Vitamin A and

Vitamin D

Aamir Ali KhanM.Phil Biochemistry

Head of pathology department

Northwest institute of health sciences

Introduction

Vitamin A is a generic term for a group of lipid soluble compounds related to retinol. Retinol is often referred to as preformed vitamin A.It is found only in animal sources, mainly as retinyl esters and in food supplements.Beta-carotene and other carotenoids that can be converted to vitamin A by an enzymatic process in the body are referred to as provitamin A.They are found only in plant sources

Functions

Retinal, the oxidized metabolite of retinol, is required for the process of vision Retinoic acid, another vitamin A metabolite, is considered to be responsible for all non-visual functions of vitamin A

The Nature of Vitamins

Retinoic acid combines with specific nuclear receptor proteins which bind to DNA and regulate the expression of various genes, thereby influencing numerous physiological processes

Retinoic acid is therefore classified as a hormone

Vision

Receptor cells in the retina of the eye (rod cells) contain a light-sensitive pigment called rhodopsin, which is a complex of the protein opsin and the vitamin A metabolite retinal .

The light-induced disintegration of the pigment triggers a cascade of events which generate an electrical signal to the optic nerve.

Rhodopsin can only be regenerated from opsin and vitamin A. Rod cells with this pigment can detect very small amounts of light, making them important for night vision.

In the pigment epithelium of the retina, all-trans -retinol is isomerizes to 11-cis–retinol and oxidized to 11-cis-retinaldehyde.

This reacts with a lysine residue in opsin, forming the holoprotein rhodopsin

The absorption of light by rhodopsin causes isomerization of the retinaldehyde from 11-cis to all trans, and a conformational change in opsin. This results in the release of retinaldehyde from the protein and the initiation of a nerve impulse.

The key to initiation of the visual cycle is the availability of 11-cis retinaldehyde, and hence vitamin A .

In deficiency, both the time taken to adapt to darkness and the ability to see in poor light are impaired.

Cellular differentiationThe many different types of cells in the body perform highly specialized functions. The process whereby cells and tissues become “programmed” to carry out their special functions is called differentiation. Through the regulation of gene expression, retinoic acid plays a major role in cellular differentiation.

Vitamin A is necessary for normal differentiation of epithelial cells, the cells of all tissues lining the body, such as skin, mucous membranes, blood vessel walls and the cornea

In vitamin A deficiency, cells lose their ability to differentiate properly

Growth and development

Retinoic acid plays an important role in reproduction and embryonic development, particularly in the development of the spinal cord and vertebrae, limbs, heart, eyes and ears

Immune functionVitamin A is required for the normal functioning of the immune system and therefore helps to protect against infections in a number of ways. It is essential in maintaining the integrity and function of the skin and mucosal cells, which function as a mechanical barrier and defend the body against infection .

Vitamin A also plays a central role in the development and differentiation of white blood cells, such as lymphocytes, killer cells and phagocytes, which play a critical role in the defense of the body against pathogens

Absorption and body stores

Vitamin A is absorbed in the upper part of the small intestine. Pro-vitamin A carotenoids can be cleaved into retinol via an enzymatic process. Preformed vitamin A occurs as retinyl esters of fatty acids. They are hydrolyzed and retinol is absorbed into intestinal mucosal cells (i.e. enterocytes). After re-esterification it is incorporated into chylomicrons, excreted into lymphatic channels, delivered to the blood and transported to the liver.

Vitamin A is stored in the liver as retinyl esters; stores are enough for one to two years in most adults.

Carotenes are not absorb 100 %

1ug of retinol is taken as equivalent to 6ug of beta carotene

For vitamin A absorption, cellular retinol binding protein II is necessary

Vitamin is then reestirified within the mucosal cells of the small intestine where absorb with chylomicrons

Bile salts help in carotene and vitamin A absorption

Effect on epithelium

Eye changes

“Xerophthalmia” bitot’s spots of cornea

“Keratomalacia” cornea becomes dull and insensitive.

Changes in respiratory tractCilia are lost and respiratory tract infections take placeVitamin A increases immunity.Xerosis (dryness) and scaling of hair follicles (Hair loss with skin shedding)Growth retardation Deformed skull bones may result nerve degeneration and paralysis Defective formation of the tooth enamel takes place

Storage and Transport

Lipocytes of liver cells store it in the form of esters Retinoic acid is transported by albumin in plasma

Hypervitaminosis AHeadache, nausea, vomiting, drowsiness, peeling of skin, anorexia, dry itchy skin, alopecia, cracking of the lips and painful areas over bones

May be hepatomegaly, splenomegaly, hypothyroidism, leucopenia, anemia, bleeding tendency because of hypoprothrombinemia, high ALP

VITAMIN DVitamin D is a fat-soluble vitamin. Vitamin D is not found in many foods. Foods that naturally contain significant amounts of vitamin D are fatty fish and eggs. To increase intake of vitamin D, foods have been fortified.Milk is the most commonly consumed products that are fortified with vitamin D. Juices, breakfast cereals, breads, and yogurt are also fortified with vitamin D.Cholecalciferol is a form of vitamin D made naturally by the body when the skin is exposed to sunlight. However, most people do not get enough sunlight to satisfy their daily recommended intake through sunlight, especially in the winter.

Vitamin D Is Synthesized in the Skin7-Dehydrocholesterol, undergoes a nonenzymic reaction on exposure to ultraviolet light, yielding previtamin D. This undergoes a further reaction over a period of hours to form the vitamin itself, Cholecalciferol, which is absorbed into the blood stream. The recommendations are 200 IU from birth to 50 years of age, 400 IUs from 51-70 years age, and 600 IUs for 71+ years of age.These recommendations meet the minimum requirements, mostly based on bone health

In the liver, Cholecalciferol, which has been synthesized in the skin or derived from food, is hydroxylated to form the 25-hydroxy derivative calcidiol. This is released into the circulation bound to a vitamin D binding globulin which is the main storage form of the vitamin.In the kidney, calcidiol undergoes either 1-hydroxylation to yield the active metabolite 1,25-dihy-droxyvitamin D (calcitriol) or 24-hydroxylation to yield an inactive metabolite, 24,25-dihydroxyvitamin D(24-hydroxycalcidiol).Ergocalciferol from fortified foods undergoes similar hydroxylation's to yield calcitriol.

Sources

Fish, including salmon and tuna are excellent sources.

Egg also contains vitamin D, the highest concentration is in the yolk

FunctionThe main function of vitamin D is in the control of calcium homeostasis, and in turn vitamin D metabolism is regulated by factors that respond to plasma concentrations of calcium and phosphate

Calcitriol acts to reduce its own synthesis by inducing the 24-hydroxylase and repressing the 1-hydroxylase in the kidney. Its principal function is to maintain the plasma calcium concentration.

Cont…Calcitriol achieves this in three ways: it increases intestinal absorption of calcium, reduces excretion of calcium, and mobilizes bone mineral.

In addition, calcitriol is involved in insulin secretion, synthesis and secretion of parathyroid and thyroid hormones, inhibition of production of interleukin by activated T lymphocytes and of immunoglobulin by activated B lymphocytes, differentiation of monocyte precursor cells, and modulation of cell proliferation. In its actions, it behaves like a steroid hormone, binding to a nuclear receptor protein.

The two main forms of calcium in supplements are carbonate and citrate. Calcium carbonate is more commonly available and inexpensive.

Both forms are absorbed well by the body, but individuals with low levels of stomach acid may absorb citrate better.

Carbonate is absorbed better when taken with food but citrate is unaffected by the presence of food.

There are two forms available for vitamin D supplements, D2 (Ergocalciferol) and D3 (Cholecalciferol).

Vitamin D2 is made by the conversion of a sterol found in plants and yeast.

Unlike calcium these two forms are not equal in absorption. Vitamin D3 is metabolized differently than D2 and research shows it is more effective in raising serum concentrations of the active form of vitamin D and is also able to maintain higher levels for longer.

Probably the most well understood function that Vitamin D has is in the absorption of calcium from the small intestine.When vitamin D is inadequate, calcium from the diet is poorly absorbed.Another well characterized and important role of vitamin D is to maintain appropriate levels of calcium and phosphate in the blood to ensure proper bone formation, mineralization, growth, and repair.Vitamin D has other roles that have been less well characterized. It is thought to improve muscle strength and immune function and reduce inflammation.

Deficiency (Complication)

People at risk for vitamin D deficiency include breast fed infants, older adults, people with limited sun exposure, people with dark skin, and people with fat malabsorption.

People age 50 and older are at increased risk of developing vitamin D deficiency because as they age the skin looses its ability to synthesize vitamin D as efficiently and the kidneys also convert less to its active form People with darker skin have more pigment melanin which reduces the skin’s ability to produce vitamin D after sun exposure.

Prolonged inadequate intake of vitamin D will lead to impaired bone metabolism.In children, under mineralization of bone causes soft and deformed bones and can lead to the condition known as rickets.

When children developed rickets, their legs were too weak to hold their weight, resulting in bowed legs, which often persisted into adulthood. Osteomalacia is the adult form of rickets, and leads to impaired mobility and bone fractures

Osteoporosis, a condition that leads to weak and porous bones.

In the vitamin D deficiency disease rickets, the bones of children are under mineralized as a result of poor absorption of calcium. Similar problems occur in adolescents who are deficient during their growth. Osteomalacia in adults results from demineralization of bone in women who have little exposure to sunlight, often after several pregnancies. Although vitamin D is essential for prevention and treatment of Osteomalacia in the elderly, there is little evidence that it is beneficial in treating osteoporosis.

Vitamin D Is Toxic in ExcessSome infants are sensitive to intakes of vitamin D as low as 50 µg/d, resulting in an elevated plasma concentration of calcium. This can lead to contraction of blood vessels, high blood pressure, and calcinosis, the calcification of soft tissues. Although excess dietary vitamin D is toxic, excessive exposure to sunlight does not lead to vitamin D poisoning because there is a limited capacity to form the precursor 7-dehydrocholesterol and to take up Cholecalciferol from the skin