Disorders of CaDisorders of Ca++++ Metabolism Metabolism

1

Dr. Othman Al-ShboulDepartment of Physiology

Overall CaOverall Ca++++ Homeostasis Homeostasis

Serum [Ca++] is determined by the interplay of:

• Intestinal absorption (not synthesized in the body)• Renal excretion • 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

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

2

Overall CaOverall Ca++++ Homeostasis 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

3

DietCa++

URINE FECES

DepositionResorption

AbsorptionFiltration SecretionReabsorption

4

Physiological Roles of CaPhysiological Roles of Ca++++

ECF [Ca++] ≈ 2.4 mM

Roles:

Contraction of skeletal, cardiac, and smooth muscles Blood clotting Transmission of nerve impulses

5

Bones Serve as Large CaBones Serve as Large Ca++++ Reservoirs Reservoirs

6

Calcium in the Plasma and Interstitial FluidCalcium in the Plasma and Interstitial Fluid

Important for Ca++ functions

7

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

8

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)

9

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

Inorganic PhosphateInorganic Phosphate

10

Inorganic Phosphate in the PlasmaInorganic Phosphate in the Plasma

Total quantity of inorganic phosphate in blood: ≈ 4 mg/dl (Children > adults)

In two forms: HPO42- & 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

11

Bone RemodelingBone Remodeling

12

Bone Cell TypesBone 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.

13

Bone and Its Relation to Extracellular Bone and Its Relation to Extracellular Calcium and PhosphateCalcium 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 plateso 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

BoneBone 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)

15

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

Bone is deposited in proportion to the compressional load that the bone must carry:

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

16

o Continual physical stress stimulates osteoblastic deposition and calcification of bone

Vitamin D (Cholecalciferol)Vitamin D (Cholecalciferol)

17

Vitamin D (Cholecalciferol)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,

11,,25-dihydroxycholecalciferol25-dihydroxycholecalciferol (1,25(OH)2D3(1,25(OH)2D3))

18

Vitamin D SynthesisVitamin D Synthesis

19

D3

Food (Ergocalciferol D2 )

Food (Ergocalciferol D2 )

Vitamin D SynthesisVitamin D Synthesis

20

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

21

Vitamin D ActionsVitamin 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

22

Parathyroid HormoneParathyroid Hormone

23

Parathyroid HormoneParathyroid 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)

24

Parathyroid Hormone EffectsParathyroid Hormone Effects

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

renal phosphate excretion > phosphate absorption from the bone renal phosphate excretion > phosphate absorption from the bone

25

Parathyroid Hormone & Vitamin DParathyroid Hormone & Vitamin D

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

26

Control of Parathyroid Secretion by Control of Parathyroid Secretion by Calcium Ion Concentration Calcium Ion Concentration

ECF Ca++ PTH secretion + parathyroid gland size

27

Summary of effects of parathyroid hormone (PTH)Summary of effects of parathyroid hormone (PTH)

28

CalcitoninCalcitonin

29

CalcitoninCalcitonin 32 amino acids peptide.

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

Increased Plasma Calcium Concentration Stimulates Calcitonin Secretion

30

Calcitonin Decreases Plasma [Calcium]Calcitonin Decreases Plasma [Calcium]

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

31

Control of parathyroid hormone (PTH)Control of parathyroid hormone (PTH)and calcitonin secretionand calcitonin secretion

32

Hypoparathyroidism 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 ???

33

Primary Hyperparathyroidism 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]

• Cystic bone disease of hyperparathyroidism is called osteitis fibrosa cystica

• Great osteoblastic activity (compensatory); increased alkaline phosphatase34

• 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.

• 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

35

Primary Hyperparathyroidism 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

36

Primary Hyperparathyroidism Primary Hyperparathyroidism

Secondary Hyperparathyroidism 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, 1,25-dihydroxycholecalciferol.

37

Rickets Caused by Vitamin D Deficiency 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

38

Osteomalacia-"Adult Rickets" 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

39

Osteoporosis-Decreased Bone Matrix Osteoporosis-Decreased Bone Matrix

The most common of all bone diseases in adults

Diminished organic bone matrix rather than poor bone calcification

Causes:• lack of physical stress on the bones • malnutrition• lack of vitamin C• postmenopausal lack of estrogen secretion (estrogens decrease

the number and activity of osteoclasts)• old age (decrease protein anabolism, decrease GH ….)• Cushing's syndrome (increased glucocorticoids secretion

increase protein catabolism)40

The ENDThe END

41