Calcium Metabolism, Homeostasis & Related Diseases.

Calcium Metabolism,Calcium Metabolism,Homeostasis Homeostasis & & Related DiseasesRelated Diseases

Objectives of LecturesObjectives of Lectures

By the end of these lectures, students should be By the end of these lectures, students should be able to: able to: Recall CalciumCalcium Sources, Distributions & Functions Understand Organ & Endocrinal Homeostasis of Calcium Homeostasis of Calcium with recognition of the roles of: - Vitamin D - Parathyroid Hormone (PTH) - Calcitonin Hormone Verify Main Causes of Hypocalcaemia & HypercalcemiaCauses of Hypocalcaemia & Hypercalcemia Recognize the biochemical and Clinical Interrelations of Metabolic Metabolic diseases of bone: diseases of bone: - Rickets & Osteomalacia - Osteoporosis

Components of BonesComponents of BonesBone is a specialized mineralized connective tissue containing:

1- Cellular ElementsCellular Elements: - OsteoblastsOsteoblasts (bone forming cells) - OsteoclastsOsteoclasts (bone resorping cells)

2- Organic Matrix Organic Matrix - ProteinsProteins: Type I Collagen Proteoglycan - Inorganic MineralsInorganic Minerals: Calcium & Phosphate - OthersOthers: small amount of hydroxide & carbonate• Calcium is tightly regulated with phosphorous in the bodyCalcium is tightly regulated with phosphorous in the body

CalciumCalcium

Calcium is the most abundant mineral in the body: about 1 kg in a 70 kg man

~ 99% of the body’s calcium is present in the bone where it is combined with phosphate

Dietary Dietary Sources of CalciumSources of Calcium

RichRich: MilkMilk, milk products milk products as cheese & yoghurt Fair :Fair : Legumes, vegetables

Total Total CalciumCalciumOf the Of the BodyBody

99 % 99 % in bonein bone

ICFICF

1 %1 %

Blood Clotting Blood Clotting

Excitability of Excitability of Nerve & MuscleNerve & Muscle

Bone Bone Formation Formation

Reservoir for Reservoir for ECF [Ca2+] ECF [Ca2+]

Metabolic Metabolic Regulation for Regulation for

Action of Action of Hormones & Hormones &

Enzyme ActivationEnzyme Activation

ECFECF

Biological Functions of CalciumBiological Functions of Calcium

Calcium in BloodCalcium in Blood

Organ Calcium HomeostasisOrgan Calcium Homeostasis

Organ Calcium Homeostasis Organ Calcium Homeostasis contcont . .

The concentration of The concentration of calciumcalcium, , phosphorous &phosphorous &magnesium in the plasma depends onmagnesium in the plasma depends on

ORGAN PHYSIOLOGYORGAN PHYSIOLOGY:: Net effect of Net effect of bonebone mineral deposition & resorption mineral deposition & resorption IntestinalIntestinal absorptionabsorption RenalRenal excretionexcretion

BloodBlood

[Ca[Ca2+2+]] is Regulated is Regulated

By:By:

Parathyroid Hormone Parathyroid Hormone ((PTHPTH))

Active Vitamin DActive Vitamin D ((CalcitriolCalcitriol or 1,25 DHCC)or 1,25 DHCC)

CalcitoninCalcitonin HormoneHormone

Vitamin DVitamin D A group of sterols with a hormone-like function.A group of sterols with a hormone-like function.

Sources of Vitamin DSources of Vitamin D

1- Skin synthesis (On Exposure to Sun Lights):1- Skin synthesis (On Exposure to Sun Lights): In the skin, 7 dehydrocholesterol 7 dehydrocholesterol is converted to vitamin D3 vitamin D3 by exposure to sunlight 2- Diet:2- Diet: - Animal Source Cholecalciferol (Vitamins D3)Vitamins D3) - Plant Source: Ergocalciferol (Vitamin D2)Vitamin D2) Vitamin D2 & D3 are NOTNOT biologically active

– Activation of cholecalciferolActivation of cholecalciferol (vitamin D3)vitamin D3) CholecalciferolCholecalciferol (Vitamin D3) is activated in the body to the biologically active form by two hydroxylations: first in the liverliver (at position 25) by 25 hydroxylase & then in the kidneykidney at positions 1 by 1 α hydroxylase

Active Vitamin DActive Vitamin D 1, 25 dihydroxycholecalciferol (Calcitriol or DHCC)1, 25 dihydroxycholecalciferol (Calcitriol or DHCC)

Vitamin DVitamin D22

plant sourceplant source

Vitamin D3Vitamin D3animal source

fatty fishLiver

egg yolk

7-dehydrocholesterol7-dehydrocholesterolIn the skinIn the skin

DIET VITAMINs DDIET VITAMINs D

SOURCES OF VITAMIN DSOURCES OF VITAMIN D

Sun Sun RaysRays

Vitamin D metabolismVitamin D metabolism

Cholecalciferol (Vitamin D3) Cholecalciferol (Vitamin D3) is derived from 7-dehydrocholesterol in the skin by sunlight or supplied in the diet

In liver:In liver: Cholecalciferol is converted to 25-hydroxycholecalciferol25-hydroxycholecalciferol (25-HCC) by the enzyme 25 hydroxylase 25-hydroxycholecalciferol25-hydroxycholecalciferol is the predominant form of vitamin D in bloodblood 25-hydroxycholecalciferol 25-hydroxycholecalciferol is the main storagestorage form of vitamin in the body In kidneys:In kidneys: The 1 α hydroxylase enzyme converts 25 hydroxycholecalciferol to 1,25-dihydroxycholecalciferol1,25-dihydroxycholecalciferol (1, 25 DHCC or Calcitriol) which is the biologicallybiologically active form of vitamin Dactive form of vitamin D

Functions of Vitamin DFunctions of Vitamin D

Active vitamin D (1, 25 DHCC or Calcitriol) regulates calcium levels in the body (calcium homeostasis)Through:

Increasing absorption of calcium by the Increasing absorption of calcium by the intestineintestine Minimizing loss of calcium by kidney Stimulating resorption of bonebone ((when necessary)when necessary)

Mechanism of Action of Vitamin DMechanism of Action of Vitamin D

Parathyroid hormone (PTH)Parathyroid hormone (PTH)

Functions of Parathyroid Hormone (PTH)Functions of Parathyroid Hormone (PTH)

The active hormone is secreted in response to al fall in plasma Ca2+ The active hormone is secreted in response to al fall in plasma Ca2+ resulting in in Ca2+ increase in blood. resulting in in Ca2+ increase in blood.

On bone:On bone: PTH stimulates bone resorption by osteoclasts resorption by osteoclasts resulting in release of calcium ions from bones to blood in cases of hypocalcemia

On kidney:On kidney: 1- PTHPTH increases reabsorption of calcium reabsorption of calcium from kidney tubules. 2- PTHPTH promotes activity of 1activity of 1hydroxylase hydroxylase of the kidney (with more hydroxylation of 25 hydroxycholecalciferol (25 HCC) to 1,25 DHCC (activation of vitamin Dvitamin D) which increases intestinalintestinal absorption of calcium So, action of PTH on intestine is So, action of PTH on intestine is indirectindirect (via Vitamin D) (via Vitamin D)

Role of Parathyroid Hormone (PTH) in Role of Parathyroid Hormone (PTH) in HypocalcemiaHypocalcemia

PTH PTH is the principal is the principal

acute regulator of acute regulator of blood [Cablood [Ca2+2+]]

PTH PTH is a hypercalcemic is a hypercalcemic hormone in case of hormone in case of

hypocalcemiahypocalcemia

Calcitonin HormoneCalcitonin Hormone

Calcitonin hormone is Calcitonin hormone is ::– Secreted by the parafollicular or “C” cells of the thyroid gland– Released in response in response to high blood calcium (hypercalcemiahypercalcemia)

In cases of hypercalcemia,In cases of hypercalcemia,Calcitonin Hormone Calcitonin Hormone blood [Ca2+] by: blood [Ca2+] by:

– Osteoclast activity Osteoclast activity (preventing release of calcium to blood)

– Renal reabsorption of calciumRenal reabsorption of calcium Net result of its action Net result of its action blood calcium blood calcium

CALCITONIN IS THE ONLY HYPOCALCEMIC HORMONECALCITONIN IS THE ONLY HYPOCALCEMIC HORMONE

MAIN CAUSES of

HYPERCALCEMIAHYPERCALCEMIA

Primary hyperparathyroidismPrimary hyperparathyroidism::

due to adenomasadenomas (single or multiple) of the parathyroid gld Blood PTH is highhigh (or upper normal range *) Blood calcium is high & high & Blood phosphate is low low Urine calcium & phosphorous are highhigh (hypercalciuria & hyperphasphatruria)

TumorsTumors Humoral hypercalcemia of malignancy due to PTHrP (PTH related protein) released

by some kinds of tumor cells. PTHrP is not responsive to negative feedback by calcium

Hypervitaminosis D:Hypervitaminosis D: Excessive intake of vitamin D Extrarenal hydroxylation of 25HCC as in granulmotaous diseases as sarcoidosis

MAIN CAUSES of

HYPOCALCEMIAHYPOCALCEMIA

Hypoparathyroidism (Hypoparathyroidism ( PTHPTH)) Vitamin DVitamin D deficiencies deficiencies RenalRenal disease : disease :low 1 low 1 hydroxylase activity & by hyperphosphaturia hydroxylase activity & by hyperphosphaturia Hypoalbuminemia: low blood Hypoalbuminemia: low blood albuminalbumin NutritionalNutritional calcium deficiency calcium deficiency Intestinal disorders causing inadequate calcium or vit.D Intestinal disorders causing inadequate calcium or vit.D absorptionabsorption

Metabolic Diseases of Bone:Metabolic Diseases of Bone: Rickets & Osteomalacia Rickets & Osteomalacia

Rickets & osteomalacia Rickets & osteomalacia are metabolic bone diseases occurring due to poor mineralization (calcium contentcalcium content) of boneCauses of poor calcification of bones:Causes of poor calcification of bones:

II. Vitamin D deficiency. Vitamin D deficiency 1- 1- Deficiency of sources of vitamin D3:Deficiency of sources of vitamin D3: BOTH:BOTH: NutrionalNutrional Vitamin D deficiency (vitamin D3) Vitamin D deficiency (vitamin D3) Poor exposure to Poor exposure to sun lightsun light

2- Impaired vitamin D metabolism:2- Impaired vitamin D metabolism: Renal RicketsRenal Rickets: deficiency of 1 hydroxylase of the kidney: deficiency of 1 hydroxylase of the kidney Deficiency of Deficiency of parathyroid hormone parathyroid hormone : decrease activity of 1 : decrease activity of 1 α hydroxylase hydroxylase GeneticGenetic defects in vitamin D metabolism (defect in its activation) defects in vitamin D metabolism (defect in its activation) GeneticGenetic defects of vitamin D receptors or abnormal ligand binding defects of vitamin D receptors or abnormal ligand binding

II. II. Calcium deficiency (Calcium deficiency (nutritionalnutritional or defect in intestinal or defect in intestinal absorptionabsorption))

Metabolic Diseases of BonesMetabolic Diseases of Bones

RICKETSRICKETS Normal formation of the collagen matrix

BUTIncomplete mineralization (poor calcification)

SoftSoft BonesBones

CLINICALLY: CLINICALLY: Bone DeformityBone Deformity

OSTEOMALACIAOSTEOMALACIADemineralization (poor calcification) of preexisting bones

with

CLINICALLYCLINICALLY: More Susceptibility to: More Susceptibility to FractureFracture

Rickets & OsteomalaciaRickets & Osteomalacia

In Chronic Renal FailureIn Chronic Renal Failure

Low activity of Renal 1Low activity of Renal 1HydroxylaseHydroxylase

Decreased ability to form theDecreased ability to form the

active form of vitamin Dactive form of vitamin D))11 , ,2525 DHCC will be lowDHCC will be low((

TreatmentTreatment: 1,25 DHCC : 1,25 DHCC ((CalcitriolCalcitriol))

Renal RicketsRenal RicketsRenal OsteodystrophyRenal Osteodystrophy

Laboratory Investigations for the Diagnosis of Laboratory Investigations for the Diagnosis of

Rickets & OsteomalaciaRickets & Osteomalacia

Investigations to Investigations to confirmconfirm the diagnosis of rickets: the diagnosis of rickets: Blood levels of 25-hydroxycholecalciferol (25 HCC) Blood levels of 25-hydroxycholecalciferol (25 HCC) Blood calcium, (hypocalcemia)Blood calcium, (hypocalcemia) Blood Alkaline phosphatase (ALP)Blood Alkaline phosphatase (ALP)

Investigations to diagnose the Investigations to diagnose the causecause of rickets: of rickets: Kidney function tests (KFT)Kidney function tests (KFT) Blood 1, 25 dihydroxycholecalciferol (1, 25 DHCC)Blood 1, 25 dihydroxycholecalciferol (1, 25 DHCC) Blood PTHBlood PTH Others i.e. molecular genetics (if indicated)Others i.e. molecular genetics (if indicated)

• MostMost prevalent metabolic bone disease in adultsadults• It means reduction in bone mass per unit volumereduction in bone mass per unit volume i.e. bone matrix composition is normal, but it is reduced. bone matrix composition is normal, but it is reduced

• Typically silentTypically silent (without symptoms) until it leads to fracturefracture at a degree of trauma that would not have caused a fracture in a non-osteoprotic skeleton.

Fractures are called fragility or osteoporotic fractures) Most affected: vertebral compression (may be asymptomatic) & hip fractures (requires surgery in most cases)

• Post-menopausal women lose more bone mass than men (primary osteoporosisprimary osteoporosis)

• Osteoporosis Osteoporosis diagnosisdiagnosis is by dual energy x-ray absorpitometry ( is by dual energy x-ray absorpitometry (DXADXA) scan) scan• Lab diagnosis: notnot conclusive

Metabolic Diseases of Bone:Metabolic Diseases of Bone: Osteoporosis Osteoporosis

Metabolic Diseases of BoneMetabolic Diseases of Bone OsteoporosisOsteoporosis

Secondary OsteoporosisSecondary OsteoporosisRisk FactorsRisk Factors

Secondary osteoporosis may be caused by Secondary osteoporosis may be caused by reduced bone mass reduced bone mass with increased consequent risk of fractureswith increased consequent risk of fractures

Risk Factors for osteoporosis:Risk Factors for osteoporosis:

Advanced age (esp. in females) Certain Drugs Family history of osteoporosis or fractures Immobilization Smoking Excess alcohol intake Cushing’s syndrome Long term glucocorticoids therapy Hyperparathyroidism Hyperthyroidism Vitamin D disorders Certain malignancies

In these cases, DXA is highly recommended to evaluate bone densityIn these cases, DXA is highly recommended to evaluate bone density