PARATHYROID GLAND PHYSIOLOGY

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PARATHYROID GLAND PHYSIOLOGY
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• 99 calcium of our body is in the crystalline
  form in the skeleton and teeth
• Of the remaining 1
• 0.9 intracellular
• less than 0.1 in the ECF

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• The extracellular fluid calcium concentration is
  about 9.4 mg/dl

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Calcium in Plasma and Interstitial Fluid

• 41 of the calcium is bound with plasma
  proteins(non-diffusible)
• 9 bound with anionic substances(citrate,
  phosphate(diffusible, non-ionized)
• Remaining 50 calcium is both diffusible and
  ionized

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Hypocalcemia(low blood calcium)

• Fall in free calcium results in over excitability
  of nerves and muscles
• Decrease in free calcium increases neuronal
  sodium permeability with resultant influx of
  sodium moving the resting potential closer to
  threshold

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Tetany

• Hypocalcemia causes tetany
• At plasma calcium ion concentration about 50
  below normal the peripheral nerve fibers become
  so excitable that they begin to discharge
  spontaneously
• Tetany usually occurs at calcium conc of 6
  mg/dl from normal value of 9 mg/dl

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Hypercalcemia (elevated blood calcium)

• Depresses neuro-muscular excitability
• Depressive effects begin to appear at calcium
  concentration of 12mg/dl (constipation, poor
  appetite, decreased QT interval)

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Role of Free Fraction of ECF Calcium

• Neuromuscular excitability
• Even minor
  variations in concentration of free ECF calcium
  have profound and immediate impact on the
  sensitivity of excitable tissues

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• Excitation-contraction coupling in cardiac and
  smooth muscles

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• Stimulus-secretion coupling
• The entry
  of calcium into secretory cells which results
  from increased permeability to calcium in
  response to appropriate stimulation triggers the
  release of secretory product by exocytosis

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• Excitation-secretion coupling
• In pancreatic beta
  cells calcium entry from the ECF in response to
  membrane depolarization leads to Insulin
  secretion

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• Maintenance of tight junctions between cells
  (part of intercellular cement)
• Clotting of blood (acts as a co-factor)

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Intracellular Calcium

• Second messenger
• Involved in cell motility
• Calcium in Bone and teeth(structural and
  functional integrity)

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Absorption of Calcium

• Calcium is absorbed from duodenum by carrier
  mediated active transport and in the rest of
  small intestine by facilitated diffusion (poorly
  absorbed)
• Vitamin D is essential for absorption of calcium
  from GIT

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Calcium Excretion

• 98-99 of the filtered calcium is reabsorbed
  from renal tubules into blood
• 90 of the filtered calcium is reabsorbed from
  the proximal tubule, loop of Henle and early
  distal tubule
• Remaining 10 is reabsorbed selectively from the
  late distal tubule and early collecting ducts
  depending on calcium conc in blood

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Calcium Homeostasis Calcium Balance

• Urinary excretion of calcium is hormonally
  controlled
• Absorption of Calcium from intestine is also
  hormonally controlled and depends on the calcium
  status of body
• Bones are the large reservoirs of calcium and
  exchange of calcium between ECF and bone is also
  subject to hormonal control

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Calcium Homeostasis

• Regulation of calcium homeostasis involves the
  immediate adjustments required to maintain a
  constant free plasma calcium concentration on a
  minute-to-minute basis.
• This is mainly accomplished by rapid exchanges
  between the bone and the ECF and to a lesser
  extent by modifications in urinary excretion of
  calcium

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Calcium Balance

• Regulation of calcium balance involves the slowly
  responding adjustments required to maintain a
  constant total amount of calcium in the body.
  Calcium is maintained by adjusting the extent of
  intestinal calcium absorption and urinary calcium
  excretion

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Phosphate

• The average total quantity of phophorus
  represented by both the ionic forms is 4mg/dl
  (3-4mg/dl in adults and 4-5mg/dl in children)
• Good Intestinal absorption
• Excretion in faeces in combination with
  unabsorbed calcium
• Remaining absorbed in blood and excreted in urine

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Excretion of Phosphate

• Renal phosphate excretion is controlled by an
  over-flow mechanism
• When phosphate conc in the plasma is below the
  critical value of 1mmol/L, all the phosphate in
  the glomerular filtrate is reabsorbed
• But above this conc the rate of phosphate loss is
  directly proportional to the additional increase

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Bone

• Tough organic matrix strengthened by deposits of
  calcium salts
• 30 matrix, 70 salts
• Newly formed bone has a higher percentage of
  matrix than salts

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Organic Matrix

• 90-95 collagen fibers(tensile strength) and the
  remaining homogeneous gelatinous medium called
  ground substance (ECF plus proteoglycans)

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Bone Salts

• Are crystalline salts containing calcium and
  phosphorus
• Major crystalline salt is Hydroxyapatite
• Magnesium, sodium, potassium and carbonate ions
  etc are also conjugated

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• Collagen fibers and the crystalline salts
  together give the bony structure extreme tensile
  and compressional strength

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• Hydroxyapatite does not precipitate in the
  extracellular fluid although the conc of calcium
  and phosphate ions is considerably greater than
  those required to cause precipitation of
  hydroxyapatite
• Role of pyrophosphate (inhibitor of precipitation)

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Bone Calcification

• Secretion of collagen molecules (monomers) and
  ground substance by osteoblasts
• Polymerization of collagen monomers to form
  collagen fibers (osteoid)
• As osteoid is formed some of the osteoblasts
  become entrapped in it and become silent
  (osteocytes)

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• Calcium salts begin to precipitate on the
  surfaces of collagen fibers
• The initial calcium salts are not hydroxyapatite
  crystals but are amorphous compounds
• By process of substitution, addition,
  reabsorption these salts are converted into
  hydroxyapatite crystals over a period of weeks or
  months

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• Some of the salts remain in the amorphous form
• The osteoblasts supposedly secrete a substance
  into the osteoid that neutralizes the
  pyrophosphate

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Calcium Exchange Between Bone and ECF

• Most of the exchangeable calcium is in the bone
• This exchangeable calcium is in equilibrium with
  the calcium ions in the extracellular fluid
• The exchangeable calcium provides a buffering
  mechanism to keep the calcium ion conc in the ECF
  from rising to excessive levels or falling to low
  levels

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Remodeling of Bone

• Deposition of bone by Osteoblasts
• Absorption of bone by Osteoclasts

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• Bone deposition and absorption are normally in
  equilibrium

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Value of Continual Bone Remodelling

• Bone can adjust its strength in proportion to the
  degree of bone stress.
• The shape of the bone can be rearranged for
  proper support of mechanical forces by deposition
  and absorption of bone in accordance with
• stress patterns
• When old bone becomes brittle and weak new
  organic matrix is laid down and normal toughness
  of bone is maintained

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HORMONAL REGULATION OF CALCIUM AND PHOSPHATE
HOMEOSTASIS

• PTH
• Vitamin D
• Calcitonin

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PARATHYROID GLANDS

• Four glands located on the posterior surface of
  the thyroid gland
• Derived from the 3rd and 4th pharangeal pouches
• Chief cells secrete the polypeptide hormone PTH

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TARGET ORGANS FOR PTH

• Bone
• Kidney

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• Hyperfunction of Parathyroid gland-------Hypercal
  cemia
• Hypofunction of Parathyroid gland---------Hypocalc
  emia

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Effect of PTH on Calcium and Phosphate
Concentrations in ECF
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• Rise in calcium levels is due to
• Effect of PTH to increase calcium and phosphate
  absorption from bone
• Rapid effect of PTH to decrease the excretion of
  calcium by kidneys

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• The decrease in Phosphate conc is due to
• Effect of PTH to increase renal phosphate
  excretion

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ACTIONS OF PTH ON BONE

• Rapid Phase - osteocytic osteolysis
• Slow Phase - osteoclastic osteolysis

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Osteocytic Osteolysis

• The calcium ion conc in the blood begins to rise
  with in minutes
• There is removal of bone salts
• From the bone matrix in the vicinity of
  osteocytes
• In the vicinity of osteoblasts along the bone
  surface

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Osteocytic Membrane System

• Long processes extend from osteocyte to osteocyte
  through out the bone structure and theses
  processes also connect with the surface
  osteocytes and osteoblasts
• This membrane separates the bone from ECF
• Between the processes and the bone there is small
  amount of bone fluid

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Osteolysis

• The osteocytic membrane pumps calcium ions from
  bone fluid into ECF
• When it becomes excessively activated the bone
  fluid calcium conc falls and calcium and
  phosphate salts are absorbed from the bone
  (osteolysis)
• When the pump is inactivated the bone fluid
  calcium conc rises and calcium and phosphate
  salts are deposited in the bone

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• The cell membranes of both osteoblasts and
  osteocytes have receptors for binding PTH
• PTH strongly stimulates Calcium pump by
  increasing the calcium permeability of bone fluid
  side of osteocytic membrane

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Slow phase of bone absorption and calcium
phosphate release

• Immediate activation of already formed
  osteoclasts
• Increased osteoclastic size and number
• Increased osteoclastic collagenase and lysosomal
  enzyme activity
• Increased osteoclastic acid phosphatase,carbonic
  anhydrase,lactic acid and citric acid
  concentrations
• Increased bone resorption

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• Osteoclasts do not have membrane receptors for
  PTH.
• The activated osteoblasts and osteocytes send
  secondary "signals" to the osteoclasts (OPGL)

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Activation of Osteoblats

• Excess PTH stimulated osteoclastic resorption of
  bone can lead to weakened bones and secondary
  stimulation of the osteoblasts that attempt to
  correct the weakened state

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PTH ACTIONS ON KIDNEY

• Increased reabsorption of calcium, magnesium and
  hydrogen ions
• Decreased reabsorption of phosphate, sodium and
  potassium ions
• Increased alpha-1-hydroxalase activity

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Effect of PTH on Intestinal Absorption of
CalciumPhosphate

• PTH greatly enhances both calcium and phosphate
  absorption from the intestines by increasing the
  formation in the kidneys of 1,25-dihydroxycholecal
  ciferol

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• cAMP mediates the effects of Parathyroid Hormone

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Vitamin D

• Several compounds derived from sterols belong to
  vitamin D family
• They all perform more or less same functions
• Vitamin D3(cholecalciferol) is the most important
  of these

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• Vitamin D receptors are present in the nuclei of
  target cells

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Actions of Vitamin D

• It promotes Intestinal calcium absorption
• Role of Calbindins in the intestinal epithelial
  cells
• It also promotes Phosphate absorption from the
  intestine (directly through calcium)
• It decreases renal calcium and phosphate
  excretion (weak effect)

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Actions on Bone

• The administration of extreme quantities of
  vitamin D causes absorption of bone
• In the absence of vitamin D the effect of PTH in
  causing bone absorption is greatly reduced
• Vitamin D in smaller quantities promotes bone
  calcification

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• These results are due to the effect of
  1,25-dihydroxycholecalciferol to increase calcium
  transport through the cellular membranes

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• Calcium ion conc controls the formation of
  1,25-Dihydroxycholecalciferol
• Formation of 1,25Dihydroxycholecalciferol in the
  kidneys is controlled by PTH

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CALCITONIN

• Polypeptide hormone
• Synthesized and secreted by the parafollicular
  C-cells of the thyroid gland

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• Increased plasma calcium concentration stimulates
  Calcitonin secretion
• Calcitonin decreases plasma calcium concentration

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ACTIONS OF CALCITONIN ON BONE

• Decreased osteoclastic activity
• Decreased osteoclastic number (decreased
  formation of osteoclasts)
• The net result is reduced osteoblastic and
  osteoclastic activity

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• The actions of calcitonin on kidneys and
  intestines are opposite to that of PTH(minor
  effects)

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• Calcitonin has a weak effect on plasma calcium
  concentration in adults

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Control of PTH secretion by Calcium Concentration

• Decrease in calcium conc increases PTH secretion
• Persistent decrease leads to hypertrophy of the
  gland
• (rickets, pregnancy, lactation)

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• Increase in calcium conc decreases PTH secretion
• Persistent increase leads to reduced activity and
  size of the glands
• (excess calcium and vitamin D in diet,
  diseases causing bone resorption)

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• Changes in ECF calcium ion conc are detected by
  calcium-sensing receptor (CaSR) in parathyroid
  cell membranes

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• CaSR is a G-protein coupled receptor when
  activated by calcium ions activates phospholipase
  C and increases intracellular inositol
  triphosophate and diacylglycerol formation. This
  stimulates release of calcium from intracellular
  stores which decreases PTH secretion. Decreased
  extracellular fluid calcium ion concentration
  inhibits these pathways and stimulates PTH
  secretion

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• Buffer Function of the Exchangeable Calcium in
  Bones-The First Line of Defense
• an increase in the concentrations of
  extracellular fluid calcium and phosphate ions
  above normal causes immediate deposition of
  exchangeable salt.
• decrease in these concentrations causes
  immediate absorption of exchangeable salt

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• Mitochondria especially of the liver and
  intestine, contain a significant amount of
  exchangeable calcium that provides an additional
  buffer system for helping to maintain constancy
  of the extracellular fluid calcium ion
  concentration

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• Hormonal Control of Calcium Ion Concentration-The
  Second Line of Defense
• At the same time that the exchangeable calcium
  mechanism in the bones is "buffering" the calcium
  in the extracellular fluid, both the parathyroid
  and the calcitonin hormonal systems begin to act.
  Within 3 to 5 minutes after an acute increase in
  the calcium ion concentration, the rate of PTH
  secretion decreases

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• In prolonged calcium excess or prolonged calcium
  deficiency, only the PTH mechanism seems to be
  really important in maintaining a normal plasma
  calcium ion concentration

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Hypoparathyroidism

• When parathyroid glands do not produce sufficient
  amounts of PTH
• During thyroid surgery surgical removal of
  parathyroid gland can cause hypoparathyroidism
• Parathyroidectomy
• Autoimmune disease
• Deficiency of receptors for PTH

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• The osteoclasts become almost totally inactive.
  As a result calcium reabsorption from the bones
  is so depressed that the level of calcium in the
  body fluids decreases.

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• When the parathyroid glands are suddenly removed,
  the calcium level in the blood falls from the
  normal of 9.4 mg/dl to 6 to 7 mg/dl within 2 to 3
  days and the blood phosphate concentration may
  double. When this low calcium level is reached
  the usual signs of tetany develop.

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Sign and Symptoms

• Hyper-reflexia and convulsions
• Carpopedal spasm
• Laryngeal stridor
• Cardiovascular changes ( e.g prolonged QT
  interval, hypotension, arrhythmia)

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SIGNS OF HYPOPARATHYROIDISM

• Positive Chvosteks (facial muscle twitch) sign
• Positive Trousseaus (carpal spasm) sign
• prolongation of the QT interval

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• Treatment of Hypoparathyroidism includes PTH and
  Vitamin D, Calcium infusion

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Hyperparathyroidism

• Disease of Bones, Stones, Abdominal groans

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Primary Hyperparathyroidism

• The cause of primary hyperparathyroidism is tumor
  of one of the parathyroid glands which are more
  common in women than in men or children mainly
  because pregnancy and lactation stimulate the
  parathyroid glands and therefore predispose to
  the development of such a tumor.

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• Hyperparathyroidism causes extreme osteoclastic
  activity in the bones. This elevates the calcium
  ion concentration in the extracellular fluid
  while usually depressing the concentration of
  phosphate ions because of increased renal
  excretion of phosphate

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Bone Disease in Hyperparathyroidism

• In mild hyperparathyroidism new bone can be
  deposited rapidly enough to compensate for the
  increased osteoclastic resorption of bone but in
  severe hyperparathyroidism the osteoclastic
  absorption is more than osteoblastic deposition,
  and the bone may be eaten away almost entirely.

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Osteitis Fibrosa Cystica

• The reason a hyperparathyroid person seeks
  medical attention is often a broken bone.
  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 "tumors." The cystic bone
  disease of hyperparathyroidism is called osteitis
  fibrosa cystica.

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• When the osteoblasts become active, they secrete
  large quantities of alkaline phosphatase.
  Therefore one of the important diagnostic
  findings in hyperparathyroidism is a high level
  of plasma alkaline phosphatase

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Effects of Hypercalcemia in Hyperparathyroidism

• Depression of the central and peripheral nervous
  systems, muscle weakness, constipation, abdominal
  pain, peptic ulcer, lack of appetite

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Parathyroid Poisoning and Metastatic Calcification

• The calcium and phosphate in the body fluids
  become greatly supersaturated, so 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.

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• The level of calcium in the blood must rise above
  17 mg/dl before there is danger of parathyroid
  poisoning, but once such elevation develops along
  with concurrent elevation of phosphate, death can
  occur in few days.

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Formation of Kidney Stones in Hyperparathyroidism

• The patients of hyperparathyroidism have an
  extreme tendency to form kidney stones. The
  reason is that the excess calcium and phosphate
  absorbed from the intestines or mobilized from
  the bones is excreted by the kidneys causing a
  proportionate increase in the concentrations of
  these substances in the urine.

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• As a result crystals of calcium phosphate tend to
  precipitate in the kidney forming calcium
  phosphate stones. Also calcium oxalate stones
  develop because even normal levels of oxalate
  cause calcium precipitation at high calcium
  levels

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Secondary Hyperparathyroidism

• In secondary hyperparathyroidism high levels of
  PTH occur as a compensation for hypocalcemia
  rather than as a primary abnormality of the
  parathyroid glands.

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• Secondary hyperparathyroidism can be caused by
  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.

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Rickets

• Rickets occurs in children.
• It results from calcium or phosphate deficiency
  in the extracellular fluid caused by lack of
  vitamin D.
• If the child is adequately exposed to sunlight,
  the 7-dehydrocholesterol in the skin becomes
  activated by the ultraviolet rays and forms
  vitamin D3, which prevents rickets by promoting
  calcium and phosphate absorption from the
  intestines

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Plasma Concentrations of Calcium and Phosphate
Decrease in Rickets

• The plasma calcium concentration in rickets is
  only slightly depressed but the level of
  phosphate is greatly depressed.

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Rickets Weakens the Bones

• During prolonged rickets the marked compensatory
  increase in PTH secretion causes extreme
  osteoclastic absorption of the bone this in turn
  causes rapid osteoblastic activity
• The osteoblasts lay down large quantities of
  osteoid which does not become calcified because
  of insufficient calcium and phosphate ions.

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Tetany in Rickets

• In the early stages of rickets, tetany almost
  never occurs because the parathyroid glands
  maintain almost normal level of calcium in the
  extracellular fluid.
• When the bones finally become exhausted of
  calcium, the level of calcium may fall rapidly.
  As the blood level of calcium falls below 7
  mg/dl, the usual signs of tetany develop.

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Treatment of Rickets

• The treatment of rickets depends on supplying
  adequate calcium and phosphate in the diet and on
  administering large amounts of vitamin D.

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Osteomalacia-Adult Rickets

• Deficiency of both vitamin D and calcium
  occasionally occur as a result of steatorrhea
  (failure to absorb fat) because vitamin D is
  fat-soluble vitamin
• This almost never proceeds to the stage of tetany
  but often is a cause of severe bone disability

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Osteomalacia and Rickets Caused by Renal Disease

• Renal rickets is a type of osteomalacia that
  results from prolonged kidney damage

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Congenital hypophosphatemia

• This results from congenitally reduced
  reabsorption of phosphates by the renal tubules.
  This type of rickets must be treated with
  phosphate compounds instead of calcium and
  vitamin D, and it is called vitamin D-resistant
  rickets.

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Osteoporosis (porous bones)-Decreased Bone Matrix

• Osteoporosis is the most common of all bone
  diseases in adults especially in old age
• It results from diminished organic bone matrix
• excessive bone resorption and decreased bone
  formation

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• Loss of bone matrix and strength
• Bones become fragile with high risk of fracture

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• lack of physical stress on the bones because of
  inactivity
• malnutrition to the extent that sufficient
  protein matrix cannot be formed

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• (4) postmenopausal lack of estrogen secretion
  because estrogens decrease the number and
  activity of osteoclasts
• (5) old age in which growth hormone and other
  growth factors diminish greatly plus the fact
  that many of the protein anabolic functions also
  deteriorate with age

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• (6) Cushing's syndrome, massive quantities of
  glucocorticoids secreted in this disease cause
  decreased deposition of protein throughout the
  body and increased catabolism of protein and have
  depressive effect on osteoblastic activity