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Vit D
This document discusses vitamin D, including its forms, functions, metabolism, and deficiency/toxicity. Some key points: - Vitamin D exists in two forms, D2 and D3. D3 is produced in the skin upon sun exposure and converted to its active form in the liver and kidneys. - Its active form, calcitriol, regulates calcium and phosphorus levels by increasing their absorption in the intestine and reabsorption in kidneys. It also mobilizes calcium from bones. - Deficiency causes rickets in children and osteomalacia in adults due to impaired bone mineralization. Toxicity leads to hypercalcemia which can damage soft tissues like kidneys.
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Vit D
- 1. VITAMIN - D Assistantprofessor Rupendra shakya MS Medical Biochemistry
- 2. Introduction Vitamin Dis a fat-soluble vitamin with hormonal functions. Vitamin D helps calcium and phosphorus homeostasis and bone metabolism. Vitamin D is naturally present in very few foods, added to others and available as a dietary supplement. It is also produced endogenously when ultraviolet rays from sunlight strike the skin and trigger vitamin D synthesis. Vitamin D obtained from sun exposure, food and supplements is biologically inert and must undergo two hydroxylations in the body for activation. Vitamin D has 2 distinct forms: vitamin D2 and vitamin D3. Vitamin D2 is a 28-carbon molecule derived from the plant sterol ergosterol, whereas vitamin D3 is a 27-carbon derivative of cholesterol. Vitamin D2 differs from vitamin D3 in that it contains an extra methyl group and a double bond between carbons 22 and 23
- 3. Only two ofthese have been found in nature. • Ergosterol: Provitamin D2 found in plants. • 7-dehydrocholesterol: Provitamin D3 found in the skin. All the provitamins D possess a certain essential structural characteristics. • OH group at C3 • Two conjugated double-bonds between C5-C6 and between C7-C8. Transformation from inactive provitamin to the active vitamin is accomplished by the ultraviolet rays. Then photochemical activation, photolysis results only in intramolecular rearrangement
- 4. Dietary Sources Fishliver oil is the richest source of vitamin D. Egg-yolk, margarine, lard, also contain considerable quantity of vitamin D. Some quantity is also present in butter, cheese. Ergosterol is widely distributed in plants. It is not absorbed well hence is not of nutritional importance. Calciferol is readily absorbed. 7-dehydrocholesterol is formed from cholesterol in the intestinal mucosa, and principally liver, passed on to the skin where it undergoes activation to vitamin D3 by the action of solar UV rays.
- 5. FUNCTIONS MAINTAIN ADEQUATELEVEL OF CALCIUM IN PLASMA INCREASE UPTAKE OF CALCIUM BY ABSORPTION FROM INTESTINE. VIT D ALONG WITH PARATHYROID HARMONE HELPS IN BONE FORMATION WHICH CAUSES ELEVATION OF CALCIUM. MINIMIZE THE EXCRETION OF CALCIUM AND PHOSPHATES AND ENHANCING REABSORPTION CLINICALIMPORTANCE Nutritional rickets Demineralization of bone
- 6. RDA Children: - 10µg/day or 400 IU Adults – :5 -10µg/day or 200IU Pregnancy , lactation :-10µg/day Above the age of 60 :- 600IU/day
- 7. Vitamin-D level inBlood serum Normal Range:-20-40ng/ml High :-60-90ng/mL Deficient:- Less than 10ng/ml Toxic:- Greater than 90ng/ml
- 8. Vitamin- D issunshine During the course of cholesterol biosynthesis 7- dehydrocholesterol is formed as an intermediate. On exposure to sunlight, 7-dehydrocholesterol is converted to cholecalciferol in the skin (dermis and epidermis) Dark skin pigment (melanin) adversely influences the synthesis of cholecalciferol Skin is the largest organ in the body The production of vitamin D in the skin is directly proportional to the exposure to sunlight and inversely proportional to the pigmentation of skin Excessive exposure to sunlight does not result in vitamin D toxicity since excess provitamin D3 are destroyed by sunlight itself
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- 11. Metabolism Absorption Diet fromanimal sources such as animal liver contains vitamin D3 Diet from plant sources contains vitamin D2 Absorption: vitamin D2 and D3 are absorbed from upper small intestine and bile is essential Mechanism: vitamin D3 and D2 form mixed micelles by combining with bile salts (micelles) Mixed micelles are presented to intestinal Lumen. Absorption occurs by passive transport
- 12. Transport VitaminD binding globulin: vitamin D is transported from intestine to the liver by binding to vitamin D binding globulin 25 – Hydroxy D3 and 1,25 – dihydroxy D3 are also transported in the blood by binding to vitamin D binding globulin Storage: 25 – hydroxycholecalciferol is the major storage and circulatory form of vitamin D
- 14. Metabolism and BiochemicalFunctions Synthesis of 1,25 – Dihydroxycholecalciferol: Active form: the active form of vitamin D is 1,25 – Dihydroxycholecalciferol and is also called as calcitriol Cholecalciferol is first hydroxylated at 25th position to 25 – hydroxycholecalciferol by a specific hydroxylase present in liver Kidney possesses a specific enzyme, 25 – hydroxycholecalciferol 1 hydroxylase 25 – hydroxycholecalciferol 1 – hydroxylase hydroxylates 25 – hydroxycholecalciferol at position 1 to produce 1,25 – Dihydroxycholecalciferol (1,25-DHCC) 1,25 – DHCC contains 3 hydroxyl groups (1, 3, 25) and called as calcitriol Both hydroxylase enzymes (of liver and kidney) require cytochrome P450, NADPH and molecular oxygen for hydroxylation process
- 15. Regulation Formationof 1,25 – DHCC is regulated by the regulation of renal 1 α – hydroxylase 1 α – hydroxylase activity is increased by hypocalcemia Hypocalcemia stimulates PTH secretion which, in turn, increases 1 α – hydroxylase 1 α – hydroxylase activity may be feedback inhibited by 1,25 – DHCC. Clinical Importance In chronic renal failure, 1 α – hydroxylase activity is decreased leading to decreased synthesis of 1,25 – DHCC The condition leads to renal osteodystrophy (renal rickets) Condition is treated by giving 1,25 – DHCC preparations 1 α – hydroxylase deficiency can also occurs as inherited disorder or due to hypoparathyroidism
- 16. Regulation of Plasmacalcium and Phosphorus Vitamin D regulates the plasma levels of calcium and phosphorous Plasma calcium levels are regulated by effects of 1,25 – DHCC on small intestine, kidney and bone It maintains the plasma calcium levels by increasing absorption of calcium from small intestine, increasing reabsorption of calcium by renal distal tubules and increasing mobilization of calcium from bone. Biochemical Functions Calcitriol (1,25 – DHCC) acts at three different levels to maintain plasma calcium Action on intestine: Calcitriol increases the intestinal absorption of calcium and phosphate In the intestinal cells, calcitriol binds with a cytosolic receptor to form a calcitriol-receptor complex. This complex interacts with a specific DNA leading to the synthesis of a specific calcium binding protein This protein increases calcium uptake by intestine.
- 17. Actionon bone: In osteoblasts of bone, calcitriol stimulates calcium uptake for deposition as calcium phosphate Calcitriol is essential for bone formation Calcitriol along with parathyroid hormone increases the mobilization of calcium and phosphate from the bone Causes elevation in the plasma calcium and phosphate. Action on kidney: Calcitriol is also involved in minimizing the excretion of calcium and phosphate through the kidney by decreasing their excretion and enhancing reabsorption.
- 18. Vitamin-D is aHormone Calcitriol is considered as an important calciotropic hormone, while cholecalciferol is the prohormone . 1. Vitamin D3 (cholecalciferol) is synthesized in the skin by the UV – rays of sunlight. 2. The biologically active form of vitamin D, calcitriol is produced in the kidney. 3. Calcitriol has target organs- intestine, bone and kidney. 4. Calcitriol action is similar to that of steroid hormones It binds to a receptor in the cytosol and the complex acts on DNA to stimulate the synthesis of calcium binding protein. 5. Calcitriol synthesis is self-regulated by a feedback mechanism i.e., calcitriol decreases its own synthesis. 6. Actinomycin D inhibits the action of calcitriol, calcitriol exerts its effect on DNA leading to the synthesis of RNA (transcription)
- 19. Deficiency of vitaminD Deficiency of vitamin D causes rickets in children and osteomalacia in adults Rickets: It is a vitamin D deficiency state in children Causes: Dietary deficiency and non-exposure to sunlight Rickets in children is characterized by bone deformities due to incomplete mineralization Causing enlargement and softening of bones Delay in teeth formation The weight bearing bones are bent to form bow-legs Decreased serum calcium. Deformation of muscles: potbelly due to weakness of abdominal muscles Biochemical findings: Decreased serum calcium (9-11mg/dl) Decreased plasma phosphorous (3-4.5 mg/dl) Increased plasma alkaline phosphatase (30-130 IU)
- 20. Osteomalcia Vitamin Ddeficiency in adults Causes: Inadequate exposure to sunlight or low dietary intake Features: Demineralization occurs mainly in spine, pelvis and lower extremities Bowing of the long bones may occur due to weight of the body Flattening of pelvis bones may cause difficulty during labour. Renal Rickets In chronic renal failure, 1 α – hydroxylase activity is decreased leading to decreased synthesis of 1,25 – DHCC The condition leads to renal osteodystrophy (renal rickets) Condition is treated by giving 1,25 – DHCC preparations 1 α – hydroxylase deficiency can also occurs as inherited disorder or due to hypoparathyroidism
- 21. Vitamin-D Toxicity VitaminD is stored mainly in liver Vitamin D is most toxic in overdoses Toxic effects include demineralization of bones and increased calcium absorption from intestine, leading increased plasma calcium (hypercalcemia) Hypercalcemia is associated with deposition of calcium in many soft tissues such as kidney and arteries It leads to formation of stones (renal calculi) High consumption is associated with loss of appetite, nausea, increased thirst, loss of weight etc
- 22. Hypervitaminosis- D Normallyvit D is well tolerated if taken in large doses but serious deleterious effects may be produced if taken in extremely large doses, 500 to 1000 times of normal requirement for prolonged periods. Effects are mainly due to induced hypercalcaemia. • Immediate effects and Delayed effects. 1. Immediate effects: Include anorexia, thirst, lassitude, constipation and polyuria. Followed later on by nausea, vomiting and diarrhoea. 2. Delayed effects: constant hypercalcaemia and hyperphosphataemia may produce: • Urinary lithiasis • Metastatic calcification which may affect kidneys, bronchi, pulmonary alveoli, muscles and gastric mucosa. Renal failure may develop and can lead to death.
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