VITAMIN D
Vitamin D is a steroid prohormone. By various metabolism changes in
the body, they give rise to a hormone known as Calcitriol, which plays a
central role in calcium and phosphorus metabolism.
Formation of vitamin D
Vitamin D is formed from their precursors or provitamins.
Ergosterol: Provitamin D2 found in plants.
7-dehydrocholesterol: Provitamin D3 found in the skin.
(Vitamin D3 occurs in fish liver)
Photolysis
7-dehydrocholesterol cholecalciferol (Vit D3)
Photolysis
Ergosterol Ergocalciferol (Vit D2)
7-dehydrocholesterol is protolyzed by UV rays resulting in the opening
of ring B followed by isomerisation to yield cholecalciferol.
This Vit D3 formed is not active.
Active derivatives or activation of vitamin D
Both the liver and kidney are involved in the formation of active
vitamin D. vitamin D binds to specific proteins and is transported to
liver.
Cholecalciferol (Vit D3) is hydroxylated on the 25 positions by hepatic
microsomal enzyme Vit.D3-25 hydroxylase to form 25-hydroxy
cholecalciferol. It is considered to be a rate-limiting step in the
pathway.
From the liver, 25-hydroxy cholecalciferol is carried by a serum 2-
globulin to renal tubules, bone cells and placenta.
Here mitochondrial 25 (OH) D3-1- hydroxylase converts it to 1, 25
dihydroxy cholecalciferol or calcitriol.
Calcitriol thus formed is the active form of vitamin D, it acts as a
hormone.
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Both hydroxylase enzymes (of liver & kidney) require cyt P 450, NADPH
and molecular oxygen for the hydroxylation process.
Liver Kidney
Cholecalciferol 25-hydroxy 1, 25 dihydroxy
25-hydroxylase cholecalciferol 1--hydroxylase
cholecalciferol or
CALCITRIOL
Regulation of vitamin D
Production of calcitriol is regulated by serum of calcium, phosphorus,
PTH and calcitriol itself.
Low serum phosphate level increases the activity 25 (OH)
cholecalciferol 1--hydroxylase.
Low serum calcium (hypocalcemia) increases the secretion of PTH which
term activates 1-hydroxylase.
Excess of calcitriol causes feed back inhibition of 1- hydroxylase.
Formation:
Cholecalciferol (Vit. D3)
Liver 25-hydroxylase
25-hydroxylase cholecalciferol
1- hydroxylase
Renal tubules 24-hydroxylase
(mitochondrial)
1, 25 dihydroxy 24, 25 dihydroxy
cholecalciferol cholecalciferol
(calcitriol)
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Regulation:
Plasma calcium
Parathyroid hormone
Calcitriol
Bone calcium Intestinal Renal absorption
mobilization absorption
Plasma calcium
Functions:
Vitamin D (calcitriol) acts on target organs like bones, kidney and
Intestinal mucosa to regulate calcium and phosphate metabolism.
Like other hormones calcitriol is carried by blood to its target organs. In
the target organs like Intestine, it resembled steroid hormones in its
mode of action.
a) Vitamin D3 promotes Intestinal absorption of calcitriol and phosphate
Calcitriol enters the target cell and binds to a cytoplasmic receptor. The
hormone receptor complex interacts DNA and causes derepression &
consequent transcription of specific genes that code for calbindin.
Calbidin bind Ca++ and pumped out of cell to the blood actively against
electrochemical gradients.
Blood Intestine cell Lumen
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Calcitriol (C) Receptor (R)
DNA binding site
CR Nucleus
Ca++ Calbindin –Ca++ Ca++
(passive)
b) Mineralization of bone is increased by increasing activity of
ostroblasts.
Calcitriol stimulates osteoblasts which secrete alkaline
phosphatase. Due to this enzyme the local concentration of
phosphate is increased.
Calcitriol induces the synthesis of Ca-binding protein like
osteocalcin.
Both these action enhance the ionic product of ca ++ and PO4-
leading to mineralization.
When dietary Ca++ is low; calcitriol along with PTH increases the
mobilization of Ca++ & PO4- from the bones for maintaining
serum calcium levels.
c) Calcitriol increases the reabsorption of Ca & phosphates by renal
tubules. Therefore both the minerals are conserved (PTH conserves only
Ca++)
Nutritional aspects:
Sources:
Fish liver oils, fish, egg yolk are good sources of Vit.D. dairy milk is
often fortified vit. D sufficient amounts are also synthesized in the skin
by the effect of UV rays of sunlight.
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Required daily allowance:
Children 10 mg
Men and Women 5 mg
During pregnancy
And lactation 10 mg
Clinical significance:
Deficiency: Deficiency is less common since this vit can be synthesized
in the body.
Causes:
o Deficiency can occur in people who are not exposed to sunlight
properly e.g. inhabitants of northern latitudes, or people who are
bedridded for long periods or those who cover the body from head
to food (purdah). In North India, deficiency may be seen in children
during winter. Nutritional deficiency of calcium and phosphate
may also produce similar clinical picture.
o Secondary to Malabsorption of vitamin (obstructive jaundice and
steatorrhea). High phytate content in diet may also reduce the
absorption of vitamin.
o Secondary to abnormality of Vit.D activation. Liver renal diseases
may retard the hydroxylation reaction.
o Secondary to abnormalities in renal absorption of phosphates.
Deficiency Manifestations:
Vit D3 deficiency causes rickets in children and osteomalacia in adults.
Vit.D is known as antirachitic vitamin.
Rickets: (Wrickken= to twist)
The classical features of rickets are bone deformities, due to
insufficient mineralization of bones. Bones become soft &
pliable. Bone growth is markedly affected.
Weight bearing bones are bent. Continued action of muscles
also causes bone malformations.
Clinical manifestations include bowlegs, knock knee rickety
rosary, bossing of frontal bones and pigeon chest. (the
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fontanelles do not close properly giving hot cross bun
appearance of head).
An enlargement of epiphysis at the lower ends of ribs and
costochondral junction leads to leading of ribs or rickety rosary.
Osteomalacia: (G.K Osteon = bone; malakia = softness)
Bones are softened due to insufficient mineralization and
increased osteoporosis.
Bone aches and pains are common.
Patients are more prone to get fractures.
(Prolonged use of phenobarbitone causes shifting of microsomal
enzymes for drug metabolism, causing deficiency in hydroxylation of
Vit.D. this may be manifested as osteamalacia)
Other type of Rickets:
1. Type I: Defect in the conversion of 25-OH-Vit D3 to calcitriol i.e. 1--
hydroxylase deficiency.
2. Type II: Defect in the DNA biding sites for calcitriol receptor complex.
This
makes the receptors nonfunctional. Absorption of Ca ++ is
affected.
3. Hypophosphotemic rickets: Defective renal tubular reabsorption of
PO4-
supplementation of Vit.D and its active form along with
phosphate is found to be useful.
4. Vitamin D resistant rickets: Found to be associated with Fanconis
syndrome,
where renal tubular reabsorption of bicarbonate, phosphate,
glucose and amino acids are also deficient. Supplementation
of Vit.D, PO4- and bicarbonate are beneficial.
5. Renal Rickets (Renal osteodystrophy): Renal parenchy ma is lost,
even if
vitamin D is available, calcitriol is not synthesized. These
cases will respond to administration of calcitriol.
Toxicity or Hyper vitaminosis:
Long-term excessive intake of vitamin D enhances the intestinal
absorption of dietary Ca++ and causes excessive mobilization of bone
Ca+2 in to the blood. Both these factors cause hypercalcemia.
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This is in turn leads to neuromuscular depression muscle hypotonicity,
irritability, calcification of soft tissues (such as cardiovascular,
respiratory and renal tissues), high urinary Calcium, renal calculi, renal
failure and abnormal bone development.
Demineralization of bones may cause spontaneous fractures. Loss of
appetite, nausea and intense thirst are also experienced.
