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SEMINAR ON
CALCIUM METABOLISM
Presented by :
Dr.
Dr Manju Koshy
CALCIUM METABOLISM
CONTENTS
INTRODUCTION
DISTRIBUTION OF CALCIUM IN THE BODY
BONE
BLOOD
MUSCLES
BONE RIGIDITY
HYPOPARATHYROIDISM
HYPERPARATHYROIDISM
PRIMARY HYPERPARATHYROIDISM
SECONDARY HYPERPARATHYROIDISM
TERTIARY HYPERPARATHYROIDISM
ECTOPIC - PTI SYNDROME
HYPOCALCEMIA
HYPERCALCEMIA
VITAMIN D DEFICIENCY
RICKETS
OSTEOMALACIA
OSTEOPOROSIS
HETEROTOPIC CALCIFICATION
DYSTROPHIC CALCIFICATION
METASTATIC CALCIFICATION
CALCINOSIS IN PULP
REFERENCES
CONCLUSION
CALCIUM METABOLISM
INTRODUCTION :
Calcium is a very important mineral in our body. It provides rigidity to bones,
muscle contraction, affects permeability of cells, blood clotting mechanism etc.
Metabolism of calcium is intimately associated with parathyroid hormone, calcitonin
and vitamin D. Importance of studying calcium metabolism has increased because : (i)
In old people, one of the major curses happens to be osteoporosis which can
cause fracture of bones.
(ii)
Calcium play vital roles in contraction of heart as well as skeletal muscles and
smooth muscles. Therefore drugs affecting calcium ion metabolism can be
used to treat hypertension or cardiac contractility.
DISTRIBUTION :
An average sized man has about 1 Kg of calcium in his body. About 99% of
this calcium is in the bone and teeth. The remaining is distributed in different tissues
as follows ;
Muscles : 8 mg per 100 gm of fresh muscle.
Plasma or serum : 9-11 mg per 100 ml of blood
RBC : Minute traces
Lymph and aqueous humour : Slightly less than plasma.
CSF : 5.3 mg per 100 ml.
Enamel ; 96% inorganic content Hydroxyapatite crystals
Dentin : 65% inorganic content
Cementum : 45-50% inorganic content
Saliva : Minute traces.
BONE CALCIUM :
Since bone constitutes the main repository for calcium, it plays a vital part in
calcium metabolism and any upsets in calcium balance can cause severe bone disease.
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Calcium in the bone mostly is in the form of calcium phosphate and partly as
calcium carbonate.
The osteoid tissue of bone is manufactured by osteoblasts and after
maturation, this osteoid undergoes mineralization with the deposition of calcium salts
in the form of Hydroxyapatite.
The bone has 2 major functions :
i)
Mechanical
- Supporting the body weight
- Providing surfaces for muscle attachment
- Protecting vital organs from trauma Eg. Skull protecting brain, Ribcage
protecting the heart, lungs etc.
ii)
Buffer : Prevents wide fluctuations of serum calcium concentration.
The ionic calcium level in the serum must remain within narrow range. If
there is fall of calcium serum, bone releases calcium.
If serum calcium level is high, calcium from serum is deposited in the bone.
All these occur under the influence of hormones mainly PTH, Vitamin D
(Calcitriol), other hormones like estrogen, calcitonin and chemicals like interleukins
(IL).
SERUM CALCIUM :
The normal serum calcium concentration is between 9-11 mg/100 ml of blood.
It exists in 3 forms :
i)
Ionized calcium : This is the active form and constitutes about 50% of the
serum calcium (4.5 mg/100 ml).
ii)
Protein bound calcium : Bound mostly to albumin, therefore it is nondiffusible (4 mg/100 ml).
iii)
Non- ionized, diffusible calcium : Smallest fraction and is present for the most
part as citrate.
In clinical practice, we only measure the concentration of serum calcium and not of
the whole blood because ;
1) Intracellular i.e. inside the RBC Concentration of calcium is very low.
2) All clinical information can be obtained by estimating calcium serum instead of
measuring that of the whole blood.
In clinical view : It is only the ionic calcium which matters as they are active.
Therefore : a) In severe hypoprotinemia of blood : Protein bound calcium falls, ionic calcium
does not fall. Therefore total serum calcium concentration is low, but still no
tetany develops.
b) In alkalosis (eg. After severe hyperventilation) the protein bound calcium
increases, but ionic calcium decreases.
Therefore total serum calcium
Thus the organic calcium of food is converted into inorganic form before it
can be absorbed.
These bind to receptors present on cell surface of target cells and initiate a process
of intra cellular signaling leads to formation of second messengers which include
cyclic AMP, cyclic GMP and calcium.
These 2nd Messengers initiate formation of bone cells namely osteoclasts and
osteoblasts which are responsible for bone remodeling.
BONE REMODELLING
Force
Bone deformation
st
1 Messengers (PTH, PG, VIP)
remodeling
Bone Remodeling
Bone resorption
Bone deposition
XII
XIIa
XI
XIa
IX
IXa
Ca
++
Ca++
VIII
Phospholipid
X
Xa
Ca++ Phospholipid
V
(II) Prothrombin
Thrombin (IIa)
XIII
XIIIa
Fibrinogen
Fibrin
Stabilized fibrin
EXTRINSIC
Tissue Damage
Tissue Factor
X
Xa
Va
VIII
II
IIa
I
VIIIa
Ia
XIIIa
Stable Fibrin
3) Muscle contraction :
For muscle contraction myosin filament should get attached with actin
muscle filament for this calcium ions are required.
Action potential on Sarcolemma
Ca2+ Channels open up
Ca release (from ECF to ICF)
AP
T Tubule
Ap to Cistern
Ca Release
Sites for myosin becomes uncovered myosin gets attached with active head of
actin Cross bridges are formed muscle contraction.
Excitation Contraction Coupling :
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AP leads to Contraction
AP excitation
electric phenomenon
Calcium coupling agents
Contraction
Mechanical phenomena
Calcium acts as coupling agent between AP and contraction.
FACTORS AFFECTING THE CALCIUM LEVEL IN BODY :
1) Parathormone : Parathormone is secreted by the chief cells of the parathyroid
glands. It is a protein in nature.
Actions of PTH :
The primary function of parathormone is to maintain the blood calcium level
within the critical range of 9 to 11 mg%.
1) It increases the blood calcium level by mobilizing calcium from bone bone
resorption.
2) It decreases the excretion of calcium through the kidneys.
3) It increases absorption of calcium from GIT.
4) It facilitates the conversion of vitamin D into its final product Calcitriol 1, 25
DHCC which causes increase absorption of calcium from GIT.
Effects on the Bone :
Bone resorption causes Increased calcium in blood
Resorption of calcium from bones occurs in 2 phases.
- Rapid phase
- Slow phase
Rapid Phase :
- Occurs within minutes after the release of parathyormone from parathyroid
glands.
- Immediately after reaching the bone, the parathormone gets attached with the
receptors on the cell membrane of osteoblasts and osteocytes.
- Osteocytic activity
- The hormone receptor complex increases the permeability of the membranes of
these cells for calcium ions.
- This increases the calcium pump mechanism allowing calcium ions to diffuse
from these cells into the plasma.
Slow Phase :
- By activation of ostoeclasts Osteoclastic activity
- Proteolytic enzymes, citric acid and lactic acid are released from these cells.
- The organic matrix of bone is dissolved, thus releasing the calcium ions which
diffuses into plasma.
- PTH causes calcium resorption and phosphate absorption from bones.
Effects on the Kidneys :
- PTH increases the reasborption of calcium from the renal tubules.
- It increases the excretion of phosphates from renal tubules.
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Effects on GIT :
- PTH increases absorption of calcium from GIT
- This is due to formation of 1, 25 DHCC from Vitamin D by kidney.
- PTH increases the absorption of phosphate ion
- For absorption of calcium from GIT, Vitamin D is necessary. For activation of
Vitamin D, PTH is necessary.
Regulation of PTH Secretion :
A) Negative feed back
Chief cells produce PTH and there are 2 substances which exert a negative
feed back effect on the production of PTH.
1) Serum calcium level : Higher the serum calcium level, lower is the production of
PTH and viceversa. Chief cells have calcium receptor in their membrane.
2) Calcitriol : Vitamin D is converted into calcitriol by PTH. High calcitriol level
inhibits PTH production and viceversa.
B) Other Regulators :
Plasma phosphates and magnesium levels can also affect the PTH production.
VITAMIN D :
Vitamin D was discovered in 1910 by McCollum.
Source of Vitamin D :
1) From 7 dehydrocholesterol present naturally in the skin.
2) Food sources like fish liver oils, particularly fish liver oils of sea fishes, milk, egg
etc.
3) Medicinal Vitamin D
Vitamin D
- Vitamin D2 : From plant sterols
- Vitamin D3 : 7 Dehydrocholesterol, fish liver oils, milk,
egg etc.
Daily Requirements :
For grown up males : Who are exposed to sunshine, may require no dietary
supplement of Vitamin D.
Pregnant, lactating women, infants, persons confined within indoor, old persons may
require Vitamin D supplements.
Chapati flour contains much phytic acid and may hinder Vitamin D absorption.
Daily supplement of 400 IU (International unit) is recommended.
Multivitamins sold in India may contain 1000 IU causing dangers of
hypervitaminosis D Hypercalcemia.
Cholecalciferol is converted into 25, hydroxycholecalciferol in liver. This process is
limited and can be inhibited by 25 HCC itself by feedback mechanism.
This inhibition is essential for 2 reasons :
a) Regulation of the amount of active vitamin D.
b) Storage of Vitamin D for months together. This is because, if Vitamin D 3 is
converted into 25 hydroxycholecalciferol, it remains in the body only 2 to 5 days.
Whereas, Vitamin D3 can be stored in the liver for months together.
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opposite to that of parathyroid hormone system. There are two major differences
between the calcitonin and parathyroid feed back systems. First the calcitonin
mechanisms operates more rapidly, reaching peak activity in less than 1 hour, in
contrast to the 3 to 4 hours required for peak activity to be attained after the onset of
parathyroid secretion. The second difference is that the calcitonin mechanism acts
only weakly and only as a short term regulator to calcium ion concentration because it
is rapidly overridden by the much more powerful parathyroid control mechanism.
Also, the calcitonin receptors on the osteoclasts seem to down regulate within minutes
to hours in response to a calcitonin stimulus. Therefore, over a prolonged period of
time, it is almost entirely the parathyroid system that sets the long term level of
calcium ions in the ECF. When the thyroid gland is removed, and calcitonin is no
longer secreted, the long term blood calcium ion concentration is not measurably
altered, which again demonstrates the overriding effect of the parathyroid hormonal
system of control.
DISORDERS OF CALCIUM METABOLISM :
Hypoparathyroidism : Can occur due to accidental damage or removal of the
parathyroids during surgery of the thyroid or in cancer of larynx.
- Spontaneous hypoparathyroidism can occur which may be hereditary.
- DiGeorge syndrome (very rare) in some cases of hereditary hypoparathyrodisim,
more than 1 endocrine gland Eg. parathyroid, ovary, adrenal cortex and thymus
may be involved.
Pseudohypoparathyyroidism :
- PTH level is high but serum calcium level is low.
- There is some fault in the PTH receptors of the target cell Thus producing signs
and symptoms characteristic of hypoparathyroidism.
TETANY :
- The outstanding sign of calcium deficiency is tetany.
- When serum calcium level falls, the irritability of nerves and NMJ rises and the
muscle contracts when subjected to subthreshold stimulus.
- Basic feature of tetany is uncontrolled, painful, prolonged contraction (spasm) of
the voluntary muscles.
- When the ECF concentration of calcium ions falls below normal, the nervous
system becomes excitable because this causes increased neuronal membrane
permeability to Na++ ions, allowing easy initiation of action potential.
- If calcium concentration in plasma is about 50% below normal, peripheral nerve
fibres become so excitable that they begin to discharge spontaneously, initiating
trains of nerve impulses that pass to the peripheral skeletal muscles to elicit tetanic
muscle contraction.
- Tetany occurs in hand before it develops in other parts of the body. This is called
carpopedal spasm or Accouchers hand.
a) Accouchers Hand :
- There is muscular spasm leading to uncontrolled prolonged flexion of the
metacarpophalangeal joints while the fingers remain extended.
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HYPERCALCEMIA :
Causes for hypercalcemia :
1) Primary hyperparathyroidism
2) Hypervitaminosis D : excessive administration of vitamin D leads to
hypercalcemia and generalized metastatic calcification. The parathyroid
hormone like activity of vitamin D potentiates this action.
3) Vitamin D sensitive states : The hypercalcemia sometimes encountered in
sarcoidosis is probably due to increased sensitivity to Vitamin D.
4) Destructive bone lesions : Extensive destruction of the skeleton by osteolytic
metastases of carcinoma, multiple myeloma, or Hodgkins disease may lead to the
release of excessive amounts of calcium.
5) Miscellaneous causes :
a) Milk alkali syndrome : Where excess milk and antacids like NaHCO 3 are
given to treat peptic ulcers.
b) Excess thiazide therapy Like in cases of congestive cardiac failure, can
cause hypercalcemic state.
c) Prolonged immobilization
d) Hyperthyroidism
e) Congenital hypophosphatasia
Effects of Hypercalcemia :
1) Fatigue, lethargy and muscle asthenia
2) Anorexia, nausea and vomiting. Constipation is prominent, possibly due to the
muscular hypotonia.
3) Pruritus
4) Psychotic manifestations
5) Symptoms of progressive renal dysfunction starting with polyuria due to an
unresponsiveness of the distal and collecting tubules to antidiuretic hormone.
There is an accompanying thirst, which may also be due to the high plasma
calcium directly stimulating the hypothalamus. Ultimately leads to disturbances
in glomerular function Renal failure.
6) Metastatic calcification.
7) ECG changes : Shortened QT interval and depressed T waves.
8) Peptic ulceration : The excess plasma calcium releases gastrin.
9) Pancreatitis, both acute and chronic Common with primary
hyperparathyroidism. Etiology is unknown but suggested factors include stones
forming in the pancreatic ducts and ioinised calcium favouring the conversion of
trypsinogen to trypsin in the pancreatic ducts.
VITAMIN D DEFICIENCY :
Deficiency of vitamin D may result from :
i)
Reduced endogenous synthesis due to inadequate exposure to sunlight.
ii)
Dietary deficiency of Vitamin D
iii)
Malabsorption of lipids due to lack of bile salts such as biliary obstruction,
pancreatic insufficiency and malabsorption syndrome.
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iv)
Secondary
Primary ostoeporosis : Results primarily from osteopenia without an underlying
disease or medication.
Increased osteoclastic resorption and slow bone formation.
Idiopathic type :
- In young and juveniles
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- Less common
Involutional type :
- Postmenopausal women and elderly people
- More common
Risk Factors :
1. Sex : More frequent in females than in males.
2. Decreased physical activity: As in old age.
3. Deficiency of sex hormones :
Oestrogen deficiency (Postmenopausal osteoporosis) in women
Androgen deficiency in men
4. Combined deficiency of calcitonin and estrogen
5. Hyperparathyroidism
6. Vitamin D deficiency
Secondary Osteoporosis : Due to number of factors and conditions.
- Immobilization
- Chronic anemia
- Acromegaly
- Hepatic disease
- Hyperparathyroidism
- Starvation
- Medications like administration of anticonvulsant drugs, heparin (large
dose).
Diagnosis :
- Radiographic evidence becomes apparent only after more than 30% of
bone mass has been lost.
- Levels of serum calcium, inorganic phosphorous and alkaline phosphatase
are usually within normal limits.
HETEROTOPIC CALCIFICATION :
- Is defined as the deposition of calcium salts in tissue other than osteoid or
enamel.
- Detected by radiographs because of its radiopacity.
Heterotopic Calcification can be of 2 types :
- Dystrophic calcification
- Metastatic calcification
DYSTROPHIC CALCIFICATION :
It is the deposition of calcium salts in dead or degenerated tissues. Eg. areas
of tuberculous necrosis, blood vessels in arteriosclerosis, scars and areas of fatty
degeneration.
Pathogenesis :
This type of calcification is not dependent upon an increase in the amount of
circulating blood calcium, but appears to be related to a change in the local condition
of the tissues. A local alkalinity in comparison with adjacent undamaged tissues
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CONCLUSION :
Calcium ions play an important role in many physiological functions bone
rigidity, permeability, muscle contraction, blood clotting, and prevention of many
disorders. But excess of calcium is harmful to the body. Thus calcium balance in the
body should be maintained.
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