Vitamin D is found to act on target organs like bones, kidneys, intestinal mucosa to regulate calcium and phosphate metabolisms.
• Intestinal absorption of calcium and phosphate: It binds to the chromatin of target tissue and expresses the genes for calcium binding protein as well as Ca++ ATPase in intestinal cells. This increases the Ca++ absorption by actively transporting Ca++ across the plasma membrane against electrochemical gradients. • Mineralisation of bones: Mineralisation of bones is promoted by 1, 25, (OH)2D3 as well as 24, 25(OH)2D3. It is believed that the synthesis of Ca++-binding proteins like osteocalcin and alkaline phosphatase is promoted which increases calcium and phosphate ions in the bone. These ions enhance the mineral deposition in the bone. 24, 25(OH)2D3 helps the deposition of hydroxyapatite in bone. Vitamin D is also believed to promote bone resorption and calcium mobilization to raise the levels of Ca and P in blood in association with PTH.
Other Functions
• Renal reabsorption of calcium and phosphorus is also done by 1,25(OH)2D3 in similar way.
• It lowers the pH in certain parts of the gut such as colon and produces increase in urinary pH.
• It counteracts the inhibitory effect of calcium ions on the hydrolysis of phytate. In adequate amounts and in case of high calcium intake, it suppresses the anticalcifying and rachitogenic effect of phytate. • In physiologically compatible intake it is found to
increase the citrate content of bone, blood, tissues and urinary level.
Deficiency of Vitamin D—Clinical Aspect
1. Rickets
Deficiency produces rickets in growing children and osteomalacia in adults. Vitamin D is required for the normal growth and mineralisation of bones. In its absence, instead of growth occurring normally, the osteoblasts proliferation does not take place in an orderly fashion and is not
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• In growing children there may be excessive mine- ralisation of the zone of provisional calcification at the expense of the diaphysis which may undergo demineralisation.
Note: Certain clinical disorders have been attributed to states of hypervitaminosis D due to increased sensitivity to the vitamin, e.g.
• “Idiopathic hypercalcaemia” of children • Boeck’s sarcoidosis.
CLINICAL ASPECTS
Recently low vitamin D level has been correlated with certain diseases:
• Heart ailments: The researchers reported that those individuals whose vitamin D levels were below a certain level (15 ng/ml) had double the risk of developing heart problems in the form of either heart attack/or strokes/or heart failure. It has been surmised from ten year follow-up study that vitamin D deficiency is a far better indicator of future heart attack than cholesterol. Most organs and tissues of human body have vitamin D receptors. Such receptors are also present in the smooth muscles of the heart and the blood vessels. The presence of vitamin D causes these smooth muscles through vitamin D receptors to relax and this in turn prevents heart attacks/strokes. This is also the reason for the recently discovered role of vitamin D in alleviating hypertension.
• Diabetes: Amongst the many recent studies highlighting several new benefits of vitamin D there are some that establish its role in preventing diabetes. This is not a surprising revelation as the ubiquitous vitamin D receptors are located in the βββββ-cells of Islet of Langerhans of pancreas. The first evidence of the vit D and diabetes link came when it was noticed, mostly through population studies that insulin dependent Type-1 diabetes (IDDM-1) occurred commonly in areas which receive less sunlight. Observational studies seem to show a link between deficient vit D status of infants and the risk of developing diabetes about 10 to 15 years later. It has been proposed that vitamin D probably stimulates not only the release of insulin but also the expression of insulin receptors. Researchers from Harvard Medical School have shown that low vitamin D levels may be a particular problem for children and teenagers with Type-1 diabetes.
• Breast cancer: Recently a link has been suggested between the occurrence of breast cancer in women and vitamin D deficiency. One study suggests that maintaining optimal vitamin D levels may actually prevent certain types of cancers particularly that of breast cancer. Breast cancer cells have vit D receptors. When these receptors are activated with vit D, it brings about some molecular reactions that can make the cancer cells slow down their growth rate or quite often even die or atleast become less aggressive.
• Peripheral artery disease (PAD): Vitamin D may protect against an arterial disease in which fatty deposits restrict blood flow to the limbs. Scientists at the Albert Einstein accompanied by vascularisation and mineralisation at the
normal rate. This results in irregularity in the zone of provi- sional calcification. The cartilage cells do not degenerate as they should and ends of the long bones become bulky and soft. The bone mineral may be reabsorbed away from shaft of long bones making it soft. • Bending of long bones giving rise to deformities such as bow legs and knock knees occur. • The ankles, knees, wrists and elbows are swollen due to swelling of epiphyseal cartilages. • The fontanelles do not close properly giving hot-cross bun appearance of head. • Ribs give beaded appearance and chest gives a pigeon breast appearance. Teeth erupt late and are deformed.
Types: There are two types of vitamin D deficiency rickets. (i) Type I: It is inherited as autosomal recessive trait characterised by defect in conversion of 25-OH-D3 to calcitriol, i.e. 1-α-Hydroxylase deficiency.
(ii)Type II: It is an autosomal recessive disorder in which there is a single amino acid change in one of the zinc fingers of the DNA binding sites for receptors. This makes the receptors nonfunctional.
2. Osteomalacia
The deficiency of vitamin D in adults is osteomalacia which is rare. It can occur:
• In pregnancy and lactation: Where there is additional requirement of this vitamin and drainage of it in milk. • In women who observe purdah or in climates
where sunshine is scanty, calcium and phosphorus absorption is decreased. Consequently mineralisation of osteoid to form bone is impaired. Such bones become soft. This particularly affects pelvic bones.
3. Renal Osteodystrophy
When renal parenchyma is lost or diseased quite significantly, it is unable to form calcitriol and calcium absorption is impaired. Hypocalcemia leads to increase in PTH which acts on bone to increase Ca++. Consequently
there is excessive bone turnover and structural changes. This condition is known as renal osteodystrophy.
HYPERVITAMINOSIS D
Normally vit 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: Persistent hypercalcaemia and hyperphosphataemia may produce:
• Urinary lithiasis
• Metastatic calcification which may affect kidneys, bronchi, pulmonary alveoli, muscles, arteries and gastric mucosa. Renal failure may develop and can lead to death.
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College of Medicine, New York, found that people with low levels of vitamin D experience an increase risk of peripheral artery disease (PAD), most often reduces blood flow to the legs causing pains, numbness, impairing the ability to work and in some cases leading to amputation.
VITAMIN E (TOCOPHEROLS)
Chemistry: The tocopherols differ from each other in the number or position of methyl groups.
• ααααα-tocopherol: 5, 7, 8 trimethyl tocol • βββββ-tocopherol: 5, 8 dimethyl tocol • γγγγγ-tocopherol: 7, 8 dimethyl tocol • δδδδδ-tocopherol: 8 methyl tocol
The α-tocopherol is the most active in vitamin E activity.
The presence of the phenolic –OH group on 6th carbon of the chromane ring is the most important group for its antioxidant activity.
Dietary Sources and Recommended Allowance
Cottonseed oil, corn oil, sunflower oil, wheat germ oil and margarine are the richest sources of vitamin E. It is also found in fair quantities in dry soyabeans, cabbage, yeast, lettuce, apple seeds, peanuts.
Units : 1 mg of d-α-tocopherol = 1.49 IU 1 mg of dl-α-tocopherol acetate = 1.0 IU Normal blood level = 1.2 mg/dl.
Recommended Allowance • Children: 10–15 IU/day • Adults: 20–25 IU/day
Special attention has to be given to the dietary intake of unsaturated fatty acids in which case the daily requirement is increased. Requirement is also more in pregnancy and lactation.
Absorption, Distribution and Excretion: Free tocophe- rols and their esters are readily absorbed in small intestine with the help of bile acids. Absorbed vitamin E is trans- ported to liver where it gets incorporated into lipoproteins and carried by blood to muscle tissues and to adipose tissue for storage. The normal value of blood level is around 1 mg/dl and it is transported chiefly in the ααααα- lipoprotein fraction. Under normal dietary conditions, there is no significant excretion of tocopherols in urine or faeces as it rapidly and extensively undergoes
destruction in the GI tract and in tissues. Placental transfer of vitamin E is limited; mammary transfer is much more extensive. Thus, the serum ααααα-tocopherol level of breast- fed infants increases more rapidly than that of bottle- fed infants.