Vitamin d3

VITAMIN D

AHAMMED KABEER M AROLL NO: 7Govt med college calicut9567751529

1. INTRODUCTION2. STRUCTURE3. BIOSYNTHESIS4. DIETARY SOURCES5. RDA6. METABOLIC FUNCTIONS7. DEFICIENCY MANIFESTATIONS 8. HYPERVITAMINOSIS D

Introduction

Fat soluble vitaminSynthesized in bodyVit D2 - calciferolVit D3 – cholecalciferolSun shine vitamin/ antirhachitic factorPhysiologically active form- calcitriolCalcitriol- 1,25(OH)2cholecalciferol (DHCC)

Structure

Biosynthesis

Endogenous synthesis of vit D in skinUV-B radiationsPhotochemical conversion of 7-dehydrocholestrol90% of vit D requirement is met by

endogenous synthesisRest 10% from Dietary sources

• In malpighian layer of skin

(secosterol)

(Secosterol)

• Directly proportional to sun exposure• Inversely proportional to skin pigmentation• Darker skin?* melanin• Excessive exposure to sunlight?*• Storage?* adipose tissues

Dietary sources

Fish Fish liver oilEgg yolkMilk

Commercially synthesised as ergocalciferol vitD2

RDA

• Children 10µg/day• Adults 5µg/day• Pregnancy and lactation 10µg/day• Above age of 60 15µg/day

Metabolism of Vit D3

• Main steps1. Photochemical synthesis of vit D / ingested2. Absorption *3. Transport to liver as bound to an α1 globulin called DBP( D Binding Protein)

3. In liver conversion into 25(OH)cholecalciferol

4. In kidney conversion into 1,25(OH)2cholecalciferol*(1,25DHCC)

How 1,25DHCC synthesis regulated?

•Hypocalcemia PTH secretion

activates α1hydroxylase

•Hypophosphatemia direct activation of

α1hydroxylase

• Feed back mechanism 1,25DHCC inhibit

α1hydroxylase

MOA

• 1,25(OH)2cholecalciferol(1,25DHCC) is the active form

• Is a steroid hormone• Binds to nuclear VDR• Association with RXR• Heterodimeric complex binds to VDRE* on

target gene

MOA

Metabolic functions

Homeostasis of minerals Ca and (PO4)3- Support metabolic functionsBone mineralisationNeuromuscular transmissionPrevents

• Rickets in children • Osteomalacia(adults)• Hypocalcemic tetany

1. Stimulate intestinal Ca absorption• In duodenum•Transription and expression of TRPV6

(Transient Receptor Potential Vanilloid 6)

• Ca influx

• To blood by calbindin

• Also absorption of (PO4)3-

2. Stimulate Ca reabsorption in kidneyDistal tubulesExpression of TRPV5 Ca influxAlso (PO4)3- influx TRPV5 also regulated by PTH in hypocalcemiaBut effect Ca reabsorption only

Regulation of blood Ca

1α,25DHCC interact with PTH

Intestine? Kidney?

In bones*?

Expression of RANKL(Receptor Activator of

NF-κB Ligand) on osteoblasts

RANKL receptors on preosteoclastsInduce differentiation into mature osteoclastSecrete HCl and protease Cathepsin K which

dissolve boneRelease Ca and (PO4)3-

4. Mineralization of boneMineralization of osteoid matrix and

epiphyseal cartilageStimulate osteoblasts to synthesise ALP and

osteocalcin ( Ca Binding Protein)Increase deposition of Ca and (PO4)3-

during bone developmentIn both endochondral and intramembranous ossification

When hypocalcemia due to vit D deficiencyPTH sys • Activate renal α1 hydroxylase

• Vit D synthesis and Ca reabsorbtion

•Bone resorption of Ca by osteoclasts

• Renal Ca excretion

• Renal excretion of phosphate

FGF23

• FGF23 (Fibroblast Growth Factor 23)Is a phophatonin

• Block intestinal absorption of (PO4)3-

• Block renal reabsorption of (PO4)3-

• Increased urinary excretion of (PO4)3-

Tumour induced osteomalacia**

Hypophosphatemic rickets

Vit D deficiency

• Normal plasma range 20-100ng/mL• < 20ng/mL vit D deficiency

Why Vit D deficiency?Dietary deficiency Inadequate exposre to sunlight*Malabsorption (obstrucive jaundice, steatorrhea)Liver* and renal* disorders( 1,25DHCC, (PO4)3- )Children born to mother who have frequent

pregnancies followed by lactationRare inherited genetic conditionsGenetic variants of VDRVit D insufficiency?*End organ resistance*

Deficiency manifestations

1. Rickets in growing childrenRickets more common during 1st year of lifeInsuffcient mineralizationSoft and pliable bonesRetarded bone growthOvergrowth of epiphyseal cartilageDistorted irregular masses of cartilage

projecting to marrow cavity

Enlargement and lateral expansion of osteochondral junction

Bow legsKnock kneeRachithic rosary*Bossing of frontal bone, squared headFlat occiputPigeon breast deformity*Harrison’s sulcus*Lumbar lordosis

Craniotabes*Earliest bony lesionSamll round unossified areas in membranous boneson applying pressure inward buckling of parietal

boneWhen pressure released elastic recoil snaps the

bones back to their original positionsAbnormal overgrowth of capillaries and fibroblasts

in microfractures

Types of Rickets

Vit D deficient rickets*HypophosphatemicVit D resistentRenal*End organ refractoriness

2. Osteomalacia in adultsDerangement of bone remodeling through out

lifeInsufficient mineralizationVague bony pains Excess of persistent osteoid- osteomalacia*Bone is weak/softVulnerable to gross fractures/microfracturesUsually vertebral bodies or femoral neckSerum ca n/l orSerum (PO4)3- ALP

Histology

Cancellous bone in osteomalacia(Goldner’s trichome stain)

Nonclassical functions of Vit D

Non skeletal functions1,25DHCC also produced by cells like macrophages, keratinocytes tissues like breast, prostate, colon Regulate expression of more than 200 genesThat are involved in proliferation, differentiation, apoptosis and angiogenesis

Reduce incidence of cancer, CADLevels of 1,25DHCC less than 20ng/mL has a

positive correlation with30% to 50% increase in breast,prostate and

colon cancersAntiproliferative* ?PTHAntihypertensiveAnti inflammatory

Immunomodulatory effect

In macrophages synthesis of 1,25DHCC by mitochondrial CYP27B

Pathogen activate TLR(Toll Like Receptor)Transcription induced increase in VDR and

CYP27B 1,25DHCC thus produced stimulate production

of Cathelicidin

Cathelicidin Derived from defensin familyantimicrobial against mycobacterium

tuberculosisRole in innate and adaptive immunity

Hypervitaminosis D

Mega doses of orally administrated vit D>45µg/day for long periodsSymptoms : weakness, polyuria, intense thirst, HTN, wt. loss, renal calculi…Metastastic calcification of kidney in childrenBone pain and hypecalcemia in adultsYou know? In sufficient large doses it is a

potent rodenticide!!!!