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The parathyroid glands and calcium
homeostasis
Calcium
• The normal adult human body contains about
one
kilogram
of
calcium
...
• Of this huge amount of calcium in the
skeleton, only about 5 gm is diffusible and
rapidly exchangeable with calcium in the blood
...
• The normal plasma calcium concentration is
10 mg/dL (range 9 - 11)
...
• It is the ionized calcium which is biologically
active and strictly adjusted by the controlling
systems
...
• The minimal daily requirement which can
maintain normal calcium balance in young
infants and normal adults is 0
...
• This amount is doubled during pregnancy,
lactation, adolescence, and in after menopause
...
Formation of bone and teeth
...
Maintenance of normal permeability of cell
membranes
...
Maintenance of normal excitability of
nerves and muscles
...
Release of neurotransmitters, hormones,
and exocrine secretions
...
Blood clotting
...
Muscle contraction
...
Acting as a second messenger to mediate
intracellular messages
...
Milk formation
...
Activity of many enzymes
...
• The main phosphate salts in bone are the
hydroxyapatites [Ca2+10x (H3O+)2x, (P043)6
(OH)2] which make the calcium salt crystals
deposited in the ground substance of bone
...
• Total plasma phosphorous is 12 mg/dL
...
• One third is found as inorganic phosphorus
(Pi), mostly HP042, H2P04
...
• Plasma calcium phosphate is continuously
deposited in, and absorbed from bone
...
• This product is called “the solubility product”
of Ca2+ and Pi in plasma, i
...
•
[Ca2+] x [Pi] = The solubility
product = Constant
• Any change in plasma Ca2 concentration leads
to a reciprocal proportionate change in Pi so
that the solubility product remains constant
...
• This increases the solubility product
...
Bone
• Bone consists of an organic matrix of collagen
fibers in a ground substance of mucopolys
ccharides and collagen protein within which
crystals hydroxapatites are deposited
...
• There are three types of cells in bone:
• 1
...
They synthesize
and secrete collagen fibers and promote the
deposition of calcium phosphate crystals in
bone
...
Osteocytes:
• These are the most abundant cells in bone
...
They
facilitate the exchange of Ca2+ of bone with
that in the ECF
...
Osteoc1asts:
• These are bone-resorbing cells
...
• They also secrete lysosomal proteases which
dissolve collagen and other proteins
...
• Bone formation and resorption occur
continuously leading to continuous bone
remodeling
...
• These are the vitamin D derivative calcitriol,
the parathyroid hormone parathormone, and
the thyroid hormone calcitonin
...
Vitamin D and Calcitriol
• Vitamin D is a term that refers to a group of
closely related sterols, the most important
members of this group to the human body are
vitamins D2 (ergocalciferol) and D3
(cholecalciferol)
...
• The active derivative of vit D2 and D3 is
calcitriol (1,25- dihydroxycholecalciferol)
...
• It is formed in the body through the following
steps
...
In the skin:
• Sunlight (ultraviolet rays) converts 7dehydrocholesterol to vit D3 (cholecalciferol)
...
In the liver:
• 25-hydroxylase enzyme converts vit D2 and D3
to 25- hydroxycholecalciferol
...
In the cells of the proximal tubules of the
kidney:
Iα-hydroxylase
enzyme converts 25-hydroxycholecalciferol to
I,25-dihydroxycholecalciferol (calcitriol)
...
• Normal or high levels of calcium or phosphate
in
the
plasma
activate
another renal enzyme 24-hydroxylase which
converts the 25-hydroxycholecalciferol into
the
inactive
metabolite
24,
25dihydroxycho1ecaIcfero1
...
It induces the formation of calbindin-D
proteins in the intestinal mucosal cells
...
• 2
...
• 3
...
• 4
...
• In vit D deficiency, there is an increased
incidence of infections
...
It stimulates the differentiation of
keratinocytes in the skin
...
The parathyroid hormone
• (Parathormone)
• The parathyroid glands are four disk-like
structures - 2 on each side - on the posterior
surface of the lobes of the thyroid gland
...
Actions of Parathmone
• Parathormone is a plasma calcium raising
hormone, its main sites of action are the bone
and kidney
...
• On the bone:
• Parathormone stimulates osteoclasts → bone
resorption → mobilization of Ca2+ from bone
→ rise in plasma Ca2+ leve1
...
• It is the parathomone which keeps the
hormonal plasma calcium at its normal level of
10 mg/dL
• On the kidney:
• 1
...
The drop in
plasma phosphate level and the concomitant rise
in plasma Ca2+ level keep the solubility product
constant
...
Stimulates the formation of calcitriol in the
kidney
...
• But this action is counterbalanced by the
increase in plasma calcium level which
increases the filtration of calcium in the renal
glomeruli — loss of calcium in urine
...
Control of secretion of parathormone
• The main factor which controls parathormone
secretion is the plasma calcium level
...
• A rise in plasma calcium directly inhibits the
secretion of parathormone
...
• It is increased by high plasma phosphate, low
plasma Mg2+ and -adrenergic stimulants
...
Calcitonin
• Calcitonin is a polypeptide hormone secreted
mainly by the parafollicular cells of the thyroid
gland
...
• That is why the term “calcitonin” is now more
widely used
...
• It inhibits osteoclastic activity’ leading to
increased calcium deposition in bone
...
• However, the exact physiological role played
by calcitonin is uncertain
...
Prevention of postprandial hypercalcemia
...
• 2
...
During pregnancy the demand for calcium
increases, calcitriol level increases and bone
resorption is stimulated
...
• 3
...
• Calcitonin stimulates bone mineralization
...
Control of secretion
• High plasma calcium concentration is the main
stimulus for calcitonin secretion
...
• There is no known disease which is’ directly
attributed to hyper or hyposecretion of
calcitonin
...
The
glucocorticoids
(cortisol
and
corticosterone):
• Lower plasma calcium by two mechanisms:
• a) Suppression of Ca2+ mobilization from bone by
inhibiting osteoclasts formation and activity
...
• Over long periods, glucocorticoids inhibit
osteoblasts formation and activity → osteoporosis
...
Thyroid hormones: In high concentrations
promote Ca2+ mobilization from bone →
hypercalcemia
→
hypercalcuria
→
osteoporosis
...
Growth hormone: Stimulates Ca2+
absorption from the intestine and calcium
excretion in urine, but the absorption is more
than the excretion
...
• 4
...
• 5
...
In
untreated diabetes, there is significant bone
loss
...
prostaglandin E (PGE): Promotes bone
erosion and Ca2+ mobilization
...
• This is the cause of hypercalcemia in cases of
cancer (20% of all cases of hypercalcemia)
...
Parathyroid
hormone-related
protein
(PTHRP): This is a protein with hormone-like
action similar to parathomone
...
• It is also secreted by the renal tubules, ovaries,
brain, and other tissues
...
• Eighty percent of cases of hypercalcemia are due
to abnormally high plasma PTHRP levels secreted
by PTHRP-secreting tumors in the breast, kidney,
ovary, or skin
...
• Vitamin D deficiency (hypovitaminosis D)
• Causes
• 1
...
• 2
...
• 3
...
g
...
• 4
...
Manifestations
• Lack of vit D reduces the absorption of
calcium from the intestine → hypocalcemia
...
• In young children, vit D deficiency produces
the disease “rickets”
...
• Ossification is retarded or stopped, but the
epiphyseal plates continue to grow producing
swellings near the joints and at the
costochondral junctions
...
• Pelvis deformity in girls could lead
subsequently to difficult childbirth
...
• The bone becomes brittle; tender or painful:
• In the early stages of hypovitaminosis D,
plasma calcium level is in the normal range,
but in later stages the calcium stores in bone
are exhausted, plasma calcium falls down to
low levels that leads to tetany which could be a
very serious consequence
...
• It differs from osteomalacia in which the protein
matrix of bone is normal but poorly calcified
...
• It is the marked osteoporosis which is
complicated by compression of the vertebrae or
fractures of long bones (e
...
the neck of the
femur)
which
is
abnormal
...
• Sex hormones, estrogen and testosterone,
reduce the risk of osteoporosis but they do not
replace bone which has already been lost
...
• High parathormone concentrations leads to
excessive bone resorption → excessive
mobilization of Ca2+ from bone → rise in
plasma Ca2+ level → filtration of more Ca2+ in
the kidney → loss of more Ca2+ in urine
(hypercalciuria)
...
• The high calcium concentration depresses the
neuromuscular excitability leading to general
depression, muscle weakness, malaise,
anorexia, constipation
...
• The renal tubules might get calcified and
damaged leading to polyuria (nephrogenic
diabetes insipidus)
...
• The case is treated by surgical removal of the
affected gland
...
• Some cases are due to refractoriness of the
target
tissues
to
parathormone
(pseudohypoparathyroidism)
• In hypoparathyroidism, osteoclastic activity,
bone resorption, and calcitriol formation are all
depressed leading to hypocalcemia which
causes the manifestations of the disease
...
• Mild hypocalcemia is associated with
paresthesia (numbness and tingling sensations)
of the hands and around the mouth
...
• There is general muscle weakness, malaise,
dizziness and gastrointestinal upset
...
• One of the most serious effects of
hypocalcemia is tetany
...
• Causes of tetany
• Causes of tetany are the causes of hypocalcemia
which include:
• 1
...
There is failure of calcitriol
formation → calcium absorption is inhibited
...
• 2
...
• 3
...
• 4
...
g
...
• Phytic acid combines with calcium to make the
unabsorbable complex calcium phytate
...
Alkalosis which decreases the solubility of
calcium and lowers the solubility product of
calcium and phosphate in plasma
...
Types of tetany
• Manifest tetany
• This is tetany which is found with severe
hypocalcemia (serum calcium below 7 mg/dL)
...
• Motor end-plate potentials and action potentials
are produced spontaneously
...
• Generalized
convulsions
might occur specially in children
...
• In-between the attacks, there is stiffness of
muscles
...
• There is neuromuscular hyperexcitability, but
tetanic attacks do not occur spontaneously
...
g
...
• Hyperventilation
could
precipitate an attack of tetany because the
resulting respiratory alkalosis precipitates
plasma calcium and reduces the plasma
ionized
calcium
level
...
Determination of serum calcium
...
• 2
...
Trousseau test: The sphygmomanometer
cuff is inflated around the arm with a pressure
above the systolic pressure for 3 minutes
...
• This is because the ischemia produced by the
test increases the excitability of the
neuromuscular junction
...
Chvostek’s test: Tapping of the facial
nerve in front of the ear in positive cases
causes twitches of the facial muscles
especially those of the upper lip
...
• c
...
Treatment of tetany
• I
...
• II
...
• Hypoparathyroidism is treated by increasing
calcium intake and high doses of vitamin D
...
• Parathormone preparations are available but
are not usually used because they are
expensive, short acting (for few hours only),
should be taken parentrally, and the tendency
of the body to produce antibodies against
them