Vitamin D

Vitamin D

PKGhatak,MD

Vitamin D is a fat soluble vitamin. It is also a hormone.

Cholecalciferol, known as Vitamin D3, is vitamin D for vertebrates. Vitamin D2 is Ergocalciferol, and it is vitamin D for invertebrates, aquatic plants, and fungi.

Our daily requirement of vitamin D recently raised to 600 IU or 15 mcg a day from 400 IU. The important dietary sources of vitamin D are fish, milk, eggs, meat and field mushrooms. In the USA   milk, cereals, and margarine are fortified with vitamin D. A serving of 3 oz fish supplies 200 to 400 IU, 15 ml of cod liver oil 1400 IU, a large egg about 40 IU, and beef 3 oz 15 IU of vitamin D. For strict vegetarians (vegans) sunlight exposed or ultraviolet B light exposed mushrooms, and yeasts are the only source of vitamin D.

Cholecalciferol - vitamin D3, however, is not an active vitamin. Vitamin D3 is taken up by the liver cells and converted to Calcidiol {25(OH) D}. It is stored in the liver cells, where it combines with alpha globulin and is released into the blood when required. Calcidiol is a weak vitamin D. When it reaches the Proximal Tubular cells of the Kidney the calcidiol is converted to Calcitriol {1,25(OH)2D} by the action of Parathyroid Hormone (PTH). Low blood levels of phosphates also stimulate the activation of vitamin 1,25(OH)2D.  Calcitriol is the active hormone/vitamin D3. It circulates in the blood bound to a protein called vitamin D binding protein (VDBP).  The active vitamin attaches to the vitamin D- Receptors (VDR) on the nucleus of cells of the small intestine, bone, heart, gonads, prostate, brain, and other tissues; and in turn, produce specific proteins for specific functions.

Cholecalciferol is produced by the cells of the deeper layers of the Skin from a normally present cholesterol derivative- 7 dehydroxycholesterol when exposed to the ultraviolet B (UVB) light of sun rays. In tropical countries, people exposed to the sun even for a short time can produce their daily requirements of vitamin D.   However, as vitamin D accumulates in the skin this process slows down and excess vitamin D is broken down. In temperate regions, there is not enough UVB light in sun rays for the skin to produce sufficient quantities of vitamin D; moreover, sun-blocking lotions and melanin pigment of the skin block UVB light. Window glass blocks UVB and indoor sun exposure has no effect on vitamin D production. Calcitriol must be supplied to the body with food.

White blood cells and macrophages are also capable of producing calcitriol for its use locally.

Vitamin D3 is manufactured for commercial use by UVB exposure of wool fat; D2 is produced by the same process on yeasts. Liver and fat cells store vitamin D as 25(OH)D. An obese person has more stored vitamin D than a thin individual. Recently questions have been raised about whether vitamin D2 can be fully converted to D3 in humans. Excess vitamin D is secreted in bile and reabsorbed in the terminal ileum.  1,25(OH)2D is broken down in various tissues by enzymes.

The vitamin D receptors (VDR) in different tissues differ in their response to 1,25(OH)2D. The receptors of the cells of the small intestine are the most active.  These activated receptors promote specific protein production by target genes which in turn combine with calcium in the intestine and carry calcium across the cells to the portal circulation and to the liver. Vitamin D also promotes phosphate absorption in the small intestine. In the proximal tubular cells of the kidney under the influence of PTH, the 1,25(OH)2D activates the VDR and thereby promotes calcium reabsorption. In bone, the 1,25(OH)2D has multiple actions by activating several genes. In osteoblasts, it promotes calcium deposition, increases bone matrix proteins and type 1 collagen production and bone growth.  Osteoclasts are activated by cytokines released by osteoblasts by the action of PTH and help bone resorption and increase serum calcium.

In parathyroid glands calcium bound VDR, depresses cell proliferation thereby lowers PTH production. It also has antiproliferative effects on keratinocytes of the skin and cancerous cells of the prostate and breast.

It should be understood that there is more than one cause of decreased vitamin D activities in humans. The most common cause of deficiency is dietary; other causes are- advanced liver disease and renal failure, diseases of the small intestine, malabsorption syndrome, and lack of exposure to sun rays, hypoparathyroidism and congenital abnormality of genes. Drugs also interfere with vitamin D e.g.-Barbiturates, Phenytoin, Ketoconazole, INH, and Rifampin.

Normal blood levels of vitamin D are 15 to 25 ng/ml or 37 to 62 nmol/L.   Laboratory reports vitamin D results as 25(OH)D. About 90% of vitamin D in the blood is bound to VDBP, free D [1,25(OH)2D] vitamin is 0.03%, and the rest is combined with serum albumin

The free active vitamin D3 remains normal in face of vitamin deficiency because the renal distal tubular cells are still capable of turning out adequate quantities of active vitamin D3[1,25(OH)2D3] by acting on the dwindling store of vitamin 25(OH)D3. 

Symptoms of vitamin D deficiency in adults are non-specific- the weakness of muscles of the shoulders, hips, and thighs may be the only symptoms. When deficiency persists in thinning of bones (osteopenia), loss of mineralization of bone (osteomalacia) may be detected by X-ray and bone densitometry respectively.   When vitamin D deficiency persists for months, Parathyroid glands become overactive and produce excess Parathyroid Hormone (PTH) in order to maintain a steady normal blood level of calcium. Due to the increase in PTH   phosphates loss continues through the kidney and bones become more demineralized and become soft. Bowing of these softened bones occurs under the weight of the body and fractures may result. At this stage, if treatment for osteomalacia is started with Bisphosphonates, (Fosamax) which prevents PTH action on osteoclasts,  an acute hypocalcemia may develop, and it may manifest as tetany or laryngospasm. The treatment should be directed to correct vitamin D and calcium deficiencies first.

In children, vitamin deficiency leads to rickets, growth retardation and hypocalcemia tetany.

A short summary of action of vitamin D.

1. Increases serum calcium levels by (a) increased calcium and phosphate absorption,(b) increased release of calcium from the bones by stimulating osteoclastic activities, and (c) increased renal reabsorption of filtered calcium in the renal tubules.

2. If adequate estrogen, growth hormone, and thyroid hormone are present, vitamin D promotes new matrix formation.

When mega dose vitamin D is taken it may bypass normal controlled vitamin D absorption in the gut, instead, combine with lipoproteins and is carried directly to macrophages in arterial plaques and promote calcification of plaques. When blood levels of vitamin D are high vitamin 25(OH) D may displace 1,25(OH)2 D from the vitamin D binding protein thereby, increasing free 1,25 (OH)2D levels. Active vitamin D [1,25(OH)2] directly attaches to the vitamin D receptors and thereby calcium blood levels increase further.  A high dose of vitamin D therapy (40,000 IU) over several months may lead to high serum calcium, large urine output, increased frequency of urination, kidney stones, kidney failure and calcification of the kidney and other tissues.  
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