Calcium and phosphate
Important minerals
Major Trace elements
elements(>100mg/day) • Iron
• Calcium • Iodine
• Magnesium • Copper
• Phosphorus • Manganese
• Sodium • Zinc
• Potassium • Molybdenum
• Chloride • Selenium
• Sulphur. • Fluoride.
Calcium
• Total calcium in the human body is about 1 to 1.5 kg.
• 99% of which is seen in bone and 1% in extracellular
fluid.
Sources of Calcium
• Milk is a good source for calcium. Calcium content of
cow’s milk is about 100 mg/100 mL. Egg, fish and
vegetables are medium sources for calcium. Cereals
(wheat, rice) contain only small amount of calcium. But
cereals are the staple diet in India. Therefore, cereals
form the major source of calcium in Indian diet.
• An adult needs 500 mg per day and a child
about 1200 mg/day. Requirement may be
increased to 1500 mg/day during pregnancy
and lactation.
• After the age of 50, there is a general
tendency for osteoporosis, which may be
prevented by increased calcium (1500
mg/day) plus vitamin D (20 μg/day).
Calcium balance
Absorption
• Calcium is taken in the diet as calcium
carbonate, phosphate and tartarate.
• About 40% of calcium is absorbed from diet.
• Absorption occurs mostly in first and second
part of duodenum.
• Two mechanisms for absorption
• passive diffusion and active transport.
• Active transport requires energy and calcium
pump. It requires a carrier protein helped by
calcium dependent ATPase.
• Both processes requires calcitriol which
regulates synthesis of calcium binding protein
calbindin.
• Factors Causing Increased Absorption
• Vitamin D: Calcitriol induces the synthesis of the carrier protein (Calbindin)
in the intestinal epithelial cells, and so facilitates the
absorption of calcium.
• Parathyroid hormone increases calcitriol production by enhancing 1 α
hydroxylase activity.
• Acidity favors the calcium absorption.
• Amino acids: Lysine and arginine increase the calcium absorption.
• Factors Causing Decreased Absorption
• Phytic acid: Hexaphosphate of inositol is present in cereals.
• Oxalates: present in leafy vegetables, which cause formation of insoluble
calcium oxalates.
• Malabsorption syndromes: Here fatty acid is not absorbed, causing
formation of insoluble calcium salt of fatty acid.
• Phosphate: High phosphate content will cause precipitation as calcium
phosphate. The optimum ratio of calcium to phosphorus which allows
maximum absorption is 1:2–2:1. Milk contains this optimum ratio.
• Calcium is mainly extracellular. The cell membrane is generally
impermeable to calcium ions.
• Calcium influx into the cell is by Na+/Ca++ exchange mechanism.
• Other calcium channels are voltage operated channels and second
messenger operated channels.
Calcium in bone
• Calcium phosphate is deposited as hydroxyapatite crystals over
the matrix of triple stranded quarter staggered collagen molecules.
Calcium in the bone is in dynamic equilibrium with serum calcium;
hydroxyl apatite intrabecular bone acts as a reservoir.
• Compact bone ← Trabecular bone ←→ Serum calcium
• Ca3(PO4)2 Ca10(PO4)6(OH)2 Ca++
• (Total 1 kg) (Total about 5 g) (Total 500 mg)
Functions of calcium
• Bone and Teeth
• The bulk quantity of calcium is used for bone and teeth formation.
• Second messenger and Activation of Enzymes
• Calmodulin can bind with 4 calcium ions. Calcium binding leads
to activation of enzymes. Calmodulin is part of various regulatory
kinases.
• Some other enzymes are activated directly by Ca++ without the
intervention of calmodulin.
• Muscles
• Calcium mediates excitation and contraction of muscle fibers.
Nerve Conduction
• Calcium is necessary for transmission of nerve impulses from
presynaptic to postsynaptic region.
• Secretion of Hormones
• Calcium mediates secretion of insulin, parathyroid hormone,
calcitonin, vasopressin, etc. from the cells.
• Vascular Permeability
• Calcium decreases the passage of serum through capillaries.
Thus, calcium is clinically used to reduce allergic exudates.
• Coagulation
• Calcium is known as factor IV in blood coagulation cascade.
• Myocardium
• Ca++ prolongs systole. In hypercalcemia, cardiac arrest is
seen in systole. In hypoglyemia iv calcium must be given
very slowly.
Calcium as second messenger
Serum calcium level
• Normal blood calcium level is 9–11 mg/dL . About 5
mg/dL of calcium is in ionized form and is
metabolically active. Another 1 mg/ dL is complexed
with phosphate, bicarbonate and citrate. These two
forms are diffusible from blood to tissues.
• About 4 mg/dL of calcium is bound to proteins in
blood and is nondiffusible.
• Homeostasis of Blood Calcium Level
• There are effective controls to maintain this narrow
range of blood calcium (9–11 mg/dL).
• Effect of Phosphorus on calcium
• There is a reciprocal relationship of calcium with phosphorus. The
ionic product of calcium and phosphorus in serum is kept as a constant.
(In normal adults, calcium = 10 mg/dL × phosphorus 4 mg/dL; so ionic
product is 40). This is important for bone mineralisation.
• Serum Proteins
• In hypoalbuminemia (e.g. nephrosis, malnutrition), the total calcium is
decreased. In such cases, the metabolically active ionized form is
normal, and so there will be no deficiency manifestations.
• Alkalosis and Acidosis
• Alkalosis favors binding of more calcium with proteins, with consequent
lowering of ionized calcium. Here total calcium level is normal, but
calcium deficiency may be manifested. Acidosis favors ionization of
calcium. HENCE
• Renal Threshold
• The renal threshold for calcium in blood is 10 mg/dL.
Regulation of blood calcium level
Blood calcium level is maintained in the
narrow range 9-11 mg/dl.
3 hormones:
Calcitriol, parathormone and calcitonin
3 organs:
Intestine, bone and kodney.
Vitamin D
• Cholecalciferol is synthesized from 7-dehydro-cholesterol in
skin under the influence of sunlight. It is then hydroxylated at
25th position in liver and further hydroxylated at the 1st
position in kidney. The active derivative is called
dihydroxycholecalciferol or calcitriol.
• Vitamin D and Absorption of Calcium
• Calcitriol promotes the absorption of calcium and phosphorus
from the intestine. Calcitriol enters the intestinal cell and
binds to a cytoplasmic receptor. The hormone-receptor
complex interacts with DNA and causes consequent
transcription of specific genes that code for calbindin. Due to
the increased availability of calcium binding protein, the
absorption of calcium is increased.
Vitamin D and Bone
• Vitamin D increases the number and activity of
osteoblasts, the bone forming cells. Vitamin D
causes mineralization of bone.
• Vitamin deficiency causes rickets in children
and osteomalacia in adults.
• Vitamin D and Renal Tubules
• Calcitriol increases the reabsorption of calcium
and phosphorus by renal tubules, therefore, both
minerals are conserved (PTH conserves only
calcium).
Parathyroid Hormone
• PTH and bones
• In the bone, PTH causes demineralization. The
numbers of osteoclasts are also increased. Osteoclasts
release lactate which solubilizes calcium.
• PTH and kidney
• In kidney, PTH causes decreased renal excretion of
calcium and increased excretion of phosphates.
• PTH and intestines: PTH stimulates 1-hydroxylation
of 25-hydroxycalciferol in kidney to produce calcitriol.
This indirectly increases calcium absorption.
Calcitonin
• Calcitonin
• It is secreted by the thyroid parafollicular cells.
Calcitonin decreases serum calcium level. It inhibits
resorption of bone. It decreases the activity of osteoclasts
and increases that of osteoblasts.
• Calcitonin and PTH are directly antagonistic. The PTH
and alcitonin together promote the bone growth and
remodeling.
• Calcitonin is a minor regulator of serum calcium.
• Calcitonin level is increased in medullary carcinoma of
thyroid and therefore, is a tumor marker.
• Calcium homeostasis.
When serum calcium is
low, PTH is stimulated,
resulting in increased
calcium release from bone
and decreased renal
calcium excretion. PTH
also stimulates increased
production of calcitriol,
which acts to increase
absorption of calcium from
intestine.
When to check serum calcium level
1.Neurological symptoms, irritability, seizures
2.Renal calculi
3.Ectopic calcification
4.Suspected malignancies
5.Polyuria and poldipsia
6.Chronic renal failure
7.Prolonged drug treatment
Causes of hypercalcemia
1. Hyperparathyroidism
2. Multiple myeloma
3. Paget’s disease
4. Metastatic carcinoma of bone
5. Prolonged immobilization
6. Tuberculosis, leprosy, sarcoidosis
7. Milk-alkali syndrome
8. Drugs
• Thiazide diuretics
• Excess vitamin D or vitamin A
• Excess calcium given IV
• Lithium, Theophylline
Symptoms of hypercalcemia
1. CNS: Lethargy, decreased alertness, confusion,
depression.
2. GI: anorexia, constipation, nausea, vomiting.
3. Skeletal: most cases of hypercalcemia due to bone
resorption thus increased bone demineralization causing
pathological fracture
4. Renal: calcium acts as diuretic causing polyuria. Also it
causes kidney stones.
5. Cardiovascular: calcium cause prolong systole, it can
cause cardiac arrest.
6. Ectopic calcification and pancreatitis
Management of hypercalcemia
• Adequate hydration, IV normal saline
• Furosemide IV to promote calcium excretion
• Steroids, if there is calcitriol excess
• Definitive treatment for the underlying
disorder
Causes of hypocalcemia
• 1. Deficiency of vitamin D
• Decreased exposure to sunlight
• Malabsorption, dietary deficiency
• Hepatic diseases
• Renal diseases causing decreased synthesis of calcitriol.
• 2. Deficiency of parathyroid
• Hypoparathyroidism
• 3. Increased calcitonin
• Medullary carcinoma of thyroid
• 4. Deficiency of calcium
• Intestinal malabsorption
• Acute pancreatitis
• Alkalosis decreasing ionized calcium
• 5. Increase in phosphorus level
• Renal failure
• Phosphate infusion
• Renal tubular acidos
Symptoms of hypocalcemia
1. Neuromuscular irritability : tetany
(Chvostek’s sign, Trousseau’s sign), Muscle
cramps, muscle twitchings
2. Paresthesia, especially in fingers
3. CNS: Irritability, seizures
4. Cardiovascular: ECG changes(prolonged QT
interval), arrythmia.
Treatment of hypocalcemia
1. Oral calcium, with vitamin D supplementation
2. Underlying cause should be treated
3. Tetany needs IV calcium (usually 10 mL 10%
calcium gluconate over 10 minutes, followed
by slow IV infusion). IV calcium should be
given only very slowly
Rickets and osteomalacia
• Deficiency of vitamin D, calcium and phosphate
in children causes rickets and in adults causes
osteomalacia.
• There is defective mineralization of bone
causes softening and weakening of bone.
• In rickets there is bone deformity like bowing of
legs.
• In osteomalacia there is bone tenderness and
pathological fracture.
osteoporosis
• It is associated with an increased risk for fractures (vertebra,
hip and forearm). The basic abnormality is decrease in bone
mass, which attains a peak by the age of 30 and starts declining
by 35–45 years of age in both men and women.
• After the age of 40–45, calcium absorption is reduced and
calcium excretion is increased; so, there is a net negative
balance for calcium. This is reflected in demineralization.
• Osteoporosis is a silent disease with no symptoms, but its
clinical consequences can be debilitating. Common sites for
osteoporotic fractures include the spine, wrist, and hip. Bone
mineral density (BMD) is measured by the dual energy X-ray
absorptiometer (DXA).
Phosphate
• Total body phosphate is about 1 kg; 80% of which is
seen in bone and teeth and 10% in muscles.
• Phosphate is mainly an intracellular ion and is seen in
all cells.
• Requirement and Source
• Requirement is about 500 mg/day.
• Milk is a good source.
Cereals, nuts and meat are moderate sources.
• Serum Level of Phosphorus
• Serum level of phosphate is 3–4 mg/dL in normal
adults.
Functions of phosphate
• 1. Phosphorous helps in the
formation of bone and teeth.
• 2. It serves as a component of
high-energy phosphate compounds
such as ATP, GTP and creatine
phosphate.
• 3. In the synthesis of nucleotide
coenzymes such as NAD+, NADP+ and
PLP.
4. DNA and RNA synthesis, (phosphodiester
linkages)
5. Formation of phosphate esters, such as
glucose-6-phosphate
6. Formation of phosphoproteins and
phospholipid.
7. Activation of enzymes by phosphorylation
8. Phosphate buffer system in blood.
Regulation of blood phosphate level
• Like calcium blood phoshate is also regulated
by calitriol and parathyroid hormone.
• Calcitriol increases phosphate absorption in
intestine and increases phosphate
reabsorption in kidney.
• PTH increases calcium and phosphate release
from bone. It increases calcium reabsorption
in kidney but decreases phosphate
reabsorption in kidney.
Causes of hyperphosphatemia
1. Increased absorption of phosphate
Excess vitamin D
Phosphate infusion
2. Increased cell lysis
Chemotherapy for cancer
Bone secondaries
3. Decreased excretion of phosphorus
Renal impairment
Hypoparathyroidism
4. Hypocalcemia
5. Massive blood transfusions
Clinical features
Hyperphosphatemia causes reciprocal decrease of calcium level in
blood causing tetany.
Causes of hypophosphatemia
1. Decreased absorption of phosphate
Malnutrition
Malabsorption
Chronic diarrhea
Vitamin D deficiency
2. Intracellular shift
Insulin therapy
Respiratory alkalosis
3. Increased urinary excretion
Hyperparathyroidism
Clinical features
Rickets and osteomalacia
Muscle weakness
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