Topics

• Metabolism• Function• Deficiency manifestation• Hypervitaminosis

• Vitamin D is fat soluble• Major function- Maintenance of normal

plasma level of calcium and phosphorous

• Major source(90%) – Endogenous synthesis in skin by photochemical conversion of a precursor , 7 dehydrocholesterol powered by solar energy

• Adequate exposure to sunlight without sunscreen before 10 am and after 3 pm at least 15 min a day

• Remaining sources – deep sea fish , plants ,grains

• In plants vitamin D is present in a precursor form , Ergosterol

• “Blacks have lower level of Vitamin D production in skin because of melanin pigmentation”

• (melanin pigmentation is protection against UV induced cancer )

METABOLISM

• 1.Absorption of Vitamin D along with other fats in the gut or synthesis from precursor in the skin

• Binding of plasma alpha 1 globulin (vit D binding protein) & transport to liver

• Conversion into 25-Hydroxyvitamin D by 25-Hydroxylase in the liver

• Conversion of 25-OH-D to 1,25-dihydroxyvitaminD by alpha1 hydroxylase

Renal production of 1,25-(OH)2-D is regulated by

• 3 mechanism• Hypocalcemia stimulates secretion of

parathyroid hormone ,which augments the conversion of 25-(OH)-D to 1,25-(OH)2-D by activating alpha1 hydroxylase

• Hypophosphatemia directly activates alpha1 hydroxylase

• In a feedback loop,increased level of 1,25-(OH)2-D downregulate the synthesis of metabolite

• I,25-(OH)2-D acts by binding to a high affinity nuclear receptor that in turn binds to regulatory DNA sequences, thereby inducing transcription of specific target genes

• The receptors are present in most nucleated cells of the body

• Vit D also appear to act through mechanism that does not require transcription of target genes

• This involves binding of 1,25-(OH)2-D to a membrane associated vit d receptor(mVDR), leading to activation of protein kinase C and opening of Ca channels

FUNCTIONS• Stimulates intestinal absorption of calcium

through upregulation of calcium transport,in enterocytes

• Stimulates calcium resorption in renal distal tubules

• Promotes the mineralization of bone vit D is needed for mineralization of osteoid matrix & epiphyseal cartilage.• Interaction with PTH in the regulation of blood

Ca

Stimulation of intestinal Ca absorption

• Through the interaction of 1,25-(OH)2-D with nuclear vit D receptor and the formation of a complex with RXR

• The complex binds to Vit D response element and activates the transcription of TRPV6, which encodes a critical Ca transport channel

• TRPV6-a member of transient receptor potential vanilloid family)

Stimulation of Ca reabsorption in kidney

• Vit D increases Ca influx in distal tubules of kidney through the increased expression of TRPV5

• TRPV5 expression is also regulated by PTH

Interaction with PTH

• Parathyroid glands have a Ca receptor that senses even small changes in blood Ca concentration

• Vit D and PTH enhance the expression of RANKL (receptor activator of NF-kB ligand) on osteoblasts

• RANKL binds to its receptor(RANK) located on preosteoclasts –inducing differentiation into osteoclasts.

• Through the secretion of HCL and activation of proteases such as cathepsin K ,osteoclasts dissolve bone and release Ca & P into circulation

Mineralisation of bone

• Stimulates osteoblasts to synthesize Ca binding protein osteocalcin involved in the deposition of Ca during bone development

• Flat bones develop by intramembraneous bone formation, in which mesenchymal cells differentiate directly into osteoblasts ,which synthesize collagenous osteoid matrix on which Ca is deposited

• Long bones develop by endochondral ossification ,through which growing cartilage at the epiphyseal plates is mineralised and progressively resorbed and replaced by osteoid matrix that is mineralised to create bone

• When hypocalcemia occurs due to Vit D deficiency ,PTH production is increased

1.Activation of 1alpha hydroxylase2.Increased resorption of Ca from bone by osteoclasts3.Decreased renal Ca excretion4.Increased renal excretion of phosphate (increase in FGF 23 ,one of a group of agents known as phosphatonins that block phosphate absorption in intestine and kidney)• Normal serum Ca level is restored,

hypophosphatemia persists

Normal level of 1,25-(OH)2-D 20-100ng/ml DEFICIENCY STATESRickets in growing childrenOsteomalacia in adults• Result from diet deficient in Ca & Vit D or

limited exposure to sunlight• Affect inhabitants of northern latitude• Heavily veiled women• Children born to mothers who have frequent

pregnancy followed by lactation

• Milder form of Vit D deficiency also called as vitamin D insufficiency .leading to increase risk of bone loss and hip fracture are common in older adults in US and Europe

RICKETS• Overgrowth of epiphyseal cartilage due to

inadequate calcification & failure of cartilage cells to mature

• Persistence of irregular masses of cartilage which project into marrow cavity

• Deposition of osteoid matrix on inadequately mineralised cartilaginous remnants

• Disruption of the orderly replacement of cartilage by osteoid matrix, with enlargement and lateral expansion of the osteochondral junction

• Abnormal overgrowth of capillaries and fibroblasts in the disorganised zone resulting from microfractures and stresses on the inadequately mineralised ,poorly formed bone

• Deformation of the skeleton due to loss of structural rigidity of the developing bones

• The gross structural changes in rickets depends on the severity and duration of the process

• During the non ambulatory stage of infancy ,the head and chest sustain the greatest stresses

• The softened occipital bones may become flattened, & the parietal bones can be buckled inwards by pressure

• With the release of pressure ,elastic recoil snaps the bones back into their orginal position (craniotabes)

• An excess of osteoid produces frontal bossing and a squared appearance to the head

• Deformation of chest results from overgrowth of cartilage at the costochondral junction ,producing the rachitic rosary

• The weakened metaphyseal areas of the ribs are subject to the pull of respiratory muscles and thus bends inwards ,creating anterior protrusion of the sternum (pigeon breast deformity)

• When an ambulating child develops rickets ,deformities are likely to affect the spine ,pelvis ,and tibia ,causing lumbar lordosis and bowing of the legs.

Osteomalacia• The newly formed osteoid matrix laid down by

osteoblasts is inadequately mineralised ,thus producing the excess of osteoid

• The contours of the bones are not affected ,the bone is weak & vulnerable to gross fractures ,likely to affect vertebral bodies and femoral necks

• The unmineralized osteoid appears as a thickened layer of matrix arranged about the more basoplilic normally mineralized trabeculae

Vitamin D Toxicity

• Prolonged exposure to normal sunlight does not produces an excess of vitamin D

• Megadoses of orally administered vit can lead to hypervitaminosis

• Causes metastatic calcification of soft tissues such as kidney

• In adult it causes bone pain and hypercalcemia• In sufficiently large doses it is a potent

rodenticide