HOMEOSTASIS CALCIUM and PARATHYROID HORMONIntegrative Teaching Bloc 9Prof. dr. Hardi Darmawan, MPH&TM, FRSTMDr. Swanny, MSc

Learning Objectives After studying this section, you will be able to :1.Learn how the body controls the calcium level.2.Understand the inter - action of Parathyroid hormone, vitamin D3 and calcitonin in homeostatic regulation of extra and intracellular calcium level.

Learning Objectives3.Recognize the clinical manifestations of calcium homeostatic disturbances.4.Recognize and understand the pathophysiology of the diseases related to disturbances of endocrine control of calcium homeostasis.

CALCIUM BALANCE99% of calcium in the body is found in BONES.Calcium pool in bone is relatively stable.1% of non bone calcium that is most critical to physiological functioning.

FUNCTION of Calcium1. Extracellular calcium : 99% of total calcium in the body. located in the bone. Function : calcified matrix of bone

CA AS BONE MATRIX

FUNCTION of Calcium2. Extracellular fluid: 0,1 % Function :- Cement for tight junctionsMyocardial and smooth muscle contractionRelease of neurotransmitters at synapsesExcitability of neurons due to effect on Na permeabilityCofactor for coagulation cascade

FUNCTION of Calcium3. Intracellular : 0,9 % Function :Signal in second messenger pathways.Muscle contraction.

1. Calcium is a signal moleculeCa is most concentrated in ECF and inside organelles; endoplasmic reticulum and sarcoplasmic reticulum.If membrane channels for Ca open, Ca moves into cytoplasma, creating a signal that initiates exocytosis of synaptic & secretory vesicles, altered activity of enzymes or transporters.

2. CEMENT

Calcium is part of the intercellular cement that holds cells together at tight junctions

3. Cofactor in the coagulation cascadeAt each step in cascade, an enzyme converts an inactive precursor into an active enzyme, with the help of calcium, such as converting of in active factor XI, IX, X to an active factor XI, IX, X.Although Ca is essential for coagulation, body Ca level never decrease to the point that coagulation is inhibited.

4. Excitability of neuronsClinically relatedHypocalcemia : neuronal permeability to Na increases, neurons depolarizes, and the nervous system become hyperexcitable.It will cause sustained contraction (Tetany) of hand: carpopedal spasm , of respiratory muscles, resulting in asphyxiation.Hypercalcemia : causes depressing neuromuscular activity.

Homeostasis of CalciumCalcium is critical to many physiological functions.Calcium level must very closely regulated.Principle of calcium homeostasis : TOTAL BODY CALCIUM = INTAKE - OUTPUT

INTAKE of calciumRequired daily amounts of Ca : 1,2 gramIntake is dietary ingestion and uptake in small intestine ( duodenum ). Calcium absorption is active transport and hormonally regulated. Absorption is exactly controlled in relation to the need of the body for calcium.

OUTPUT of calciumCalcium loss : primarily through Kidney. small amounts in fecesIonized Ca is freely filtered at glomerulus.Reabsorbed along the length of nephron. Hormonally regulated reabsorption occurs in distal nephron.

Normal distribution and movements of calcium in the body. (ICF, intracellular fluid; ECF, extracellular fluid)

EXTRACELLULAR CALCIUM1. PLASMA CALCIUM. Ca concentration : 9 10 mg/dl. Equivalent to 2,4 mmol Ca / liter.40% (1 mmol/ l ) is combined with plasma protein. This form is nondiffusible to capillary membrane.10% (0,2 mmol/ l ) is combined with other substances of plasma and interstitial fluid (citrate , phosphate). Diffusible to capillary membrane.50% is ionized and diffusible.

INTRACELLULAR CALCIUMThe concentration of free calcium in cytosol is about 0,001 mM. Calcium is concentrated inside mitochondria and sarcoplasmic reticulum.These electrochemical gradients favor movement of Ca++ into cytosol when Ca++ channels open.

EXTRACELLULAR MATRIX (BONE)Bone is the largest reservoir of Ca++ in the body. Most bone Ca++ in the form of HYDROXYAPATITE crystals.Bone Ca++ in equilibrium with Ca++ of the interstitial fluid.Only small fraction is ionized and readily exchangeable.Bone is constantly remodelling.

Osteoblast controls deposition of Ca++ into bone.Osteoclast controls movement of Ca++ out of hydroxyapatite and into ionized Ca++ pool. Osteoclast are responsible for dissolving bone or RESORPTION.

PHOSPHATE HOMEOSTASISClosely links to Calcium homeostasis.Most found in bone, especially in hydroxyapatite of bone , Ca10(PO4)6(OH)2 .Phosphate homeostasis parallels that of Ca++.Absorbed in intestines, filtered, reabsorbed in kidneys.Divided between bones, ECF, and intracellular.

FUNCTION of PHOSPHATE

Energy transferStorage in high energy-phosphate bondsActivation and deactivation of enzymes, transporters, and ion channels.Part of the DNA and RNA backbone.

Sites of control of extracellular calcium concentration1. PLASMA

2. INTESTINE

3. KIDNEY

4. BONE

HORMONAL CONTROL of CALCIUM BALANCE1. Parathyroid hormone2. Vitamin D3 ( Calcitriol, 1,25 dihydroxycholecalciferol )3. Calcitonin4. Cortisol5. Growth Hormone6. Sex steroid ( estrogen, testosteron )

Parathyroid hormoneEssential for life.Cell of origin : parathyroid glandsChemical nature : 84-amino acids peptideBiosynthesis : continuous production, little storedTransport : dissolved in plasmaHalf life : less than 20 minutes

Parathyroid hormoneFactor affecting release : decrease plasma Ca++Target cell : Kidney, bone, intestineTarget receptor : membrane receptor acts via cAMPWhole body or tissue action : increase plasma Ca++

Actions of parathyroid hormone (PTH) on the kidney and bone

Parathyroid hormoneAction at cellular level :Increase vit.D3 synthesisIncrease renal reabsorption of Ca++Increase bone resorption

Action at molecular level :Rapidly alters Ca++ transport but also initiates protein synthesis in osteoclasts.

Activation of vitamin D (25 (OH) vitamin D3, 25 - hydroxyvitamin D3; 1,25(OH)2 vitamin D3, 1,25-dihydroxyvitamin D3)

Parathyroid hormoneOnset of action :2 3 hours for bone, with increased osteoclast activity requiring 1 2 hours; 1 2 days for intestinal absorption; within minutes for kidney transport.

Feed back regulation : Negative feed back by increasing plasma Ca++

Other informationOsteoclast have no PTH receptors, so are affected by PTH induced paracrines.

PTH is ESSENTIAL FOR LIFE.Absence of PTH causes hypocalcemic tetany, which may lead to death.

How PTH raises Ca++ concentration 1. PTH mobilizes calcium from bone.Increased bone resorption by osteoclasts takes about 12 hours to become measurable.Osteoclasts do not have PTH receptors.PTH effects are mediated by paracrines, such as osteoprotegerin (OPG) and osteoclast differentiation factor called RANKL.

PTH raises Ca++2. PTH enhances renal reabsorption of calcium.Takes place in the distal nephron.PTH simultaneously enhances renal excretion of phosphate by reducing its reabsorption.

Actions of parathyroid hormone (PTH) on the kidney and bone

PTH raises Ca++

3. PTH indirectly increases intestinal absorption of calcium by its influence on vit.D3.

Calcitriol ( 1,25-dihydroxycholecalciferol) or vitamin D3Chemical nature : SteroidBiosynthesis : formed by sunlight on precursor molecules or ingested in food; converted in 2 steps (liver & kidney) to 1,25-(OH)2 D3.Transport in circulation : bound to plasma proteins

Actions of vitamin D on the gastrointestinal tract, bone, and kidney

CalcitriolStimulus for synthesis : decrease of Ca++; indirectly via PTH, prolactin also stimulates synthesis.Target cells/tissues : Intestine, bone, kidneyTarget receptor : nuclearWhole body or tissue action : increase of plasma calcium

Calcitriol

Action at molecular level : stimulates production of calbindin, a Ca++ -binding protein; associated with intestinal transport by unknown mechanism.Feed back regulation : plasma Ca++ shuts off PTH secretion

CalcitoninCell of origin : C cells of thyroid gland (parafollicular cells)Chemical nature : 32-amino acid peptideBiosynthesis : typical peptideTransport : dissolved in plasmaHalf life : less than 10 minutesFactor affecting release : increase plasma Ca++.

CalcitoninTarget cell/tissues : bone and kidneyTarget receptor : G-protein-coupled membrane receptorWhole body action : prevents bone resorption; enhances kidney excretion.Action at molecular level : signal transduction pathways appear to vary during cell cycle.

CalcitoninOther information :Experimentally decreases plasma Ca++, but has little apparent physiological effect in adult humans; possible effect on skeletal development; possible protection of bone Ca++ stores during pregnancy and lactation.

CalcitoninPlays a minor role in daily calcium balance in adult human.Medically, used to treat patients with PAGET disease, a genetic disorder in which osteoclasts are overactive and bone is weakened by resorption.Speculation : most important during childhood growth, pregnancy and lactation

Actions of calcitonin on the kidney and bone

Cortisol Minor role.At low levels : necessary for normal bone growth.At high levels : inhibits bone formation, that may leads to osteoporosis.

Growth HormoneMinor roleIncrease the formation of bone at normal level. Action of GH on bone is mediated via Somatomedin.

Sex SteroidsMinor role.Estrogen and testosteron causes closure of epiphyse of bone.After menopause, estrogen level decreases, bone resorption increases which is may cause osteoporosis.

Integrated control of extracellular calcium In HYPOCALCEMIA :1. PTH increases :- increase bone resorption. - increase renal reabsorption - increase phosphate excretion - increase renal synthesis of vit. D3

2. Increase synthesis of vit.D3 :-increase absorption of Ca++ in intestine-increase renal reabsorption-increase PTH action on bone.

NET RESULT: plasma Ca++ increases hypocalcemia is restore back to calcium balance again.

HYPOCALCEMIACauses :1. Hypoparathyroidsm : caused by : a. autoimmune atrophy. b. inadvertent removal of parathyroid glands at thyroidectomy PTH level low Ca++ level low Phosphate level high

2. Pseudohypoparathyroidism. a rare hereditary disorder.failure of target cells to response to PTH.PTH levels high.Ca++ lowPhosphate levels high

3. Vitamin D deficiency.Causes : a. inadequate enzymatic conversion. b. increase rate of metabolism c. insufficient sun or intakePTH levels high.Ca++ levels lowPhosphate levels low

4. Renal disease. Failure to excrete phosphate and reabsorp Ca++.Ca++ levels lowPhosphate levels highPTH level high

Symptoms and signs of hypocalcaemia

HYPERCALCEMIA1. HyperparathyroidismCaused by : tumor of parathyroid glandPTH levels highCa++ levels highPhosphate levels low

2. Vitamin D toxicity. Ca++ levels high Phosphate levels high PTH levels low

Symptoms and signs of hypercalcaemia

Parathyroid and Bone diseases1. Hypoparathyroidism. PTH level low---osteocytic reabsorption of exchangeable calcium decreases. Osteoclasts become inactive. Bone resorption decreases, so that plasma Ca++. Phosphate in blood increases.Symptoms : muscle weakness, increase of neuromuscular activity, such as hyperactive reflex, seizures and tetany.

HyperparathyroidismCaused by tumor of parathyroid glands.Occurs more frequently in women, because pregnancy and lactation stimulates the glands.Osteoclastic activity increases elevates Ca++ concentration in ECF, depressed phosphate concentration due to increased renal excretion.

Bone disease in hyperparathyroidismDue to increased activity of osteoclasts ; bone undergoes extensive decalcification cystic areas easily fracture : Osteitis fibrosa cystica.Activity of osteoblast increases also secrete alkaline phosphatase.One of important diagnostic finding in hyperparathyroidism is a high level of plasma alkaline phophatase.

Effects of hypercalcemia in hyperparathyroidismPlasma calcium level : 12 -15 mg/ dl.Cause depression of CNS and peripheral nervous system --- muscle weakness, constipation, abdominal pain, peptic ulcer, lack of appetite, depressed relaxation of heart during diastole.

Parathyroid poisoning and Metastatic calcificationIf PTH level extremely increased; level of calcium in body rises rapidly. Phosphate level often rises also. Calcium and phosphate in ECF becomes supersaturated--CaHPO4 crystals deposited in alveoli of lung, tubules of kidney, thyroid gland, acid producing area of stomach mucosa, walls of arteries throughout body.Extensive metastatic deposition of calcium phosphate ----death.

Kidney stonesCrystals of calcium phosphate tend to precipitate in kidney forming kidney stones.Tendency for forming renal calculi is greater in alkaline urine, because the solubility of renal stones is slight in alkaline media.

RICKETSOccur mainly in children.Caused by : deficiency of vit. D.Plasma level of calcium and phosphate decreases.Ordinarily, plasma calcium is slightly depressed, but phosphate concentration is greatly depressed.

Effects of Rickets on bonesProlonged Rickets PTH increased (compensatory mechanism) osteoclastic absorption of bone increases bone becomes weaker easily fractured.Lack of calcium and phosphate new bone is uncalcified, and weak osteoid takes place of the older bone that is being reabsorbed.

Tetany in RICKETSTetany occurs when the blood concentration of calcium falls below 7 mg%.The child may die of tetanic respiratory spasm. Treatment of tetany : intravenous calcium.

Signs and symptoms caused by ricketsRickets (Childhood)Knock- knees or bow-legs caused by bending of the long bones.Chest deformities, back deformities (e.q. kyphosis) and protruding forehead.Features of hypocalcaemia.

OsteomalaciaAdult Rickets.Deficiency of vit. D or calcium is caused by steatorrhea ( failure to absorb fat).Prolonged kidney damage renal rickets.Caused by renal failure to form 1,25-(OH)2 vit.D3. Often a serious problem for patients whose kidneys have been removed or destroyed and are being treated by hemodialysis.

Signs and symptoms caused by osteomalaciaOsteomalacia (adulthood)Bone painBones appear thin on X-ray, with localized lucencies (called Loosers zones)Fractures (common in the neck of the femur)Features of hypocalcaemia (e.q. proximal myopathy causes waddling gait)

OSTEOPOROSISMost common bone diseases in adults, especially in old age.Disease of bone loss, due to bone resorption exceeding bone deposition. The result is fragile, weakened bones that are easily fractured.Particularly affect spongy trabecular bone, in vertebrae, hip and wrist.

A complex disease with genetic and environmental components.Risk factors include small, thin body type, postmenopausal age, smoking and low dietary Calcium intake.Most common in women after menopause when estrogen level falls.

Causes of Osteoporosis1. Inactivity lack of physical stress on bone.2. Malnutrition.3. Lack of vit. C necessary for making osteoid.4. Postmenopausal lack of estrogen.5. Old age GH, growth factors diminish protein anabolic function decreases poor bone matrix deposition.6. Cushings diseases cortisol increases increased protein catabolism depressing osteoblastic activity.

Calcium Regulation

The regulation of Ca++ involves 3 tissues :BoneIntestineKidneyThe regulation of Ca++ involves 3 hormones :ParathormoneCalcitoninActivated vitamin D3 (activated calciferols)

The regulation of Ca++ involves 3 cell types :OsteoblastsOsteocytesOsteoclasts

Hormonal ControlPituitary gld does not play a major role in the regulation of the cells that produce parathormons, calcitonin, vitamin D3

ParathormonePolypeptide : 84 amino acid residuesSecreted by : chief cells of 4 parathyroid gldsHypercalcemic hormone of the bodyEffect on the : bone, intestine, kidneyRegulates only : plasma concentration of ionic form of Ca++

Inverse linear relationship between [Ca++] and parathormons secretion.[Ca++] and parathormons secretion [Ca++] and parathormons secretion

Calcitonin32 amino acid residue polypeptideSecreted by parafollicular cells (c cells) of the thyroid gldHypocalcemic hormoneEffect on the: bone, intestine, kidneyPositive linear relationship between [Ca++] and calcitonin secretion

[Ca++] , calcitonin secretion [Ca++] , calcitonin secretion

Calcitonin release : stimulate by pentagastrin

Vitamin D3 (Cholecalciferol)Vitamin hormone : secosteroid (27 carbonatomes) largest (steroid hormone)

Active metabolites of this hormone : exert biologic activity

Calcidiol (25 hydroxyvitamin D3 or 25 hydroxycholecalciferol)One of active metabolite of Vitamin DMajor blood form2-5 > more effective than Vitamin D3 in preventing rickets.Calcitriol (1.25-dihydroxyvitamin D3 or 1.25 dihydroxycholecalciferol)Another active metabolite of vitamin D3On weight basis : 100x > potent than calcidiol.

The synthesis of active vitamin D37-dehydrocholesterol vitamin D3 (skin) uv light

Vitamin D3 25 hydroxyvitamin D3 25-hydroxylase (in the liver)

25 hydroxyvitamin D3 1.25 dihydroxy 1 = hydroxylase vitamin D3 (kidney)

Cellular Aspects of Bone MetabolismOsteoblastsHighly differentiated cellsNon mitotic in their differentiated stateBone forming cellsLocated on the bone forming surface

OsteoblastsSynthesize and secrete collagenThey contain abundant alkaline phoshatase activity

OsteocytesAre osteoblasts that have become burried in bone matrixEach cell is surrounded by its own lacunaExtensive canalicular system connects osteocytes and surface osteoblasts, forming a functional syncytium in the osteocyticform : no longer synthesize collagenOsteocytes : have an osteolytic activity stimulated by performanceOsteocytic osteolysis :In the bone matrix providerRapid movement of Ca++ from bone ECF space

OsteolaclastsLarge, multinucleated cellsNumerous lysosomesMediate bone resorption at bone surfacesContain acid phosphataseForm significant amounts of lactic and hyaluromic acidsCause bone dissolution via increasedLocal concentration of H+ which solubilizes bone mineral activity of enzymes that degrade matrix

Physiologic actions of ParathormoneOsseous TissueParathormone action on bone : increased Ca++ phosphate mobilization (bone dissolution) from non readily exchangeable Ca++ pool.Long term effects of PTH on bone : release of Ca ++ from bone : related to bone remodelling, involves bone resorption & accretionPTH: stimulate bone synthesisPTH effects on osteogenesis can be both anabolic and catabolic in term of collagen metabolism

Parathormone has 3 important effects on bone account for its overall osteolytic activityIt stimulates osteoclastic & osteolytic activityIt stimulates fusion of progenitor cells to form multinucleated osteoclastic cellsParathormone causes transcient suppresion of osteoblastic activity

References.1. Guyton and Hall, Text book of Medical Physiology.2. Ganong, W.F. , Review of Medical Physiology.3. Silverthorn, D.U., Human Physiology, An integrated approach.

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