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PARATHYROID GLAND PHYSIOLOGY

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Title: PARATHYROID GLAND PHYSIOLOGY


1
PARATHYROID GLAND PHYSIOLOGY
2
  • 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

3
  • The extracellular fluid calcium concentration is
    about 9.4 mg/dl

4
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

5
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

6
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

7
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)

8
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

9
  • Excitation-contraction coupling in cardiac and
    smooth muscles

10
  • 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

11
  • Excitation-secretion coupling
  • In pancreatic beta
    cells calcium entry from the ECF in response to
    membrane depolarization leads to Insulin
    secretion

12
  • Maintenance of tight junctions between cells
    (part of intercellular cement)
  • Clotting of blood (acts as a co-factor)

13
Intracellular Calcium
  • Second messenger
  • Involved in cell motility
  • Calcium in Bone and teeth(structural and
    functional integrity)

14
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

15
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

16
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

17
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

18
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

19
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

20
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

21
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

22
Organic Matrix
  • 90-95 collagen fibers(tensile strength) and the
    remaining homogeneous gelatinous medium called
    ground substance (ECF plus proteoglycans)

23
Bone Salts
  • Are crystalline salts containing calcium and
    phosphorus
  • Major crystalline salt is Hydroxyapatite
  • Magnesium, sodium, potassium and carbonate ions
    etc are also conjugated

24
  • Collagen fibers and the crystalline salts
    together give the bony structure extreme tensile
    and compressional strength

25
  • 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)

26
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)

27
  • 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

28
  • Some of the salts remain in the amorphous form
  • The osteoblasts supposedly secrete a substance
    into the osteoid that neutralizes the
    pyrophosphate

29
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

30
Remodeling of Bone
  • Deposition of bone by Osteoblasts
  • Absorption of bone by Osteoclasts

31
  • Bone deposition and absorption are normally in
    equilibrium

32
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

33
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34
HORMONAL REGULATION OF CALCIUM AND PHOSPHATE
HOMEOSTASIS
  • PTH
  • Vitamin D
  • Calcitonin

35
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

36
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37
TARGET ORGANS FOR PTH
  • Bone
  • Kidney

38
  • Hyperfunction of Parathyroid gland-------Hypercal
    cemia
  • Hypofunction of Parathyroid gland---------Hypocalc
    emia

39
Effect of PTH on Calcium and Phosphate
Concentrations in ECF
40
  • 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

41
  • The decrease in Phosphate conc is due to
  • Effect of PTH to increase renal phosphate
    excretion

42
ACTIONS OF PTH ON BONE
  • Rapid Phase - osteocytic osteolysis
  • Slow Phase - osteoclastic osteolysis

43
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

44
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

45
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46
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

47
  • 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

48
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

49
  • Osteoclasts do not have membrane receptors for
    PTH.
  • The activated osteoblasts and osteocytes send
    secondary "signals" to the osteoclasts (OPGL)

50
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

51
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

52
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

53
  • cAMP mediates the effects of Parathyroid Hormone

54
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55
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56
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

57
  • Vitamin D receptors are present in the nuclei of
    target cells

58
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59
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60
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)

61
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

62
  • These results are due to the effect of
    1,25-dihydroxycholecalciferol to increase calcium
    transport through the cellular membranes

63
  • Calcium ion conc controls the formation of
    1,25-Dihydroxycholecalciferol
  • Formation of 1,25Dihydroxycholecalciferol in the
    kidneys is controlled by PTH

64
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65
CALCITONIN
  • Polypeptide hormone
  • Synthesized and secreted by the parafollicular
    C-cells of the thyroid gland

66
  • Increased plasma calcium concentration stimulates
    Calcitonin secretion
  • Calcitonin decreases plasma calcium concentration

67
ACTIONS OF CALCITONIN ON BONE
  • Decreased osteoclastic activity
  • Decreased osteoclastic number (decreased
    formation of osteoclasts)
  • The net result is reduced osteoblastic and
    osteoclastic activity

68
  • The actions of calcitonin on kidneys and
    intestines are opposite to that of PTH(minor
    effects)

69
  • Calcitonin has a weak effect on plasma calcium
    concentration in adults

70
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)

71
  • 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)

72
  • Changes in ECF calcium ion conc are detected by
    calcium-sensing receptor (CaSR) in parathyroid
    cell membranes

73
  • 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

74
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75
  • 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

76
  • 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

77
  • 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

78
  • 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

79
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

80
  • 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.

81
  • 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.

82
Sign and Symptoms
  • Hyper-reflexia and convulsions
  • Carpopedal spasm
  • Laryngeal stridor
  • Cardiovascular changes ( e.g prolonged QT
    interval, hypotension, arrhythmia)

83
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84
SIGNS OF HYPOPARATHYROIDISM
  • Positive Chvosteks (facial muscle twitch) sign
  • Positive Trousseaus (carpal spasm) sign
  • prolongation of the QT interval

85
  • Treatment of Hypoparathyroidism includes PTH and
    Vitamin D, Calcium infusion

86
Hyperparathyroidism
  • Disease of Bones, Stones, Abdominal groans

87
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.

88
  • 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

89
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.

90
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.

91
  • 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

92
Effects of Hypercalcemia in Hyperparathyroidism
  • Depression of the central and peripheral nervous
    systems, muscle weakness, constipation, abdominal
    pain, peptic ulcer, lack of appetite

93
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.

94
  • 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.

95
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.

96
  • 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

97
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.

98
  • 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.

99
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

100
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.

101
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.

102
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.

103
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.

104
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

105
Osteomalacia and Rickets Caused by Renal Disease
  • Renal rickets is a type of osteomalacia that
    results from prolonged kidney damage

106
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.

107
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

108
  • Loss of bone matrix and strength
  • Bones become fragile with high risk of fracture

109
  • lack of physical stress on the bones because of
    inactivity
  • malnutrition to the extent that sufficient
    protein matrix cannot be formed

110
  • (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

111
  • (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
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