CALCIUM METABOLISM

MODERATOR- DR RUCHIKA BHATNAGAR

PRESENTOR- DR PRAVEEN KUMAR
 Physiological roles of calcium:-
• Extracellular fluid calcium is normally regulated precisely seldom rising or
falling more than a few percent of normal value of about 9.4 mg/dl which
is equivalent to 2.4 Mmol/L . This precise control is essential because
calcium plays a key role in many physiological processes such as:-
1. Contraction of skeletal muscle
2. Contraction of cardiac muscle
3. Contraction of smooth muscle
4. Hemostasis and blood clotting
5. Transmission of nerve impulse
6. Acts as a second messenger to initiate various cellular functions.
7. Developement and maintainance of bone density
8. Developement of teeth

TEXTBOOK OF MEDICAL PHYSIOLOGY- GUYTON & HALL (11TH EDITION)

REVIEW OF MEDICAL PHYSIOLOGY-WILLIAM F.GANONG 22ND EDITION
Different forms of calcium:-
• Calcium in plasma is in 3 forms-
I. 41% ( 1 mmol/l ) is combined with the plasma protein and is non
diffusible through the capillary membrane.
II. 9% (0.2 mmol/l) is diffusible through the capillary membrane but
is combined with the anionic substances of the plasma and
interstitial fluid.
III. 50% is diffusible through the capillary membrane and is ionised.

TEXTBOOK OF MEDICAL PHYSIOLOGY- GUYTON & HALL (11TH EDITION)

TEXTBOOK OF MEDICAL PHYSIOLOGY- GUYTON & HALL (11TH EDITION)
• The ionic calcium is the form that is important for most of the
functions of calcium in the body, including the effect of calcium on
the heart, the nervous system, and bone formation.

TEXTBOOK OF MEDICAL PHYSIOLOGY- GUYTON & HALL (11TH EDITION)

Body Requirement:-

RDA for calcium in different age groups:-

Age group RDA (mg/day)
0-6 month 200
7-12 month 260
1-3 year 700
4-8 year 1000
9-18 year 1300
Pregnant or lactating
<18 year 1300
18-21 year 1000
NELSON TEXTBOOK OF PEDIATRICS- INTERNATIONAL
(20TH EDITION )
Sources:-
• Milk and dairy products
• Green leafy vegetables
• Seafood
• Almonds
• Blackstap molasses
• Broccoli
• Enriched soy and rice milk products, figs
• Soybeans and tofu
Absorption:-
• Absorption is taking place from the first and second part of duodenum
against concentration gradient.
• Absorption requires a carrier protein, helped by Ca-dependent ATPase.
Incresed absorption:-
• Calcitriol, active form of vit D
• PTH
• Acidic pH

Inhibiting absorption:-
• Phytic acid
• Oxalates
• Phosphtes
• Caffeine
Calcium Turnover:-
Daily interorgan calcium fluxes:- The daily interorgan calcium intake being
approximately 1000 mg/day, about 90% of the daily intake of calcium is
excreted in the faces.

Intestinal absorption of calcium- Vitamin D promotes calcium absorption by

the intestines and about 35 % of ingested calcium is usually absorbed, the
calcium remaining in the intestine is excreted in the feces. An additional 250
mg/day of calcium enters the intestine via secreted gastrointestinal juices and
sloughed mucosal cells.

Renel excretion of calcium- Approximately 10 % (100 mg/day) of ingested

calcium is excreted in urine.

•About 41 % of the plasma calcium is bound to plasma proteins therefore not

filtered by glomerular capillaries. The rest is combined with anions such as
phosphate (9%) or ionized (50%) and filtered through the glomeruli into the
renel tubules.
TEXTBOOK OF MEDICAL PHYSIOLOGY- GUYTON & HALL (11TH EDITION)
•Normally the renel tubules reabsorb 99% of filtered calcium and
about 100 mg/day are excreted in urine. Approximately 90 % of the
calcium in the glomerular filtrate is reabsorbed in the proximal tubules,
loop of henle and early distal tubules.
•Then in the late distal tubules and early collecting duct reabsorption
of ramaining 10 % is selective, depending on the calcium ion
concentration in the blood.
•The most important factor controlling this absorption of calcium in
the distal portion of nephron and therefore controlling the rate of
calcium excretion is PTH.

TEXTBOOK OF MEDICAL PHYSIOLOGY- GUYTON & HALL (11TH EDITION)

 Calcium Turnover

TEXTBOOK OF MEDICAL PHYSIOLOGY- GUYTON & HALL (11TH EDITION)

 Mechanism of bone calcification:-
Sites of calcium storage:- Bone is composed of tough matrix that is
greately strengthened by deposits of calcium salts. Average compact
bone contains by weight about 30% matrix and 70% salts.
Approximately 99 % of calcium in the body is stored in bones and teeth.

Organic matrix of bone:- The organic matrix of bone is 90 to 95%

collagen fibres, and the remainder is a homogenous gelatinous medium
called the ground substance.

Bone salts:- The crystalline salts deposited in the organic matrix of bone
are composed principally of calcium and phosphate. The formula for
the major crystalline salt, known as hydroxyapatite, is the following:
Ca10(PO4)6(OH)2

TEXTBOOK OF MEDICAL PHYSIOLOGY- GUYTON & HALL (11TH EDITION)

Calcium exchange between bone and extraellular fluid:- Bone contain a
type of exchangeable calcium that is always in equilibrium with the
calcium ion in the extracellular fluid. It normally amounts to 0.4% to
1% of total bone calcium. This calcium is deposited in the bones in the
form of readily mobilized salt, such as CaHPO4 and other amorphous
calcium salts.

Deposition of bone by osteoblast:-Bone is continually being deposited

by osteoblasts and is continually being absorbed where the osteoclasts
are active. Osteoblasts are found on the outer surfaces of bone and in
the bone cavities.

Absorption of bone- Function of osteoclasts:- Bone is also being

continually absorbed in the presence of osteoclasts, which are large,
phagocytic multinucleated cells, derivatives of monocytes or
monocytes like cells formed in the bone marrow.

TEXTBOOK OF MEDICAL PHYSIOLOGY- GUYTON & HALL (11TH EDITION)

•PTH stimulates osteoclast activity and bone resorption but this occurs
through an indirect mechanism. PTH binds to the receptors on the
adjacent osteoblast, causing them to release cytokine, including
osteoprotegrin ligand (OPGL) which is also called RANK ligand.

TEXTBOOK OF MEDICAL PHYSIOLOGY- GUYTON & HALL (11TH EDITION)

Parathyroid hormone:-
• It is synthesized as pre-pro-PTH (115aa) and is cleaved to pro-PTH
(90aa) before secretion of PTH (84 aa).
• Intact PTH T1/2 3-4 mins
• Normal levels 1.3 – 6.8 pmol/L
• Secreted from the chief cells of the parathyroid glands.

Functions:
Increase renal phosphate excretion , and increases plasma calcium by:-
• Increasing osteoclastic resorption of bone (occurring rapidly).
• Increasing intestinal absorption of calcium (a slower response).
• Increasing synthesis of 1,25-(OH)2D3 (stimulating GIT absorption).
• Increasing renal tubular reabsorption of calcium.
TEXTBOOK OF MEDICAL PHYSIOLOGY- GUYTON & HALL (11TH EDITION)
PTH action:-
• The overall action of PTH is to increase plasma Ca++ levels and
decrease plasma phosphate levels.
• PTH acts directly on the bones to stimulate Ca++ resorption and
kidney to stimulate Ca++ reabsorption in the distal tubule of the
kidney and to inhibit reabosorptioin of phosphate (thereby
stimulating its excretion).
• PTH also acts indirectly on intestine by stimulating 1,25-(OH)2-D
synthesis.
• PTH indirectly increases Calcium absorption from GIT.
Regulation of PTH:-
• The dominant regulator of PTH is plasma Ca2+.
• Secretion of PTH is inversely related to [Ca2+].
• Maximum secretion of PTH occurs at plasma Ca2+ below 3.5 mg/dL.

TEXTBOOK OF MEDICAL PHYSIOLOGY- GUYTON & HALL (11TH EDITION)

•At Ca2+ above 5.5 mg/dL, PTH secretion is maximally inhibited.
•PTH secretion responds to small alterations in plasma Ca2+ within
seconds.
•A unique calcium receptor within the parathyroid cell plasma
membrane senses changes in the extracellular fluid concentration of
Ca2+.
•This is a typical G-protein coupled receptor that activates
phospholipase C and adenylate cyclase—result is increase in
intracellular Ca2+ via generation of inositol phosphates and decrease in
cAMP which prevents exocytosis of PTH from secretory granules.
•When Ca2+ falls, cAMP rises and PTH is secreted.
•1,25-(OH)2-D inhibits PTH gene expression, providing another level of
feedback control of PTH.
•Despite close connection between Ca2+ and PO4, no direct control of
PTH is exerted by phosphate levels.

TEXTBOOK OF MEDICAL PHYSIOLOGY- GUYTON & HALL (11TH EDITION)

Vitamin D:-
• Dietary cholesterol is converted into 7-dehydrocholesterol and
transported to skin.
• UV sunlight (290-320nm) penetrates the skin to break provitamine
( 7-dehydrocholesterol ) to previtamine and it is then converted to
Cholecalciferol by the process of isomerisation.
• In the liver, cholecalciferol undergoes 25-hydroxylation to yield
25(OH) Vit-D ( calcidiol).
• In the kidney , calcidiol undergoes further 1α-hydroxylation to
produce 1,25 –dihydroxy Vit-D (Calcitriol). Its production in the
kidney is catalyzed by 1α -hydroxylase .
1α -hydroxylase activity is increased by :
Decreased serum Ca2+
Increased PTH level
Decreased serum phosphate
TEXTBOOK OF MEDICAL PHYSIOLOGY- GUYTON & HALL (11TH EDITION)
 Action of 1,25-dihydroxycholecalcififerol (Calcitriol)
• Increases intestinal Ca2+ absorption
• Increases intestinal phosphate absorption
• Increase renal reabsorption of Ca2+ and phosphate
• Increases osteoclast activity

TEXTBOOK OF MEDICAL PHYSIOLOGY- GUYTON & HALL (11TH EDITION)

Vitamin D3 and Calcium Control
Calcitonin:-
• This is produced from the C-cells of the thyroid.
• Polypeptide (32aa), MW-32 KD, T 1/2- 10 mins
• The major stimulus for calcitonin secretion is rise in plasma Ca++
levels.
• Calcitonin is a physiological antagonist to PTH with regard to Ca++
homeostasis.
• The target cell for calcitonin is the osteoclast.
• Calcitonin acts via increased cAMP concentrations to inhibit
osteoclast motility and cell shape and inactivates them.
• The major effect of calcitonin administration is a rapid fall in Ca2+
caused by inhibition of bone resorption.

TEXTBOOK OF MEDICAL PHYSIOLOGY- GUYTON & HALL (11TH EDITION)

Summary of control of calcium ion
concentration
HYPOCALCEMIA
 HYPOCALCEMIA
• Hypocalcemia is defined as total serum calcium of less than 7
mg/dL (1.75 mmol/L) or ionized calcium less than 4 mg/dL (1
mmol/L) in preterm infants and less than 8 mg/dL (2 mmol/L; total)
or < 4.8 mg/dl (1.2 mmol/L) in term neonates.

•Clinical Features:-
1. Carpopedal and muscle spasm
2. Tetany
3. Laryngospasm
4. Paresthesias
5. Seizure
6. Irritability, depression and pschosis
7. Intraranial hypertension
8. Prolonged QT interval
• Risk factors for neonatal hypocalcemia-
I. Prematurity.
II. Infant of diabetic mother.
III. Perinatal asphyxia.
IV. Maternal hyperparathyroidism.
V. IUGR.
VI. Maternal intake of anticonvulsants (phenobarbitone, phenytoin
sodium)
VII. Iatrogenic (alkalosis, use of blood products, diuretics,
phototherapy, lipid infusions)
• Prematurity: This may be related to premature termination of
trans-placental supply, increased calcitonin and diminished target
organ responsiveness to parathyroid hormone.

• Infant of diabetic mother (gestational and insulin dependent):

This may be related to increased calcium demands of a
macrosomic baby. Magnesium depletion in mothers with
diabetes mellitus causes hypomagnesemic state in the foetus.
• This hypomagnesemia induces functional hypoparathyroidism
and hypocalcemia in the infant.
• A high incidence of birth asphyxia and prematurity in infants of
diabetic mothers are also contributing factors.
• Perinatal asphyxia: Delayed introduction of feeds, increased
calcitonin production, increased endogenous phosphate load, renal
insufficiency, and diminished parathyroid hormone secretion all
may contribute to hypocalcemia.

• Maternal hyperparathyroidism: This causes intrauterine

hypercalcemia suppressing the parathyroid activity in the fetus
resulting in impaired parathyroid responsiveness to hypocalcaemia
after birth. Hypocalcaemia may be severe and prolonged.

• Intrauterine growth restriction (IUGR): Infants with IUGR may have

hypocalcemia if they are born preterm and/or have had perinatal
asphyxia. IUGR or Small for gestational age (SGA) is not an
independent risk factor for hypocalcemia.
• Maternal anticonvulsants: Intake of anticonvulsants like
phenobarbitone and phenytoin alters the vitamin D metabolism
and predisposes them to its deficiency. The infants of epileptic
mothers may be at risk of neonatal hypocalcemia. It can be
prevented by vitamin D supplementation to mothers.

• Iatrogenic: Any condition causing alkalosis increases the binding of

the calcium with albumin and causes decrease in calcium.

• There is no universal recommendation regarding routine screening

of at-risk infants for hypocalcemia. However following categories of
infants may be considered for the same:
(a) Preterm infants born before 32 wks
(b) Infants of diabetic mothers
(c) Infants born after severe perinatal asphyxia defined as Apgar score
< 4 at 1 minute of age
HYPERCALCEMIA
 HYPERCALCEMIA
• Hypercalcemia is defined as serum calcium level greater than 11
mg/dl. Because calcium metabolism normally is tightly controlled
by body, even mild persistent elevations should be investigated.
• Clinical features:-
1. Lethargy, confusion, depression, coma
2. Hyporeflexia
3. Muscle weakness
4. Constipation
5.Polyuria
6.Bradycardia, hypertension
7. Nephrocalcinosis
8. Nephrolthiasis
9. Reduced QT interval
 HYPERPARATHYROIDISM
• Childhood hyperparathyroidism is uncommon.

• Onset during childhood is usually the result of a single benign

adenoma.

• It usually becomes manifested after 10 yr of age.

• In some hyperparathyroidism occurs as part of the

constellation known as the multiple endocrine neoplasia
(MEN) syndromes or of the hyperparathyroidism–jaw tumor
syndrome.
• Features consist of anorexia, irritability, lethargy, constipation, and
failure to thrive.

• Radiographs reveal subperiosteal bone resorption, osteoporosis,

and pathologic fractures.

• MEN type I is an autosomal dominant disorder characterized by

hyperplasia or neoplasia of the endocrine pancreas (which secretes
gastrin, insulin, pancreatic polypeptide, and occasionally glucagon),
the anterior pituitary (which usually secretes prolactin), and the
parathyroid glands.
 JAW TUMOUR SYNDROME
• Hyperparathyroidism–jaw tumor syndrome is an autosomal
dominant disorder characterized by parathyroid adenomas and
fibroosseous jaw tumors.

• Affected patients can also have polycystic kidney disease, renal

hamartomas, and Wilms tumor.

• Although the condition affects adults primarily, it has been

diagnosed as early as age 10 yr.
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