Dermatologic Manifestations of Vitamin A Deficiency 

Updated: Mar 26, 2021
Author: Robert A Schwartz, MD, MPH; Chief Editor: William D James, MD 

Overview

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. 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] It is a public health concern in developing countries, with male preschoolers being a particularly at-risk population.[6] Both dietary quality and diversity can deteriorate in economic crises.[7] 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.[8]

Also see the Medscape Drugs & Diseases articles Vitamin A Deficiency and Vitamin A Toxicity.

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.

Etiology

VAD occurs where diets contain insufficient amounts of vitamin A for growth and development, physiological functions, and periods of added stress due to illness.[9]

Avitaminosis A is often diagnosed in persons with alcoholism who are malnourished and in patients who are chronically ill with intestinal malabsorption disorders,[10] 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.[11] 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.[12, 13]

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.[14]

Epidemiology

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.[15]

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.[16]

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.

Prognosis

Early recognition and treatment is the key to preventing blindness due to secondary infections and/or ocular ulceration.

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.

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.[17]

Patient Education

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.[18] Vitamin A deficiency has also been shown to worsen iron deficiency.[19]

 

Presentation

History

Avitaminosis A generally accompanies states of severe malnutrition, such as kwashiorkor and marasmus, and may be suspected in individuals with an unusual susceptibility to infectious diseases, such as measles. Bitot spots, dry eyes, and night blindness strongly point to vitamin A deficiency.[20] Note the following:

  • Impaired vision, particularly at night: Because of the essential role of vitamin A in photoreceptor function, night blindness is the earliest and most common symptom of its deficiency.

  • Xerophthalmia: VAD may produce xerophthalmia. Its ocular manifestations include conjunctival and corneal xerosis (drying), keratomalacia (corneal necrosis/ulceration), nyctalopia (night blindness), and Bitot spots (conjunctival lesions).[4] Maternal night blindness is common during pregnancy in poor countries. Maternal night blindness during pregnancy has been associated with low birthweight, morbidity, and poor growth in South India.[21]

  • Photophobia

  • Erythema

  • Dry, thickened skin (toad skin)

  • Diarrhea

  • Recent history of biliopancreatic diversion bariatric surgery, with phrynoderma and ocular symptoms rarely noted[22, 23]

Physical Examination

The most distinctive clinical features of VAD are present in the ocular system; however, numerous skin findings have also been reported.

Conjunctival xerosis is typically found on the temporal, interpalpebral, and bulbar conjunctivae. Characteristically, it is seen as a dry, granular patch that can exhibit thickening, wrinkling, loss of pigmentation, and transparency.

Bitot spots are triangular, perilimbal, gray plaques of keratinized conjunctival debris overlying an area of conjunctival xerosis. See the image below. Use of a Wood lamp (a blacklight or ultraviolet-A light) may aid in detecting Bitot spots.[24]

Bitot spots caused by vitamin A deficiency. Courte Bitot spots caused by vitamin A deficiency. Courtesy of the Centers for Disease Control and Prevention Nutrition Program via Wikimedia Commons.

Xerophthalmia results from instability of the precorneal tear film, which can lead to a dull corneal appearance and a superficial punctate keratopathy noted with the use of fluorescein.

Corneal ulcerations can be partial or full thickness. Keratomalacia is a full-thickness liquefactive necrosis of the cornea. Clinically, it is a sharply demarcated lesion with an opaque, grayish yellow appearance. The stroma can slough, either leaving a descemetocele or, in severe cases, causing perforation and loss of the anterior chamber.

Generalized xerosis with fine wrinkles and scales may be present.

Phrynoderma (follicular hyperkeratosis) is characterized by red-brown follicular papules that are approximately 2-6 mm in diameter, with a central keratotic spinous plug. These lesions are usually found clustered around the bony prominences of the elbows and the knees, although they may extend up the thighs and the arms.

Complications

Note the following possible complications:

  • Acute gastroenteritis

  • Growth retardation

  • Infections

  • Vitamin A toxicity (secondary to treatment)

An association between pediatric pseudotumor cerebri and low serum vitamin A levels has been observed even when other manifestations of xerophthalmia are not evident.[25]

 

DDx

 

Workup

Laboratory Studies

The diagnosis should be suspected in children who are malnourished or in patients with predisposing factors for its development. Note the following:

  • Serum vitamin A levels: The biochemical definition of vitamin A deficiency (VAD) is a plasma level of 35 µmol/dL or less. Several techniques are available, but high-pressure liquid chromatography is the most reliable. An important factor is that, with protein deficiency, serum vitamin A levels may be decreased despite good vitamin A intake and adequate vitamin A stores.

  • Total and holo retinol-binding protein (RBP) test: These tests (complex of vitamin A and RBP) for serum RBP tend to correlate with measures of serum vitamin A. These levels can also be decreased in the presence of protein deficiency.

  • Conjunctival impression cytology: This is a technique useful for detecting preclinical xerophthalmia. It is a noninvasive method of obtaining a specimen to assess the histologic appearance of the superficial conjunctival layers. Squamous metaplasia is evident by the presence of enlarged, irregular, and keratinized epithelial cells and the loss of goblet cells. Results are closely correlated with baseline serum vitamin A levels and with clinical improvement after treatment.

 

Treatment

Medical Care

A person with xerophthalmia requires immediate treatment if corneal destruction, blindness, and even death are to be avoided.

Oral administration of vitamin A 200,000 IU at presentation, the following day, and a third dose a week later is recommended. Children younger than 1 year should receive one half the standard dose, and infants younger than 6 months should receive a quarter of the standard dose.

Children with marasmus or kwashiorkor need further nutritional supplementation and monitoring with additional doses of vitamin A at monthly intervals until they are clinically improved.

Concurrent illness (eg, malaria, intestinal parasites, dehydration, tuberculosis) must be treated.

Pregnant women should not receive large doses of vitamin A because it may be teratogenic, but a daily dose of 10,000 IU over 2 weeks is safe.

In all cases, a diet rich in vitamin A should be advised.

Surgical Care

Full-thickness keratomalacia is usually inoperable. The entire cornea is involved, and patients who are affected are too debilitated to undergo anesthesia.

Consultations

Consultation with the following specialists may be helpful:

  • Ophthalmologist

  • Gastroenterologist

  • Nutritionist

Diet

Common dietary sources of preformed vitamin A include liver, dairy products, and fish. Carrots are the major source of beta-carotene. Other contributors of beta-carotene are cantaloupe, broccoli, squash, peas, and spinach.

A food-based approach may be a desirable and sustainable complement to supplementation programs. A good example is the orange-fleshed sweet potato, which is rich in beta-carotene and has been well accepted by young children. Orange-fleshed sweet potatoes were found to increase vitamin A intake and serum retinol concentrations in young children in rural Mozambique.[26] However, fried potatoes contain no vitamin A, and mentally challenged children consuming fried potatoes almost exclusively have been described with vitamin A deficiency.[27]

Prevention

Improving vitamin A status reduces childhood mortality and the risk of blindness. Prevention relies on the maintenance of adequate vitamin A stores either by increasing vitamin A intake in the diet or by periodically administering vitamin A. For prophylaxis, newborns should receive 50,000 IU of vitamin A, children younger than 1 year should receive 100,000 IU every 4-6 months, adults and children older than 1 year should receive 200,000 IU every 4-6 months, and pregnant or lactating women should receive 20,000 IU each week.

Public health programs studying the prevalence of vitamin A deficiency (VAD) are investigating the most effective ways of distributing supplements, from linking them to immunization programs to fortifying common foods (ie, iodized salt). They also strive to promote nutritional education in an effort to increase consumption of red, orange, and leafy green vegetables by endemic populations.

VAD and child survival in sub-Saharan Africa were assessed by Aguayo and Baker in 2005.[28] Effective and sustained control of VAD represents one of the most cost-effective and high-impact child-survival interventions in sub-Saharan Africa. The urgent solutions are known, effective, and affordable.

Although the orange-fleshed sweet potato is an extremely rich plant-based source of pro-vitamin A (beta-carotene), in sub-Saharan Africa consumer preference favored the white-fleshed sweet potato, which is completely lacking in beta-carotene.[29] Accordingly, efforts are being undertaken to alter consumer choice to address the high levels of vitamin A deficiency among children. Another effort was undertaken by supplementing processed foods, balancing flavor/ingredient combinations.[30]

It is possible that a high dietary vitamin A diet may reduce the risk of ultraviolet-light–induced cutaneous squamous cell carcinoma.{ref30

Long-Term Monitoring

Dietary modifications should include foods rich in vitamin A and periodic oral doses of vitamin A.

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce vitamin A deficiency (VAD), reduce morbidity, and prevent complications.

Vitamins

Class Summary

These are essential for normal cell function.

Vitamin A

Vitamin A prevents night blindness, diarrhea, follicular keratosis, and infections.