Major Sources a. Sunlight: The skin, where ultraviolet radiation converts 7-dehydrocholesterol to vitamin D3 (cholecalciferol). b. Dietary sources of

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1 Vitamin D consists of 2 forms: i) Calciferol [Vit D2] ii) Cholecalciferol [Vit D3] Vitamin D itself is metabolically inactive but it requires conversion to 25 HCC & 1:25 DHCC which are active metabolite.

2 Major Sources a. Sunlight: The skin, where ultraviolet radiation converts 7-dehydrocholesterol to vitamin D3 (cholecalciferol). b. Dietary sources of vitamin D3: fish (marine), liver, and egg yolks, butter,cheese Fish liver oil is the richest source,human milk also contains water soluble Vit D sulfate. c. Foods fortified with vitamin D2 (ergocalciferol): dairy foods, margarine, and cereals Foods: Liver,Egg,Butter,Cheese Adequate intake of vitamin D is : 5 1ug/day (in the absence of adequate sunlight)

3 Activation After endogenous production from cholesterol by UV light on 7-dehydrocholesterol in the skin. Vitamin D is carried to the liver, where it is converted to 25-hydroxychole-calciferol [25(OH)D3]. After 25-hydroxylation in the liver, it is completely activated by 1-hydroxylation in the kidney. The kidney converts 25(OH)D3 to the active form, 1,25(OH)2D3. PTH, which is secreted in response to low serum calcium, stimulates the conversion to 1,25(OH)2D3.

4 Recommended Dietary Allowance Adults: 2.5 mcg/day Infants & Children: 5mcg/day Pregnancy & Lactation: 10.0 mcg/day

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6 Recommended Dietary Allowance Recommended Dietary Allowance Adults: 2.5 mcg/day Infants & Children: 5mcg/day Pregnancy & Lactation: 10.0 mcg/day

7 Functions of Vitamin D include 1. Regulation of calcium ion (Ca+ +) metabolism a. It facilitates intestinal absorption of dietary phosphorus and calcium by stimulating synthesis of calcium-binding protein in the intestinal mucosa, in combination with parathyroid hormone (PTH). b. It promotes normal bone demineralization by stimulating osteoblast activity, thus releasing Ca++ into the blood. c. It stimulates Ca++ reabsorption by the distal renal tubules, which also elevates blood Ca+ + It thus effects calcium and phosphorus metabolism. It also enhances bone resorption, and affects collagen maturation. Promotes normal growth.

8 Vitamin D Deficiency Vitamin D Deficiency is a common major problem worldwide, especially among the dark-skinned or at very high latitudes. All the sun exposure that's required for a light-skinned person is 5-10 minutes, 2-3 times weekly, arms-and-legs or arms-handsface. Women in countries where they are required to remain veiled when they go outdoors are at greatly increased risk for rickets (e.g. in sunny Kuwait, can you believe it?!)

9 Other causes of vitamin D deficiency, apart from poor intake and poor sun exposure include malabsorption, nephrotic syndrome (loss of vitamin D and its binding protein in the urine), abuse of antacid some odd inborn errors of metabolism (vitamin D resistant rickets; type I lacks 1- hydroxylase in the kidney, type II

10 The bony lesions of vitamin D deficiency are called "rickets" in growing children, and "osteomalacia" in grown-ups. The essential lesion in both rickets and osteomalacia is failure of osteoid (bone matrix) to mineralize. Vitamin D deficiency after epiphyseal fusion causes osteomalacia, which may present as bone pain and muscle weakness, and produces less deformity than rickets. In cases of osteomalacia (which occurs in adults) noncalcified bone looks pale on x-ray, and tends to break due to demineralization of existing bones, with pathologic fractures Bone demineralization may also result from the conversion of vitamin D to inactive forms, which is stimulated by glucocorticoids. Patients also experience joint pain, and muscle weakness

11 The result of vitamin D deficiency in young children is called rickets, a constellation of skeletal abnormalities most strikingly seen as deformities of the legs, but many other developing bones are affected. Rickets is due to improperly mineralized, soft bones and stunted growth. Rickets occurs in children up to 2 yrs of age. There is hypocalcemia, laryngeal spasm and seizures, listleness, irritability, muscular weakness, RACHITIC ROSARY, curved legs, deformed pelvis, pigeon chest & Harrisons groove. In rickets the epiphyseal cartilage does not calcify, and overgrows.

12 Features of rickets include "craniotabes" (inward buckling of skull bones), "frontal bossing" and "square head", "rachitic rosary" (knobs on the costochondral junctions), "pigeon breast" (anterior protrusion of the sternum, pulled forward by the respiratory muscles), "lumbar lordosis [ spine curve] and "bow legs".

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21 Vitamin D Toxicity Vitamin D toxicity, which occurs with high doses (> 250 ~g/day in adults, 25~g/day in children). Excess vitamin D ingestion (i.e., taking too much) may lead to the following conditions: a. Hypercalcemia due to enhanced Ca++ absorption and bone resorption b. Metastatic calcification in soft tissue C. Bone demineralization d. Hypercalcuria, resulting in kidney stone formation

22 Vitamin D Toxicity A 45-year-old man had a 3-week history of weakness, excessive urination, intense thirst, and staggering walk. For most of his adult life, he took excessive amounts of vitamin C because he was told it would be beneficial in preventing the common cold. But in the past month, he took excessive amounts of vitamin D and calcium every day because he learned that he was developing osteoporosis. When he took the vitamin D, laboratory tests revealed that his serum calcium was greatly elevated compared with normal levels. Vitamin D toxicity was the diagnosis.

23 Vitamin D is highly toxic at consumption levels that continuously exceed lo times the RDA, resulting in hypercalcemia. Unlike water-soluble vitamins, which are excreted in excess amounts, vitamin D can be stored in liver as 25- hydroxycholecalciferol. The excess vitamin D can promote intestinal absorption of calcium and phosphate. The direct effect of excessive vitamin D on bone is resorption similar to that seen in vitamin D deficiency. Therefore, the increased intestinal absorption of calcium in vitamin D toxicity contributes to hypercalcemia. Rather than helping the man's osteoporosis, a large amount of vitamin D can contribute to it. Hypercalcemia can impair renal function, and early signs include polyuria, polydipsia, and nocturia. Prolonged hypercalcemia can result in calcium deposition in soft tissues, notably the kidney, producing irreversible kidney damage.

24 VITAMIN D AND CALCIUM HOMEOSTASIS Hypocalcemia (below-normal blood calcium) stimulates release of parathyroid hormone (PTH), which in turn binds to receptors on cells of the renal proximal tubules. The receptors are coupled through camp to activation of a lalpha-hydroxylase important for the final, rate-limiting step in the conversion of vitamin D to 1,25-DHCC (dihydroxycholecalciferol or calcitriol). Once formed, 1,25-DHCC acts on duodenal epithelial cells as a lipid-soluble hormone. Its intracellular receptor (a Zn-finger protein) binds to response elements in enhancer regions of DNA to induce the synthesis of calcium-binding proteins thought to play a role in stimulating calcium uptake from the GI tract. 1,25-DHCC also facilitates calcium reabsorption in the kidney and mobilizes calcium from bone when PTH is also present. All these actions help bring blood calcium levels back within the normal range. The relation of vitamin D to calcium homeostasis and its in vivo activation are shown in Figure

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26 Synthesis of 1,25-Dihydroxycholecalciferol (Calcitriol) Humans can synthesize calcitriol from 7-dehydrocholesterol derived from cholesterol in the liver. Three steps are involved, each occurring in a different tissue: 1.Activation of 7-dehydrocholesterol by UV light in the skin produces cholecalciferol (vitamin D3) This step is insufficient in many people in cold, cloudy climates, and vitamin D3 supplementation is necessary Hydroxylation in the liver (patients with severe liver disease may need to be given 25-DHCC or 1,25-DHCC). 3.lalpha-Hydroxylation in the proximal renal tubule cells in response to PTH. Genetic deficiencies or patients with endstage renal disease develop renal osteodystrophy because of insufficiency of 1,25-DHCC and must be given 1,25-DHCC or a drug analog that does not require metabolism in the kidney. Such patients include those with: End-stage renal disease secondary to diabetes mellitus Fanconi renal syndrome (renal proximal tubule defect) Genetic deficiency of the loc-hydroxylase (vitamin D-resistant rickets)