AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The word vitamin was originally derived from Funk's term "vital amine." In 1912, he was referring to Christian Eijkman's discovery of an amine extracted from rice polishings that could prevent beriberi. Funk's recognition of the antiberiberi factor as vital for life was indeed accurate. Researchers have since found that vitamins are essential organic compounds that the human body cannot synthesize. Vitamins A, D, K, and E are classified as fat-soluble vitamins, whereas others are classified as water-soluble vitamins.^{1, 2}

Vitamin A was the first fat-soluble vitamin to be discovered. Early observations by ancient Egyptians recognized that night blindness could be treated with consumption of liver. Two independent research teams, Osborne and Mendel at Yale University and McCollum and Davis at the University of Wisconsin, simultaneously discovered vitamin A in 1913. Vitamin A is made up of a family of compounds called the retinoids. The retinoid designation resulted from finding that vitamin A had the biologic activity of retinol, which was originally isolated from the retina.

There are essentially 3 forms of vitamin A: retinols, beta carotenes, and carotenoids. Retinol, also known as preformed vitamin A, is the most active form and is mostly found in animal sources of food. Beta carotene, also known as provitamin A, is the plant source of retinol from which mammals make two-thirds of their vitamin A. Carotenoids, the largest group of the 3, contain multiple conjugated double bonds and exist in a free alcohol or in a fatty acyl-ester form.

In the human body, retinol is the predominant form, and 11-cis-retinol is the active form. Retinol-binding protein (RBP) binds vitamin A and regulates its absorption and metabolism. Vitamin A is essential for vision (especially dark adaptation), immune response, bone growth, reproduction, the maintenance of the surface linings of the eyes, epithelial cell growth and repair, and the epithelial integrity of the respiratory, urinary, and intestinal tracts. Vitamin A is also important for embryonic development and the regulation of adult genes. It functions as an activator of gene expression by retinoid alpha-receptor transcription factor and ligand-dependent transcription factor.

Deficiency of vitamin A is found among malnourished, elderly, and chronically sick populations in the United States, but it is more prevalent in developing countries. Abnormal visual adaptation to darkness, dry skin, dry hair, broken fingernails, and decreased resistance to infections are among the first signs of vitamin A deficiency (VAD).³

Related eMedicine topics:
Avitaminosis A
Malnutrition
Vitamin A Toxicity

Related Medscape topic:
Resource Center Nutrition

Pathophysiology

Once ingested, provitamins A are released from proteins in the stomach. These retinyl esters are 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.

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.⁴

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 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.

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 of 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. In the 1960s, the World Health Organization (WHO) undertook the first global survey of VAD with associated xerophthalmia and complicated measles.⁵ In 1973, an international vitamin A board was set up to alleviate global malnutrition.

The 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. The Cochrane Database Systemic Review concluded that daily treatment with 200,000 IU of vitamin A for at least 2 days reduces mortality rates.^{6, 7}

Pregnant women do not require increased vitamin A supplementation. In fact, the Teratology Society advocates that women be informed of the possible risk of cranial neural crest defects and other malformations resulting from excessive use of vitamin A shortly before or during pregnancy.⁸ The recommended daily allowance (RDA) of 800 mcg for all adult females is also appropriate for pregnant women, because their stores of vitamin A meet the fetal accretion rate. The requirements for lactating women have been debated, but the current RDA is 1300 mcg in the first 6 months and 1200 mcg in the second 6 months.

The RDAs of vitamin A for various age groups are as follows:

• Infants aged 1 year or younger - 375 mcg
• Children aged 1-3 years - 400 mcg
• Children aged 4-6 years - 500 mcg
• Children aged 7-10 years - 700 mcg
• All males older than 10 years - 1000 mcg
• All females older than 10 years - 800 mcg

Frequency

United States

Statistics from the US Centers for Disease Control and Prevention, based on a 1988-1991 survey, showed that age-specific intakes of carotenes were higher among males than females during that period and were higher among adults than children.⁹ Significant differences in intake existed among different ethnic groups.

International

Clinical and subclinical VAD are problems in at least 75 countries.¹⁰ In 1994, the WHO classified countries as having clinical or subclinical, severe, moderate, or mild VAD. Clinical VAD (in which children demonstrate ophthalmic signs and symptoms, including blindness) occurs mainly in countries in Southeast Asia and sub-Saharan Africa.⁵ Severe VAD is also found in persons in refugee settlements and in displaced populations.

Mortality/Morbidity

• 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 - An estimated 250 million children are at risk for vitamin deficiency syndromes. The most widely affected group includes up to 10 million malnourished children, who develop xerophthalmia and have an increased risk of complications and death from measles. 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%.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Subclinical forms of VAD may not cause any symptoms, but the risk of developing respiratory and diarrheal infections is increased, the growth rate is decreased, and bone development is slowed. Patients may have a recent history of increased infections, infertility secondary to impaired spermatogenesis, or recent spontaneous abortion secondary to impaired embryonic development. The patient may also report increased fatigue, as a manifestation of VAD anemia.

Physical

Signs and symptoms of vitamin A deficiency include the following: 

• Bitot spots - Areas of abnormal squamous cell proliferation and keratinization of the conjunctiva can be seen in young children with VAD.
• Blindness due to retinal injury - 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.¹¹ 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. 
• Poor adaptation to darkness (nyctalopia)
• Dry skin
• Dry hair
• Pruritus
• Broken fingernails
• Keratomalacia
• Xerophthalmia
• Corneal perforation
• Follicular hyperkeratosis (phrynoderma) secondary to blockage of hair follicles with plugs of keratin.
• Other signs of VAD include excessive deposition of periosteal bone secondary to reduced osteoclastic activity, anemia, keratinization of mucous membranes, and impairment of the humoral and cell-mediated immune system.

Causes

The risk of VAD is increased in patients suffering from fat malabsorption, cystic fibrosis, sprue, pancreatic insufficiency, IBD, or cholestasis, as well as in persons who have undergone small-bowel bypass surgery. The risk is also increased 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to Be Considered

Refractory errors
Zinc deficiency

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• A serum retinol study is a costly but direct measure using high-performance liquid chromatography. A value of less than 0.7 mg/L in children younger than 12 years is considered low.
• A serum RBP study is easier to perform and less expensive than a serum retinol study, because RBP is a protein and can be detected by an immunologic assay. RBP is also a more stable compound than retinol with respect to light and temperature. However, RBP levels are less accurate, because they are affected by serum protein concentrations and because types of RBP cannot be differentiated.^{12, 13, 14}
• A zinc level is useful because zinc deficiency interferes with RBP production.
• An iron panel is useful because iron deficiency can affect the metabolism of vitamin A.
• Albumin levels are indirect measures of vitamin A levels.
• Obtain a complete blood count (CBC) with differential if anemia, infection, or sepsis is a possibility.
• An electrolyte evaluation and liver function studies should be performed to evaluate for nutritional and volume status.

Imaging Studies

• In children, radiographic films of the long bones may be useful when an evaluation is being made for bone growth and for excessive deposition of periosteal bone.

Procedures

• Dark-adaptation threshold should be tested.¹⁵

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• In the United States, VAD can easily be prevented through the consumption of foods recommended in the Diet subsection.
• Treatment for subclinical VAD includes the consumption of vitamin A–rich foods, such as liver, beef, chicken, eggs, fortified milk, carrots, mangoes, sweet potatoes, and leafy green vegetables.
• For VAD syndromes, treatment includes daily oral supplements, as follows:
• • Children aged 3 years or younger - 600 mcg (2000 IU)
  • Children aged 4-8 years - 900 mcg (3000 IU)
  • Children aged 9-13 years - 1700 mcg (5665 IU)
  • Children aged 14-18 years - 2800 mcg (9335 IU)
  • All adults - 3000 mcg (10,000 IU)
• Therapeutic doses for severe disease include 60,000 mcg (200,000 IU), which has been shown to reduce child mortality rates by 35-70%.

Consultations

• Consult endocrinologists, gastroenterologists, ophthalmologists, nutritionists, infectious disease specialists, and dermatologists, as indicated.

Diet

• The Dietary Guidelines for Americans, from the US departments of Agriculture and Health and Human Services, recommend consumption of a variety of foods for a comprehensive nutrient intake.¹⁶ Vitamin A–rich foods include the following^{16, 17}:
• • Liver
  • Beef
  • Chicken
  • Eggs
  • Whole milk
  • Fortified milk
  • Carrots
  • Mangoes
  • Orange fruits
  • Sweet potatoes
  • Spinach, kale, and other green vegetables
• Eating at least 5 servings of fruits and vegetables per day is recommended in order to provide a comprehensive distribution of carotenoids.
• A variety of foods, such as breakfast cereals, pastries, breads, crackers, and cereal grain bars, are often fortified with 10-15% of the RDA of vitamin A.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.¹⁸

Drug Category: Vitamins

Essential for normal deoxyribonucleic acid (DNA) synthesis and the metabolism of proteins, carbohydrates, and fats. They may also work as cofactors used in aerobic cellular respiration.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients with VAD seldom need to be admitted to the hospital unless they also have a serious associated condition. Patients with sepsis, severe dehydration, and/or metabolic derangements should be admitted to the hospital.

Further Outpatient Care

• Follow-up care with a primary care physician is recommended.

In/Out Patient Meds

• Patients should take oral vitamin A at prescribed doses until the deficiency resolves.

Deterrence/Prevention

• Liver, beef, chicken, eggs, whole milk, fortified milk, carrots, mangoes, orange fruits, sweet potatoes, spinach, kale, and other green vegetables are among foods rich in vitamin A.
• Eating at least 5 servings of fruits and vegetables per day is recommended in order to provide a comprehensive distribution of carotenoids.
• A variety of foods, such as breakfast cereals, pastries, breads, crackers, and cereal grain bars, are often fortified with 10-15% of the RDA of vitamin A.

Prognosis

• 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.

Patient Education

• Eating at least 5 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).

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Evaluation for subclinical symptoms is important in high-risk groups (eg, patients suffering from a malabsorption syndrome or alcoholism, persons with low socioeconomic status, and patients who have, or have had surgery for, small-bowel disease). Follow-up care upon completion of all standard vaccination regimens, especially for measles, is imperative in children.

Special Concerns

• Studies comparing the association of vitamin A and cancer have yielded mixed results.^{19, 20} Two randomized, controlled trials indicated that beta-carotene supplementation can increase the risk of developing lung cancer.¹⁵ No convincing data exist concerning a reduction in the risk of colorectal cancer with beta-carotene supplementation. Similarly, clinical data on an association between vitamin A and breast cancer are lacking.

Related Medscape topic:
CME Multivitamins Do Not Reduce Risk for Lung Cancer, and Vitamin E May Raise It 

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Combs GF Jr. Vitamins. In: Mahan LK, Escott-Stump S, eds. Krause's Food, Nutrition, and Diet Therapy. 10^th ed. Philadelphia, Pa: WB Saunders; 2000.
2. Pazirandeh S, Burns DL. Overview of fat-soluble vitamins I. UpToDate. 2002.
3. Russell RM. Vitamin and trace mineral deficiency and excess. In: Braunwald E, Fauci A, Kasper D, et al, eds. Harrison's Principles of Internal Medicine. vol 1. 15^th ed. New York, NY: McGraw-Hill; 2001:465-6.
4. Munoz EC, Rosado JL, Lopez P, et al. Iron and zinc supplementation improves indicators of vitamin A status of Mexican preschoolers. Am J Clin Nutr. Mar 2000;71(3):789-94. [Medline]. [Full Text].
5. Reddy V. History of the International Vitamin A Consultative Group 1975-2000. J Nutr. Sep 2002;132(9 Suppl):2852S-6S. [Medline]. [Full Text].
6. D'Souza RM, D'Souza R. Vitamin A for treating measles in children. Cochrane Database Syst Rev. 2002;(1):CD001479. [Medline].
7. Gungor S, Olmez A, Pinar Arikan Firat, et al. Serum retinol and beta-carotene levels in subacute sclerosing panencephalitis. J Child Neurol. Mar 2007;22(3):341-3. [Medline].
8. Rothman KJ, Moore LL, Singer MR, et al. Teratogenicity of high vitamin A intake. N Engl J Med. Nov 23 1995;333(21):1369-73. [Medline]. [Full Text].
9. Alaimo K, McDowell MA, Briefel RR, et al. Dietary intake of vitamins, minerals, and fiber of persons ages 2 months and over in the United States: Third National Health and Nutrition Examination Survey, Phase 1, 1988-91. Adv Data. Nov 14 1994;1-28. [Medline]. [Full Text].
10. Lee V, Ahmed F, Wada S, et al. Extent of vitamin A deficiency among rural pregnant women in Bangladesh. Public Health Nutr. Jun 12 2008;1-6. [Medline].
11. Al-Saleh I, El-Doush I, Billedo G. Age and gender-related reference values for serum dl-alpha-tocopherol and all-trans-retinol levels in Saudi population. Int J Vitam Nutr Res. Sep 2007;77(5):326-35. [Medline].
12. de Pee S, Dary O. Biochemical indicators of vitamin A deficiency: serum retinol and serum retinol binding protein. J Nutr. Sep 2002;132(9 Suppl):2895S-901S. [Medline]. [Full Text].
13. Weinman AR, Jorge SM, Martins AR, et al. Assessment of vitamin A nutritional status in newborn preterm infants. Nutrition. Jun 2007;23(6):454-60. [Medline].
14. Gorstein JL, Dary O, Pongtorn, et al. Feasibility of using retinol-binding protein from capillary blood specimens to estimate serum retinol concentrations and the prevalence of vitamin A deficiency in low-resource settings. Public Health Nutr. May 2008;11(5):513-20. [Medline].
15. Russell RM. The vitamin A spectrum: from deficiency to toxicity. Am J Clin Nutr. Apr 2000;71(4):878-84. [Medline]. [Full Text].
16. Dietary Guidelines for Americans, 2005. 6^th ed. Department of Health and Human Services, Department of Agriculture; Jan 2005. [Full Text].
17. Dietary Supplement Fact Sheet: Vitamin A and Carotenoids. National Institutes of Health, Office of Dietary Supplements; Apr 23 2006. [Full Text].
18. Fletcher RH, Fairfield KM. Vitamin supplementation in disease prevention II. UpToDate. 2002.
19. Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: scientific review. JAMA. Jun 19 2002;287(23):3116-26. [Medline]. [Full Text].
20. Willett WC, Hunter DJ. Vitamin A and cancers of the breast, large bowel, and prostate: epidemiologic evidence. Nutr Rev. Feb 1994;52(2 Pt 2):S53-9. [Medline].

Article Last Updated: Jun 16, 2008