Disorders of

++ Ca

Metabolism

Dr. Othman Al-Shboul Department of Physiology

Overall Ca++ Homeostasis

Serum [Ca++] is determined by the interplay of:
1. Intestinal absorption (not synthesized in the body) 2. Renal excretion 3. Bone remodeling (bone resorption and formation). Each component is hormonally regulated.

To maintain Ca++ balance, net intestinal absorption must be exactly balanced by urinary excretion
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Overall Ca++ Homeostasis

Positive Ca++ balance
Intestinal Ca++ absorption > urinary excretion Seen in growing children The difference is deposited in the growing bones

Negative Ca++ balance (Ca++ dumping syndrome)

Intestinal Ca++ absorption is < urinary excretion Seen in women during pregnancy or lactation The difference comes from the maternal bones
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Resorption

Deposition

Filtration

Reabsorption

Secretion

Absorption

Ca++

Diet

URINE

FECES
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Physiological Roles of Ca++

ECF [Ca++] 2.4 mM Roles:
Contraction of skeletal, cardiac, and smooth muscles Blood clotting Transmission of nerve impulses

Bones Serve as Large Ca++ Reservoirs

Calcium in the Plasma and Interstitial Fluid

Important for Ca++ functions

Physiologic Effects of Altered [Ca++] in the Body Fluids

Even slight increases or decreases of calcium ion in the ECF can cause extreme immediate physiological effects 1. Hypocalcemia:
Causes nervous system excitement and tetany; increased
neuronal membrane permeability to sodium ions

Great decrease causes tetany/siezures; increasing excitability in the brain carpopedal spasm

(Hypocalcemic tetany in the hand)

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Physiologic Effects of Altered [Ca++] in the Body Fluids

2. Hypercalcemia:
Depresses nervous system and muscle activity

Decreases the QT interval of the heart

Lack of appetite (affect some hormonal actions)

Constipation (depressed contractility of the muscle walls of

the gastrointestinal tract)
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Inorganic Phosphate

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Inorganic Phosphate in the Plasma

Total quantity of inorganic phosphate in blood: 4 mg/dl (Children > adults) In two forms: HPO4
2-

& H2PO4

Almost all the dietary phosphate is absorbed into the blood from the gut and later excreted in the urine. Changing the level of phosphate in the extracellular fluid from far below normal to two to three times normal does not cause major immediate effects on the body PTH increases phosphate excretion by the kidneys
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Bone Remodeling

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Bone Cell Types

1. Osteoblasts: the differentiated bone-forming cells; secrete bone matrix (osteoid) on which Ca++ and PO precipitate. 2. Osteocytes, quiescent osteoblasts enclosed in bone matrix. 3. Osteoclasts: large multinucleated and phagocytic cells derived from monocytes; resorb bone.
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Bone and Its Relation to Extracellular Calcium and Phosphate

99% of the Calcium in our bodies is found in our bones which serve as a reservoir for Ca++ storage. 10% of total adult bone mass turns over each year during remodeling process During growth, rate of bone formation exceeds resorption and skeletal mass increases. o Linear growth occurs at epiphyseal plates o Increase in width occurs at periosteum Once adult bone mass is achieved, equal rates of formation and resorption maintain bone mass until age of about 30 years when rate of resportion begins to exceed formation and bone mass slowly decreases. 14

Bone
Bone = organic matrix 30% + calcium salts 70%
Organic matrix:
Mainly collagen fibers (tensile strength), The remainder is a homogeneous gelatinous medium called ground substance (ECF + proteoglycans)

Calcium salts:
Mainly hydroxyapatite crystals (Ca++ + phosphate, Ca10(PO4)6(OH)2), (compressional strength) + other ions (magnesium, sodium, potassium, and carbonate ions)

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Control of the Rate of Bone Deposition by Bone "Stress"

Bone is deposited in proportion to the compressional load that the bone must carry:
o Continual physical stress stimulates osteoblastic deposition and calcification of bone

Bone stress also determines the shape of bones under certain circumstances (e.g. fractures with angle)
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Vitamin D (Cholecalciferol)

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Vitamin D (Cholecalciferol)
A steroid hormone, role in regulating body levels of calcium and phosphorus, and in mineralization of bone.
Vitamin D itself is not the active substance that actually causes these effects. Instead, vitamin D must first be converted through a succession of reactions in the liver and the kidneys to the final active product, 1,25-dihydroxycholecalciferol (1,25(OH)2D3)

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Vitamin D Synthesis

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Vitamin D Synthesis

Food (Ergocalciferol D2 )

PTH

D3

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Plasma [1,25-dihydroxycholecalciferol] is inversely affected by the plasma [calcium]

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Vitamin D Actions
Increases calcium absorption from the intestinal tract
o Increasing, over a period of about 2 days, formation of calbindin, a calcium-binding protein, in the intestinal epithelial cells

Increases phosphate absorption by the intestines

Decreases renal calcium and phosphate excretion Absorption of bone augments the effect of PTH

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Parathyroid Hormone

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Parathyroid Hormone
84-amino acids polypeptide hormone
PTH is released from the chief cells of the parathyroid gland. Works on PTH receptors on osteoblasts & osteocytes No known pituitary trophic hormone direct action unlike (adrenal, gonads, and thyroid)
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Parathyroid Hormone Effects

Ca++ absorption from bone Ca++ excretion by kidneys

renal phosphate excretion > phosphate absorption from the bone

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Parathyroid Hormone & Vitamin D

PTH the formation in the kidneys of 1,25dihydroxycholecalciferol from vitamin D

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Control of Parathyroid Secretion by Calcium Ion Concentration

ECF Ca++ PTH secretion + parathyroid gland size

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Summary of effects of parathyroid hormone (PTH)

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Calcitonin

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Calcitonin
32 amino acids peptide. Calcitonin is released from parafollicular (C or clear cells) of the thyroid gland.

Increased Plasma Calcium Concentration Stimulates Calcitonin Secretion

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Calcitonin Decreases Plasma [Calcium]

Main effect of calcitonin is reducing the calcium absorption from bone by decreasing osteoclasts activity & formation.

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Control of parathyroid hormone (PTH) and calcitonin secretion

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Hypoparathyroidism
Level of calcium in the body fluids decreases (bone usually remains strong due to Decreased bone resorption)
Signs of tetany (laryngeal muscles) Rx; vitamin D/ 1,25-dihydroxycholecalciferol & calcium PTH ???

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Primary Hyperparathyroidism
Cause: Tumor of one of the parathyroid glands (F>M; pregnancy and lactation stimulate the parathyroid glands) Leads to extreme osteoclastic activity in the bones elevating ECF [Ca++] depressing [phosphate] Bone disease; radiographs of the bone typically show extensive decalcification and, occasionally, large punched-out cystic areas of the bone that are filled with osteoclasts in the form of so-called giant cell osteoclast. Cystic bone disease of hyperparathyroidism is called osteitis fibrosa cystica Great osteoblastic activity (compensatory); increased alkaline phosphatase
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Primary Hyperparathyroidism
Hypercalcemia (up to 12-15 mg/dl ) depression of the central and peripheral nervous systems, muscle weakness, constipation, abdominal pain, peptic ulcer, lack of appetite, and depressed relaxation of the heart during diastole

Metastatic calcification: calcium phosphate (CaHPO4) crystals begin to deposit in the alveoli of the lungs, the tubules of the kidneys, the thyroid gland, the acid-producing area of the stomach mucosa, and the walls of the arteries throughout the body.
Parathyroid poisoning calcium in the blood must rise above 17 mg/dl; can lead to death
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Primary Hyperparathyroidism
Great excretion of Ca++ and PO in urine increases the tendency of precipitation of these crystals in the kidneys kidney stones
Calcium oxalate stones the predominant composition all kidney stones Acidotic diets and acidic drugs are frequently used for treating renal calculi

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Secondary Hyperparathyroidism
High levels of PTH occur as a compensation for hypocalcemia
Causes: Vitamin D deficiency or chronic renal disease in which the damaged kidneys are unable to produce sufficient amounts of the active form of vitamin D, 1,25dihydroxycholecalciferol.

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Rickets Caused by Vitamin D Deficiency

Mainly in children (indoors) Calcium or phosphate deficiency in the extracellular fluid, usually caused by lack of vitamin D

Weak bones
Signs of tetany Rx: calcium and phosphate in the diet/vitamin D

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Osteomalacia-"Adult Rickets"
Occur as a result of steatorrhea (failure to absorb fat) "Renal rickets" is a type of osteomalacia that results from prolonged kidney damage. failure of the damaged kidneys to form 1,25-dihydroxycholecalciferol, the active form of vitamin D Congenital hypophosphatemia (vitamin D-resistant rickets): congenitally reduced reabsorption of phosphates by the renal tubules

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Osteoporosis-Decreased Bone Matrix

The most common of all bone diseases in adults
Diminished organic bone matrix rather than poor bone calcification Causes: i. lack of physical stress on the bones ii. malnutrition iii. lack of vitamin C iv. postmenopausal lack of estrogen secretion (estrogens decrease

the number and activity of osteoclasts)

v. vi. old age (decrease protein anabolism, decrease GH .) Cushing's syndrome (increased glucocorticoids secretion increase protein catabolism)
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The END
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