Overview of vitamin A

INTRODUCTION — Vitamins are a number of chemically unrelated families of organic substances that cannot be synthesized by humans and must be ingested in the diet in small quantities to facilitate normal metabolism. They are divided into water-soluble and fat-soluble vitamins (table 1).

Ancient Egyptians recognized that night blindness could be treated by consumption of liver [1]. In the late 1920s, through the efforts of a Swiss scientist named Karrer and his colleagues, the fat-soluble compound in liver was isolated and termed vitamin A [2].

This topic review will focus on issues related to vitamin A. Overviews of the other fat-soluble vitamins, minerals, and water-soluble vitamins are available elsewhere. (See "Overview of vitamin D" and "Overview of vitamin E" and "Overview of vitamin K" and "Overview of dietary trace elements" and "Overview of water-soluble vitamins" and "Vitamin intake and disease prevention".)

CHEMISTRY — Vitamin A is a subclass of a family of lipid-soluble compounds referred to as retinoic acids. These consist of four isoprenoid units joined in a head-to-tail fashion. There are two main forms of vitamin A: provitamin A carotenoids (beta-carotene and others) and preformed vitamin A.

●Provitamin A carotenoids are found in plants. There are many forms of provitamin A, primarily beta-carotene, alpha-carotene, and beta-cryptoxanthin. These are metabolized by mammals into vitamin A, with varying efficiencies [3].

●Preformed vitamin A (retinol, retinal, retinoic acid, and retinyl esters) is the most active form of vitamin A; it is mostly found in animal sources of food and is also the form supplied by most supplements. Some supplements provide a combination of provitamin A (beta-carotene) and preformed vitamin A.

SOURCES — The common food sources of preformed vitamin A (retinols) are liver, kidney, egg yolk, and butter. Provitamin A (beta-carotene) is mostly found in green leafy vegetables, sweet potatoes, and carrots. Because vitamin A from animal sources or supplements is preformed, it is more likely to cause toxicity than the provitamin A from plant sources. (See 'Metabolism' below and 'Excess' below.)

METABOLISM — The initial steps in metabolism depend on the type of vitamin A ingested. The metabolism of provitamin A (beta-carotene and others) into active vitamin A is a highly regulated step, so excessive intake of vitamin A from plant sources is very unlikely to cause toxicity. By contrast, absorption and storage of preformed vitamin A (eg, in animal liver or dietary supplements) is efficient, and toxicity can occur if excessive quantities are ingested. (See 'Excess' below.)

●Provitamin A (mostly beta-carotene, from plant sources) must be cleaved to retinal before absorption. This step is subject to feedback regulation, which depends on vitamin A status.

●Preformed vitamin A (retinol, retinal, retinoic acid, and retinyl esters, from supplements or animal sources) is hydrolyzed into retinol in the lumen of the small intestine. A number of retinyl ester hydrolases are involved in this process at the level of the mucosal brush-border [4]. It also appears that pancreatic enzymes have a role in retinoid assimilation [5]. Bile salts form micelles, which allow water solubilization of the products of lipolysis and absorption through the intestinal mucosa. These steps are highly efficient and not subject to feedback regulation.

Within the small intestine, retinols are re-esterified into retinyl esters, incorporated into chylomicrons, and excreted into lymphatics and plasma [3]. In the blood, chylomicrons are then broken down into multiple remnants including apolipoproteins B and E, which contain retinyl esters.

The apolipoproteins are then taken up by the liver via a receptor-mediated endocytosis on the surface of the hepatocytes, and the retinyl esters are released [3]. These are further metabolized to eventually combine with retinol-binding proteins (RBPs) before storage in vitamin A-containing lipid globules within the hepatic stellate cells (formerly known as Ito cells).

Approximately 50 to 85 percent of the total body retinol is stored in the liver [6]. It is also found in many other tissues in much smaller concentrations. In order for vitamin A to reach its target organs, it binds to RBP molecules for release into plasma as a retinol-RBP complex.

ACTIONS — Vitamin A has a number of biologic actions.

Vision — In the eye, vitamin A has two major roles: prevention of xerophthalmia (abnormalities in corneal and conjunctival development) and phototransduction.

Two types of retinal photoreceptor cells are involved in the visual process. The cone cells are responsible for the absorption of light and 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-retinal is converted to 11-cis-retinal, which then combines with a membrane-bound protein called opsin to yield rhodopsin [7,8]. A similar type of reaction occurs in the cone cells of the retina to produce iodopsin. The visual pigments absorb light at different wavelengths depending upon the type of cone cells. As an example, the red-sensitive cone cells absorb any light stimulus in the wavelength of the color red. This leads to the absorption of the three basic colors, red, green, and blue. The light-activated isomerization of these complexes leads to a cascade of hyperpolarization of rod cell membrane, therefore enabling the transmission of light stimuli to the central nervous system [7].

Cellular differentiation — Other than its importance in vision, vitamin A is crucial to cellular differentiation and integrity in the eye. All the cells in the conjunctiva and the retina have retinol-binding proteins (RBPs), suggesting the dependence of these tissues on retinoic acid. Normal fetal development of the eye also requires adequate vitamin A intake and stores [9]. Studies in vitamin A-depleted animals show abnormal fetal eye tissue development [10].

DEFICIENCY — Vitamin A deficiency is rarely seen in the United States and other resource-rich countries.

However, fat-soluble vitamin deficiencies, including vitamin A, are being increasingly identified in patients that have undergone bariatric surgery. As examples, among patients that have had biliopancreatic diversion or duodenal switch procedures, 69 percent developed vitamin A deficiency [11]. Among gastric bypass patients, vitamin A deficiency was identified in a significant proportion of patients postoperatively; 35 percent at six weeks and 18 percent at one year. Among these patients, vitamin A levels correlated with prealbumin levels. Interestingly, the presence of fat-soluble vitamin deficiency did not correlate to roux limb length [12]. Patients that have had bariatric surgical procedures routinely are supplemented with multivitamins containing vitamin A to prevent deficiency and should be assessed periodically. Management of vitamin A supplementation after bariatric surgery is discussed in detail elsewhere. (See "Bariatric surgery: Postoperative nutritional management", section on 'Vitamin A'.)

Nonetheless, the prevalence of vitamin A deficiency is approximately 30 percent among children under age 5 worldwide and nearly 50 percent in young children in South Asia and sub-Saharan Africa [13]. These areas have been designated as high priorities for distribution programs, along with a few countries in Central and South America. In many of the countries with high rates of vitamin A deficiency, distribution programs have been disrupted by loss of delivery platforms, leading to a sharp decline in effective supplementation. In many resource-limited countries, night blindness, complete blindness, and advanced stages of xerophthalmia occur in many malnourished children and adults (figure 1A-B) [14,15]. This represents a major public health problem; approximately 500,000 preschool children become blind each year and many die [16]. Routine distribution of vitamin A to children in endemic areas prevents these ophthalmic complications [17,18]. In addition, one study suggests that vitamin A supplementation to children in undernourished populations reduces the long-term risk of hearing loss among those with ear discharge (a marker for otitis) [19].

Routine distribution of vitamin A to children in endemic areas leads to a modest reduction of childhood mortality of approximately 5 to 15 percent [13]. This was shown in a well-executed cluster-randomized trial (the DEVTA trial) that included more than two million children aged six months to five years in North India, a population with a high frequency of vitamin A deficiency [20]. Supplementation for five years with high-dose vitamin A (200,000 international units every six months, with or without a deworming protocol) reduced the prevalence of severe vitamin A deficiency and ophthalmopathy but did not achieve a significant reduction in mortality (mortality ratio 0.96, 95% CI 0.89-1.03). This finding contrasts with previous smaller studies that suggested that periodic vitamin A supplementation yielded a 12 percent reduction in all-cause mortality and a similar reduction in diarrhea-associated mortality [21]. A meta-analysis that included the DEVTA and eight previous trials yielded a modest weighted average mortality reduction of 11 percent (95% CI 5-16) [20].

Vitamin A deficiency with or without xerophthalmia can also be seen in resource-rich countries in patients with disorders associated with fat malabsorption, such as cystic fibrosis and other causes of pancreatic insufficiency, celiac disease, cholestatic liver disease such as primary biliary cholangitis, small bowel Crohn disease, short bowel syndrome, and in patients who have undergone certain types of bariatric surgery. Xerophthalmia also has been reported in individuals with extremely limited diets due to mental health disorders [22]. Patients with these or other disorders associated with fat malabsorption who experience visual changes, particularly in low light or at night, should be evaluated for vitamin A deficiency. (See "Vitamin and mineral deficiencies in inflammatory bowel disease", section on 'Vitamin A'.)

Measurement — The diagnosis of vitamin A deficiency is usually made by clinical findings but can be supported by measurement of serum retinol levels (levels less than 20 micrograms/dL [0.7 micromol/L] suggest deficiency) [23]. Fasting specimens are preferred [24]. Serum carotene levels are typically low in patients with vitamin A deficiency, and low serum carotene can be used as a surrogate marker of malabsorption and nutritional status.

Serum vitamin A concentrations do not reflect total vitamin A stores under certain conditions: Serum retinol levels may be artificially low (ie, underestimate vitamin A stores) in the setting of severe systemic inflammatory disease and severe malnutrition. In setting of inflammation, there is a decrease in many carrier protein levels, including retinol-binding protein (RBP), due to redistribution resulting from capillary leak [25]. In severe malnutrition, serum retinol levels are low because dietary protein, energy, and zinc are required for synthesis of RBP [3]. Conversely, in a patient with vitamin A deficiency, a dose of vitamin A may cause a transient rise in serum retinol concentrations, leading to overestimation of the patient's vitamin A stores.

Clinical manifestations

●Xerophthalmia describes a spectrum of eye disease caused by vitamin A deficiency. It is characterized by pathologic dryness of the conjunctiva and cornea, caused by inadequate function of the lacrimal glands, and is manifested by Bitot spots (picture 1) (areas of abnormal squamous cell proliferation and keratinization of the conjunctiva), progressing to corneal xerosis (dryness) and keratomalacia (softening) (picture 2) [3,26]. Vitamin A deficiency also causes night blindness (nyctalopia) and retinopathy because vitamin A is a substrate for the photosensitive visual pigments in the retina. The advanced stages of xerophthalmia may be irreversible.

●Poor bone growth.

●Nonspecific dermatologic problems, such as hyperkeratosis, phrynoderma (follicular hyperkeratosis), and the destruction of hair follicles and their replacement with mucus-secreting glands [10].

●Impairment of the humoral and cell mediated immune system via direct and indirect effects on the phagocytes and T cells [27-30]. Supplementation with vitamin A at the community level in resource-limited countries is recommended by the World Health Organization (WHO) because of its beneficial effects on immunity. (See "Vitamin intake and disease prevention".)

Replacement — Vitamin A deficiency is common among populations in resource-limited countries. For populations in which vitamin A deficiency is endemic (figure 1A-B), the WHO recommends the following replacement approaches [26]:

Universal periodic distribution — Periodic supplementation is recommended for populations endemic for vitamin A deficiency, at the following doses (where 1 microgram retinol = 3.3 international units) [26]:

●Infants 6 to 12 months of age: 100,000 international units orally (30 mg retinol equivalent) – One dose

●Children 12 to 59 months of age: 200,000 international units orally (60 mg retinol equivalent) – Dose repeated every four to six months

Pregnant females living in areas where there is a severe public health problem related to vitamin A deficiency should receive vitamin A supplementation to prevent night blindness; supplements should be provided as frequent small doses not exceeding 10,000 international units daily or 25,000 international units, given weekly for a minimum of 12 weeks during pregnancy until delivery [31]. This corresponds approximately to the upper limit (UL) for adults set by the Food and Nutrition Board in the United States (table 2) [3]. High-dose supplements should not be given in pregnancy because of potential teratogenic effects. Replacement should be avoided in the first 60 days of gestation. (See 'Teratogenic effects' below.)

Routine supplementation is no longer recommended for neonates, infants one to five months of age, or to mothers during the postpartum period living in endemic areas [32-34]. In several large studies and systematic reviews, vitamin A supplementation had no consistent health benefits and may have had side effects in young infants [35]. Supplementation for neonates has been particularly controversial because of mixed results from many large studies [36]. A meta-analysis of 11 randomized trials suggests that neonatal supplementation may reduce infant mortality only in high-risk populations [37]. This analysis found that vitamin A supplementation modestly reduced infant mortality in South Asia (relative risk 0.87, 95% CI 0.77-0.98), a region with high prevalence of vitamin A deficiency and infant mortality, but not in Africa, where these risk factors are lower.

Targeted supplementation for disease — For children at high risk of vitamin A deficiency, such as those with measles, diarrhea, respiratory disease, or severe malnutrition, who live among populations at risk for vitamin A deficiency, and who have not received supplements within the past one to four months, the WHO recommends an (additional) one-time vitamin A supplementation at the following age-specific doses [38].

●Infants < 6 months of age: 50,000 international units orally

●Infants 6 to 12 months of age: 100,000 international units orally

●Children >12 months: 200,000 international units orally

High-risk measles — For children with measles who are living in areas where the measles case fatality rate is high, and/or children with severe and complicated measles, the same dose should be given twice, on two successive days [39]. If there are ocular manifestations of vitamin A deficiency, a third dose should be given four to six weeks later. (See "Measles: Clinical manifestations, diagnosis, treatment, and prevention", section on 'Vitamin A'.)

Xerophthalmia — For treatment of xerophthalmia, vitamin A is given in three doses at the age-specific doses listed above.

The dose for adolescents and adults is 200,000 international units orally in three doses for a total of 600,000 units [38]. The first dose is given immediately upon diagnosis, the second on the following day, and the third dose at least two weeks later.

However, females of reproductive age or who are pregnant and have night blindness should be treated with frequent small doses of vitamin A, rather than high doses used for other adults. (See 'Universal periodic distribution' above.)

EXCESS — The majority of the vitamin A toxicity cases are due to the chronic ingestion of large amounts of synthetic (or "preformed") vitamin A (approximately 10 times higher than the Recommended Dietary Allowance [RDA], or approximately 50,000 international units) [40]. Water-miscible, emulsified, and solid forms of retinol supplements, which include those in candy-like supplements marketed for children, are more toxic than oil-based preparations [41].

By contrast, metabolism of provitamin A (beta-carotene, from plant sources) is highly regulated, so excessive ingestion of this form of vitamin A is very unlikely to cause toxicity. As an example, individuals who ingest large amounts of provitamin A (from plant sources) may develop yellow-tinged skin (carotenemia) without developing vitamin A toxicity. Carotenemia is particularly common among infants and toddlers who are eating large amounts of pureed vegetables (particularly carrots and green leafy vegetables), and may be initially confused with jaundice. The skin discoloration resolves spontaneously if the intake of these foods is reduced. Less commonly, carotenemia may also be caused by some diseases, including nephrosis, diabetes mellitus, anorexia nervosa, liver disease, and hypothyroidism, due to decreased conversion of beta carotene into retinol. (See 'Metabolism' above and "The pediatric physical examination: Back, extremities, nervous system, skin, and lymph nodes", section on 'Yellow discoloration'.)

Three syndromes of vitamin A toxicity have been recognized: acute, chronic, and teratogenic. Large supplemental doses of retinol are very toxic to the liver, but due to the large storage capacity of the liver for vitamin A, the actual toxic doses are not well established [42].

Treatment of vitamin A toxicity consists of stopping vitamin A supplements and restricting vitamin A-rich foods (especially sources of pre-formed vitamin A, such as liver, kidney and egg yolk). If the patient has evidence of hepatotoxicity or pseudotumor cerebri, supportive treatment is indicated. Most case reports of chronic toxicity suggest gradual resolution of the symptoms after withdrawal of vitamin A, although hepatic fibrosis may persist [43,44].

Acute toxicity — Acute toxicity occurs in adults when a single dose of >660,000 international units (>200,000 micrograms) of vitamin A is ingested. Symptoms include nausea, vomiting, vertigo, and blurry vision [40]. In very high doses, drowsiness, malaise, and recurrent vomiting can follow the initial symptoms listed above. In infants under six months of age, as little as 20,000 international units (6000 micrograms) daily, given briefly (eg, for one month or less), may produce toxic effects [45].

Chronic toxicity — Chronic toxicity occurs with long-term ingestion of vitamin A doses in amounts higher than 10 times the RDA (ie, toxicity may occur with chronic ingestion of approximately 33,000 international units [10,000 micrograms] of retinol in adults) (table 2) [46]. Some toxic effects of vitamin A also have been observed in infants fed large amounts of chicken liver daily for one month or longer; each serving contained 36,000 international units (11,000 micrograms retinol), which is more than 20 times the RDA for this age group [47]. Signs of chronic toxicity may include ataxia, alopecia, hyperlipidemia, hepatotoxicity, bone and muscle pain, visual impairments, hypercalcemia (rarely), and many other nonspecific signs and symptoms [48].

Circulating vitamin A concentrations do not consistently reflect vitamin A stores, because most vitamin A is stored in the liver, so they are not a reliable means of detecting vitamin A toxicity. Patients with hypervitaminosis A may have low, normal, or high serum levels of retinol, depending on the timing, quantity, and form of vitamin A ingested, and the patient's age [49,50].

Serum retinyl esters in the fasting state are sometimes used as a marker for chronic hypervitaminosis A; retinyl ester concentrations >10 percent of the total vitamin A pool are considered abnormal (ie, a molar ratio of plasma retinyl esters to the sum of plasma retinol and retinyl esters) [51-53]. However, this ratio may still not reflect hepatic stores long after the toxic ingestion has stopped. Elevated serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and/or calcium, have been reported.

Symptoms and signs of toxicity include dry skin, nausea, headache, fatigue, irritability, hepatomegaly, alopecia, hyperostosis, and increased cerebrospinal fluid pressure (pseudotumor cerebri). Although children with cystic fibrosis (CF) are at risk for fat-soluble vitamin deficiency due to their pancreatic insufficiency, standard supplementation regimens may lead to excessive levels of vitamin A. In one study of children with CF who were given standard supplements, total vitamin A intake and serum retinol values were elevated, raising concerns about the possibility of chronic toxicity which may contribute to CF-associated liver and bone disease [54]. (See "Cystic fibrosis: Nutritional issues", section on 'Vitamin A'.)

Hepatotoxicity can lead to cirrhosis and has been associated with veno-occlusive disease [42,50]. A prominent histologic finding is the proliferation of hepatic stellate cells. Several factors can increase the toxicity of vitamin A, including underlying liver and kidney disease, alcoholism, and the use of some drugs, such as tetracyclines.

Adverse effects on bone — There is some evidence that intake levels of vitamin A in the high-normal range may have adverse effects on bone health. In a prospective cohort study of postmenopausal females, long-term intake of a diet high in retinol (vitamin A) was associated with an increased risk of osteoporotic fractures [55]. Similarly, high serum retinol levels were associated with an increased fracture risk in men [56]. Thus high doses of vitamin A may compromise bone health, but the threshold at which clinically relevant effects are seen remains to be determined [57]. (See "Drugs that affect bone metabolism", section on 'Vitamin A and synthetic retinoids'.)

Cancer — Diets rich in beta carotene appear to be associated with lower risks of cancer. However, clinical trials of beta carotene supplementation have not confirmed a beneficial effect, and some suggest that beta carotene supplements may modestly increase the risk for lung cancer but not other cancers. (See "Vitamin intake and disease prevention", section on 'Vitamin A and the carotenoids' and "Chemoprevention of lung cancer", section on 'Vitamins and minerals'.)

Teratogenic effects — Retinoic acid has been known to be very teratogenic in the first trimester of pregnancy, leading to spontaneous abortions and fetal malformations, including microcephaly and cardiac anomalies [46]. Effects may occur at doses only several times the RDA [58]. Many animal models as well as human studies have shown high incidence of birth anomalies in mothers who ingested therapeutic doses of retinoic acid for dermatologic uses [46]. A safe upper limit for vitamin A intake during pregnancy has been recognized at approximately 10,000 international units daily (approximately 3000 micrograms) [3].

THERAPEUTIC USES — Retinoic acid and carotenoids have several therapeutic uses.

Measles — Vitamin A treatment of children with measles infection in resource-limited countries appears to reduce complications and mortality, although effects on blindness have not been evaluated [59,60]. Thus, vitamin A treatment is recommended for children with measles in resource-limited countries and other areas in which vitamin A deficiency is endemic, and in selected circumstances in developed countries. (See "Measles: Clinical manifestations, diagnosis, treatment, and prevention", section on 'Vitamin A'.)

Dermatology — Retinoic acid has been used for many hyperkeratotic and hyperproliferative disorders of skin. Synthetic oxidative metabolites of vitamin A such as isotretinoin can be used topically or systemically for treatment of a variety of skin disorders. Systemic forms have been used in some forms of psoriasis and other disorders of keratinization and even skin cancer. 13-cis-retinoic acid reduces the proliferation of sebaceous glands, and due to such properties it is used for treatment of acne and acne-related disorders. At the lower range of the toxic dose, some of the conjugated forms of retinoic acids (ie, retinol beta-glucuronide) have been used as topical creams or ointments for hyperpigmentation or for reducing wrinkling associated with sun exposure [61].

Atherosclerosis — Because carotenoids are antioxidants, they were investigated for possible prevention of cardiovascular disease. However, randomized trials of vitamin A and beta-carotene have shown no benefit for primary or secondary prevention of coronary heart disease; furthermore, there is some evidence that beta-carotene supplementation may increase mortality from cardiovascular disease and may increase the risk of lung cancer. Therefore, in resource-rich countries where dietary intake of vitamin A is generally adequate, supplementing with vitamin A for disease prevention is not recommended. (See 'Cancer' above and "Vitamin intake and disease prevention".)

Acute promyelocytic leukemia — All-trans retinoic acid (ATRA, or tretinoin) is a synthetic oxidative metabolite of retinoic acid and has been used in acute promyelocytic leukemia (a subgroup of acute myelocytic leukemia). (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults".)

Initial studies demonstrated a remarkable response to high-dose daily treatment with all-trans-retinoic acid (approximately 45 mg/m²/day) [62]. However, later experience demonstrated that such high doses can lead to a dangerous condition known as the "differentiation syndrome" (previously "retinoic acid syndrome") characterized by respiratory distress, fevers, kidney failure, and hypotension. Because a large number of patients who developed this have died, the drug is administered for short periods of time, in conjunction with other standard chemotherapy [62]. (See "Differentiation syndrome associated with treatment of acute leukemia".)

Very low birthweight infants — Limited evidence suggests that vitamin A supplementation may help to prevent bronchopulmonary dysplasia in very low birthweight infants, as discussed in a separate topic review [63,64]. There is no good clinical evidence for a role in preventing retinopathy of prematurity or necrotizing enterocolitis [65]. (See "Bronchopulmonary dysplasia (BPD): Prevention".)

REQUIREMENTS

General population — The Recommended Dietary Allowance (RDA) for vitamin A is given as retinol activity equivalents (RAE), where one RAE = 1 microgram retinol or 3.3 international units [3].

The RDA for adult males is 3000 international units (900 micrograms retinol) daily, and for females it is 2300 international units (700 micrograms retinol) daily. The RDA for other groups is shown in the table (table 2).

Special populations — Individuals with clinically significant fat malabsorption due to pancreatic insufficiency or other digestive disorders are at risk for deficiency of vitamin A and other fat-soluble vitamins.

●Pancreatic insufficiency – Patients with cystic fibrosis or Shwachman-Diamond syndrome are routinely treated with supplements of fat-soluble vitamins, which provide doses that are several-fold higher than the RDA. Patients with chronic pancreatitis generally do not develop clinically significant malabsorption and related vitamin deficiencies until almost all pancreatic function is lost.

•(See "Cystic fibrosis: Nutritional issues", section on 'Fat-soluble vitamins'.)

•(See "Shwachman-Diamond syndrome", section on 'GI/nutrition'.)

•(See "Chronic pancreatitis: Clinical manifestations and diagnosis in adults", section on 'Steatorrhea' and "Chronic pancreatitis: Clinical manifestations and diagnosis in adults", section on 'Laboratory findings'.)

●Chronic liver disease – Individuals with chronic liver disease are typically treated with a standard multivitamin that includes vitamin A. If vitamin A deficiency is detected in these patients, standard replacement doses should be given. High levels of alcohol consumption appear to potentiate the hepatotoxic effects of vitamin A [66]. (See "Nutritional issues in adult patients with cirrhosis".)

Individuals with marked cholestasis may require higher doses of vitamin A and other fat-soluble vitamins in order to maintain adequate levels. Children with cholestatic liver disease often require between 5000 and 25,000 international units (1500 to 7500 micrograms retinol) daily of water-miscible vitamin A [67,68]. For patients treated with these high doses of vitamin A, monitoring for clinical or laboratory evidence of vitamin A toxicity (usually assayed as serum retinyl esters in the fasting state) is recommended [69]. (See 'Replacement' above and 'Chronic toxicity' above and "Overview of the management of primary biliary cholangitis", section on 'Fat-soluble vitamins' and "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis", section on 'Steatorrhea and vitamin deficiency' and "Biliary atresia", section on 'Fat-soluble vitamin supplements'.)

●Bariatric surgery – Recommendations for vitamin supplementation after bariatric surgery are discussed in a separate topic review. (See "Bariatric surgery: Postoperative nutritional management" and "Surgical management of severe obesity in adolescents", section on 'Nutritional supplements'.)

●Short bowel syndrome – For individuals with short bowel syndrome, the need for vitamin supplementation depends on the degree of fat malabsorption and whether the patient is receiving parenteral versus enteral nutrition. Vitamin supplements should be guided by regular assessment of nutritional status in the individual patient, particularly during transitions off of parenteral nutrition. (See "Management of short bowel syndrome in children", section on 'Common micronutrient deficiencies' and "Management of short bowel syndrome in adults", section on 'Weaning parenteral nutrition'.)

●Crohn disease – Patients with Crohn disease and extensive small bowel involvement are at risk for fat-soluble vitamin deficiency. Patients with active small bowel disease may require nutritional monitoring, with additional vitamin supplementation as necessary.

●Celiac disease – Patients with newly diagnosed celiac disease may have vitamin deficiencies. The evaluation at diagnosis should include laboratory screening for deficiencies and temporary supplementation as needed. After they have been effectively treated with a gluten-free diet, their vitamin requirements should be the same as for a healthy population. (See "Management of celiac disease in adults", section on 'Repletion of nutritional deficiencies' and "Management of celiac disease in children", section on 'Screening and prevention of micronutrient deficiencies'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vitamin deficiencies".)

SUMMARY AND RECOMMENDATIONS

●Vitamin A is a subclass of a family of lipid-soluble compounds referred to as retinoic acids. Because vitamin A from animal sources or supplements (eg, retinol) is preformed, it is more likely to cause toxicity than the provitamin A from plant sources (eg, beta-carotene). (See 'Chemistry' above.)

●Vitamin A crucial to cellular differentiation and integrity in the eye, and deficiency causes xerophthalmia (dryness, fragility and clouding of the cornea) (picture 2). Vitamin A also has an important role in phototransduction, and deficiency causes night blindness. (See 'Actions' above and 'Clinical manifestations' above.)

●Vitamin A deficiency is also associated with poor bone growth, nonspecific dermatologic problems (eg, hyperkeratosis), and impaired immune function. (See 'Clinical manifestations' above.)

●Vitamin A deficiency is common among populations in resource-limited countries (figure 1A-B). In resource-limited regions where vitamin A deficiency is endemic, routine vitamin A supplementation in children ages 6 to 59 months is associated with decreased risk of mortality. Additional doses are given to individuals with xerophthalmia and children at high risk of vitamin A deficiency, such as those with measles, diarrhea, respiratory disease, or severe malnutrition. (See 'Replacement' above.)

●The diagnosis of vitamin A deficiency is usually made by clinical findings but can be supported by measurement of serum retinol levels or the ratio of retinol:retinol-binding proteins (RBP); a molar ratio <0.8 suggests deficiency). (See 'Deficiency' above.)

●In populations where dietary intake of vitamin A is adequate, there is no evidence that supplementation of vitamin A is helpful for preventing cardiovascular disease, and supplementation may even have harmful effects on cardiovascular mortality, cancer, and bone health. Therefore, in resource-rich countries where dietary intake of vitamin A is generally adequate, we recommend not supplementing vitamin A for disease prevention (Grade 1B). (See 'Atherosclerosis' above and "Vitamin intake and disease prevention", section on 'Vitamin A and the carotenoids'.)

●Acute vitamin A toxicity occurs in adults when a single dose of >660,000 units (>200 mg) of vitamin A is ingested. Chronic toxicity occurs with long-term ingestion of vitamin A doses in amounts higher than 10 times the Recommended Dietary Allowance (RDA). Preformed vitamin A can have teratogenic effects during the first trimester of pregnancy, at doses of only several times the RDA. Circulating vitamin A concentrations do not consistently reflect vitamin A stores, because most vitamin A is stored in the liver; measurement of serum retinyl esters may be helpful. (See 'Excess' above.)