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Vitamin A Deficiency

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Dec.08.2022

Vitamin A Deficiency

Synopsis

Key Points

  • Vitamin A deficiency is a condition associated with inadequate serum levels of vitamin A, including retinoid compounds
  • Manifestations of vitamin A deficiency are primarily ocular and cutaneous
    • Nyctalopia (night blindness) is highly suggestive of vitamin A deficiency
    • Bitot spots are pathognomonic for this condition and appear as focal, foamy areas of the conjunctiva or cornea r1
    • Hyperkeratotic follicular papules are a typical cutaneous sign r2
  • Dietary lack of vitamin A or carotenoid precursors is the main cause of vitamin A deficiency; other causes include:
    • Increased demand for vitamin A, particularly during pregnancy r3
    • Vitamin A malabsorption and reduced/absent ability to convert carotene to active vitamin A (the latter problem may occur in fat-malabsorptive conditions)
  • People inhabiting some areas of Southeast Asia and sub-Saharan Africa, especially children, consume diets that have inadequate amounts of vitamin A and therefore are at elevated risk for vitamin A deficiency r4
  • Diagnosis is made primarily through history and physical examination; if there is uncertainty, a serum retinol level less than 0.7 micromoles (20 mcg/dL) indicates vitamin A deficiency, whereas less than 0.35 micromoles (10 mcg/dL) indicates severe vitamin A deficiency r5r6
  • Treatment is with oral vitamin A preparations
    • In children, dosing is age dependent r7r8
    • In adults, give high-dose vitamin A 100,000 international units for 3 days followed by 50,000 international units for 2 weeks; continue with a daily dose of 5000 international units thereafter r7r8
  • When vitamin A deficiency is recognized and treated early, night blindness resolves and cutaneous hyperkeratosis clears
  • Permanent blindness can ensue if vitamin A deficiency goes untreated r7r8

Urgent Action

  • Treat severe vitamin A deficiency immediately on establishing a diagnosis; corneal lesions are indicative of a medical emergency and require urgent treatment with a high dose of vitamin A

Pitfalls

  • Prompt recognition and treatment of vitamin A deficiency is essential; complete, permanent blindness ensues when vitamin A deficiency is not treated before permanent eye damage occurs

Terminology

Clinical Clarification

  • Vitamin A deficiency is a condition associated with inadequate serum levels of vitamin A, which includes any of the following classes of retinoid compounds:
    • Retinols (preformed vitamin A, the most active form)
    • Beta carotene (provitamin A)
    • Carotenoids
  • Ocular manifestations include nyctalopia (night blindness) and xerophthalmia (dryness of conjunctiva and cornea) r2
    • Additional manifestations may include cutaneous changes (eg, phrynoderma, onychoschizia, xeroderma, hyperkeratosis) and development of anemia
  • Vitamin A deficiency is rare in high-income countries overall; however, malabsorption, liver disease, and small-bowel surgery may result in deficiency even in those countries
    • Represents the leading cause of preventable blindness in young children worldwide r9
    • Associated with increased rates of death from severe infections (eg, measles), particularly in low- and middle-income countries r9

Classification

  • Classification is based on ocular signs related to xerophthalmia, which comprises a spectrum of ocular manifestations of vitamin A deficiency r1r10
    • Combination of manifestations leads to the following grades of xerophthalmia: r1r10
      • XN: nyctalopia only
      • X1: conjunctival xerosis (dryness)
        • X1A: without Bitot spots
        • X1B: with Bitot spots
      • X2: corneal xerosis
      • X3: corneal xerosis with corneal ulceration
        • X3A: ulcer covers less than one-third of cornea
        • X3B: ulcer covers one-third or more of cornea (called keratomalacia)
      • XS: corneal scarring
      • XF: xerophthalmic fundus (yellow-white retinal lesions)

Diagnosis

Clinical Presentation

History

  • Ocular symptoms r5
    • Nyctalopia (night blindness) c1
      • Highly suggestive of vitamin A deficiency and the first ocular symptom observed
    • Photophobia c2
    • Xerophthalmia (inability to produce tears) c3
  • Skin symptoms
    • Pruritus c4
    • Hyperkeratosis (thickening of skin) c5
  • Recent experience of any of the following symptoms or conditions is consistent with subclinical vitamin A deficiency:
    • Diarrhea (reflecting malabsorption) c6
    • Fatigue (suggestive of anemia) c7
    • Decelerated growth in children c8
    • Recent spontaneous abortion c9
    • Infertility c10

Physical examination

  • Eyes
    • Bitot spots r1c11
      • Lesions are pathognomonic for this condition
      • Areas of the conjunctiva or cornea have a white, foamy appearance
      • Consist of superficial keratin deposits built up in the conjunctiva and typically have a triangular or ovoid shape
      • Lesions may not disappear completely, even after treatment
    • Conjunctival and/or corneal xerosis r1
    • Corneal ulceration or scarring r1c12c13
    • Reduced visual acuity, generally bilateral but not necessarily equal in both eyes c14
  • Skin, hair, and nails r11
    • Xeroderma (dry, rough skin) c15
    • Onychoschizia (splitting, brittle, soft, or thin nails) c16
    • Phrynoderma (follicular hyperkeratosis) c17
      • Skin lesions are typically distributed symmetrically on the face, skull, and extensor surfaces of the shoulders, buttocks, and extremities r2
      • Appearance of any of the following are indicative of phrynoderma:
        • Diffuse, hyperkeratotic follicular papules
        • Rough, elevated, cone-shaped papules, sometimes with encrusted sebum plugs
      • Note that phrynoderma is a nonspecific finding associated with several contemporaneous nutritional deficiencies r2
  • Signs of anemia r12
    • Pallor c18
    • Tachycardia c19
    • Systolic ejection murmur c20

Causes and Risk Factors

Causes

  • Dietary lack of vitamin A due to any of the following: c21
    • In low- and middle-income countries, poor availability of vitamin A–rich foods such as: c22
      • Brightly colored fruits and vegetables such as melons, carrots, sweet potatoes, and tomatoes
      • Liver, milk, and eggs
    • Vegan diet c23
    • Eating disorder causing deficiencies of multiple micronutrients including vitamin A c24
  • Increased demand for vitamin A occurring particularly during pregnancy r3c25
  • Vitamin A malabsorption and reduced/absent ability to convert carotene to active vitamin A, which commonly occurs in fat-malabsorptive conditions such as: c26c27
    • Inflammatory bowel disease (eg, Crohn disease) c28
    • Pancreatic insufficiency c29
    • Short bowel syndrome c30
    • Cystic fibrosis c31
    • Celiac disease c32
    • History of certain types of bariatric surgery, such as Roux-en-Y gastrointestinal bypass surgery c33

Risk factors and/or associations

Age
  • Children are at higher risk than adults for dietary vitamin A deficiency r13c34c35
Sex
  • Females are at elevated risk for dietary vitamin A deficiency r13c36c37
Genetics
  • Single nucleotide variants in 12 genes are associated with retinol and beta carotene levels and with beta carotene bioavailability r14r15c38
  • Populations with different allele frequencies for these single nucleotide variants may differ in ability to absorb dietary beta carotene and thus in risk for vitamin A deficiency r14
Other risk factors/associations
  • Most cases of vitamin A deficiency due to lack of vitamin A in diet occur in the following geographic areas: r4
    • Southeast Asia c39
    • Sub-Saharan Africa c40
  • Incidence of vitamin A deficiency due to lack of vitamin A is high among refugees and populations under economic stress r16c41c42
  • End-stage liver disease due to conditions such as alcoholic cirrhosis and hepatitis C r17c43c44c45

Diagnostic Procedures

Primary diagnostic tools

  • Diagnosis is usually made by reviewing history and physical examination findings, primarily of the eyes r5c46
    • Nyctalopia noted on history is highly suggestive of vitamin A deficiency
      • Strongly suspect diagnosis in a patient with fat-malabsorptive status who reports night blindness
    • Further ocular findings support the diagnosis
  • Laboratory studies are available to support a diagnosis but are not often used owing to limited medical access where the condition is most prevalent
    • Serum retinol level is a direct measure of vitamin A and is the laboratory measure of choice
    • An alternative is the serum retinol-binding protein immunoassay
  • Empirical vitamin A trial
    • Empirical vitamin A supplementation may be initiated, in part as a diagnostic measure, to assess for improvement when deficiency is clinically apparent (in lieu of laboratory studies)
    • Empirical vitamin A supplementation is often initiated while results of laboratory studies are pending
  • Additional specialized testing is rarely necessary and may include dark adaptometry and conjunctival impression cytology
  • Ancillary laboratory studies that may be indicated to evaluate malnutrition include CBC and comprehensive chemistry panel with electrolyte levels and liver function tests

Laboratory

  • Serum retinol level r5c47
    • Normal range is 1 to 2 micromoles r5
    • Less than 0.7 micromoles (20 mcg/dL) indicates vitamin A deficiency and suggests that hepatic vitamin A reserves have dropped below approximately 20 mcg/g in liver r6
    • Less than 0.35 micromoles indicates severe vitamin A deficiency r5
  • Serum retinol-binding protein immunoassay c48
    • Less accurate than serum retinol level but easier to perform and thus may be more practical in rural settings r18
    • Normal range is 30 to 75 mcg/mL r19
    • Retinol-binding protein level reflects retinol level; therefore, retinol-binding protein level less than 30 mcg/mL suggests vitamin A deficiency r18
  • CBC c49
    • Indicated in patients with symptoms/signs of anemia, a coexisting infectious process, or sepsis
    • Laboratory picture of anemia related to vitamin A deficiency is not well characterized and is often influenced by several factors (eg, concomitant infection, iron deficiency, medications) r20
      • Often described as hypochromic with or without microcytosis
  • Iron studies r21c50
    • Useful in patients with anemia because iron deficiency and vitamin A deficiency may exacerbate each other in terms of anemic manifestations

Functional testing

  • Dark adaptometry r10c51
    • Electrophysiologic study that measures amount of time retina takes to recover sensitivity to very dim light after being desensitized via exposure to bright light
    • Indicated for patients with complaints of nyctalopia when diagnosis is unclear or complaints are equivocal; may be used for monitoring treatment response in patients with vitamin A deficiency
    • May require referral to specialized center with testing capabilities
    • Other conditions in which abnormal test results may be seen include congenital stationary night blindness, gyrate atrophy, choroideremia, retinitis pigmentosa, macular degeneration, and postprocedure changes associated with panretinal photocoagulation

Procedures

Conjunctival impression cytology r10r22r23c52
General explanation
  • Testing is usually limited to academic centers and research settings
  • Bulbar conjunctiva is anesthetized
  • A small piece of filter paper is pressed against the conjunctiva for a few seconds to obtain cells
  • Paper is pressed onto a glass slide, which is then stained
Indication
  • Suspected vitamin A deficiency
Interpretation of results
  • Xerophthalmia is suggested by loss of goblet cells and/or appearance of enlarged and/or keratinized epithelial cells

Differential Diagnosis

Most common

  • Diabetic retinopathy r24c53d1
    • Neurovascular complication of diabetes mellitus that leads to visual loss; also common after treatment (eg, panretinal photocoagulation) for proliferative diabetic retinopathy
    • Presents similarly to vitamin A deficiency with visual disturbance and presence of yellow lesions in macula
    • In contrast to vitamin A deficiency, examination of the retina in patients with diabetic retinopathy finds microaneurysms, hemorrhages, and usually engorgement of blood vessels; corneal ulceration, scarring, and Bitot spots are absent
    • Definitive diagnosis may be confirmed with fluorescein angiography
  • Cataracts c54d2
    • Clouding of lens of eye owing to degenerative changes
    • Presents similarly to vitamin A deficiency with visual disturbances
    • Corneal ulceration, scarring, and Bitot spots are absent
    • Definitive diagnosis is confirmed with slitlamp examination
  • Uncorrected myopia c55
    • Ocular condition in which light focuses in front of the retina rather than directly on it
    • Presents similarly to vitamin A deficiency with visual disturbances and diminished night vision
    • Unlike vitamin A deficiency, myopia is measurable with visual acuity testing and corrects with refractive lenses; corneal ulceration, scarring, and Bitot spots are absent
    • Definitive diagnosis is confirmed with vision testing and refraction testing
  • Glaucoma c56d3
    • Condition caused by elevated intraocular pressure, leading to optic nerve damage d4
    • Presents similarly to vitamin A deficiency with visual disturbances
    • In contrast to vitamin A deficiency, glaucoma does not have the signs of corneal ulceration, scarring, or Bitot spots
    • Diagnosis is made via either of the following:
      • Definitive changes seen on optic nerve head
      • Repeated changes seen in visual field assessed via standard achromatic perimetry
  • Retinitis pigmentosa r25c57
    • Disease of progressive retinal degeneration characterized by pigmentary changes, arteriolar attenuation, optic atrophy, and worsening vision
      • May be inherited in either autosomal dominant or autosomal recessive manner
      • Children inheriting the autosomal recessive form lose vision around age 10 years, whereas those with the autosomal dominant form become symptomatic in their twenties r25
    • Similarly to vitamin A deficiency, retinitis pigmentosa often presents with impairment of night vision or dark adaptation as the first clinical manifestation
    • In contrast to vitamin A deficiency, the usual course is one of progressive peripheral vision loss, often in the form of an expanding ring scotoma
    • Retinal pigment is dispersed and aggregated so that visible changes are apparent on ophthalmoscopic examination, ranging from granularity or mottling of the retinal pigment pattern to distinctive focal pigment aggregates with the configuration of bone spicules
    • Condition is differentiated from vitamin A deficiency based on results of ophthalmoscopic examination

Treatment

Goals

  • Reverse ocular symptoms and signs of vitamin A deficiency such as nyctalopia and xerophthalmia
  • Abate nonocular manifestations such as anemia and cutaneous changes (eg, phrynoderma, onychoschizia, xeroderma, hyperkeratosis)
  • Prevent complications such as permanent blindness, increased risk of maternal and fetal mortality, and increased risk of infectious diseases
  • Manage underlying cause of deficiency (eg, malabsorption, liver disease)

Disposition

Admission criteria

  • Associated severe malnutrition causing life-threatening electrolyte imbalances

Recommendations for specialist referral

  • Consult an ophthalmologist for all patients with vitamin A deficiency
  • Refer all patients with vitamin A deficiency to a nutritionist to assist with meal planning

Treatment Options

Treat vitamin A deficiency with vitamin A replacement r7r8

  • Doses are age-specific and depend on presence of symptoms (xerophthalmia); minor variations in specific dosing regimens are noted among various sources (eg, package inserts, WHO guidelinesr8)
    • Treat severe vitamin A deficiency immediately on establishing a diagnosis; corneal lesions are indicative of a medical emergency and require urgent treatment with a high dose of vitamin A
  • Initial intramuscular dose may be given to neonates, infants, and children, followed by high-dose oral therapy for 10 to 14 days
  • When treatment is initiated, oral dosing is preferred in most adults except in cases associated with malabsorption, which require ongoing intramuscular dosing
  • After initial intramuscular and high-dose oral therapy, prescribe ongoing daily oral vitamin A supplementation to be continued for 2 months

Manage underlying cause of deficiency (eg, malabsorption, liver disease) in consultation with appropriate specialist

Drug therapy

  • Vitamin A r7r8c58
    • Initial intramuscular doses
      • 1 international unit = 0.3 mcg retinol activity equivalents = 0.3 mcg retinol
      • Vitamin A (Palmitate) Solution for injection; Premature Neonates†: Dosage regimen has not been established. Most regimens begin soon after birth, usually by day 4, and continue up to 28 days. Dosage regimens have included: 1,200 to 1,500 mcg RAE (4,000 to 5,000 International Units) IM 3 times weekly; 600 to 1,200 mcg RAE (2,000 to 4,000 International Units) IM every other day; and 450 to 900 mcg RAE (1,500 to 3,000 International Units) IM on days 1, 3, and 7. High-dose regimens (3,000 mcg RAE [10,000 International Units] IM 3 times weekly for 4 weeks and 4,500 mcg RAE [15,000 International Units] IM weekly for 4 weeks) have also been studied, but have shown no additional benefit.
      • Vitamin A (Palmitate) Solution for injection; Neonates: 2,250 to 4,500 mcg RAE (7,500 to 15,000 International Units) IM once daily for 10 days. Follow with an oral supplement.
      • Vitamin A (Palmitate) Solution for injection; Infants: 2,250 to 4,500 mcg RAE (7,500 to 15,000 International Units) IM once daily for 10 days. Follow with an oral supplement.
      • Vitamin A (Palmitate) Solution for injection; Children 1 to 8 years: 5,300 to 10,600 mcg RAE (17,500 to 35,000 International Units) IM once daily for 10 days; follow with an oral supplement.
      • Vitamin A (Palmitate) Solution for injection; Children and Adolescents 9 to 17 years: 30,000 mcg RAE (100,000 International Units) IM once daily for 3 days, then 15,000 mcg RAE (50,000 International Units) IM once daily for 14 days; follow with an oral supplement.
      • Vitamin A (Palmitate) Solution for injection; Adults: 30,000 mcg RAE (100,000 International Units) IM once daily for 3 days, then 15,000 mcg RAE (50,000 International Units) IM once daily for 14 days; follow with an oral supplement.
    • Continued oral therapy for the treatment of vitamin A deficiency
      • 1 international unit = 0.3 mcg retinol activity equivalents = 0.3 mcg retinol
      • Vitamin A Oral capsule, liquid filled; Premature Neonates: 210 to 450 mcg/kg/day RAE (700 to 1,500 International Units/kg/day) PO is recommended by AAP. Most specialized feeding formulas for premature infants provide this amount of vitamin A; however, breast milk will require supplementation to provide adequate amounts of vitamin A.
      • Vitamin A Oral capsule, liquid filled; Neonates: 1,500 to 3,000 mcg RAE (5,000 to 10,000 International Units) PO once daily for 2 months after initial IM dosing for 10 days.
      • Vitamin A Oral capsule, liquid filled; Infants and Children 1 to 8 years: 1,500 to 3,000 mcg RAE (5,000 to 10,000 International Units) PO once daily for 2 months after initial IM dosing for 10 days.
      • Vitamin A Oral capsule, liquid filled; Children and Adolescents 9 to 17 years: 3,000 to 6,000 mcg RAE (10,000 to 20,000 International Units) PO once daily for 2 months after initial IM dosing for 17 days.
      • Vitamin A Oral capsule, liquid filled; Adults: 3,000 to 6,000 mcg RAE (10,000 to 20,000 International Units) PO once daily for 2 months after initial IM dosing for 17 days.
    • For the treatment of xerophthalmia secondary to deficiency of vitamin A
      • 1 international unit = 0.3 mcg retinol activity equivalents = 0.3 mcg retinol
        • Vitamin A Oral capsule, liquid filled; Infants 1 to 5 months: 15,000 mcg RAE (50,000 International Units) PO once daily for 2 days, followed by another dose at least 2 weeks later for a total of 3 doses. Treatment should begin immediately upon diagnosis; corneal lesions are indicative of a medical emergency and require urgent treatment after first vitamin A dose.
        • Vitamin A Oral capsule, liquid filled; Infants 6 to 11 months: 30,000 mcg RAE (100,000 International Units) PO once daily for 2 days, followed by another dose at least 2 weeks later for a total of 3 doses. Treatment should begin immediately upon diagnosis; corneal lesions are indicative of a medical emergency and require urgent treatment after first vitamin A dose.
        • Vitamin A Oral capsule, liquid filled; Children: 60,000 mcg RAE (200,000 International Units) PO once daily for 2 days, followed by another dose at least 2 weeks later for a total of 3 doses. Treatment should begin immediately upon diagnosis; corneal lesions are indicative of a medical emergency and require urgent treatment after first vitamin A dose.
        • Vitamin A Oral capsule, liquid filled; Adult and Adolescent females of childbearing age without severe xerophthalmia (i.e., night blindness or Bitot's spots): 1,500 to 3,000 mcg RAE (5,000 to 10,000 International Units) PO once daily or 7,500 mcg RAE (25,000 International Units) PO once weekly for at least 4 weeks. Max: 3,000 mcg/day RAE (10,000 International Units/day) PO, unless administering the weekly regimen.
        • Vitamin A Oral capsule, liquid filled; Adult Males and Geriatric patients (male and female): 60,000 mcg RAE (200,000 International Units) PO once daily for 2 days, followed by another dose at least 2 weeks later for a total of 3 doses. Treatment should begin immediately upon diagnosis; corneal lesions are indicative of a medical emergency and require urgent treatment after first vitamin A dose.

Comorbidities

  • Conditions of malnutrition can make vitamin A deficiency more severe, thus requiring additional nutrient supplementation alongside vitamin A
    • Kwashiorkor (protein deficiency) c59
    • Marasmus (deficiency of total ingested calories) c60

Special populations

  • Patients with end-stage liver disease
    • Standard vitamin A replacement is often required for patients with chronic liver disease
    • High doses of vitamin A are potentially hepatotoxic, so extra caution is needed to avoid excessive supplementation r17
    • Monitoring serum retinol levels may be advisable
  • Patients who have had bariatric surgery
    • Give vitamin A supplementation to patients according to surgical procedure: r26
      • Sleeve gastrectomy: vitamin A 5000 to 10,000 international units/day
      • Laparoscopic gastric banding: vitamin A 5000 international units/day
      • Roux-en-Y gastric bypass: vitamin A 5000 to 10,000 international units/day
      • Biliary pancreatic diversion or duodenal switch: vitamin A 10,000 international units/day
  • Patients with a malabsorptive status (eg, Crohn disease, celiac disease, cystic fibrosis)
    • Conditions associated with malabsorption of fat-soluble vitamins (ie, vitamins A, D, E, and K) may require repletion of additional vitamins followed by maintenance dosing of fat-soluble vitamin supplementation

Monitoring

  • Monitor patients periodically for improvement in nyctalopia c61
  • Consider obtaining serum retinol levels if symptoms worsen or do not improve c62

Complications and Prognosis

Complications

  • Permanent blindness r7r8c63c64
    • Vitamin A deficiency is the leading cause of preventable blindness in young children worldwide r9
  • Increased risk of maternal and fetal mortality r5r7c65c66
    • Risk is greatest in the last trimester when demand by both fetus and mother is highest c67c68
      • Maternal vitamin A deficiency is reflected by high prevalence of night blindness during this period
    • Fetal death or morphologic malformations range from organ agenesis to rudimentary or hypoplastic organs r7c69
  • Increased risk of infectious diseases including measles and gastroenteritis r7c70c71c72
  • Impaired bone growth in children c73

Prognosis

  • Prognosis is good when vitamin A deficiency is recognized and treated early, before permanent eye damage develops
    • Night blindness responds rapidly to treatment and generally resolves
    • Hyperkeratosis of the skin clears
  • Vitamin A deficiency and advanced stages of xerophthalmia that go untreated before permanent eye damage ensues result in complete, permanent blindness
  • Untreated vitamin A deficiency is associated with increased risk of infectious morbidity and mortality, especially in low- and middle-income countries r27

Screening and Prevention

Prevention

  • Vitamin A deficiency is preventable in most countries (including the United States) by eating a well-balanced diet c74
    • Sources of dietary preformed vitamin A include: r28
      • Animal-derived foods that are rich in vitamin A (eg, liver, fish, beef, chicken)
    • Sources of provitamin A carotenoids include: r29
      • Brightly colored fruits and vegetables (eg, carrots, mangoes, apricots, broccoli, cantaloupe, squash, leafy greens) c75
      • Red palm oil
  • In areas where malnutrition is endemic such as portions of Southeast Asia and sub-Saharan Africa, vitamin A supplementation for children reduces mortalityr30r31 and prevents ophthalmic complications c76c77c78
    • WHO recommends periodic supplementation in endemic areas
      • Infants aged 6 months to 1 year: a single dose of 100,000 international units or 30 mg retinol activity equivalents r7
      • Children aged 1 to 6 years: a dose of 200,000 international units or 60 mg retinol activity equivalents, repeated every 4 to 6 months r7
      • Pregnant patients: a dose of 25,000 international units every week during pregnancy until delivery r7
  • Recommended daily allowances: r28
    • Note: 1 mcg retinol activity equivalent = 3.3 international units of vitamin A
    • Children (girls and boys)
      • Aged 1 to 3 years: 300 mcg retinol activity equivalents/day
      • Aged 4 to 8 years: 400 mcg retinol activity equivalents/day
      • Aged 9 to 13 years: 600 mcg retinol activity equivalents/day
    • Adult males
      • Aged 14 years and older: 900 mcg retinol activity equivalents/day
    • Adult females (nonpregnant)
      • Aged 14 years and older: 700 mcg retinol activity equivalents/day
    • Adult females (pregnant)
      • Aged 14 to 18 years: 750 mcg retinol activity equivalents/day
      • Aged 19 to 50 years: 770 mcg retinol activity equivalents/day
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