calcium metabolism

Mineral Metabolism

Gandham. Rajeev

• 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

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

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

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

• 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

• 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

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

• 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

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

• 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

• 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

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

• 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

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

• 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

• 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

• 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

• 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

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

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

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

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

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

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

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

Calcitonin, calcitriol & PTH act together

• 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

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

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

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

• 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

• 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

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

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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