Download - CALCIUM METABOLISM
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Mineral Metabolism
Gandham. Rajeev
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• Minerals are essential for the normal growth & maintenance of the body
• Essential for calcification of bone, blood coagulation, neuromuscular
irritability, acid-base equilibrium, fluid balance & osmotic regulation
• If the daily requirement is more than 100 mg, they are called major
elements or macro minerals
• If the daily requirement is less than 100 mg, they are called as micro
minerals
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Classification of minerals according to their essentiality
Major elements Minor elements
Calcium Iron
Magnesium Iodine
Phosphorous Copper
Sodium Manganese
Potassium Zinc
Chloride Molybdenum
Sulfur Selenium
Fluoride
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Calcium metabolism
• Most abundant mineral in the human body
• Total Calcium in the human body is about 1 to 1.5 kg, 99% of which is
seen in bone together with phosphate
• Small amounts in soft tissue & 1% in extracellular fluid
• Dietary Sources of calcium:
• Milk is a good source for calcium
• Egg, fish, cheese, beans, lentils, nuts, cabbage and vegetables are
sources for calcium
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Daily requirement of calcium
• Adults = 500 mg/day
• Children’s = 1200 mg/day
• Pregnancy & lactation = 1500 mg/day
• After the age of 50, tendency for osteoporosis, prevented by increased
calcium (1500 mg/day) & vitamin D (20 μg/day)
• Body distribution of Calcium:
• About 99% of calcium is found in bones
• It exists as carbonate or phosphate of calcium
• About 0.5% in soft tissue and 0.1% in extracellular fluid
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• Calcium in plasma is of 3 types
• Ionized or free or unbound calcium:
• In blood, 50% of plasma calcium is free & is metabolically active
• It is required for the maintenance of nerve function, membrane
permeability, muscle contraction and hormone secretion
• Bound calcium: 40% of plasma calcium is bound to protein mostly albumin
• These two forms are diffusible from blood to tissues
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• Complexed calcium:
• 10% of plasma calcium is complexed with anions including bicarbonate,
phosphate, lactate & citrate
• All the three forms of calcium in plasma remain in equilibrium with each
other
• Normal Range:
• The normal level of plasma calcium is 9-11mg/dl
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Absorption
• Mechanism of absorption of calcium:
• Calcium is taken in the diet as calcium phosphate, carbonate & tartarate
• About 40% of dietary calcium is absorbed from the gut
• Absorption occurs form the first & second part of duodenum
• Absorbed against a concentration gradient & requires energy
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• Requires a carrier protein, helped by calcium-dependent ATPase
• 400 mg is excreted in stool & 100 mg is excreted through urine
• Two mechanisms for absorption of calcium:
• Simple diffusion
• An active transport - Process involving energy & Ca2+ pump
• Both processes require 1, 25 DHCC (Calcitriol) which regulates the synthesis
of Ca-binding proteins & transport
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Factors causing increased absorption
• Vitamin D:
• Calcitriol induces the synthesis of carrier protein (Calbindin) in the
intestinal epithelial cells & facilitates the absorption of calcium
• Parathyroid hormone:
• It increases calcium transport from the intestinal cells by enhancing
1α-hydroxylase activity
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• Acidity:
• Favors calcium absorption because the Ca-salts, particularly PO4 &
carbonates are quite soluble in acidic solutions
• In alkaline medium, the absorption of calcium is lowered due to the
formation of insoluble tricalcium PO4
• High protein diet:
• A high protein diet favors calcium absorption
• If the protein content is low, only 5% may be absorbed
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• Amino acids:
• Lysine & arginine increases calcium absorption
• Amino acids increase the solubility of Ca-salts & thus its absorption
• Sugars and organic acids:
• Organic acids produced by microbial fermentation of sugars in the gut,
increases the solubility of Ca-salts & increases their absorption
• Citric acid may also increase the absorption of calcium
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Factors causing decreased absorption
• Phytic acid: Cereals contain phytic acid (Inositol hexaphosphate) forms
insoluble Ca-salts & decreases the absorption
• Oxalates: Present in some leafy vegetables, causes formation of insoluble
calcium oxalates
• Fibres: Excess of fibres in the diet interferes with the absorption
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• Malabsorption syndromes:
• Causing formation of insoluble calcium salt of fatty acid
• Glucocorticoids:
• Diminishes intestinal transport of calcium
• Phosphate:
• High phosphate content will cause precipitation as calcium phosphate
• Magnesium: High content of Mg decreases the absorption
• Ca: P Ratio: 2:1
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Biochemical functions
• Development of bones and teeth:
• Bone is regarded as a mineralized connective tissue
• Bones also act as reservoir for calcium
• The bulk quantity of calcium is used for bone and teeth formation
• Osteoblasts induce bone deposition and osteoclasts produce
demineralization
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• Muscles:
• Calcium mediates excitation & contraction of muscles
• C2+ interacts with troponin C to trigger muscle contraction
• Calcium activates ATPase, increases action of actin and myosin and
facilitates excitation-contraction coupling.
• Calcium decreases neuromuscular irritability.
• Calcium deficiency causes tetany
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• Nerve conduction:
• It is necessary for transmission of nerve impulses
• Blood coagulation:
• Calcium is known as factor IV in blood coagulation process
• Prothrombin contains γ-carboxyglutamate residues which are chelated by
Ca2+ during the thrombin formation
• Calcium is required for release of certain hormones from cells include
insulin, parathyroid hormone, calcitonin, vasopressin
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• Activation of enzymes:
• Calmodulin is a calcium binding regulatory protein, with a molecular
weight of 17,000 Daltons
• Calmodulin can bind with 4 calcium ions
• Calcium binding leads to activation of enzymes
• Calmodulin is part of various regulatory kinases
• Enzymes activated by Ca2+ include pancreatic lipase, enzymes of
coagulation pathway, and rennin
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• Second messenger:
• Calcium and cAMP are second messengers for hormones e.g.
epinephrine in liver glycogenolysis
• Calcium serves as a third messenger for some hormones e.g, ADH
acts through cAMP and then Ca2+
• Myocardium:
• Ca2+ prolongs systole
• In hypercalcemia, cardiac arrest is seen in systole
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Regulation of plasma calcium level
• Dependent on the function of 3 main organs
• Bone
• Kidney
• Intestine
• 3 main hormones
• Calcitriol
• Parathyroid hormone
• Calcitonin
• Also by GH, glucocorticoids, estrogens, testosterone & thyroid
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Regulation of plasma calcium level by Calcitriol
• Role of calcitriol on bone:
• In osteoblasts of bone, calcitriol stimulates calcium uptake for
deposition as calcium phosphate
• Calcitriol is essential for bone formation
• Calcitriol along with parathyroid hormone increases the mobilization
of calcium and phosphate from the bone
• Causes elevation in the plasma calcium and phosphate
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Role of calcitriol on kidneys
• Calcitriol minimizing the excretion of Ca2+ & phosphate by decreasing their
excretion & enhancing reabsorption
• Role of calcitriol on intestine:
• Calcitriol increases the intestinal absorption of Ca2+ & phosphate
• Calcitriol binds with a cytosolic receptor to form a calcitriol-receptor complex
• Complex interacts with DNA leading to the synthesis of a specific calcium
binding protein
• This protein increases calcium uptake by intestine
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Regulation by parathyroid hormone (PTH)
• Parathyroid hormone (PTH) is secreted by two pairs of parathyroid glands
• Parathyroid hormone (mol. wt. 95,000) is a single chain polypeptide,
containing 84 amino acids
• It is originally synthesized as prepro PTH, whch is degraded to proPTH and,
finally, to active PTH
• The rate of formation & secretion of PTH are promoted by low Ca2+
concentration
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Mechanism of action of PTH
• Action on the bone:
• PTH causes decalcification or demineralization of bone, a process carried
out by osteoclasts.
• This is brought out by pyrophosphatase & collagenase
• These enzymes result in bone resorption
• Demineralization ultimately leads to an increase in the blood Ca2+ level
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Action on the kidney
• PTH increases the Ca2+ reabsorption by kidney tubules
• It most rapid action of PTH to elevate blood Ca2+ levels
• PTH promotes the production of calcitriol (1,25 DHCC) in the kidney by
stimulating 1- hydroxyaltion of 25-hydroxycholecalciferol
• Action on the intestine:
• It increases the intestinal absorption of Ca2+ by promoting the synthesis
of calcitriol
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Calcitonin
• Calcitonin is a peptide containing 32 amino acids
• lt is secreted by parafollicular cells of thyroid gland
• The action of CT on calcium is antagonistic to that of PTH
• Calcitonin promotes calcification by increasing the activity of osteoblasts
• Calcitonin decreases bone resorption & increases the excretion of Ca2+
into urine
• Calcitonin has a decreasing influence on blood calcium
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Calcitonin, calcitriol & PTH act together
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• Serum Proteins:
• In hypoalbuminemia, total calcium is decreased
• In such cases, the metabolically active ionized Ca2+ is normal & so there will
be no deficiency manifestations
• Alkalosis and Acidosis: Alkalosis favors binding of Ca2+ with proteins, with
consequent lowering of ionized Ca2+
• Total calcium is normal, but Ca2+ deficiency may be manifested
• Acidosis favors ionization of Ca2+
• The renal threshold for calcium in blood is 10 mg/dl
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Hypercalcemia
• The serum Ca2+ level >11 mg/dl is called as Hypercalcemia
• Causes:
• Hyperparathyroidism:
• Decrease in serum phosphate (due to increased renal losses) and increase
in ALP activity are found in hyperparathyroidism
• Urinary excretion of Ca2+ & P resulting in formation of urinary calculi
• The determination of ionized Ca2+ (elevated to 6-9mg/dl) is useful for the
diagnosis of hyperparathyroidism
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Clinical features of hypercalcemia
• Neurological symptoms such as depression, confusion, inability to
concentrate
• Generalized muscle weakness
• Gastrointestinal problems such as anorexia, abdominal pain, nausea,
vomiting & constipation
• Renal feature such as polyuria & polydipsia
• Cardiac arrhythemias
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Hypocalcemia
• Decreased serum Ca2+ < 8.8 mg/dl is called as hypocalcemia
• Causes:
• Hypoproteinaemia:
• If albumin concentration in serum falls, total calcium is low because the
bound fraction is decreased
• Hypoparathyroidism:
• The commonest cause is neck surgery, idiopathic or due to magnesium
deficiency
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• Vitamin D deficiency:
• May be due to malabsorption or an inadequate diet with little exposure
to sunlight
• Leads to bone disorders, osteomalacia & rickets
• Renal disease:
• In kidney diseases, the 1, 25 DHCC (calcitriol) is not synthesized due to
impaired hydroxylation
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• Pseudohypoparathyroidism:
• PTH is secreted but there is failure of target tissue receptors to respond to
the hormone
• Clinical features of hypocalcemia:
• Enhanced neuromuscular irritability
• Neurologic features such as tingling, tetany, numbness (fingers and toes),
muscle cramps
• Cardiovascular signs such as an abnormal ECG
• Cataracts
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Rickets
• Rickets is a disorder of defective calcification of bones
• This may be due to a low levels of vitamin D in the body or due to a
dietary deficiency of Ca2+ & P or both
• The concentration of serum Ca2+ & P may be low or normal
• An increase in the activity of alkaline phosphatase is a characteristic
feature of rickets
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Osteoporosis
• Osteoporosis is characterized by demineraIization of bone resulting in the progressive
loss of bone mass
• After the age of 40-45, Ca2+ absorption is reduced & Ca2+ excretion is increased; there
is a net negative balance for Ca2+
• This is reflected in demineralization
• After the age of 60, osteoporosis is seen
• There is reduced bone strength and an increased risk of fractures
• Decreased absorption of vitamin D and reduced levels of androgens/estrogens in old
age are the causative factors
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