Minerals, Calcium, and Magnesium Metabolism

Minerals

• Minerals are essential for normal growth and maintenance of the body.
• They are essential for:
  • Calcification of bone
  • Blood coagulation
  • Neuromuscular irritability
  • Acid-base equilibrium
  • Fluid balance
  • Osmotic regulation
• Major elements (macro minerals): Daily requirement > 100 mg.
• Micro minerals: Daily requirement < 100 mg.

Classification of Minerals

• Major Elements:
  • Calcium
  • Magnesium
  • Phosphorous
  • Sodium
  • Potassium
  • Chloride
  • Sulfur
• Minor Elements:
  • Iron
  • Iodine
  • Copper
  • Manganese
  • Zinc
  • Molybdenum
  • Selenium
  • Fluoride

Calcium Metabolism

• Most abundant mineral in the human body.
• Total calcium: 1 to 1.5 kg.
  • 99% in bone (with phosphate).
  • Small amounts in soft tissue.
  • 1% in extracellular fluid.
• Dietary Sources:
  • Milk (good source)
  • Egg, fish, cheese, beans, lentils, nuts, cabbage, and vegetables.

Daily Calcium Requirements

• Adults: 500 mg/day
• Children: 1200 mg/day
• Pregnancy & Lactation: 1500 mg/day
• After 50: 1500 mg/day (to prevent osteoporosis) with Vitamin D (20 µg/day).

Body Distribution of Calcium

• 99% in bones (as carbonate or phosphate of calcium).
• 0. 5% in soft tissue.
• 0. 1% in extracellular fluid.

Calcium in Plasma

• Three types:
  • Ionized (free or unbound):
    • 50% of plasma calcium.
    • Metabolically active.
    • Required for nerve function, membrane permeability, muscle contraction, and hormone secretion.
  • Bound calcium:
    • 40% of plasma calcium.
    • Bound to protein, mostly albumin.
    • Diffusible from blood to tissues.
  • Complexed calcium:
    • 10% of plasma calcium.
    • Complexed with anions (bicarbonate, phosphate, lactate, citrate).
• Equilibrium: All three forms remain in equilibrium.
• Normal Range: 9-11 mg/dl.

Absorption of Calcium

• Calcium is ingested as calcium phosphate, carbonate & tartarate.
• About 40% of dietary calcium is absorbed from the gut.
• Absorption occurs from the first & second part of the duodenum.
• Absorbed against a concentration gradient & requires energy.
• Requires a carrier protein, helped by calcium-dependent ATPase.
• 400 mg excreted in stool & 100 mg excreted through urine
• Two mechanisms:
  • Simple diffusion.
  • Active transport: Process involving energy & Ca^{2+} pump.
• Both processes require 1, 25 DHCC (Calcitriol), which regulates the synthesis of Ca-binding proteins & transport.
• Vitamin D is needed for absorption of Calcium.

Factors Increasing Calcium 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 PO_4 & carbonates are quite soluble in acidic solutions.
  • In alkaline medium, the absorption of calcium is lowered due to the formation of insoluble tricalcium PO_4.
• 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 Decreasing Calcium Absorption

• Phytic Acid:
  • Cereals contain phytic acid (Inositol hexaphosphate) which forms insoluble Ca-salts & decreases the absorption.
• Oxalates:
  • Present in some leafy vegetables, causes formation of insoluble calcium oxalates.
• Fibers:
  • 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 of Calcium

• 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.
  • C^{2+} 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 Ca^{2+} during the thrombin formation.
• Hormone Release:
  • 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 Ca^{2+} 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 Ca^{2+}.
• Myocardium:
  • Ca^{2+} 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 (active form of Vitamin D)
  • Parathyroid hormone
  • Calcitonin (thyroid hormone)
• Also by GH, glucocorticoids, estrogens, testosterone & thyroid.

Regulation by Calcitriol

• Role 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 on Kidneys:
  • Calcitriol minimizing the excretion of Ca^{2+} & phosphate by decreasing their excretion & enhancing reabsorption.
• Role on Intestine:
  • Calcitriol increases the intestinal absorption of Ca^{2+} & 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)

• 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, which is degraded to proPTH and, finally, to active PTH.
• The rate of formation & secretion of PTH are promoted by low Ca^{2+} concentration
• PTH increases Ca^{2+} release from bones, uptake in intestines, and reabsorption from urine

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 Ca^{2+} level.
• Action on the Kidney:
  • PTH increases the Ca^{2+} reabsorption by kidney tubules.
  • It most rapid action of PTH to elevate blood Ca^{2+} 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 Ca^{2+} by promoting the synthesis of calcitriol.

Calcitonin

• Calcitonin is a peptide containing 32 amino acids.
• It 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 Ca into urine.
• Calcitonin has a decreasing influence on blood calcium.

Calcitonin, Calcitriol & PTH Interaction

• Calcitonin decreases blood calcium levels by:
  • Increasing Ca^{2+} deposition in bones
  • Decreasing Ca^{2+} uptake in intestines
  • Decreasing Ca^{2+} reabsorption from urine
• PTH increases blood calcium levels by:
  • Increasing Ca^{2+} uptake in intestines
  • Increasing Ca^{2+} reabsorption from urine
  • Increasing Ca^{2+} release from bones

Serum Proteins, Alkalosis and Acidosis Effect on Calcium

• Serum Proteins:
  • In hypoalbuminemia, total calcium is decreased.
  • The metabolically active ionized Ca^{2+} is normal & so there will be no deficiency manifestations.
• Alkalosis and Acidosis:
  • Alkalosis favors binding of Ca^{2+} with proteins, with consequent lowering of ionized Ca^{2+}.
  • Total calcium is normal, but Ca^{2+} deficiency may be manifested.
  • Acidosis favors ionization of Ca^{2+}.
• The renal threshold for calcium in blood is 10 mg/dl.

Hypercalcemia

• The serum Ca^{2+} level >11 mg/dl.
• Causes:
  • Hyperparathyroidism:
    • Decrease in serum phosphate (due to increased renal losses) and increase in ALP activity.
    • Urinary excretion of Ca^{2+} & P resulting in formation of urinary calculi.
    • Ionized Ca^{2+} (elevated to 6-9mg/dl) is useful for diagnosis of hyperparathyroidism.

Clinical Features of Hypercalcemia

• Neurological symptoms: depression, confusion, inability to concentrate.
• Generalized muscle weakness.
• Gastrointestinal problems: anorexia, abdominal pain, nausea, vomiting & constipation.
• Renal feature: polyuria & polydipsia.
• Cardiac arrhythmias.

Hypocalcemia

• Decreased serum Ca^{2+} < 8.8 mg/dl.
• Causes:
  • Hypoproteinaemia:
    • Low albumin concentration in serum falls causes low total calcium because the bound fraction is decreased.
  • Hypoparathyroidism:
    • Commonest cause is neck surgery, idiopathic or due to magnesium deficiency.
  • Vitamin D Deficiency:
    • 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:
  • 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.
• May be due to low levels of vitamin D or a dietary deficiency of Ca^{2+} & P or both.
• The concentration of serum Ca^{2+} & P may be low or normal.
• An increase in the activity of alkaline phosphatase is a characteristic feature.

Osteoporosis

• Osteoporosis is characterized by demineralization of bone resulting in the progressive loss of bone mass.
• After the age of 40-45, Ca^{2+} absorption is reduced & Ca^{2+} excretion is increased; there a net negative balance for Ca^{2+}.
• This is reflected in demineralization.
• After the age of 60, osteoporosis is seen:
  • 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.

Magnesium

• Fourth most abundant cation in the body.
• Mainly seen in Intracellular fluid.
• Second most prevalent intracellular cation.

Body Distribution of Magnesium

• Human body contains 25g of magnesium.
• About 60% of which is complexed with calcium & phosphorous in bones
• 30% in soft tissues & 1% is in ECF

Sources of Magnesium

• Cereals, beans, vegetables, potatoes, meat, milk, fruits & fish

Recommended Daily Allowance (RDA) of Magnesium

• Adult man: 400 mg/day
• Women: 300 mg/day
• During pregnancy & lactation: 450 mg/day

Absorption of Magnesium

• Small intestine & excreted in feces.
• Calcium, phosphate & alcohol decreases & PTH increases magnesium absorption.

Biochemical Functions of Magnesium

• Magnesium is required for:
  • Formation of bones & teeth
  • To maintain neuromuscular irritability
• Co-factor:
  • More than 300 enzymes requires magnesium as a cofactor
    • Hexokinase
    • Glucokinase
    • Phospho fructokinase
    • Pyruvate carboxylase
    • Peptidases
    • Ribonucleases
    • Adenylate cyclase

Normal Plasma Levels of Magnesium

• Serum magnesium: 1.7 - 3 mg/dl
• 70% of magnesium exists in free state & 30% is protein bound (albumin)
• Small amount is complexed with anions like phosphate & citrate.

Disorders of Magnesium Metabolism

• Hypomagnesaemia:
  • Decrease in serum magnesium levels <1.7 mg/dl.
  • Causes:
    • Decreased intake – due to malnutrition
    • Decreased absorption – due to malabsorption
    • Increased renal loss - due to renal tubular acidosis
  • Symptoms:
    • Impaired neuromuscular function
    • Hypocalcemia - due to decreased PTH secretion
    • Tetany, Convulsions & Muscle weakness
• Hypermagnesaemia:
  • Increase in serum magnesium > 3.5 mg/dl
  • Causes:
    • Uncommon but is occasionally seen in renal failure decreased excretion
    • Excess intake orally or parenterally
    • Hyperparathyroidism
  • Symptoms:
    • Depression of the neuromuscular system, lethargy
    • Hypotension, bradycardia