsiveness to PTH Serum PTH levels high PTH Resistance Pseudohypoparathyroidism Congenital defect Absent metacarpal, short stature, round face, mental disability Target organ unresponsiveness to PTH Serum PTH levels high

22. Thank You