Dermatologic Manifestations of Vitamin A Deficiency
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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. Epidermal vitamin A deficiency may result from a deficit of nutritional vitamin A, exposure to sunlight or any UV source, oxidative stress or chronological aging. Accordingly, increasing epidermal vitamin A may be beneficial. [1] Retinoic acid’s immune regulatory role may include pivotal effects on leukocyte function. [2]
In areas where vitamin A deficiency (VAD) is prevalent, vitamin A repletion reduces child mortality rates by an average of 23%. [3] 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. [4] Liver disease patients evaluated for liver transplantation often have vitamin A deficiency. [5] Both dietary quality and diversity can deteriorate in economic crises. [6] The prevalence of vitamin A deficiency with night blindness may have increased during the 2008 world economic crisis and may not have recovered once food prices waned later in 2008. Vitamin A deficiency remains preventable amid economic instabilities through breast feeding promotion, vitamin A supplementation, fortification of foods targeted to the poor, and homestead food production that can bolster income and diversify the diet. Early dietary intervention, preferably within the first 1,000 days of life, is important to break the cycle of malnutrition and its undesirable consequences. [7]
Also see the Medscape Drugs & Diseases articles Vitamin A Deficiency and Vitamin A Toxicity.
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.
VAD occurs where diets contain insufficient amounts of vitamin A for growth and development, physiological functions, and periods of added stress due to illness. [8]
Avitaminosis A is often diagnosed in persons with alcoholism who are malnourished and in patients who are chronically ill with intestinal malabsorption disorders, [9] such as sprue, bypass surgery, cystic fibrosis, pancreatitis, metastatic cancer, regional enteritis, and chronic gastroenteritis. 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.
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. In endemic countries, the disease is largely confined to lower socioeconomic groups who cannot afford vitamin A–rich foods.
Women of childbearing age are at high risk of 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]
VAD can be assumed to have profound effects because vitamin A supplementation reduces child mortality and severe morbidity in underdeveloped countries. Vitamin A supplementation enhances infants’ immune responses to hepatitis B vaccine. [13]
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. [14]
Blinding xerophthalmia, as identified clinically by corneal xerosis, corneal ulcers, keratomalacia, and corneal scars related to VAD, has been documented in children in Pakistan’s North West Frontier Province and adjoining Federally Administered Tribal Areas. [15]
Females and males are affected equally.
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.
Early recognition and treatment is the key to preventing blindness due to secondary infections and/or ocular ulceration.
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.
A Cochrane Review that included 43 randomized trials representing 215,633 children provides strong support for the importance of vitamin A supplementation in preventing childhood mortality. [16]
The promotion of community, school, and household gardens, especially the cultivation of foods rich in provitamin A activity, is currently one of the more common strategies to promote dietary change. Nutritional education is often incorporated into gardening projects and is provided at health centers in conjunction with the distribution of vitamin A supplements.
Social marketing techniques are used to influence the acceptability of social action and to create programs that elicit desired behaviors. Behavioral changes perceived by the community as beneficial are the target for this approach. Social marketing requires the active involvement of community members and a mixture of communication strategies.
Vitamin A deficiency has a number of undesirable effects. A finding of vitamin A deficiency, which is common in the developing world, should encourage oral vitamin A supplementation to enhance the success of vaccines against HIV-1 and other mucosal pathogens in the developing world, as there is a pivotal relationship between host nutritional status and vaccine efficacy. [17] Vitamin A deficiency has also been shown to worsen iron deficiency. [18]
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Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi
Disclosure: Nothing to disclose.
Santiago A Centurion, MD Dermatologist, Dermatology Associates of Central NJ
Santiago A Centurion, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society for Dermatologic Surgery, American Society for MOHS Surgery, American Society of Dermatopathology, Sigma Xi
Disclosure: Nothing to disclose.
Pere Gascon, MD, PhD Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology, IDIBAPS, University of Barcelona Faculty of Medicine, Spain
Pere Gascon, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, New York Academy of Medicine, New York Academy of Sciences, Sigma Xi
Disclosure: Nothing to disclose.
David F Butler, MD Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society for MOHS Surgery, Association of Military Dermatologists, Phi Beta Kappa
Disclosure: Nothing to disclose.
Jeffrey J Miller, MD Associate Professor of Dermatology, Pennsylvania State University College of Medicine; Staff Dermatologist, Pennsylvania State Milton S Hershey Medical Center
Jeffrey J Miller, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Society for Investigative Dermatology, Association of Professors of Dermatology, North American Hair Research Society
Disclosure: Nothing to disclose.
William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine
William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology
Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.
Shyam Verma, MBBS, DVD, FAAD Clinical Associate Professor, Department of Dermatology, University of Virginia School of Medicine; Adjunct Associate Professor, Department of Dermatology, State University of New York at Stonybrook School of Medicine; Adjunct Associate Professor, Department of Dermatology, University of Pennsylvania School of Medicine
Shyam Verma, MBBS, DVD, FAAD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Cristina S. Solis, MD, to the development and writing of this article.
Dermatologic Manifestations of Vitamin A Deficiency
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