VITAMIN D

A. History. The first demonstration of the existence of vitamin D was shown by Elmer McCollum in 1922 who found that cod liver oil was effective in preventing rickets, a disease induced in rats by providing low calcium diet. On account of its preventive action on rickets, vitamin D is often called as antirachitic factor. It is also known as ‘sunshine vitamin’ as its provitamin form present in human skin is easily converted to the active form by irradiation with ultraviolet light. At least 10 different compounds are known to have antirachitic properties and are designated as D2, D3 etc, but the two, namely, vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) are more important. Vitamin D3 was, however, first isolated by Brockmann and others.

B. Occurrence. The best natural sources of vitamin D are the liver oils of many fishes such as cod and halibut. The flesh of oily fishes (e.g., sardine, salmon, herring ) is also excellent source. Egg yolks are fairly good but milk, butter and mushrooms are poor. The diets of infant may contain only small amounts of vitamin D; cow’s milk contains only 0.1 to 1 μg/quart (1 μg = 40 IU). Cereals, vegetables and fruits contain only negligible amounts. Eggs and yolks contain 3 to 10 μg/g. Most marketed cow’s milk is fortified with 10 μg of vitamin D per quart and most commercially–prepared milks for infant formulae are also fortified. Vitamin D2 is of plant origin and is produced commercially by irradiation with ultraviolet light of a provitamin known as ergosterol which is found in plants, especially in ergot (hence so named) and yeast. Vitamin D3,

C. Structure. The transformation of ergosterol (C28H44O) to the active form D2 takes place through a series of intermediate steps illustrated as below :
Ergosterol→Lumisterol→Protachysterol→Tachysterol→Precalciferol→Calciferol→Toxisterol (and)Suprasterols

Similarly, cholecalciferol (C27H44O) is produced from 7-dehydrocholesterol through a seriesof intermediaries as follows :
7-dehydrocholesterol→Lumisterol3→Tachysterol3→Precalciferol3→Cholecalciferol
During the activation of the provitamins, the ring B is cleaved between carbon atom 9 and 10 to produce vitamins D2 and D3 Note that in both the cases, the effect of irradiation is the opening of ring B. It may, however, be noted that the two vitamins, D2 and D3 and also D4 and D5 (in Fig. ), differ only in their side chains attached to C17. Other forms of vitamin D may be obtained by irradiation of other sterols. Vitamin D4, for example, is produced by irradiation of22-dihydroergosterol. Its potency is 50—70% that of vitamin D2.

However, researches conducted by DeLuca et al (1968) indicate that the biologically active form of vitamin D3, present in animals such as rat, has a slightly different structure. It is identified as 25-hydrocholesterol (in Fig.). It is a more polar compound and has an additional OH group at C25. It is one and a half times more potent than the vitamin in curing ricket. Also, it stimulates bone metabolism and intestinal calcium transport more rapidly than the vitamin. It is synthesized in the liver and is then converted into 1,25-dihydroxycholecalciferol [1,25(OH)2D3] in the kidneys.
Cholecalciferol and its derivatives are seco-steroids, i.e., ring A is not rigidly fused to ring B. Because of its conformational mobility, ring A of a seco-steroid exists in two equilibrated conformers. Now as the in vitro mode of action of vitamin D is understood, it has been proposed that 1,25(OH)2D3 is actually a hormone and not a vitamin as it fits the traditional description of a hormone. 1,25(OH)2D3 is produced in the kidneys (organ) and transported by the blood to intestinal mucosa and bone (target tissues), where it functions in the processes for the absorption, reabsorption and mobilization of calcium and phosphate ions. In conjunction with parathormone and calcitonin, it has a major role in homeostasis of Ca and P in the body’s fluids and tissues. Now because a hormone-receptor protein has been identified for 1,25(OH)2D3, the status of vitamin D as a hormone is well established.
D. Properties. Vitamin D is a white and almost odourless crystalline substance, soluble in fat and fat solvents. It is fairly heat resistant and also relatively resistant to oxidation. It is not affected by acids and alkalies.

E. Metabolism. The provitamin D3 can be synthesized within the human body so that it may, in fact, not be required in the diet. This may, henceforth, not be treated as a vitamin. In the past when man lived mainly outdoors and with minimum clothing, there was no hindrance for the penetration of ultraviolet light from the sun to convert it into the active form. In the far northern
areas, however, the amount of light is not adequate for conversion and as such fish liver oils serve as excellent source of vitamin D in these areas. The increased need of this vitamin is usually felt in growth and in pregnancy to provide for the needs of the foetus.
Vitamin D plays an important role in calcification of bones and teeth. It encourages the absorption, into the blood, of calcium salts and phosphates. Calcium passage across duodenum occurs mainly by diffusion and active transport of Ca2+ occurs across the ileal mucosa. Both these processes are related in dificiency of vitamin D. The subsequent release of bound calcium is also Conten markedly stimulated by vitamin D but only in the presence of parathyroid hormone. On the whole, the function of vitamin D is to cause increased absorption, longer retention and better utilization of calcium and phosphorus in the body. There is considerable difference in the potency of these 2 common forms of vitamin D. For example, vitamin D2 is a powerful antirachitic agent for man and for the rat but not for the chicken. Vitamin D3, on the contrary, is much more potent for the chicken than either for man or
the rat.
F. Deficiency. The most characteristic symptom of vitamin D deficiency is the childhood disease known as rickets. Deficiency of it in human adults leads to osteomalacia, a condition that might also be termed “adult rickets”. Rickets (derived from an old English word, wrickken = to twist) is primarily a disease of growing bones. In it, the deposition of inorganic materials on the matrix of bones (i.e., calcification) fails to occur, although matrix formation continues. Rickets is unusual below the age of 3 months (mo). It may occur in older children with malabsorption. Clinical manifestations of rickets in children usually manifest in the first year or in the second year. One of the early signs of rickets is craniotabes, which is due to thickening of the outer table of the skull and is detected by pressing firmly over the occiput or posterior parietal bones. A ping-pong ball like sensation will be felt. Craniotabes near the suture line may, sometimes, be present in normal premature infants. Costochondral junctions become prominent to give appearance of a beaded ribs, the rachitic rosary. Thickening of the wrists and ankles are other early evidences of osseous changes. Increased sweating, especially around the head, may also be present.

Signs of advanced rickets are easily identified. These are listed below :
1. Head : Craniotabes may obliterate before the end of the 1st year, although the rachitic process continues. The softness of the skull may result in flattening and, at times, permanent asymmetry of the head. The anterior fontenel is larger than normal; its closure may be delayed until after the 2nd year of life. The central parts of the parietal and frontal bones are usually thickened, forming prominences or bosses, which give the head a box-like appearance (catput quadratum).
2. Thorax : The sides of the thorax become flattened, and the longitudinal grooves develop posterior to the rosary. The sternum with its adjacent cartilage projects forward leading to protruding chest (pigeonbreast). Along the lower border of the chest develops a horizontal depression (Harrison groove), which corresponds with the costal insertions of the diaphragm.
3. Spinal cloumn : Moderate degree of lateral curvature (scoliosis) is common and a kyphosis (=increased convexity in the region of thoracic spine) may appear in the dorsolumbar region when sitting. Lordosis (=forward curvature of the lumbar spine) may be seen in the erect position.
4. Pelvis : The pelvic entrance is narrowed by a forward projection of the promontory; the exit, by a forward displacment of the caudal part of the sacrum and coccyx. In the female, these changes, if they become permanent, add to the hazards of childbirth and necessitate caesarean section.
5. Extremities : The epiphyseal enlargement at the wrists and ankles becomes more noticeable. Bending of the softened shafts of the femur, tibia and fibula results in bowlegs (knockknees) ; the femur and the tibia may also acquire an anterior convexity. Coxa vara is sometimes the result of rickets. Deformities of the spine, pelvis and legs results in reduced stature, rachitic dwarfism.
6. Ligaments : Relaxation of ligaments helps to produce deformities and partly accounts for knock-knees, weak ankles, kyphosis and scoliosis.
7. Muscles : The muscles are poorly developed and lack tone. As a result, the rachitic children are late in standing and walking. Abdomen becomes protuberant (potbelly) because of marked hypotonia of abdominal wall muscles, visceroptosis and lumbar lordosis.
8. Sense organ : Avitaminosis D in early infancy results in bilateral lamellar cataracts.
9. Dentition : Eruption of temporary teeth may be delayed in rachitic children. The first tooth in such babies appears between 6th and 9th month, at which time it has appeared in half of the normal babies. In deficiency of vitamin D, the formation of teeth becomes defective and leads to the development of dental caries. Chemical analysis of the bones of rachitic children reveals the presence of low inorganic and high organic and water contents in them. The ratio of calcium to phosphorus (C/P), however, remains constant. In the blood serum, there is usually a normal content of calcium but the phosphate content is reduced (1.5–3.5 mg/dL), against a normal value of 4.5–6.5 mg/dL in healthy infants. Vitamin D deficiency is also accompanied by generalized aminoaciduria, a decrease of citrate in bone and its increased urinary excretion, decreased ability of the kidneys to make an acid urine, phosphaturia, and, occasionally, mellituria. The parathyroid glands hypertophy in rickets. Rickets in itself is not a fatal disease but complications and intercurrent infections such as pneumonia, tuberculosis, and enteritis are more likely to cause death in rachitic children than in normal children. Rickets is most prevalent where climate or custom prevents individuals from exposure to sun, where by checking vitamin D production by irradiation of the skin. In the seventeenth century. this disease was so common in England that it used to be known as “English disease”. A study conducted by the Indian Social Institute, New Delhi (1981) shows that about 168 children per 1,000 of live births die of rickets in India. In osteomalacia (osteonG = bone ; malakiaG = softness), the action of bones is essentially like that in rickets. However, the bones become softer than the rachitic bones and the C/P ratio does not remain constant. The loss of calcium is greater than that of phosphorus and there is a relative gain in magnesium content. The disease is prevalent in India, China and Arab, particularly among women because of the custom that keeps them indoor and also prevents them from exposure to sun. This is particularly true of Bedouin Arab women who are clothed so that only their eyes are exposed to sunlight. The serum calcium is reduced, sometimes to such an extent that tetany develops. Vitamin D3 deficiency also leads to a disease called idiopathic steatorrhea or celiac disease. Like osteomalacia, the disease is characterized by demineralization of the bones which may result in deformities or dwarfism. In fact, celiac disease is indirectly a vitamin D deficiency because the primary abnormality appears to be, in part, a fatty diarrhea. The fat is not absorbed in the intestine and is passed out in stool along with calcium salts and vitamin D.
G. Hypervitaminosis D. Overdosing of calciferol to the children and adults as well produces demineralization of bone. Serum concentrations of both calcium and phosphate are greatly raised, resulting in metabolic calcification of many soft tissues and the formation of renal calculi. The latter disorder may block the renal tubules causing hydronephrosis. Contents The use of very high doses of vitamin D is not danger-free, however. The toxic effects caused by excess dosage include anorexia, nausea, polyuria, weakness, headache etc. The toxicity is due to the diminished excretion of this vitamin, rather than its storage in the liver. The water-soluble vitamins, on the contrary, if given in excess pass out immediately in the urine and are henceforth nontoxic. Much of the whole milk available in urban areas and evaporated milk are fortified with vitamin D concentrate so that 1 quart of fresh, whole milk or a cane of evaporated milk contains the required amount (i.e., 10 μg).
H. Human requirements. Vitamin D requirement is greatly influenced by the amount of
ultraviolet light to which the individual is exposed. Half an hour of direct sunlight on the cheeks
of a baby each day is sufficient to generate the minimal daily requirement of vitamin D. For adults also, exposure to sunlight for 30 minutes a day is believed to satisfy the daily requirement (about 10 μg or 400 IU) of vitamin D. As effective UV rays do not penetrate glass windows, exposure to sun through window glass is of little importance. Smoke also hinders the progress of these rays and as such city sunshine is not much beneficial. It is for these and some other reasons that vitamin D should be included in the diet. This is particularly true for older people. The recommended daily allowance of vitamin D is 400 I.U. for infants, pregnant women and lactating mothers. For adults, 400 units are adequate. One International Unit is defined as the biologic activity of 0.025 μg of pure crystalline vitamin D3.