Wednesday, 23 October 2019

Vitamin D

Vitamin D

What is Vitamin D?

The term vitamin D designates a group of chemically related compounds that possess antirachitic activity. The two most prominent members of this group are vitamin D 2 (ergocalciferol) and vitamin D 3 (cholecalciferol). Vitamin D 2 is derived from a common plant steroid, ergosterol, and is the form that was employed for nutritional vitamin D fortification of foods from the 1940s to 1960s. Vitamin D 3 is the form of vitamin D obtained when radiant energy from the sun strikes the skin and converts the precursor 7-dehydrocholesterol. Since the body is capable of producing vitamin D 3, vitamin D does not meet the classical definition of a vitamin. A more accurate description of vitamin D is that it is a prohormone; thus, vitamin D is metabolized to a biologically active form that functions as a steroid hormone.

History of Vitamin D

Rickets, a deficiency disease of vitamin D, appears to have been a problem in ancient times. About 50,000 BC evidence that rickets occurred in Neanderthal man. The first scientific descriptions of rickets were written by Dr. Daniel Whistler in 1645 and by Professor Francis Glisson in 1650. Rickets became a health problem in northern Europe, England, and the United States during the Industrial Revolution when many people lived in urban areas with air pollution and little sunlight. Before the discovery of vitamin D, the theories on the causative factors of rickets ranged from heredity to syphilis.

Structure of Vitamin D

Structure of Vitamin D

Chemistry and irradiation pathway for the production of vitamin D 3 (a natural process) and vitamin D2 (commercial process). In each instance, the provitamin, with a D5, D7 conjugated double-bond system in the Bring, is converted to this co-B previtamin, with the 9, 10 carbon-carbon bond broken. Then the vitamin D thermally isomerizes to the vitamin form, which contains a system of three conjugated double bonds. In solution, vitamin D is capable of assuming a large number of conformations because of the rotation about the 6, 7 carbon-carbon bond of the Bring. The 6-s-cis conformer (the steroid-like shape) and the 6-s-trans conformer (the extended shape) are presented for both vitamin D 2 and vitamin D 3.

Isolation of Vitamin D

Many of the studies that have led to our understanding of the mode of action of vitamin D have involved the tissue localization and identification of vitamin D and its 37 metabolites. Since vitamin D is a steroid, it is isolated from the tissue by methods that extract total lipids. The technique most frequently used for this extraction is the method of Bligh and Dyer.

There are lots of wide variety of chromatographic techniques have been used to separate vitamin D and its metabolites. These include a thin layer, paper, column, and gas chromatographic methods. Paper and thin-layer chromatography usually require long development times, unsatisfactory resolutions, and have limited capacity. Column chromatography, using alumina, Floridin, celite, silica acid, and Sephadex LH-20 as supports, has been used to rapidly separate many closely related vitamin D compounds. However, none of these methods is capable of resolving and distinguishing vitamin D 2 from vitamin D 3 . Gas chromatography is able to separate these two compounds, but in the process vitamin Disthermally converted to pyrocalciferol and isopyrocalciferol, resulting in two peaks. High-pressure liquid chromatography (LC)has become the method of choice for the separation of vitamin D and its metabolites. This powerful technique is rapid and gives good recovery with high resolution.

Foods Source of Vitamin D

Foods Source of Vitamin D

Vitamin D occurs naturally in unfortified foods. Generally derived from animal products, salt-water fish such as herring, salmon, and sardines contain substantial amounts of vitamin D, and fish-liver oils are extremely rich sources. However, veal, beef, eggs, unfortified milk, and butter supply only small quantities of the vitamin, see this picture:

Foods Source of Vitamin D

Vitamin D Deficiency Diseases

Vitamin D Deficiency Diseases

A deficiency of vitamin D results in inadequate intestinal absorption and renal reabsorption of calcium and phosphate. As a consequence, serum calcium and phosphate levels fall and serum alkaline phosphatase activity increases. In response to these low serum calcium levels, hyperparathyroidism occurs. Increased levels of PTH, along with whatever 1α, 25(OH)2D3 is still present at the onset of the deficiency, result in the demineralization of bone. This ultimately leads to rickets in children and osteomalacia in adults. The classical skeletal symptoms associated with rickets, that is, bowlegs, knock-knees, the curvature of the spine, and pelvic and thoracic deformities, resulting from the application of normal mechanical stress to the demineralized bone. Enlargement of the bones, especially in the knees, wrists, and ankles, and changes in the costochondral junctions also occur. Since in children bone growth is still occurring, rickets can result in epiphyseal abnormalities not seen in adult osteomalacia. Rickets also results in inadequate mineralization of tooth enamel and dentin. If the disease occurs during the first 6 months of life, convulsions and tetany can occur. Few adults with osteomalacia develop tetany.

Low serum calcium levels in the range of 5–7 mg=100 ml and high serum alkaline phosphatase activity can be used to diagnose rickets and osteomalacia. In addition, a marked reduction in circulating 25(OH)D3 levels in individuals with osteomalacia or rickets have been reported. As noted earlier in the section Nutritional Requirements for Vitamin D, a substantial proportion of the US population is exposed to suboptimal levels of sunlight; this is particularly true during winter months. Under these conditions, vitamin D useful, which indicates that it must be supplied in the diet on a regular basis. In the past 5 years, a substantial number of clinical reports from many countries and on many endpoints have indicated that there is likely a widespread vitamin D deficiency as defined by a serum level of 25(OH)D3 that is lower than 50 nmol=L (20 ng=ml). Low 25(OH)D3 levels in patients have been found to be associated with increased periodontal disease. Secondary hyperparathyroidism linked with increased rates of hip fracture and osteoporosis in northern Europe and the North American continent and reduced bone mineral density (BMD) in persons with a primary knee injury in association with osteoarthritis [416] and in both veiled and unveiled Bangladeshi women.

Intestinal Disorders

The intestine functions as the site of dietary vitamin D absorption and is also a primary target tissue for the hormonally active 1α, 25(OH)2D3. Impairment of intestinal absorption of vitamin D can occur in intestinal disorders that result in the malabsorption of fat. Patients suffering from such disorders as tropical sprue, regional enteritis, and multiple jejunal diverticulosis often develop osteomalacia because of what appears to be malabsorption of vitamin D from the diet. Surgical conditions, such as gastric resection and jejunal–ileal bypass surgery for obesity, may also impair vitamin D absorption. In addition, patients receiving total parenteral nutrition in the treatment of the malnutrition caused by the profound gastrointestinal diseases often develop bone disease.

The intestinal response to vitamin D can be affected by certain disease states. Patients suffering from idiopathic hypercalciuria exhibit an increased intestinal absorption of calcium that may result from an enhanced intestinal sensitivity to 1α, 25(OH)2D3 or from an overproduction of 1α, 25(OH)2D3. Sarcoidosis is characterized by hypercalcemia and hypercalciuria in patients receiving only modest amounts of vitamin D. The enhanced sensitivity to the parent vitamin D is because of elevated levels of serum 1α, 25(OH)2D3. The excess 1α, 25(OH)2D3 is likely of extrarenal origin and therefore not regulated by circulating levels of PTH. Other experiments have clearly shown that macrophages from patients with sarcoidosis can produce 1α, 25(OH)2D3.

Other disease states that can result in extrarenal production of 1α, 25(OH)2D3 are tuberculosis, leprosy, and some lymphomas. In one study of polymorphisms related to susceptibility to leprosy in more than 200 individuals from northern Malawi, it was found that individuals homozygous for a silent T!C change in codon 352 of the VDR gene appeared to be at high risk for this disease.

Liver Disorders

The liver plays an important role in the vitamin D endocrine system; not only it is the primary site for the production of 25(OH)D and the synthesis of plasma DBP, but it is also the source of the bile salts that aid in the intestinal absorption of vitamin D. Hence, malfunctions of the liver can interfere with the absorption, transport, and metabolism of vitamin D. Malabsorption of calcium and the appearance of bone disease have been reported in patients suffering from either primary biliary cirrhosis or from the prolonged obstructive jaundice. The disappearance of radioactive vitamin D from the plasma of these patients is much slower than that in normal subjects, and their plasma 25(OH)D levels are reduced. Although these patients respond poorly to vitamin D treatment, they immediately respond if treated with 25(OH)D3. Thus, it appears that the bone disease experienced by these patients results from their inability to produce 25(OH)D.

Renal Disorders

Since the kidney functions as the endocrine gland for 1α, 25(OH)2D3, disease states that affect the kidney can alter the production of this calcium homeostatic hormone. It is well known that patients with renal failure often also suffer from skeletal abnormalities, termed renal osteodystrophy, a spectrum of disorders including growth retardation, osteitis fibrosa, osteomalacia, and osteosclerosis. Support for the idea that renal osteodystrophy is a result of the failure of the kidney to make 1α, 25(OH)2D3 came from studies on the metabolism of the radioactively labeled vitamin D in normal persons versus patients with chronic renal failure. In normal subjects, the circulating level of 1α, 25(OH)2D3 is in the range of 30–35 pg=ml, whereas in chronic renal failure the levels have been reported as low as 3–6 pg=ml. A successful renal transplant results in the return of 1α, 25(OH)2D3 levels to the normal range. In addition, the administration of 1α, 25(OH)2D3 to these patients results in the stimulation of ICA and an elevation of serum calcium levels.

Parathyroid Disorders

Since PTH stimulates the production of 1α, 25(OH)2D3 in the kidney, any disease state that affects the secretion of PTH may, in turn, have an effect on the metabolism of vitamin D. Hyperactivity of the parathyroid glands, as in primary hyperparathyroidism, results in the appearance of bone disease resembling osteomalacia. Circulating 1α, 25(OH)2D3 levels in these subjects have been reported to be significantly elevated, as is their ICT. On the other hand, in hypoparathyroidism, hypocalcemia occurs. In these patients as a light reduction in circulating 1α, 25(OH)2D3 levels have been reported. When these patients are treated with 1α, 25(OH)2D3, their serum levels of PTH and calcium return to normal. There are several review articles on the role of vitamin D in disease.


Current evidence supports the concept that the classical biological actions of the nutritionally important fat-soluble vitamin D in mediating calcium homeostasis are part of a complex vitamin D endocrine system that coordinates the metabolism of vitamin D 3 into 1α,25(OH)2D3 and 24R,25(OH)2D3. Further, it is clear that the vitamin D endocrine system embraces many more target tissues than simply the intestine, bone, and kidney. Notable additions to this list include the pancreas, pituitary, breast tissue, placenta, hematopoietic cells, hair follicle, skin, and cancer cells of various origins. Key advances in understanding the mode of action of the steroid hormone, 1α,25(OH)2D3, have been made by a thorough study of the VDR as a classical nuclear receptor as well as the emerging studies describing the presence of VDR in the plasma membrane caveolae. Efforts are underway to define the signal transduction systems that are activated by the nuclear and membrane receptors for 1α,25(OH)2D3 and to obtain a thorough study of the tissue distribution and subcellular localization of the gene products induced by this steroid hormone.

There are clinical applications for 1a,25(OH) 2 D 3 and related analogs for the treatment of the bone diseases of renal osteodystrophy and osteoporosis, psoriasis, and secondary hyperparathyroidism. Other clinical targets for 1a,25(OH) 2 D 3 currently under investigation include its use in leukemia, breast, prostate, and colon cancer as well as use as an immunosuppressive agent. An emerging human nutritional issue is the question of whether the RDA for vitamin D 3 should be adjusted upward.

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