VITAMIN DHISTORY

Reports of symptoms of ‘Rickets’ – As early as 2nd Century ADExperimental Rickets induced by dietary deficiency: Leonard Findlay in 1908 in puppies; Mc Collum in 1919 in rats1919 – Mellanby showed beneficial effects of cod liver oil in rickets1931 – Angus & Co-workers isolated Vitamin D & named it ‘CALCIFEROL’Structure – Otto Diels & Klurt Alder, Nobel Prize in 1950

Nomenclature & Occurrence

D Vitamins are a group of sterols having hormone-like functionProvitamin D2 : Ergosterol (Plants)Provitamin D3 : 7 – dehydrocholesterol

(Animals)Vitamin D2 : ErgocalciferolVitamin D3 : CholecalciferolCalcitriol : 1, 25 – dihydroxycholecalciferol

(Active form)

ChemistryVitamin D Structure closely resembles that of CholesterolIt is made up of 4 rings: A, B,C & D(Cyclopentanoperhydrophenanthrene Nucleus)B ring has a open structureA hydrocarbon chain attached at C17 positionHydroxyl group (OH) is present at C3

4 methyl groups are attached at C13, C18, C25

27 carbon atoms are presentErgocalciferol : contains a double dond between C22- C23 & an additional methyl group at C24

SourcesExposure of skin to sunlight – converts subcutaneous 7-dehydrocholesterol to cholecalciferolRich sources: Fish liver oil, liver, fish, egg yolk, fortified milkPlant sources: Fruits & Vegetables –supplies ergocalciferolPoor source: Cow’s & Buffallo’s Milk, unless fortified with Vitamin D

RDAPreschool children :

5 – 10 μg OR 200 – 400 I.UOlder Children & Adults :

2.5 – 5 μg OR 100 – 200 I.UPregnancy & Lactation and Elderly :

5 – 10 μg OR 200 – 400 I.U

Absorption, Transport, Storage & Excretion

o As of all fat soluble vitamins, Vitamin D also requires bile salts for its absorption

o Vitamin D is absorbed from duodenum & jejunum

o It is transported to blood by chylomicronso It is stored in the livero In plasma, it is transported to the target tissues

bound to α2 globulino Unabsorbed Vitamin D is excreted in faeces

Formation of Vitamin DVitamin D is formed from ergosterol or

7 – dehydrocholesterol by the action of Ultraviolet radiationsErgosterol is present in plants7 – dehydrocholesterol is present in the

Malphigian layer of epidermisUV – B photons (290 –315 nm) causes

photolysis of between position 9 & 10 →opening of ring B As a result, it forms ‘Ergocalciferol’ in plants

& ‘Secosterol’ in skin of animals

Formation…(Contd)Secosterol containing a cis-double bond is isomerised to trans-double bond, forming ‘Cholecalciferol’Production of Vitamin D in skin is directly

proportional to the exposure to the sunlight & inversely proportional to the pigmentation of the skinVitamin D2 & D3 present in the body are not biologically activeThey are converted to an active form by two

sequential hydroxylation reactions, occurring in liver & kidney respectively

Activation of Vitamin DCholecalciferol is first transported to

liver, where it undergoes first hydroxylation reaction at 25th positionThe reaction is catalysed by enzyme

‘25 α - hydroxylase’ requiring oxygen, NADPH & Mg2+ ions25-hydroxycholecalciferol formed is the

predominant form in plasma & a major storage form of Vitamin D

Activation of Vitamin D (Contd)25-hydroxycholecalciferol is transported to

kidneys, where it is further hydroxylated at 1st positionThe reaction is catalysed by enzyme

‘1 α - hydroxylase’ requiring oxygen, NADPH & Mg2+ ionsThis results in formation of ‘active

Vitamin D’ 1,25 – dihydroxycholecalciferolAlso called ‘Calcitriol’

CALCITRIOLCalcitriol is the most potent Vitamin D metaboliteIts formation is tightly regulated by the

plasma levels of calcium & phosphate ions and also calcitriol itself1 α - hydroxylase activity is increased

- directly by low plasma phosphate - indirectly by low plasma calcium & by

parathyroid hormone1 α - hydroxylase activity is decreased by

excess of calcitriol, the product of reaction itself

CALCITRIOL‘Calcitriol’ is called so because –- It has 3 hydroxyl groups at 1,3 & 25 positions- It is predominantly involved in calcium metabolism- ‘ol’ hydroxyl groups

Action of Active Vitamin D

Calcitriol acts as steroid hormoneIt induces the synthesis of calcium binding protein ‘Calbindin D’Calcitriol enters the target cell & binds to a cytoplasmic receptorCalcitriol-receptor complex carries it to the nucleus, where it interacts with DNAThis causes derepression & consequent transcription of specific genes that code for ‘Calbindin - D’

Action of Active Vitamin DThus there is an increased synthesis of this calcium binding protein, wherein the absorption of calcium is increasedTarget organs of calcitriol are intestine, bones & kidneysEffects of calcitriol on all tissues is inhibited by ‘Actinomycin D’Half life of calcitriol is 10 hours

Functions

Overall function: maintenance of adequate serum CALCIUM level (8.5 –10.5 mg/dl)The sites of action are:- Villi of Intestinal cells- Cells of Bones- Distal tubular cells of Kidneys

Villi of Intestinal CellsCalcitriol stimulates & promotes the absorption of calcium & phosphateMechanism of action : typical of

steroid hormonesResults in increased synthesis of

specific calcium binding proteins ‘Calbindin – D’

Bone – Dual Action☯ Calcitriol stimulates mobilisation of

calcium & phosphate from bones☯ The process requires protein

synthesis & presence of parathyroid hormone☯ Net result : ↑ Serum Calcium &

Phosphate levels☯ Function : DECREASED SERUM

CALCIUM LEVELS

Bone: Another ActionCalcitriol independently acts & increases the number & activity of ‘Osteoblasts’↑ Secretion of enzyme ‘Alkaline Phosphatase’ by osteoblastsIncreases the ionic concentration of calcium & phosphate to supersaturation levelsDeposition of calcium & phosphate as ‘Hydroxyapatite’ crystals → New bone formation / remodelling of existing bonesFunction : NORMAL SERUM CALCIUM LEVELS

Distal Tubular Cells of KidneysCalcitriol increases the reabsorption of

filtered calcium & phosphorus↓ the excretion of calcium & phosphorus

from kidneys

Other functionFormation of Teeth

- Calcitriol plays a very important role in the formation of teeth

Deficiency ManifestationsAs Vitamin D is synthesised in the body,

deficiency is comparatively rareUsually seen in children, during pregnancy &

lactation & in elderlyDeficiency can occur in people who do not

adequately expose skin to sunlight as in :- Inhabitants of polar region- People bedridden for long periods- People following ‘Purdah’ systemDeficiency leads to ‘RICKETS’ in children &

‘OSTEOMALACIA’ in adults

RICKETS

Mostly affects children between the age of 1 & 3 YearsIn rickets – Insufficient minealisation

of new bone matrix → Bones becomes soft & pliable, bending of weight bearing bones & Retardation of bone growth at epiphysis

Rickets - CausesNutritional – deficiency of Vitamin DMalabsorption – Bile salts deficiency &

diarrhoeaAbnormality in Activation – Enzyme

deficiencyDiseases of Liver & Kidneys – Cirrhosis

& Renal failureEnd organ resistance – Lack of

receptors

Rickets – Signs & SymptomsClinical Manifestations include :

- Bow legs- Knock knee- Ricketry rosary- Bossing of frontal bones- Pigeon chest- Harrison’s sulcus- Delayed mile stones : walking & teething

Osteomalacia

Bones become softInsufficient mineralisationIncreased osteoporosisBone achesFracture tendencies

Assessment of DeficiencyDecreased serum Calcium levelDecreased serum Phosphate levelDecreased Serum Vitamin D levelIncreased Serum Alkaline

Phosphatase ActivityIncreased Parathyroid hormone level

in serum

Treatment & PreventionAdequate exposure of skin to

sunlightPeriodic dosing of preschool

children with Vitamin DVitamin D fortification of foods

HYPERVITAMINOSIS D

Most toxic of all vitaminsReadily formed, stored in adequate quantities, slowly metabolised & sparingly excretedAdministration of high doses (about 1 lakh I.U.) of Vitamin D for weeks

FeaturesSymptoms include: Weakness, polyuria, loss of appetite, intense thirst, nausea, weight lossCalcification of soft tissues – kidneys & arteriesHypercalcemia, Hypokalemia & Metabolic alkalosisTreatment : Symptomatic, avoiding exposure of skin to sunlight & avoiding diet containing Vitamin D & calcium rich foods

Wish You All

a ‘Happy & Safe Diwali’