Xerophthalmia: Vitamin A Deficiency

Xerophthalmia is a progressive ocular condition arising from insufficient levels of vitamin A within the body. This deficit can lead to desiccation of the eyes and tear ducts. If not addressed, it could progress to nocturnal blindness or the emergence of blemishes on the eyes. In severe instances, it might even inflict damage upon the cornea, potentially resulting in loss of vision. Vitamin A assumes a pivotal role in diverse ocular functions, and its insufficiency can present a spectrum of ocular indications and symptoms affecting the conjunctiva, cornea, and retina.

While this affliction is infrequent within the United States, it exhibits a more pronounced presence in developing nations, where nutritional scarcities are more prevalent. Vitamin A deficiency remains a notable global public health concern, afflicting more than half of all countries, and disproportionately impacting young children residing in underprivileged regions.

Children aged 3 to 6 years face an elevated susceptibility to nocturnal blindness due to xerophthalmia. This disorder affects approximately one-third of the worldwide pediatric populace and is culpable for causing blindness in 250,000 to 500,000 children each year within developing countries.

Xerophthalmia stems from inadequate consumption of vitamin A. Unlike certain other compounds, the human body lacks the ability to synthesize its own vitamin A and must derive it from dietary sources. A shortage of vitamin A in the diet can be attributed to factors like malnutrition, compromised nutrient assimilation, chronic alcoholism, or highly restrictive eating habits.

Vitamin A, predominantly acquired through dietary means, is a fat-soluble vitamin and serves as a critical player in bodily processes encompassing cellular growth, metabolism, immune reactions, vision, and reproduction.

Regarding vision, vitamin A is indispensable as it constitutes a component of the protein responsible for capturing light within retinal receptors. An insufficiency of vitamin A can lead to abnormal transformations in mucus-secreting epithelial tissue, contributing to conditions such as desiccation of the conjunctiva and cornea, corneal ulcers, keratomalacia, and corneal scarring.

Prominent indications of xerophthalmia involve:

~Desiccation, thickening, and wrinkling of the conjunctiva, the delicate covering of the eyelid and eye surface.
~Nocturnal blindness, which impedes vision in conditions of low light.
~Corneal ulcers or scars.
~White patches on the conjunctiva identified as Bitot's spots.
~Softening of the cornea.

Prominent dietary sources of vitamin A consist of animal-derived products like cod liver oil, liver, butter, cheese, eggs, and fish. Among plant-based options, vitamin A-rich sources include sweet potatoes, carrots, broccoli, sweet red peppers, spinach, and lettuce.
Xerophthalmia: Vitamin A Deficiency

Carotenoid pigments in plant and vegetables

Plant pigments fall into three major groups: carotenoids, chlorophylls and flavonoids. Plant carotenoids are responsible for the red, orange and yellow pigments found in fruits and roots such as tomatoes, red peppers, pumpkins and carrots.

Carotenoids pigments are hydrocarbon chains with 40 carbon atoms. They can be seen in the petals of many flowers and are the primary pigments responsible for the fall coloration of deciduous trees.

More than 450 carotenoids occur in nature. The carotenoids can be divided into two basic types:
*Carotene which contain no oxygen atoms
*Xanthophyll which does contain oxygen Heat affects the color of vegetables, most likely because it modifies the pigments’ chemical structure.

Vegetables containing β–carotenes should not be overheated, because this pigment not only contributes to color but can also be converted to vitamin A; therefore, its destruction would be doubly undesirably.
Carotenoid pigments in plant and vegetables 

Storage of vitamin A

It has long been established that vitamin A (retinol) is an essential component of human diet and must be acquired from the diet as either preformed A or provitamin carotenoids, which subsequently converted in the body to the biologically active retinoids, retina and all-trans retinoic acid.

Vitamin A is normally transported in the blood linked to a specific protein, retinol binding protein (RBP). Specific proteins on cell surfaces and within cells are also involved with intracellular transport of the vitamin.

RBP circulates as a 1:1 molar complex; filtration and loss from the kidney are prevented by prealbumin, The normal concentrations in plasma are 40 to 50 ug per mL for RBP and 200 to 300 ug per mL for prealbumin.

Human liver

RBP binds retinol and this RBP-retinol complex is then secreted into circulation where it is transported to the target tissue to meet tissue vitamin A needs.

Vitamin A is fat soluble and is primarily stored in the liver, where RBP is synthesized. The liver holds over 90 percent of the body’s vitamin A reserves, with the rest deposited in fat tissue, lungs and kidneys.

The liver plays a pivotal role in the uptake, storage and maintenance of circuiting plasma vitamin A levels by mobilizing its vitamin A store.

In a well nourished person, vitamin A stores are generally sufficient to last many months on a vitamins A-deficient diet before signs of deficiency appear.
Storage of vitamin A

What is β-carotene?

β-carotene is an organic compound and fat-soluble vitamin. Along with giving carrots, sweet potatoes and other foods their orangey color, β-carotene provides a non-toxic way for people to satisfy their need for vitamin A.

The liver converts β-carotene to vitamin A. Diets rich in carotenoids typically supply 5 mg to 10 mg of β-carotene each day. The conversion of β-carotene only as much as is needed, thus avoiding possible toxicity and therefore making β-carotene superior to preformed vitamin A.

β-carotene

β-carotene prevents the breakdown of cells and tissues that is brought on by oxidation and free radicals. This aids the immune system whole slowing the rate at which the people age.

Since β-carotene acts as an antioxidant, it serves as a protector against potential cancer causing agents. It is stored in the liver for later use. When taken with vitamins: C, D, and E, zinc, choline, selenium and the essential fatty acids, β-carotene appears to function with more effect.

Foods that are contain β-carotene include orangey foods such as carrots, sweet potatoes, cantaloupes, pumpkin, winter squash, mangoes, and apricots, as well as goji berries, spinach, kale, chard, dandelion greens and broccoli.
What is β-carotene?

Carotenoid pigments as food colorants

Many colorants are natural and these include the yellow, from the annatto seed; green form chlorophyll; orange from carotene; brown form burnt sugar; and red from beets tomatoes and the cochineal insect. 

The carotenoids, particularly their nature-identical synthetic counter parts, beta-app-8’-carotenal,beta-carotene and canthaxanthin, are popular food colorants.

Carotenoids are classified as oil soluble but most foods require water soluble colorants; thus their approaches were used to provide water dispersible preparations. Carotenoids colorants are appropriate for a wide variety of foods.

The carotenoids add yellow, red and orange pigmentation to foods. Beta-carotene and beta-apo-8’-carotenal have vitamin activity but canthaxanthin does not.

Federal regulations permit addition of beta-carotene to foods at any concentration but specify maximum limits fro beta-app-8’ carotenal (1.5 mg/lb or pinto food).

Beta-carotene is used to colour margarine, shortening, butter, cheese, baked goods, confections, ice cream, egg nog, macaroni products, soups, juices, pudding and beverages. Beta-carotene has good tinctorial strength fair light stability, poor oxidation stability and good pH stability.

Beta-apo-8’-carotenal may be used to colour juices, fruit drink, soups, jams, jellies, gelatine, processed cheese, margarine, sale dressing and fats and oils.
Carotenoid pigments as food colorants

Vitamin A and immune system

Among the micronutrients, the role of vitamin A in immune system function has probably been the most extensively characterized, and studies have shown a multifaceted role of vitamin A in many aspect of immunity.

Individuals deficient in vitamin A are more susceptible to infectious disease in general but especially viral infections.

Vitamin A deficiency is associated with increased mortality in children and pregnant women. An estimated 253 million children are at risk of immunodeficiency due to vitamin A deficiency (WHO) and millions of pregnant and lactating women are also at high risk in developing countries.

Vitamin A plays an important function in host defense mechanism, including both cell-mediated immunity and humoral immune mechanisms.

This vitamin involves in the maintenance of mucosal surfaces, in the generation of antibody responses, in hematopoiesis and in the function of T and B lymphocytes, natural killer cells and neutrophils.

Vitamin A also acts to eliminate free radicals before they can do severe cell damage, thus strengthening the immune system.

Researchers have found that children with low vitamin A had abnormally low levels of T-cells in their blood. Vitamin A makes T-cells more active and stronger.
Vitamin A and immune system

Dietary sources of vitamin A

Actual intake of vitamin A depends on the patterns of consumption of vitamin A-bearing animal food products and provitamin A-bearing fruits and particularly in green leafy vegetables. Animal sources of vitamin A include meat, liver, eggs, cow’s butter or ghee, milk and poultry.

The richest readily available dietary source of vitamin A is fish liver oil, especially cod liver. In particular, all–trans dehydroretinol, previously known as vitamin A2, is a vitamin A-related compound found in freshwater fish flesh and liver and to a lesser extent, on some marine fish. Cod liver and halibut fish oil contain high levels of vitamin A and have been used therapeutically.

Margarine, fluid milk and dry milk are typically fortified with retinyl palmitate in many countries. These products play a dramatic role in preventing vitamin A deficiency in countries where fortification is mandatory.

In the United States, milk is fortified with not less than 2000 IU vitamin A (retinyl palmitate).

The principal source of vitamin in the diet is likely to b from the carotenes which are widespread in those plant foods that have high green or yellow coloring.

There is a direct correlation between the greenness of a leaf and its carotene content. Dark green leaves, such as beet greens, collards, dandelion, greens, kale, mustard greens, spinach, Swiss chard, and turnip greens are rich in carotene.
Dietary sources of vitamin A

Acute hypervitaminosis A

Toxicity has been observed in people who have either chronically or acutely consumed more than 10 times the RDA. Hypervitaminosis A is caused by excessive intake of preformed vitamin A and has never been attributed to consumption of carotenoids.

The Tolerable Upper Intake Level (UL) for preformed vitamin A is 3,000 ug RAE (10,000 IU) per day. Ingesting larger amounts (such as 50,000 IU) of vitamin A in a short time may result in acute hypervitaminosis A.

Acute hypervitaminosis A can be defined as any toxicity manifested following the ingestion of a single very high does or several repetitive very high doses over a few days. It may occur at any age from digestion of excessive amounts of vitamin A.

Symptoms of acute hypervitaminosis A include loss of appetite, nausea, vomiting, double or blurred visions, hemorrhage, nose bleeding, increased interracial pressure, headache, dizziness, skin desquamation, and muscle incoordination.

Desquamation of the skin and mucous membranes may begin within 36 hours and becomes severe. There are no skeletal changes.
Acute hypervitaminosis 

Chronic hypervitaminosis A

Vitamin A toxicity is relatively rare. Hypervitaminosis A is caused by excessive intake of preformed vitamin A.

The risk of developing hypervitaminosis A is derived from total cumulative vitamin A intake rather than a specifically daily usage level.

Chronic hypervitaminosis A results from continued ingestion of high doses. Chronic hypervitaminosis A is more common than acute hypervitaminosis A.

Serum levels of vitamin A are generally less than 3.49 umol/ liter and there are increased levels of the unbound retinol resulting in a change in the ratio of free retinol to retinol bound to RBP as well as increase in retinyl esters.

Symptoms of hypervitaminosis A include dryness of the skin, headache, anorexia, bone fragility, weakness, hair loss, malaise, itching joint pain, vertigo, vomiting, irritability, and in babies, a bulging fontanelle and increased intracranial pressure.

It may also cause emotional lability and hepatosplenomegaly.   Epimetaphyseal abnormalities may be observed in chronic hypervitaminosis A, including invagination of the epiphysis into the metaphysis and thinning of the physeal plate.

Chronic hypervitaminosis A usually develops after doses of more than 100,000 IU/day have been taken for months.
Chronic hypervitaminosis A

Notes
*RBP – retinol binding protein 

What is retinoids?

Human body gets its vitamin A from two classes of chemicals:
Retinoids
Carotenoids

The retinoids have been recognized for over 50 years for their profound impact in biological functions. The term retinoids refers to compounds whose names all start with ret: retinol, retinaldehyde, retinoic acid, and other chemically similar cofounds, both natural and synthetic.

These fat soluble substance are found in several foods of animal origin: liver and whole milk, eggs and butter. Retinoids give preformed vitamin A, the kind of nutrient that body can use right away.

The retinoids also can be synthesized by cleavage from the pro-vitamin beta-carotene.

Retinoid acid, for example, can substitute for vitamin A in maintenance of epithelial tissue and growth but is not adequate for vision or reproduction.

Retinoids also play significant roles in epithelial cell differentiation and immune function.

The standard unit for quantifying the biologic activity of the various forms of vitamin A and its precursors is known as a retinal activity equivalent (RAE).
What is retinoids?

Vitamin A deficiency

Where it is the limiting nutrient, vitamin A deficiency causes anemia, growth retardation and xerophthalmia; increase the incidence and/or severity of infectious episodes and reduces childhood survival.

Vitamin A deficiency is a major global problem. Vitamin A deficiency is rare in the US, but it is still a major public health problem in the developing world. It is most often associated with protein/calorie malnutrition and affects over 120 million children worldwide.

Vitamin A affects many physiological systems; it plays a essential role in vision and eye health and it affects growth and susceptibility to infection and anemia in children.

In ancient Egypt it was known that night blindness could be cured after eating liver, which was later found to be a rich source of vitamin A. Vitamin A deficiency contributes to blindness by making the eye very dry, damaging the cornea of the eye (called xerophthalmia), and promoting damage to the retina of the eye.

The consequences of vitamin A deficiency include blindness, poor growth, severe infection and death; it control and prevention are central in child health and survival programs.

Other less well known consequences of vitamin A deficiency include:
*Increases mortality rates among infants 6 months to 6 years of age.
*Augments the severity, complications and risk of death associated with measles.
*Associated with increased infant morbidity, particularly in the severity of disease episodes, such as diarrhea and pneumonia.
Vitamin A deficiency

Overview of Vitamin A

Vitamin A is a generic name for a variety of related compounds. Briefly they include retinol, its ester and retinoic acid.

Vitamin A is released as needed into the bloodstream, becoming available for use by cells throughout the body, including those of the eye.

Vitamin A is a fat soluble substance found in ester form in animal and dairy products. It is hydrolyzed in cells of the small intestine to alcohol.

About half the dietary vitamin A intake comes from animal food sources as preformed vitamin A, retinoid. The other half of dietary vitamin A intake comes from fruits and vegetables in the form of pro-vitamin A carotenoids especially beta carotenes. Whole eggs, whole milk, and liver are among the few foods that naturally contain vitamin A. Vitamin A is present in the fat portion of whole milk.

There are many other fortified foods such as breakfast cereals that also provide vitamin A. Carotene, the naturally occurring progenitor of vitamin A found in certain vegetables and fruits, is split in the intestinal cells to retinaldehyde, most of which is promptly reduced to retinol.

It is important to regularly eat foods that provide vitamin A or beta-carotene even though the body can store vitamin A in the liver. Stored vitamin A will help meet body needs when the intake from food is low.

Vitamin A functions to maintain normal reproduction, vision and immune function.

Vitamin A allows human to see in dim light and plays a role in the production of tears, which lubricate and moisten the eye.

People without enough of this vitamin develop eyes that are so dry and ulcerated that the cornea can burst, leading to total blindness.
Overview of Vitamin A

Vitamin fortification in milk

The term fortification is usually used to designated the addition of nutrients not naturally present in a food, whereas the term enrichment generally means the addition of nutrients already present in a food. Often the terms are used interchangeably.

Many milks are fortified with vitamins A and D. Vitamin D is found naturally in very few foods and was initially added to milk, a staple food, to reduce the incidence of rickets, a bone softening condition in children that was at one time endemic in North America.

The fortification of milk and infant milk with 400 IU of vitamin D2 or vitamin D3 has eliminated rickets as a health problem in the United States and Canada.

Because vitamins A and D are fat soluble they are found in the milk fat of whole milk. For this reason, whole milk is not required to be fortified with either vitamin, although many milk manufacturers add both.

Vitamin A and carotene are in the fat portion of the milk, the vitamin A activity is removed in reduced fat (2% fat) and fat free milks, dried whole milk and evaporated skim milk, so vitamin A fortification is required.

The fortification of dried skim milk with vitamin A is viewed by WHO and FAO as an important measure to combat vitamin A deficiency in developing countries.

Fortification with vitamin D in reduced fat and fat free milks is optional. Vitamin D fortification is required for evaporated whole and fat free milks.
Vitamin fortification in milk

Deficiency of vitamin A

Vitamin A deficiency is common among children. Night blindness and eye changes are often early sign.

This nutritional deficiency is widespread in developing countries, and the problem is exacerbated by a tendency by some to withhold vegetables from children for cultural or other reason.

Where it is the limiting nutrient, vitamin A deficiency causes anemia, growth retardation and xerophthalmia; increases the incidence and/or severity of infectious episodes.

Reduced survival is the most severe and potentially the most widespread consequence of vitamin A deficiency, and the one that has generated the most interest.

It is also common knowledge that an adequate levels of vitamin A is essential for animal vision and that prolonged low levels of vitamin A can lead to xerophthalmia and ultimately, blindness.

Vitamin A deficiency decreases resistance to infections and increases the severity, complications and risk of death from various diseases.

When vitamin A deficient, the epithelial cells of growth skin, oral cavities and respiratory, genitourinary and gastrointestinal tracts become dry and flat, hardening so that absorption of nutrients is reduced.

Moreover, vitamin A deficiency may increase the risk of bacteria colonization or delay recovery.

Deficiency of vitamin A

Vitamin A (Retinol)

Vitamin A (Retinol)
Vitamin A has a number of varied functions in the body. It is necessary for growth and development. It helps to keep the skin and epithelial tissues healthy and resistant to infection.

Vitamin A occurs in the retina of the eye, as a part of substance rhodopsin or visual purple.

Visual purple is bleached in the presence of light and regenerated in the dark with the help of vitamin A.

Vitamin A is needed visual cycle, which enables a person to adjust to light of varying intensity. Thus, Vitamin A is needed for normal vision in light and darkness (night).

The earliest symptom of Vitamin A deficiency is night blindness, the inability to see normally in dim light.

Other symptoms of Vitamin A deficiency which develop progressively are dryness of conjunctiva, xerosis of cornea and corneal infection, which if unchecked may lead to blindness.

In addition, severe deficiency of Vitamin A results in growth failure and skin changes (dryness, wrinkling, thickness).

Being fat-soluble, vitamin A is present only in the fat of animal foods, such as whole milk products ghee, butter, egg yellow, liver etc.

A plant pigment (red-orange in color) called carotene is converted to vitamin A in the body.

Therefore, foods which contain carotene are indirect sources of vitamins A. Such foods include dark green leafy vegetables, such as amaranth, coriander drumstick, radish leaves and spinach, and orange-yellow vegetables and fruit, such as carrot, pumpkin, papaya and mango.

Severe deficiency of vitamin A leads to growth failure skin changes infections of the eye and eventual loss of vision.
Vitamin A (Retinol)

Vitamin A

Vitamin A
Vitamin A is a fat soluble vitamin. It is found only in animals, although a number of plants contain carotene, from which vitamin A can be produced in the body once the plants contain carotene are eaten.

Vitamin A may be formed in the body from the yellow pigments (containing carotene) of many fruits and vegetables, especially carrots. Vitamin A is required for vision.

Epithelial cells (those cells present in the lining of body cavities and in the skin and glands) require vitamin A. This vitamin also required for resistance to infection.

Deficiency of Vitamin A may cause impairment in bone formation, impairment of night vision, malfunction of epithelial tissues, and defect inn the enamel of teeth.
Vitamin A

Isolation of Vitamin A

Isolation of Vitamin A
In nature vitamin A is largely found as an ester and consequently, is highly soluble in organic solvents but not in aqueous solutions.

The major pro vitamin carotenoid, B-carotene, has similar solvent properties. One of the richest sources of vitamin A is liver tissue, in particular the liver oils of marine fish and mammals.

The ester can be directly isolated from these oils by molecular distillation at very low pressure, a procedure that has been used extensively for the commercial preparation of vitamins A - rich oils.

Alternatively, vitamin A might be directly extracted with chloroform or with some other solvent combination, such as hexane together with ethanol, followed by purification of vitamin A by chromatographic means.

To hydrolyze esters not only of vitamin A and carotenoids but also of triglycerides and other lipids saponification with KOH is commonly used, followed by extraction with organic solvents.

Retinol or its esters can be readily crystallized at low temperature from a variety of organic solvents, including ethyl format, propylene oxide, and methanol.
Isolation of Vitamin A

Vitamin A

Vitamin A
Vitamin A (retinol) functions in reproduction, growth, the maintenance of skin and mucous membranes and the visual process.

Vitamin A is normally transported in the blood linked to a specific protein, retinol binding protein (RBP).

Specific proteins on cell surfaces and within cells are also involved with intracellular transport of the vitamin.

Vitamin A is fat soluble and is primarily stored in the liver, where RBP is synthesized. In a well nourished person, vitamin A stores are generally sufficient to last many months on a vitamins A-deficient diet before signs of deficiency appear.

The initial symptoms of vitamin A deficiency are night blindness and keratinization of hair follicles.

Continued deficiency leads to damage to eye tissue and irreversible blindness.

The US recommended Daily Allowance (RDA) of vitamin A for adults is 5000 IU (1000 retinol equivalents).

Rich dietary sources of retinol (preformed vitamin A) include dairy products, eggs and organ meats.

Some carotenoids (found in deep-yellow and dark green vegetables) can be converted to vitamin A during digestion.

In the US diet, approximately half of the vitamin A activity is derived from B-carotene and other carotenoids.
Vitamin A

Vitamin A in History

Vitamin A in History
Probably the first nutritional deficiency to be clearly recognized was night blindness. The ancient Egyptians, as indicated in the Papyrus Ebers and later in the London Medical Papyrus, recommended that juice squeezed from cooked liver topically applied to the eye to cure night blindness.

This writings date from 1500 BC, but the observations probably are of much earlier origin. The Greeks, who depended heavily on Egyptian medicine, recommended both the ingestion of cooked liver and its topical application as a cure for night blindness, a tradition that has persisted in many societies to his day.

Although interesting references to vitamin A deficiency and their cure can be found throughout history, the modern science of nutrition is only about a century old. The observation that experimental animals lose weight and die on purified diets was noted by many investigations toward the end of the nineteenth century.

In the early part of this century, specific factors necessary for growth and survival were beginning to be identified. Frederick Gowland Hopkins in England, for example, during the period 1906-1912 found that a growth stimulating principle from milk was present in an alcoholic extract of milk rather than in the ash.

During the same period, Stepp in Germany identified one of these “minimal quantitative factors” as a lipid. Soon thereafter, E. V. McCollum and Marquerite Davis in Wisconsin showed that butter or egg yolk, but not lard, contained a lipid soluble factor necessary for the growth of rats. In 1913 they coined the term “fat soluble A” and thereby attributed for the first time the growth stimulating property of these extracts to a single compound.

Approaching the problem is a very different way, Osborne and Mendel at Yale concomitantly found that cod liver oil or butter was an essential growth-promoting food for rats. The year 1913, therefore, was the beginning of the modern age of vitamin A exploration.
Vitamin A in History