Calcium HomeostasisCalcium Homeostasis

Ihab SamyLecturer of Surgical Oncology

National Cancer InstituteCairo University

2010

Ihab SamyLecturer of Surgical Oncology

National Cancer InstituteCairo University

2010

Facts About CalciumFacts 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

Physiological importance of CalciumPhysiological 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

Calcium HomeostasisCalcium 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

Calcium RegulationCalcium 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

Calcium RegulationCalcium 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.

Calcium RegulationCalcium Regulation

PTH secretion responds to small alterations in plasma Ca2+ within seconds.

A unique calcium receptor within the parathyroid chief cell membrane senses changes in the extracellular fluid concentration of Ca2+.

This is a typical G-protein coupled receptor that activates phospholipase C and inhibits adenylate cyclase increase in intracellular Ca2+ 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 Ca2+ within seconds.

A unique calcium receptor within the parathyroid chief cell membrane senses changes in the extracellular fluid concentration of Ca2+.

This is a typical G-protein coupled receptor that activates phospholipase C and inhibits adenylate cyclase increase in intracellular Ca2+ via generation of inositol phosphates and decrease in cAMP which prevents exocytosis of PTH from secretory granules.

Calcium regulates

PTH

secretion

Calcium regulates

PTH

secretion

Calcium Regulation

• When Ca2+ 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 Ca2+ and PO4, no direct control of PTH is exerted by phosphate levels.

Calcium HomeostasisCalcium 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

Parathyroid “C” Cells

PTH Calcitonin

BoneKidney

Intestine

BoneKidney

[Ca++] [Ca++]

Stim

ulat

e Stim

ulate

Inhi

bit

Inhi

bit

In plasma In plasma

Calcium HomeostasisCalcium Homeostasis

Maximum secretion of PTH occurs at plasma Ca2+ below 3.5 mg/dL.

At Ca2+ above 5.5 mg/dL, PTH secretion is maximally inhibited.

Maximum secretion of PTH occurs at plasma Ca2+ below 3.5 mg/dL.

At Ca2+ above 5.5 mg/dL, PTH secretion is maximally inhibited.

HypercalcemiaHypercalcemia

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”

Etiologies of HypercalcemiaEtiologies of Hypercalcemia

Increased GI AbsorptionMilk-alkali syndromeElevated calcitriol

Vitamin D excessExcessive dietary

intakeGranuomatous

diseasesElevated PTHHypophosphatemia

Increased Loss From BoneIncreased net bone resorption

Elevated PTHHyperparathyroidism

MalignancyOsteolytic

metastasesPTHrP secreting

tumorIncreased bone turnover

Paget’s disease of boneHyperthyroidism

Increased GI AbsorptionMilk-alkali syndromeElevated calcitriol

Vitamin D excessExcessive dietary

intakeGranuomatous

diseasesElevated PTHHypophosphatemia

Increased Loss From BoneIncreased net bone resorption

Elevated PTHHyperparathyroidism

MalignancyOsteolytic

metastasesPTHrP secreting

tumorIncreased bone turnover

Paget’s disease of boneHyperthyroidism

Decreased Bone Mineralization

Elevated PTH

Aluminum toxicity

Decreased Urinary Excretion

Thiazide diuretics

Elevated calcitriol

Elevated PTH

Familial Hypocalciuric Hypercalcemia

(FHH)

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

Etiologies of HypocalcemiaEtiologies of HypocalcemiaDecreased 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 MineralizationLow PTH (aka hypoparathyroidism)

PTH resistance (aka pseudohypoparathyroidism)

Vitamin D deficiency / low calcitriol

Hungry bones syndrome

Osteoblastic metastases

Decreased GI AbsorptionPoor 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 MineralizationLow 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 I131 treatment

Autoimmune hypoparathyroidism

PTH resistance

Vitamin D deficiency / low calcitriol

HypocalcemiaHypocalcemia

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

Thank YouThank You