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Vitamin A Deficiency
Introduction
Vitamin A is a fat-soluble vitamin essential for cell development, metabolism, immune competency, vision, and reproductive functions.[1][2] Vitamin A deficiency (VAD) is a highly prevalent health concern associated with substantial morbidity and mortality, mostly affecting young children in impoverished regions throughout the world. Insufficient intake of absorption leads to deficiency and compromise of essential physiologic processes. Natural sources of vitamin A include dark leafy greens, orange-colored vegetables, milk products, liver, and fish.[3] Vitamin A is absorbed in the duodenum after hydrolyzation by pancreatic and intestinal enzymes and emulsified with dietary fats and bile acids.[4] The majority is then stored in the hepatic stellate cells.[5] Significant amounts are also stored in adipose tissue and the pancreas.[6]
The recommended dietary allowance (RDA) of vitamin A by the Institute of Medicine in healthy adults is 700 micrograms/day for women and 900 micrograms/day for men.[7][8] For children, pregnant women, and lactating women, the RDA is 300 to 900, 770, and 1300 micrograms/day, respectively. The minimum requirement to prevent symptomatic VAD in children 1 to 5 years of age is about 200 micrograms/day. Serum retinol levels are a good marker of vitamin A nutritional status. Deficiency is defined as a retinol concentration of fewer than 20 micrograms/dL.[8]
Vitamin A deficiency-associated ocular symptoms have been shown to develop at concentrations less than 10 micrograms/dL.[8] Dietary vitamin A is ingested as either carotenoid from fruits and vegetables or retinoid from animal products. Carotenoids are a provitamin A, most commonly beta-carotene, and retinoids are active forms of vitamin A, such as retinol and retinyl esters. Retinoids have been shown to have 75% to 100% absorption, whereas carotenoid absorption varies greatly depending on the food matrix and type of carotenoid.[9][10] A 12 to 1 ratio of beta-carotene to retinol absorption in a diet of mixed fruits and vegetables is the estimated conversion used by the Centers for Disease Control and Prevention.[7] Many populations in developing countries rarely ingest meat, dairy, or carotenoid-rich vegetables leading to difficulty obtaining sufficient quantities of vitamin A.
Etiology
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Etiology
In resource-poor regions of the world, insufficient nutrition complicated by chronic inflammation from regular gastrointestinal (GI) infections leads to frequent micronutrient deficiencies and is the most common etiology of vitamin A deficiency worldwide.[11] Adequate vitamin A intake in children in these regions is often further complicated by a concomitant deficiency of zinc, which is required for the absorption of vitamin A and synthesis of retinol-binding protein, the intravascular transport protein.[12] Measles is endemic in many of these regions as well and has been shown to cause precipitous drops in serum retinol levels by greater than 30%.[13] Vitamin A reduces the synthesis of RBP and results in high amounts of vitamin A excretion in the urine. Physiologic demand is also higher in measles infection due to the damage to gastrointestinal epithelial tissues.[13]
Vitamin A concentration in breast milk varies based on maternal nutrition status. In resource-poor settings, the average breastmilk vitamin A concentration only meets the infant's minimum daily need. This does not allow the build-up of liver reserves, resulting in high levels of vitamin A deficiency shortly after weaning.[14] Conversely, VAD is extraordinarily rare in the developed world due to the abundance of foods rich in vitamin A, better sanitation, water, and healthcare. Vitamin A deficiency cases in the developed world are typically due to various primary and secondary intestinal malabsorptive pathologies.
In the developed world, pancreatic, liver, and intestinal pathology are the leading causes of VAD. Similar to the frequent GI infections seen in the developing world, inflammatory bowel disease (IBD) causes chronic inflammation of the intestinal mucosa, and, when combined with decreased oral intake, it can lead to vitamin A deficiency.[15] Chronic liver disease of any type has been associated with vitamin A deficiency. The mechanism by which the deficiency develops is not entirely known: proposed mechanisms include decreased production of bile acids needed for absorption as well as altered storage patterns.[6]
Pancreatic insufficiency can result in VAD due to poor exocrine function and insufficient production of the hydrolases required for absorption.[16] Bariatric surgeries, designed to prevent fat absorption by bypassing the duodenum, consequently cause insufficient absorption of needed fat-soluble vitamins, including vitamin A. Premature neonates are at risk for vitamin A deficiency due to an immature GI tract without efficient vitamin A absorption, minimal vitamin A stores, and increased needs in a time of rapid development.[17]
Epidemiology
Worldwide, most vitamin A deficiency cases occur in children less than 5 years of age in developing countries. Global vitamin A deficiency estimates in young children are decreasing but have been approximated at 30% in children less than 5 years of age and account for about 2% of all deaths in this age group.[18] Pregnant and lactating women are also at increased risk of VAD due to increased daily requirements. Results from a 2019 study in rural Ethiopia revealed vitamin A deficiency in 76% of lactating mothers.[19] VAD does not appear to have a gender predilection.[20][21]
In the United States (US) general population, vitamin A deficiency is rare, estimated at 0.3% in 2013. In fact, the prevalence of vitamin A toxicity in the US is much greater than deficiency.[7] Symptomatic deficiency usually involves a malabsorptive process or a severely restrictive diet. Sixteen percent of children with IBD in the United States have vitamin A deficiency at diagnosis. A higher prevalence is found in Crohn disease than in ulcerative colitis.[15] Patients with liver cirrhosis eligible for transplant have a 70% prevalence of vitamin A deficiency, with a positive correlation between the severity of cirrhosis and the prevalence of VAD.[22] Thirty-five percent of patients with chronic exocrine pancreatic insufficiency have VAD despite 84% of them being on pancreatic enzyme replacement therapy.[16] Seventy percent of patients who had a biliopancreatic diversion had developed VAD at 3 years post-procedure.[23] At birth, 66% of premature infants are vitamin A deficient and at 36 weeks post-menstrual age, 82% had deficiency due to high requirements and low absorption.[17]
Pathophysiology
Vitamin A has a role in the regeneration of visual pigment, maintenance of mucosal membranes, and immune function. Deficiency can lead to night blindness due to poor regeneration of visual pigment in retinal rods. If the deficiency is allowed to persist, the rods will degenerate, and xerophthalmia will develop, leading to true blindness.[24][25][26] Intestinal and pulmonary mucosal membrane xerosis and breakdown, along with immune dysfunction, lead to frequent infections and anemia of chronic inflammation.[27][28][29][30]
History and Physical
A well-performed history of a patient can raise suspicion for vitamin A deficiency. The presence of a malabsorptive process, such as IBD, chronic GI infection, cirrhosis, pancreatic insufficiency, prematurity, rubeola infection (measles), a history of living in a resource-poor country, or current pregnancy or lactation in the setting of poor nutrition should raise concern for vitamin A deficiency. The natural progression of chronic VAD most commonly presents with the gradual development of night blindness, increased frequency of GI, pulmonary, and urinary infections, and development of xeroderma and phrynoderma (follicular hyperkeratosis often found on extensor surfaces, shoulders, and buttocks).[30][31]
As the severity of deficiency worsens, signs of xerophthalmia develop with Bitot spots (conjunctival, triangular or oval, foamy lesions) and conjunctival xerosis (appears as conjunctival wrinkling). If VAD continues to persist, its later stages present as corneal xerosis, corneal ulceration, and eventually keratomalacia as the corneal ulcers heal, corneal scarring and blindness result. In the setting of an infection, particularly measles, patients with an acute deficiency may present with corneal xerosis and ulceration without preceding night blindness or Bitot’s spots.[26] Phrynoderma (a form of follicular hyperkeratosis) may also be seen in VAD but is associated with other nutritional deficiencies as well.[31]
Evaluation
A clinical diagnosis of vitamin A deficiency can be made in classical exam findings and confirmatory laboratory testing. The presence of xerophthalmia is nearly pathognomonic for vitamin A deficiency.[32] The provider can order serum retinol testing for patients with a less clear history and physical exam, with deficiency defined as less than 20 micrograms/dL.[8] However, serum retinol concentration may be normal, even if the total body stores are low, due to maintenance of circulating retinol levels by hepatic stores. The gold standard for evaluating total body vitamin A is quantifying liver retinol concentration on biopsy.[33] Given the risks associated with liver biopsies, they are not routinely used for evaluating vitamin A levels outside of the research setting.
Treatment / Management
Treatment of vitamin A deficiency is vitamin A supplementation (VAS). A multitude of studies has concluded that VAS in vitamin A deficient populations reduce childhood morbidity and mortality.[34] VAS makes a definitive clinical difference in patients with serum retinol concentrations less than 20 micrograms/dL. Any patient with a concentration greater than 30 micrograms/dL will not benefit from supplementation and should follow the recommended dietary allowance.[35](A1)
In regions with a high prevalence of VAD, the World Health Organization (WHO) recommends universal VAS of select populations. They recommend a one-time dose of 100,000 IU in children 6 to 11 months of age followed by doses of 200,000 international units (IU) every 4 to 6 months up to 5 years of age.[36] At-risk pregnant women should receive supplementation at lower doses due to concern for fetotoxicity; the recommended dosing is 10,000 IU daily or 25,000 IU weekly for 12 weeks.[37] The WHO no longer recommends universal supplementation for children less than 6 months of age or postpartum women.[38][39][40]
International guidelines do not clearly outline dosing of VAS for asymptomatic vitamin A deficiency in resource-rich regions. Instead, dosing of VAS is based on the severity of deficiency and provider discretion. The WHO recommends treating xerophthalmia with VAS of 50,000 IU for children less than 6 months of age, 100,000 IU for children 6-12 months of age, and 200,000 IU for children greater than 12 months of age daily for 2 days followed by an additional dose after 2 weeks. For any patient with a severe case of measles, the WHO recommends the aforementioned dosing once daily for 2 days, regardless of whether the patient is known to be vitamin A deficient or not.[41] Regarding specific VAS strategies, zinc-deficient patients have a poor response to VAS and should undergo concomitant zinc supplementation.[12] If the patient’s VAD is from malabsorption, providers should consider intramuscular VAS formulations.(A1)
In resource-rich countries, post-bariatric patients and neonates have particular dosing recommendations. Post-bariatric surgery patients are recommended to take 10,000 IU VAS daily and adjust as needed based on regular serum retinol level monitoring. Some bariatric patients have been known to need up to 100,000 IU VAS daily.[42] For premature infants, guidelines do not exist yet for VAS. Still, recent studies have shown that VAS of 10,000 IU every other day in very low birth weight neonates for 4 weeks has significant results, decreasing all-cause mortality by 56% and decreasing rates of oxygen requirement, sepsis, PDA, and length of hospital stay.[43] Supplementation of 1500 IU daily in extremely premature infants had a significant decrease in retinopathy of prematurity (1.6% vs 6.9%) and a nearly 50% decrease in bronchopulmonary dysplasia.[44] VAD associated with other malabsorptive processes is treated on a case-by-case basis.(A1)
Differential Diagnosis
When evaluating vitamin A deficiency, it is important not to overlook other causes of similar signs and symptoms. Night blindness is the first presenting symptom of retinitis pigmentosa and some rare retinal dystrophies.[45][46] Additionally, cataracts and myopia are both degenerative ophthalmologic diseases that can present with night blindness. Bitot spots are also associated with niacin deficiency.[47] Pinguecula and pterygium may resemble Bitot spots.
Prognosis
The prognosis of vitamin A deficiency depends on the severity of the disease at treatment initiation.[26] If treated promptly, patients with subclinical VAD have a very good prognosis without long-term sequelae. Treatment at any stage of severity can show improvement within a week.[48] The early ophthalmologic signs, such as night blindness, conjunctival xerosis, and Bitot spots, will resolve completely within about 2 months of supplementation, while corneal xerosis and ulceration results in scarring that may lead to permanent vision loss despite treatment.[49][26] At the onset of visual manifestations, patients develop an increased susceptibility to infection. In preschool children with VAD, the presence of ophthalmologic signs indicates increased overall mortality from gastrointestinal, pulmonary, and other VAD-related mucosal infections.[26] Mortality in children with night blindness is triple the mortality found in children with subclinical VAD. Children with both Bitot’s spots and night blindness have mortality nine times that of children with subclinical VAD. Nearly two-thirds of children with keratomalacia die within months.[26]
Complications
Severe vitamin A deficiency may lead to permanent vision loss or blindness, increased susceptibility to infections, and impaired immune function, leading to high mortality.[26]
Deterrence and Patient Education
A well-balanced, nutrient-rich diet prevents vitamin A deficiency in generally healthy patients able to absorb nutrition. In resource-rich regions, the majority of the population has access to vegetables, meats, and staple foods that are fortified with vitamin A. In resource-poor countries, large scale vitamin A supplementation programs have been implemented in attempts to provide high dose vitamin A at the WHO-recommended intervals.[50]
Associated programs educate people on nutrition, breastfeeding, and VAD symptoms. These have had variable success depending on the region.[51][52] More programs are starting to focus on the root cause of VAD by focusing on food fortification and education rather than simply supplementation. In fact, many staple foods are now fortified with important micronutrients, and genetic modifications have been made to rice, potatoes, wheat, and soybeans, among others, to increase concentrations of vitamin A.[53][54][55][56][57] These biofortified crops can be economically and agriculturally viable.[58]
Enhancing Healthcare Team Outcomes
An interprofessional team greatly contributes to the effective treatment and prevention of vitamin A deficiency. The initial care in resource-rich settings typically falls to the primary care physician, who then coordinates with dietitians and pharmacists to ensure optimal nutrition and medical treatment. Gastroenterologists, bariatric surgeons, and transplant surgeons can help treat malabsorptive patients, post-bariatric surgery patients, and liver cirrhosis patients, respectively. Ophthalmologists are vital in evaluating and treating the multitude of VAD-related eye disorders. After acute evaluation and management of vitamin A deficiency, the primary care physician resumes preventive care.[59]
In regions of the world with limited medical care, public health nurses are vital in providing high-dose VAS to the most rural areas. They are instrumental in making appropriate specialty referrals for those with more severe disease. Governments and international health organizations play huge roles in providing the funds and organization for continued supplementation, education, and fortification programs.[34] Overall, though simple to diagnose and treat, vitamin A deficiency still affects millions worldwide and continues to be a topic of international attention.
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