Introduction: fat soluble vitamin maintains adequate plasma levels of calcium and phosphorus CALCIUM AND PHOSPHORUS support * metabolic functions * bone mineralization * neuromuscular transmission Sources: Endogenous synthesis (90%) : - In skin, 7-dehydrocholesterol (precursor) undergoes photochemical reaction by UVB Radiation (290 to 315 nm) results in Cholecalciferol (Vitamin D3) - dark skin ---> lower level of vitamin D synthesis 2. Exogenous sources - diet : absorption same as that of other fat soluble vitamins Deep sea fish Plants (present as ergosterol) and grains Milk Effects on Calcium and Phosphorus homeostasis - acts on duodenum, kidney and osteoblasts of bone: 1. Stimulates intestinal calcium absorption : Increases transcription of TRPV 6 gene → encodes calcium channel → calcium absorption 2. Stimulates renal calcium reabsorption : increases transcription of TRPV 5 gene → encodes Calcium channel → calcium reabsorption Note : i) TRPV 5 expression is also increased by PTH when hypocalcemia occurs. ii) TRPV stands for Transient Receptor Potential Vanilloid 3. Interacts with PTH in calcium level regulation : 1,25 dihydroxycholecalciferol and PTH increases expression of RANKL on osteoblasts → RANKL binds to its receptor (RANK) on preosteoclasts →Preosteoclasts differentiate into mature osteoclasts → Mature osteoclasts secrete hydrochloric acid and actives proteases (cathepsin K) → Acid and protease dissolve bone → Calcium and phosphorus are released into circulation Note: RANKL - Receptor Activator of NF- kB Ligand 4. Mineralization of osteoid (unmineralized matrix) and epiphyseal cartilage : by stimulating osteoblasts to synthesize osteocalcin, a calcium binding protein which deposits calcium Nonskeletal effects: MACROPHAGES : 1,25 dihydroxycholecalciferol is synthesized in macrophages by mitochondrial CYP27B Pathogen induced Toll Like Receptors cause increased expression of Vitamin D receptors and CYP27B Thus there is vitamin D dependent gene expression in macrophages and neighboring immune cells OTHER CELLS AND TISSUES : keratinocytes, breast, prostate, colon also synthesize 1,25 dihydroxycholecalciferol where it has antiproliferative effects Deficiency states: Circulating 25-hydroxycholecalciferol concentration < 20ng/mL (Normal : 20 to 100 ng/mL) Causes rickets in growing children and osteomalacia in adults ETIOLOGY : Intake of Diets deficient in calcium and vitamin D Limited exposure to sunlight Frequent pregnancies Renal disorders, Malabsorption disorders, Rare inherited disorders Toxicity: due to megadoses of oral Vitamin D In children metastatic calcification of kidneys In adults, bone pain and hypercalcemia RDA = 200 IU/day in adults

1. Vitamin D
Angelin.A

2. Synopsis
Vitamin D
● Sources
● Metabolism
● Receptors
● Effects on :
☆ Calcium and phosphorus homeostasis
☆ Other cells and tissues (nonskeletal effects)
● Deficiency states
● Toxicity

3. Vitamin D
- fat soluble vitamin
- maintains adequate plasma levels of calcium and phosphorus
- Calcium and phosphorus support
* metabolic functions
* bone mineralization
* neuromuscular transmission

4. Sources of Vitamin D
1. Endogenous synthesis (90%) :
- In skin, 7-dehydrocholesterol (precursor)
undergoes photochemical reaction by UVB
Radiation (290 to 315 nm)
- results in Cholecalciferol (Vitamin D3)
- dark skin ---> lower level of vitamin D
synthesis

5. 2. Exogenous sources - diet : absorption same as that of other fat
soluble vitamins
Deep sea fish
Plants (present as ergosterol) and grains
Milk

6. Metabolism of Vitamin D (cholecalciferol)
In circulation, Vitamin D is bound to α1 globulin (D Binding Protein)
and Transported to liver
In Liver, 25 hydroxylases (CYP27A1and other CYPs) convert :
Cholecalciferol ----> 25-hydroxycholecalciferol
In Kidney, 1α hydroxylase converts :
25-hydroxycholecalciferol ----->1,25 dihydroxycholecalciferol

8. Regulation of 1,25-dihydroxycholecalciferol synthesis
increase in synthesis by
upregulation of 1α hydroxylase
● PTH secretion due to
Hypocalcemia
● Hypophosphatemia
decrease in synthesis by inhibition
of 1α hydroxylase
● 1,25 dihydroxycholecalciferol
itself (negative feedback)

10. Receptors to which 1,25-di hydroxycholecalciferol binds
NUCLEAR VITAMIN D RECEPTOR :
- forms heterodimer with RXR
- heterodimer binds DNA
response elements in the
regulatory sequences of
target genes
MEMBRANE ASSOCIATED VITAMIN D
RECEPTOR :
- Activation of protein kinase C
--> opening of calcium channels
- No transcription of target
genes

11. Effects on Calcium and Phosphorus homeostasis - acts on
duodenum, kidney and osteoblasts of bone
1. Stimulates intestinal calcium absorption :
Increases transcription of TRPV 6 gene → encodes
calcium channel → calcium absorption
2. Stimulates renal calcium reabsorption :
increases transcription of TRPV 5 gene → encodes
Calcium channel → calcium reabsorption
Note : i) TRPV 5 expression is also increased by PTH when hypocalcemia occurs.
ii) TRPV stands for Transient Receptor Potential Vanilloid

12. 3. Interacts with PTH in
calcium level regulation :
1,25 dihydroxycholecalciferol and PTH
increases expression of RANKL on osteoblasts
→ RANKL binds to its receptor (RANK) on
preosteoclasts
→Preosteoclasts differentiate into mature
osteoclasts
→ Mature osteoclasts secrete hydrochloric acid
and actives proteases (cathepsin K)
→ Acid and protease dissolve bone
→ Calcium and phosphorus are released into
circulation
Note: RANKL - Receptor Activator of NF- kB Ligand

13. 4. Mineralization of osteoid (unmineralized
matrix) and epiphyseal cartilage :
- by stimulating osteoblasts to synthesize osteocalcin, a
calcium binding protein which deposits calcium

14. MESENCHYMAL OSSIFICATION :
In flat bones of skull, mesenchymal cells differentiate into
osteoblasts → matrix formation and calcium deposition
ENDOCHONDRAL OSSIFICATION :
In Epiphyseal cartilage of long bones
Chondrocyte proliferation and hypertrophy → temporary
mineralization → chondrocyte apoptosis and matrix resorption →
osteoid matrix deposition → mineralization again

16. Nonskeletal effects
MACROPHAGES : 1,25 dihydroxycholecalciferol is synthesized in
macrophages by mitochondrial CYP27B
Pathogen induced Toll Like Receptors cause increased expression of Vitamin
D receptors and CYP27B
Thus there is vitamin D dependent gene expression in macrophages and
neighboring immune cells
OTHER CELLS AND TISSUES : keratinocytes, breast, prostate, colon also
synthesize 1,25 dihydroxycholecalciferol where it has antiproliferative
effects

17. Deficiency states
- Circulating 25-hydroxycholecalciferol concentration < 20ng/mL
(Normal : 20 to 100 ng/mL)
- Causes rickets in growing children and osteomalacia in adults
ETIOLOGY :
● Intake of Diets deficient in calcium and vitamin D
● Limited exposure to sunlight
● Frequent pregnancies
● Renal disorders, Malabsorption disorders, Rare inherited disorders

18. PATHOGENESIS :
Nearly normal calcium and low
phosphorus levels
Poor bone mineralization which
causes weak and soft bones

19. Rickets
MORPHOLOGY :
● epiphyseal cartilage overgrowth
● disorganized matrix deposition on
unmineralized cartilage
● overgrowth of capillaries and fibroblasts

20. GROSS SKELETAL CHANGES :
In Nonambulatory infants…...
Head
- CRANIOTABES = softened parietal bones buckled inward by pressure, elastic
recoil with release of pressure
- FRONTAL BOSSING and SQUARE BOX LIKE SKULL = due to excess of osteoid
- softened occipital bones

21. Chest
- RACHITIC ROSARY = due to overgrowth of cartilage at costochondral junction
- PIGEON BREAST = anterior protrusion of sternum due to action of respiratory
muscles
- HARRISON’S SULCUS = due to indrawing of soft ribs during inspiration

22. In an ambulating child,
- Bowing of legs
- Knock knees
- lumbar lordosis

23. Osteomalacia
MORPHOLOGY :
H & E : unmineralized osteoid (which stains pink) arranged within the
normally mineralized basophilic trabeculae
Von Kossa’s stain : calcified bone is stained black.
Wide areas of unmineralized osteoid is marked out
CLINICAL FEATURES :
Vulnerable to Gross and microfractures

24. Vitamin D Toxicity
- due to megadoses of oral Vitamin D
- In children, ______________ (dystrophic/metastatic) calcification of
kidneys
- In adults, bone pain and hypercalcemia
RDA = 200 IU/day in adults
400 IU/day In children, pregnant and lactating women