Calcium Metabolism

Gandham. Rajeev

• Calcium metabolism • Sources & RDA• Factors affecting calcium absorption• Biochemical functions• Regulation of plasma calcium• Disease states• Case report

• Metabolism of phosphorous• Sources & RDA• Biochemical functions• Disease states• RGUHS questions

• Essential for • Normal growth & maintenance of the body• Calcification of bone• Blood coagulation• Neuromuscular irritability• Acid-base equilibrium• Fluid balance & osmotic regulation

• Daily requirement is >100 mg/day - macro minerals/macro elements• Daily requirement is <100 mg/day - micro minerals/micro elements

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.• Total body calcium is about 1 to 1.5 kg.• 99% is seen in bone together with phosphate & 1% in ECF• Dietary Sources of calcium:• Milk is a good source for calcium • Egg, fish, cheese, beans, nuts, cabbage and vegetables are

good sources for calcium

Daily requirement of calcium

• Adult men & women = 500 mg/day• Children’s = 1200 mg/day• Pregnancy & lactation = 1500 mg/day• Calcium in plasma is of 3 types • Ionized or free or unbound calcium• Bound calcium• Complexed calcium

• Ionized or free or unbound calcium or diffusible: 5.5 mg/dl • In blood, 50% of plasma calcium is free & is metabolically active• It is required for

• Maintenance of nerve function• Membrane permeability• Muscle contraction• Hormone secretion

• Bound calcium or non diffusible: 4.5 mg/dl• 40% of plasma calcium is bound to proteins – albumin

• Complexed calcium: 1 mg/dl• 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 9-11 mg/dl• Urine calcium:100-250 mg/day

Absorption

• From upper small intestine - first & second part of duodenum.• About 40% of dietary calcium is absorbed.• Absorbed against a concentration gradient & requires

energy.• Requires a carrier protein, helped by calcium-dependent

ATPase.

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 absorption through increased

synthesis of calcitriol

• Acidity favors calcium absorption (enhance solubility of calcium)• Amino acids: • Lysine & arginine increases calcium absorption • Amino acids increase the solubility of Ca-salts & thus its

absorption

Factors causing decreased absorption

• Phytates oxalates: • Phytates & oxalates form insoluble Ca-salts & decreases

the absorption.• High phosphate content will cause precipitation as

calcium phosphate.• Alkaline condition is unfavorable for absorption.• Calcium forms insoluble soaps with fatty acids• Vitamin D deficiency states.

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 & teeth

formation • Osteoblasts induce bone deposition & osteoclasts produce

demineralization.

• Muscles: • Calcium mediates excitation & contraction of muscles • Ca2+ interacts with troponin C to trigger muscle contraction• Calcium activates ATPase, increases action of actin &

myosin and facilitates excitation-contraction coupling. • Calcium decreases neuromuscular irritability.

• 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 -

insulin, parathyroid hormone, calcitonin & vasopressin

• Activation of enzymes:• Calmodulin is a calcium binding regulatory protein.• Calmodulin can bind with 4 calcium ions & molecular weight of 17,000 • Calcium binding leads to activation of enzymes • Enzymes activated by Calcium

• Glycogen synthase • Pancreatic lipase• Adenylate cyclase• Glycerol 3-P-DH• Pyruvate carboxylase• PDH & Pyruvate kinase

• Second messenger: • Calcium & 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 & 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

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• At low calcium levels, calcitriol along with parathyroid

hormone increases the mobilization of calcium & 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: • It increases intestinal absorption of Ca2+ & phosphate.• It binds with cytosolic receptor to form 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)

• PTH is secreted by two pairs of parathyroid glands. • PTH (mol. wt. 95,000) is a single chain polypeptide,

containing 84 amino acids.• It is synthesized as prepro PTH, whch is degraded to proPTH

& 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 is 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. • 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 Ca2+ into urine• Calcitonin has a decreasing influence on blood calcium

Calcitonin, calcitriol & PTH act together

Hypercalcemia• The serum Ca2+ level >11 mg/dl is called as Hypercalcemia.• Causes: • Hyperparathyroidism: • Due to increased activity of parathyroid gland or PTH

secreting tumor• Increase in calcium & ALP & decrease in phosphate levels.• Excretion of calcium & phosphorous in urine.• Determination of ionized Ca2+ (elevated to 6-9 mg/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: calcification of renal tissue • Increased myocardial contractility & susceptibility to factures.

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.

• Vitamin D deficiency:• May be due to malabsorption or 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

• Clinical features of hypocalcemia:• Enhanced neuromuscular irritability• Neurologic features • Tingling, tetany, numbness (fingers & toes), muscle cramps

• Cardiovascular signs - 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

• 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+ • After the age of 60, osteoporosis is seen• There is reduced bone strength & an increased risk of

fractures.• Decreased absorption of vitamin D & reduced levels of

androgens/estrogens in old age are the causative factors.

Case report• A 5 year old girl had bone deformities such as bow legs and

pigeon chest. She had delayed eruption of teeth. The girl was from a strict vegetarian family and she used to take very low amount of milk. Interpret the following laboratory findings.

Investigations Report Serum calcium 8.5 mg/dlSerum inorganic phosphate 2.2 mg/dlSerum alkaline phosphatase 175 IU/L

Serum calcitriol 12 pg/ml (Reference Range: 15 – 60 pg/ml)

Phosphorous Metabolism

Gandham. Rajeev

• Human body contains - 1 kg of phosphorous• Body distribution:• 80% of phosphorous is found in bones & teeth in

combination with calcium. • 15% of phosphorous is present in soft tissues, as a

component of phospholipids, phosphoproteins, nucleic acids & nucleoproteins.• 1% is found in ECF, as inorganic form

Dietary sources and RDA

• The food rich in calcium is also rich in phosphorous• i.e. milk, cheese, beans, eggs, cereals, fish & meat• Milk is good source of phosphorous

• RDA:• Adults: 800 mg/day • During pregnancy and lactation: 1,200 mg/day• Ca : P of 1:1 is recommended

Biochemical functions

• Phosphorous is essential for formation of bones & teeth • It is a constituent of hydroxyapatite in bone & provides

structural support.• Formation & utilization of high energy phosphate compounds

like• ATP, ADP, GTP, Creatine phosphate, etc. contains

phosphorous.• Essential for the formation of • Phospholipids, phosphoproteins, nucleic acids, nucleotides

• Component of nucleotide coenzymes – NAD+, NADP, ATP, ADP • Several enzymes & proteins are activated by

phosphorylation & dephosphorylation.• Phosphate buffer system is important for maintenance of

blood pH• Formation of phosphate esters - glucose-6-p.

Absorption

• 90% of dietary phosphorous is absorbed from small intestine. • Absorption is stimulated by both PTH & calcitriol.• Excretion: • 500 mg of phosphate is excreted through urine per day• Renal threshold for phosphorous is 2 mg/dl. • Normal range: • Plasma phosphorous: 2.5 to 4.5 mg/dl in adults• In children’s: 5.0 to 6.0 mg/dl

• Calcium & phosphorous have reciprocal relationship.• In particular, if phosphate rises, calcium falls. • Fasting phosphate levels are higher• Postprandial decrease of phosphorous is due to the

utilization of phosphorous for metabolism.

Hypophosphataemia

• Serum inorganic phosphate concentration <2.5 mg/dl is called as Hypophosphataemia • Causes:• Decreases intake, Decreased absorption, Increased loss:• In the treatment of Diabetes the effect of insulin in causing the shift of

glucose into cells also enhances the transport of phosphate into cells, which may result into hypophosphataemia

• Renal rickets is associates with low phosphate & increased ALP concentration.• Congenital defect of tubular phosphate reabsorption, e.g.

Fanconi’s syndrome, in which phosphate is lost. • Symptoms: • Symptoms:• Hemolytic anemia, weakness, bone fractures, Muscle pain.• Rickets in children’s & osteoporosis in adults may develop.

Hyperphosphataemia

• Increase in serum inorganic phosphate levels than the normal levels is called as hyerphosphataemia• Causes:• Increased intestinal absorption, decreased renal excretion, cellular release of phosphorous.• Symptoms:• Chronic renal failure, soft tissue calcification.

RGUHS Questions

1. Explain the sources, daily requirement, absorption,

biochemical functions & disorders of calcium metabolism.

2. Blood calcium homeostasis.

3. Rickets & osteoporesis.

4. Metabolism of phosphorous.