Excerpt from Avitaminosis A

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Background

Vitamin A can be considered the most important vitamin in supporting animal life. Deficiency occurs in endemic proportions in developing countries and is considered to be the most common cause of blindness in children throughout the world. Besides its essential role in vision, vitamin A is also important in cellular differentiation (eg, growth, reproduction, immune response) and in maintenance of epithelial integrity. No nutritional deficiency is more synergistic with infection than vitamin A. The 2 main mechanisms involved in the prevention of disease are the effect of vitamin A on the immune system and on epithelial integrity.

In areas where vitamin A deficiency (VAD) is prevalent, vitamin A repletion reduces child mortality rates by an average of 23%.¹ Biannual vitamin A supplementation is a cost-effective and high-impact child survival intervention in countries such as Mozambique.

Although VAD manifestations are more common in underdeveloped countries, they are evident in the United States when induced by liver cirrhosis, malnutrition, or alcoholism.²

The eMedicine articles Vitamin A Deficiency and Vitamin A Toxicity may be helpful resources. Additionally, the Medscape CME course Vitamin D Deficiency: A Risk Factor for Heart Disease and the Medscape Nutrition Resource Center might of interest.

Pathophysiology

When ingested in the presence of fat, vitamin A is well absorbed from the intestinal lumen. It is metabolized, in part, in the intestinal mucosa and is then carried via chylomicra to the liver and other tissues. Most of the vitamin A in the liver is stored as retinyl esters in specialized cells termed stellate cells. Retinol is transported in the plasma on a specific protein called retinol-binding protein.

Once within tissues, retinol is bound by cellular retinoid-binding proteins, cellular retinoid-binding protein I (CRBPI) and cellular retinoid-binding protein II (CRBPII). In these complexes, retinol may be either esterified or further oxidized via retinol to retinoic acid, which ultimately binds to a set of transcription factors in the nucleus. Intracellular retinol in peripheral tissues can also combine with plasma retinol-binding protein within that tissue, or it can be incorporated into retinyl esters in lipoproteins. The cycling between the major storage organs, such as the liver, and epithelial tissues that require vitamin A for cellular differentiation is extensive and efficient.

Dietary vitamin A not absorbed in the intestine is excreted in the feces, and inactivated metabolic derivatives are primarily excreted in the urine. When vitamin A intake is low, the absorption efficiency remains high, carotenoid cleavage is enhanced, the plasma transport remains at essentially normal levels, recycling and utilization mechanisms become more efficient, and the excretion of metabolites markedly decreases. When vitamin A intakes are high, the absorption efficiency is reduced, the plasma transport of vitamin A remains the same, recycling becomes less efficient, the oxidation of vitamin A is enhanced, biliary excretion markedly increases, and urinary and fecal excretion is augmented.
 
Thus, under normal physiological conditions, the function of vitamin A is minimally affected by wide variations of intake. Marked reductions in absorption efficiency, whether due to disease, parasitic infestation, or lack of fat in the diet, and impaired liver and kidney functions adversely affect vitamin A status.

Deficiencies of vitamin A depress both humoral immunity and cell-mediated immunity. The principal effects of vitamin A inadequacy on immune function may be a consequence of impaired growth and differentiation of myeloid tissues. Vitamin A has been labeled the anti-infection vitamin from early in this century, and the reason for this may be due to the depression in plasma retinol caused by infection. The depression in serum retinol levels may expose an individual to inadequate plasma vitamin A concentrations in areas where the dietary intake was already marginal. In particular, vitamin A is specifically important for the integrity of the epithelium and the maintenance of mucosal secretions, which, if impaired, may increase exposure to microorganisms and the risk of infection.

Epithelial tissues of the eyes, the lungs, and the gut are impaired by VAD. These are all tissues where epithelial cell turnover is high. In humans, numerous studies using the impression cytology test have shown that low circulating vitamin A levels are associated with an increased risk of epithelial damage in the eye. Impaired gut integrity is common in malnutrition. Damage to the integrity of epithelia and mucosal barriers facilitates translocation of microorganisms and contributes to the increased severity of infections. Thus, low plasma vitamin A levels may compromise immune function by impairing epithelial integrity and by depressing lymphocyte numbers, and, although the capacity of immune cells may still be normal, the overall immune response is depressed.

Vitamin A has essentially 2 roles in ocular metabolism. First, in the retina, vitamin A serves as a precursor to the photosensitive visual pigments that participate in the initiation of neural impulses from the photoreceptors. Second, it is necessary for conjunctival epithelial cell ribonucleic acid (RNA) and glycoprotein synthesis, which helps to maintain the conjunctival mucosa and the corneal stroma.

The retina contains 2 distinct photoreceptor systems, the rods and the cones. The rods are responsible for vision in dim or low light, and the cones are responsible for color vision and vision in bright light. Vitamin A is the backbone of the visual pigments for both the rods and the cones, the major difference being the type of protein that is bound to the retinol. In rod cells, the aldehyde form of vitamin A (retinol) and the protein opsin combine to create rhodopsin, which is the photosensitive pigment. When light hits the rod cells, the pigment isomerizes, which leads to the nerve impulse and results in the visual signal.

The precise mechanism is still not known, but vitamin A is necessary for the maintenance of the specialized epithelial surfaces of the body. A lack of vitamin A leads to atrophic changes in the normal mucosal surface, with loss of goblet cells, and replacement of the normal epithelium by an inappropriate keratinized stratified squamous epithelium. In addition, the substantia propria of the cornea breaks down and liquefies, resulting in keratomalacia.

Loewenthal first described the cutaneous findings associated with VAD in 1933 when he described polygonal papules on the extensor surfaces of the extremities of patients who also had night blindness and xerophthalmia. The skin changes were later coined phrynoderma by Nicholls when he described the findings in East African workers with VAD.

Frequency

United States

In developed countries, VAD is a rare condition.

International

An estimated one fourth to one half million children annually develop keratomalacia and become partially or totally blind, and 13-14 million children exhibit xerophthalmia of lesser severity. The World Health Organization (WHO) estimates that approximately 190 million preschool-aged children live in areas where VAD is known to occur. These areas are mainly in the developing world where an estimated 40% (70-80 million) of the children are likely to be subclinically deficient. Thus, 90-100 million children worldwide are likely to be vitamin A deficient, with the consequence that their health and likelihood of survival are compromised. In 1 Kakuma refugee camp in Kenya and 7 refugee camps in Nepal, VAD was found in 15% of adolescents in Kenya and 30% of adolescents in Nepal.³

Mortality/Morbidity

Mortality rates of 30-60% or more occur for children with keratomalacia and mild xerophthalmia, and the fatality risk for those even subclinically deficient is increased by 20-30%. At any one time, as many as 230 million children are at risk of clinical/subclinical VAD, and, annually, more than 1 million deaths in children are associated with VAD.

Sex

Females and males are affected equally.

Age

Avitaminosis A is most common in children aged 1-6 years, with the most severe, blinding complications affecting children aged 6 months to 3 years. The incidence is skewed toward children because infants born to mothers who are vitamin A deficient have small vitamin A stores at birth and, subsequently, get little from breastfeeding. Furthermore, the demands of rapid growth and susceptibility to infectious disease place an even greater demand on the meager body stores of vitamin A they do possess.

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