Vitamin A Deficiency

Once ingested, provitamin A is released from proteins in the stomach. This retinyl ester is then hydrolyzed to retinol in the small intestine because retinol is more efficiently absorbed. Carotenoids are cleaved in the intestinal mucosa into molecules of retinaldehyde, which is subsequently reduced to retinol and then esterified to retinyl esters. The retinyl esters of retinoid and carotenoid origin are transported via micelles in the lymphatic drainage of the intestine to the blood and then to the liver as components of chylomicrons. In the body, 50-80% of vitamin A is stored in the liver, where it is bound to the cellular RBP. The remaining vitamin A is deposited into adipose tissue, the lungs, and the kidneys as retinyl esters, most commonly as retinyl palmitate.

Vitamin A can be mobilized from the liver to peripheral tissue by a process of deesterification of the retinyl esters. In blood, vitamin A is bound to RBP, which transports it as a complex with transthyretin. The hepatic synthesis of RBP is dependent on the presence of zinc and amino acids to maintain its narrow serum range of 40-50 mcg/dL. Through a receptor-mediated process, the retinol is taken up by the peripheral tissues from the RBP-transthyretin complex.

Vitamin A deficiency (VAD) may be secondary to decreased ingestion, defective absorption and altered metabolism, or increased requirements. An adult liver can store up to a year's reserve of vitamin A, whereas a child's liver may have enough stores to last only several weeks. Serum retinol concentration reflects an individual's vitamin A status. Because serum retinol is homeostatically controlled, its levels do not drop until the body's stores are significantly limited. The serum concentration of retinol is affected by several factors, including RBP synthesis in the liver, infection, nutritional status, and the existing level of other nutrients, such as zinc and iron. ^[3]

In zinc deficiency, impaired synthesis of proteins occurs with rapid turnover (eg, RBP). In turn, this impairment affects retinol transport by RBP from the liver to the circulation and to other tissues. The mechanism by which iron affects vitamin A metabolism has not been identified, but randomized, double-blind studies have shown that vitamin A supplementation alone is not sufficient to improve VAD in the presence of coexisting iron deficiency.

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. 

The epithelial tissues of the eyes, the lungs, and the gut 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.

Besides affecting the epithelium of the eye, VAD causes the substantia propria of the cornea to break down and liquefy, resulting in keratomalacia.

Vitamin A has a major role in phototransduction. The cone cells are responsible for the absorption of light and for color vision in bright light. The rod cells detect motion and are responsible for night vision. In the rod cells of the retina, all-trans-retinol is converted into 11-cis -retinol, which then combines with a membrane-bound protein called opsin to yield rhodopsin. ^[4] A similar type of reaction occurs in the cone cells of the retina to produce iodopsin. The visual pigments absorb light at different wavelengths, according to the type of cone cell they occupy. VAD leads to a lack of visual pigments; this reduces the absorption of various wavelengths of light, resulting in blindness.

The bioavailability of the carotenoids varies; this availability depends on absorption and on their yield of retinol. Only 40-60% of ingested beta carotene from plant sources is absorbed by the human body, whereas 80-90% of retinyl esters from animal proteins are absorbed. Carotenoid absorption is affected by dietary factors, including zinc deficiency, abetalipoproteinemia, and protein deficiency.

Because vitamin A is a fat-soluble vitamin, any GI diseases affecting the absorption of fats also affect vitamin A absorption. Patients with cystic fibrosis, sprue, pancreatic insufficiency, inflammatory bowel disorder (IBD), or cholestasis, as well as persons who have undergone small-bowel bypass surgery, are at increased risk for VAD. These patients should be advised to consume vitamin A. (A retrospective study by Kamel et al found that in patients with IBD, 53.3% with Crohn disease and 52.9% with ulcerative colitis, had VAD. ^[5] )

One factor affecting the metabolism of vitamin A is alcoholism. Alcohol dehydrogenase catalyzes the conversion of retinol to retinaldehyde, which is then oxidized to retinoic acid. The affinity of alcohol dehydrogenase to ethanol impedes the conversion of retinol to retinoic acid.

Increased requirements for vitamin A most commonly occur among sick children. The American Academy of Pediatrics has recommended vitamin A supplementation for infants aged 6-24 months who are hospitalized with measles and for all hospitalized children older than 6 months.

Similarly, the World Health Organization (WHO) and the United Nations International Children's Emergency Fund (UNICEF) have issued joint statements recommending that vitamin A be administered to all children, especially those younger than 2 years, who are diagnosed with measles. Coexistent VAD in young children increases the risk of death. A Cochrane Database of Systematic Reviews article concluded that daily treatment with 200,000 IU of vitamin A for at least 2 days reduces mortality rates. ^{[6, 7]}

Another Cochrane Review article included 43 randomized trials representing 215,633 children, and provided strong support for the importance of vitamin A supplementation in preventing childhood mortality in children aged from 6 months to 5 years. ^[8]  There is no evidence of vitamin A supplementation related reduction in mortality and morbidity for children aged 1-6 months. ^[9]

The risk of VAD is increased in patients suffering from fat malabsorption, cystic fibrosis, sprue, pancreatic insufficiency, IBD, metastatic cancer, regional enteritis, chronic gastroenteritis, or cholestasis, as well as in persons who have undergone small-bowel bypass surgery. The risk is also greater in vegans, refugees, recent immigrants, persons with alcoholism, and toddlers and preschool children living below the poverty line. These patients should be advised to consume vitamin A.

Other patients with avitaminosis A include those with liver disease that causes abnormal or decreased storage of vitamin A. ^[10] Patients receiving total parenteral nutrition can also show signs and symptoms of avitaminosis A secondary to loss of vitamin A with prolonged use.

Women of childbearing age are at high risk for VAD and its consequences because of increased vitamin A requirements during pregnancy and lactation. Their newborns, having been vitamin A depleted, require vitamin A supplements. Otherwise, after the initial 4-6 months of breastfeeding, the babies are likely to develop VAD.

Infections, such as measles, may precipitate a child into clinical VAD. ^{[11, 12]}

Frequency

United States

The Second National Report on Biochemical Indicators of Diet and Nutrition in the US Population, released in 2012 by the US Centers for Disease Control and Prevention, indicated that less than 1% of the US population has VAD. ^[13]

Suzuki et al evaluated the prevalence of VAD in pregnant women of different ethnic groups. They found that the prevalence in Hispanic/Latino women was 65.9% (29 out of 44 Hispanic study participants); in non-Hispanic Black women, 53.3% (8 of 15 African American participants); and in women of other ethnicities, 37.5% (3 of 8 participants). ^[14]

International

Avitaminosis A is a problem wherever the combination of vitamin A and protein deficiency exists. In developed countries, VAD is a rare condition. However, it is a problem of enormous magnitude worldwide, particularly in the underdeveloped regions of Asia, where the diet often consists of little more than rice.

Avitaminosis A is fairly well controlled in much of Latin America and the Caribbean, with the exception of Haiti, where the incidence is as high as that in some Asian countries. Some reports suggest that the prevalence of xerophthalmia in parts of Africa may be as high as that found in Southeast Asia, whereas in other areas, particularly West Africa, the prevalence is lower, mostly because the red palm oil widely used for cooking is a good source of vitamin A supplementation. Clinical VAD (in which children demonstrate ophthalmic signs and symptoms, including blindness) occurs mainly in countries in Southeast Asia and sub-Saharan Africa. ^[15] In endemic countries, the disease is largely confined to lower socioeconomic groups who cannot afford vitamin A–rich foods.

Severe VAD is also found in persons in refugee settlements and in displaced populations. ^{[16, 17, 18]}

A literature review by Song et al estimated that in 2019, 333.95 million children suffered from VAD and 556.13 million children had marginal VAD, in 165 low- and middle-income countries. This came to a prevalence of 14.73% and 24.54%, respectively, of the pediatric population of these countries. ^[19]

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.

The prognosis is good if patients are treated when the deficiency is subclinical. Morbidity increases once blindness has progressed or an infection has been acquired. Irreversible conditions include punctate keratopathy, keratomalacia, and corneal perforation.

Morbidity/mortality

United States

VAD is uncommon in the general population, but subgroups of patients suffering from fat malabsorption, cholestasis, or IBD or who have undergone small-bowel bypass may have subclinical deficiency with dark-adaptation abnormalities in the range of 60%. Vegans, persons with alcoholism, toddlers and preschool children living below the poverty line, and recent immigrants or refugees from developing countries all have increased risk of VAD secondary to decreased ingestion.

Developing countries

Annually, more than 1 million deaths in children are associated with VAD.

Each year, 250,000-500,000 children become blind because of VAD. Improving the vitamin A status of children with deficiencies (aged 6-59 mo) can reduce measles and diarrhea mortality rates by 50% and 33%, respectively, and can decrease risk rates from all causes of mortality by 23%.

Routine distribution of vitamin A to children in endemic areas leads to a decrease of childhood mortality of 5-15%. A meta-analysis that included the DEVTA trial and eight other trials found a modest mortality reduction of 11%. ^[20]

Eating at least five servings of fruits and vegetables per day is recommended in order to provide a comprehensive distribution of carotenoids.

Patients may visit the National Institutes of Health (NIH) website for more information (see Dietary Supplement Fact Sheet: Vitamin A and Carotenoids).