Chapter 48  ◆  Vitamin A Deficiencies and Excess  317

METABOLISM OF VITAMIN A
Ingested retinyl esters must first be hydrolyzed in the intestinal lumen,
Chapter 48 a process that liberates unesterified retinol, for the absorption of
vitamin A. Most of the retinol is then reesterified in the enterocytes.
Vitamin A Deficiencies The absorption of preformed vitamin A is very efficient. Approximately
70-90% of dietary preformed vitamin A is absorbed as long as there
is ~10 g or more fat in the meal. Chronic intestinal disorders or
and Excess lipid malabsorption can result in vitamin A deficiency. Uncleaved
provitamin-A carotenoids in the intestine are also incorporated into
A. Catharine Ross and Libo Tan chylomicrons and delivered to various tissues. The estimated absorp-
tion efficiency of carotenoids is approximately 20-50%, and appears to
be more variable among individuals than for preformed vitamin A. The
efficiency of conversion of B-carotene to retinol is much lower than
OVERVIEW OF VITAMIN A expected. The carotene cleavage enzyme β-carotene monooxygenase,
Vitamin A is a fat-soluble micronutrient that cannot be synthesized de present in the enterocyte, exhibits certain single nucleotide polymor-
novo by the mammalian body, thus it is an obligatory dietary factor. phisms that reduce the efficiency of conversion of β-carotene to retinol.
The term vitamin A is generally used to refer to a group of compounds Once retinol is esterified in the enterocyte, retinyl ester is then pack-
that possess the biologic activity of all-trans retinol (Fig. 48-1). As a aged into nascent chylomicrons, which are then secreted into the lym-
fat-soluble micronutrient, vitamin A is recognized as being essential phatic vessels and transported via the circulation to the liver or to other
for all vertebrates for normal vision, reproduction, cell and tissue dif- tissues. When vitamin A status is adequate, most mammals, including
ferentiation, and functions of the immune system. Vitamin A plays humans, store most of their total body vitamin A in the liver, within
critical roles in neonatal development. It is required for normal embry- stellate cells. When their vitamin A status is deficient, vitamin A stores
onic development, hematopoiesis, immune response, metabolism, and can be mobilized; the released retinol can be used by extrahepatic
growth and differentiation of many types of cells. tissues. Stored vitamin A is released from the liver into the circulation
Vitamin A can be obtained from the diet where its main form is as as retinol bound to its specific transport protein, retinol-binding
retinyl esters, such as retinyl palmitate, which are called preformed protein (RBP), which binds to the thyroid hormone transport protein,
vitamin A. They are found primarily in certain foods of animal origin. transthyretin (TTR); this complex delivers retinol (as well as the
Organ meats (especially liver, kidney) are very rich in vitamin A, while thyroid hormone) to a large number of vitamin A target tissues. The
other meats, milk, and cheese contain moderate levels. Other sources major physiologic mediator of retinol uptake by cells in many tissues
of vitamin A include several provitamin A carotenoids, which are is Stra6, a widely expressed multitransmembrane domain protein that
found naturally in many fruits and vegetables, especially yellow-orange functions as a cell-surface receptor for retinol bound to RBP.
vegetables (pumpkin, squash, sweet potato), and leafy green vegetables In target tissues, retinol is either esterified into retinyl esters for
(chard, spinach, broccoli). One of the most abundant carotenoids is storage or oxidized into retinoic acid for function. In the eye, 11-cis-
β-carotene. α-Carotene and β-cryptoxanthin also possess vitamin A retinal is formed.
activity at a lower bioactivity. In the body, these precursors are used
for the synthesis of 2 essential metabolites of vitamin A. One is all-trans Vitamin A Status in Neonates
retinoic acid, the form of vitamin A required for cell differentiation Neonates begin life with low levels of vitamin A, in plasma, liver, and
and the regulation of gene transcription. It is the most bioactive form extrahepatic tissues, compared with those in adults. Normal plasma
of vitamin A. The other is 11-cis retinal, required for vision. It functions levels of retinol are 20-50 µg/dL in infants, and increase gradually as
as the light-absorbing chromophore of the visual pigments rhodopsin children become older. Median serum retinol values are 1.19 µmol/L
and iodopsin. in both boys and girls ages 4-8 yr; 1.4 and 1.33 µmol/L in boys and

Retinol ␤-Carotene

R = CH2OH, retinol
R = CH2O-fatty acyl group, retinyl ester
A R = COOH, retinoic acid

␤-carotene and
Dietary Preformed
provitamin A
forms: vitamin A
carotenoids

Intestinal Intestinal
Absorption: hydrolysis cleavage
Esterification
Intracellular and storage Oxidation Oxidation
Oxidized
RE Retinol Retinal RA
metabolism: Hydrolysis, Reduction metabolites
[chylomicron mobilization
transport, Conjugation
storage in liver, reactions
eyes (RPE), kidneys,
testes, etc.] Deactivation products

B Excretion
Figure 48-1  Vitamin A structures (A) and overview of vitamin A metabolism (B). 
318  Part VI  ◆  Nutrition

girls, respectively, ages 9-13 yr; and 1.71 and 1.57 µmol/L in boys and bone development, in addition to respiratory, gastrointestinal, hema-
girls, respectively, ages 14-18 yr (for conversion, 1 µmol/L = 28.6 µg/ topoietic, and immune functions. The role of vitamin A in immune
dL). Values of 1.96 and 1.85 µmol/L are found in 19-30 yr old adult function and host defense is particularly important in developing
men and women, respectively. countries, where vitamin A supplementation or therapy reduces the
Retinol levels are even lower in neonates in developing countries morbidity and mortality rates of various diseases, such as measles (see
where vitamin A intakes may be low and vitamin A deficiency is a Chapter 246).
common and significant nutritional problem. Lower vitamin A stores Vitamin A plays a critical nongenomic role in vision. The human
and plasma retinol concentrations are seen in low birthweight infants retina has 2 distinct photoreceptor systems: the rods, containing rho-
and in preterm newborns. Malnutrition, particularly protein nutrition, dopsin, which can detect low-intensity light, and the cones, containing
can cause vitamin A deficiency because of the impaired synthesis iodopsin, which can detect different colors. The aldehyde form of
of RBP. vitamin A, retinal, is the prosthetic group on both visual proteins. The
mechanism of vitamin A action in vision is based on the ability of the
Inflammation as a Cause of Low Plasma Retinol vitamin A molecule to photoisomerize (change shape when exposed
Inflammation is a cause of reduced levels of plasma retinol as a result to light). Thus, in the dark, low-intensity light isomerizes the rhodop-
of reduced synthesis of RBP and TTR. This condition may mimic a sin prosthetic group, 11-cis retinal, to all-trans-retinal, generating an
lack of vitamin A, but will not be corrected by supplementation. In U.S. electrical signal that is transmitted via the optic nerve to the brain and
adults, those with moderately elevated levels of C-reactive protein, results in visual sensation.
indicative of mild inflammation, had lower average plasma retinol
levels. The extent to which inflammation is a factor in low plasma VITAMIN A DEFICIENCY
retinol in children is uncertain but it is likely to be significant in acute If the growing child has a well-balanced diet and obtains vitamin A
infectious diseases such as measles, and possibly in chronic inflamma- from foods that are rich in vitamin A or provitamin-A (Table 48-1),
tory conditions such as cystic fibrosis. the risk of vitamin A deficiency is small. However, even subclinical
vitamin A deficiency can have serious consequences.
FUNCTIONS OF VITAMIN A AND Deficiency states in developed countries are rare, except in some
MECHANISMS OF ACTION impoverished populations (see Chapter 46) or after mistakes in food
Except for its role in vision, the pleiotropic actions of this micronutri- preparation or with fad diets, but they are common in many developing
ent include many systemic functions that are mediated at the gene level countries and are often associated with global malnutrition (see
by all-trans-retinoic acid (RA), which is a ligand for specific nuclear Chapter 46). In the clinical setting, vitamin deficiencies can also occur
transcription factors, the retinoid receptors: RARs and RXRs. When as complications in children with various chronic disorders or diseases.
an RAR is activated by the presence of RA, it combines with an RXR, Information obtained in the medical history related to dietary habits
and the resulting heterodimer binds to specific DNA sequences present can be important in identifying the possibility of such nutritional prob-
in retinoid responsive genes (RAREs and RXREs, respectively) and lems. Except for vitamin A, toxicity from excess intake of vitamins is
therefore induce or repress the expression of a large number of genes. rare. Table 48-1 summarizes the food sources, functions, and defi-
In this manner, vitamin A, via its active form, RA, regulates many ciency and excess symptoms of the vitamins.
genes that are involved in the fundamental biologic activities of cells,
such as cell division, cell death, and cell differentiation. The term reti- Clinical Manifestations of Vitamin A Deficiency
noids includes both natural and synthetic compounds with vitamin A The most obvious symptoms of vitamin A deficiency are associated with
activity and is most often used in the context of vitamin A action at the requirement of this vitamin for the maintenance of epithelial func-
the gene level. A large number of synthetic retinoids have been pro- tions. In the intestines, a normal mucus-secreting epithelium (normal
duced and some have gained clinical acceptance, such as in the treat- goblet cell function) is an effective barrier against pathogens that can
ment of skin disorders and certain cancers. cause diarrhea. Similarly, in the respiratory tract, a mucus-secreting
Retinoic acid is among the most important signaling molecules epithelium is essential for the disposal of inhaled pathogens and
in vertebrate ontogenesis. It affects many physiologic processes, includ- toxicants. Characteristic changes as a result of vitamin A deficiency in
ing reproduction, growth, embryonic and fetal development, and the epithelia include a proliferation of basal cells, hyperkeratosis, and

Table 48-1 Vitamin A Characteristics

NAMES AND BIOCHEMICAL EFFECTS OF EFFECTS OF
SYNONYMS CHARACTERISTICS ACTION DEFICIENCY EXCESS SOURCES
Retinol (vitamin A1); Fat-soluble; heat- In vision, as retinal, for Nyctalopia Anorexia, slow Liver, fish liver oils
1 µg retinol = stable; destroyed by synthesis of the visual Photophobia, growth, drying and Dairy products,
3.3 IU vitamin A = oxidation, drying pigments rhodopsin xerophthalmia, Bitot cracking of skin, except skim milk
1 RAE Bile necessary for and iodopsin spots, conjunctivitis, enlargement of Egg yolk, fortified
Provitamins A: the absorption In growth, reproduction, keratomalacia liver and spleen, margarine,
plant pigments α-, Stored in liver embryonic and fetal leading to blindness swelling and pain fortified skim milk
β-, and γ-carotenes Protected by vitamin E development, bone Faulty epiphyseal bone of long bones, Carotenoids from
and cryptoxanthin growth, immune and formation bone fragility, plants: green
have partial retinol epithelial functions, Defective tooth increased vegetables, yellow
activity: 12 µg via retinoic acid as a enamel intracranial fruits, and
β-carotene, or ligand for specific Keratinization of pressure, alopecia, vegetables
24 µg other nuclear transcription mucous membranes carotenemia
provitamin A factors, regulating and skin Fetal abnormalities
carotenoids = 1 µg genes involved in Retarded growth
retinol many fundamental Impaired resistance to
cellular processes infection, anemia,
reproductive failure,
fetal abnormalities
RAE, retinol activity equivalent.
 Chapter 48  ◆  Vitamin A Deficiencies and Excess  319

formation of stratified cornified squamous epithelium. Squamous meta- Diagnosis

plasia of the renal pelves, ureters, vaginal epithelium, and the pancreatic Dark adaptation tests can be used to assess early-stage vitamin A defi-
and salivary ducts can lead to increased infections in these areas. In the ciency. Although Bitot spots develop relatively early, those related to
urinary bladder, loss of epithelial integrity can result in pyuria and active vitamin A deficiency are usually confined to preschool-age chil-
hematuria. Epithelial changes in the skin caused by vitamin A deficiency dren. Xerophthalmia is a very characteristic lesion of vitamin A defi-
are manifested as dry, scaly, hyperkeratotic patches, commonly on the ciency. Caution must be exercised to exclude other, similar eye
arms, legs, shoulders, and buttocks. The combination of defective epi- abnormalities from those associated with vitamin A deficiency. There
thelial barriers to infection, low immune response, and lowered response are 3 useful indicators for detecting marginal vitamin A status,
to inflammatory stress, all because of insufficient vitamin A, can cause although they are mostly limited to research settings: conjunctival
poor growth and serious health problems in children. impression cytology, relative dose response, and modified relative dose
The most characteristic and specific signs of vitamin A deficiency response. A diet history can also be useful in suggesting or ruling out
are eye lesions, but they may be manifest rather late in the progression low intake as a cause. There is a relatively high prevalence of marginal
of vitamin A deficiency. Lesions caused by vitamin A deficiency vitamin A status among pregnant and lactating women. The plasma
develop insidiously and rarely occur before 2 yr of age. An early retinol level is not an accurate indicator of vitamin A status unless the
symptom is delayed adaptation to the dark, a result of reduced resyn- deficiency is severe and liver stores are depleted, in which case low
thesis of rhodopsin; later, when vitamin A deficiency is more advanced, plasma retinol is likely to be evident. In children, plasma retinol values
it leads to night blindness as a consequence of the absence of retinal of <0.35 µmol/L are considered to be very deficient, 0.35-0.7 µmol/L
in the visual pigment, rhodopsin, of the retina. Photophobia is a are considered to be deficient, 0.7-1.05 µmol/L are considered to be
common symptom. The pigment epithelium, the structural element of marginal, and >1.05 µmol/L are considered to be adequate. It has long
the retina, keratinizes. When the pigment epithelium degenerates, the been thought that the liver vitamin A concentration must be 20 µg/g
rods and cones have no support and eventually break down, resulting or higher to support a normal rate of secretion of retinol-RBP into
in blindness. plasma.
As vitamin A deficiency progresses, the corneal and conjunctival
epithelial tissues of the eye become severely altered; this change results Epidemiology and Public Health Issues
from a lack of sufficient RA for normal epithelial cell morphology and Vitamin A deficiency and xerophthalmia still occur throughout much
function. The cornea protects the eye from the environment and is also of the developing world and are linked to undernourishment and com-
important in light refraction. In early vitamin A deficiency, the cornea plicated by illness. Programs to provide periodic large doses of vitamin
keratinizes, becomes opaque, is susceptible to infection, and forms dry, A have been instituted in many low-income countries in which vitamin
scaly layers of cells (xerophthalmia). The conjunctiva keratinizes and
develops plaques (Bitot spots [Fig. 48-2]). In later stages, infection
occurs, lymphocytes infiltrate, and the cornea becomes wrinkled; it
degenerates irreversibly (keratomalacia and corneal ulceration), result-
ing in blindness. Advanced xerophthalmia (Fig. 48-3) and xerophthal-
mia with permanent damage to the eye (Fig. 48-4) may develop if
untreated. These eye lesions are primarily diseases of the young and
are a major cause of blindness in developing countries. Although rates
of xerophthalmia have fallen, the number of affected children is still
too high.
Other clinical signs of vitamin A deficiency include poor overall
growth, diarrhea, susceptibility to infections, anemia, apathy, mental
retardation, and increased intracranial pressure, with wide separation
of the cranial bones at the sutures. There may be vision problems as a
consequence of bone overgrowth causing pressure on the optic nerve.
Malnutrition, particularly protein deficiency, can cause vitamin A
deficiency by the impaired synthesis of retinol transport protein. In
developing countries, subclinical or clinical zinc deficiency can increase Figure 48-3  Advanced  xerophthalmia  with  an  opaque,  dull  cornea 
the risk of vitamin A deficiency. There is also some evidence of mar- and some damage to the iris in a 1 yr old boy. (From Oomen HAPC:
Vitamin A deficiency, xerophthalmia and blindness, Nutr  Rev 6:161–
ginal zinc intakes in children in the United States. 166, 1974.)

Figure 48-4  Recovery  from  xerophthalmia,  showing  a  permanent 

Figure 48-2  Bitot spots with hyperpigmentation seen in a 10 mo old  eye lesion. (From Bloch CE: Blindness and other disease arising from
Indonesian  boy.  (From Oomen HAPC: Vitamin A deficiency, xeroph- deficient nutrition [lack of fat soluble A factor], Am J Dis Child 27:139,
thalmia and blindness, Nutr Rev 6:161–166, 1974.) 1924.)
320  Part VI  ◆  Nutrition

Table 48-2 Dietary Reference Intakes for Vitamin A in Children

RECOMMENDED DIETARY UPPER LEVEL (UL)
ALLOWANCE (RDA) (µg retinol (µg retinol equivalents
AGE RANGE equivalents per day) per day) COMMENTS
0-6 mo 400 600 The recommended intake for infants is an adequate intake,
7-12 mo 500 600 based on the amount of vitamin A normally present in
breast milk
1-3 yr 300 600 The UL applies only to preformed vitamin A (retinol).
4-8 yr 400 900
9-13 yr 600 1,700
14-18 yr 900 male; 700 female 2,800

A deficiency is still a public health problem. Vitamin A supplementa-

tion is considered part of the strategy of the World Health Organiza-
tion’s Millennium Development Goals to reduce <5 yr mortality. Other
strategies being tested include improving the content of β-carotene in
staple foods through plant breeding (biofortification).

Dietary Reference Intakes for the

Healthy Population
Table 48-2 summarizes the dietary reference intakes for infants and
children. Dietary reference intake values include the estimated average
requirement, which is the mean biologic requirement for the nutrient
in the population; the recommended dietary allowance (RDA), which
is set to cover the needs of >97% of the population (thus the needs of
many people are more than covered by the RDA); and the upper level
(UL), an intake level above which risk of adverse effects may increase;
the UL pertains only to chronic consumption of preformed vitamin A.
The RDA is expressed as retinol activity equivalents (RAEs; 1 RAE =
1 µg all-trans-retinol; equivalents for provitamin-A in foods = 12 µg
β-carotene, 24 µg α-carotene, or 24 µg β-cryptoxanthin). From
infancy to age 18 yr, the RDA increases as a consequence of increased
body size, becoming higher for boys than girls during adolescence.
During pregnancy, the RDA is 750-770 µg, and during lactation, the
RDA is increased to 1,200-1,300 µg to ensure sufficient vitamin A
content during breastfeeding.
It is noteworthy that, especially for young children, the UL is not far
above the RDA, differing by only 2-fold in some age groups. This sug-
gests that for children whose diet is good, care should be taken not to
overuse dietary supplements containing preformed vitamin A and/or
to avoid excessive consumption of foods that are rich in vitamin A,
such as liver. A B

Vitamin A for Treatment of Deficiency Figure 48-5  Hyperostosis of the ulna and tibia in an infant 21 mo of 

age, resulting from vitamin A positioning. A, Long, wavy cortical hyper-
The safety and efficacy of vitamin A supplementation depend on the ostosis  of  the  ulna  (arrow).  B,  Long,  wavy  cortical  hyperostosis  of  the 
patient’s state of health and the regimens of other treatments. A daily right  tibia  (arrow),  with  a  striking  absence  of  metaphyseal  changes. 
supplement of 1,500 µg of vitamin A is sufficient for treating latent (From Caffey J: Pediatric  x-ray  diagnosis, ed 5, Chicago, 1967, Year
vitamin A deficiency, after which intake an at RDA level should be the Book, p. 994.)
goal. In children without overt vitamin A deficiency, morbidity and
mortality rates from viral infections, such as measles, have been
reduced by administration of weekly doses equivalent to the RDA level
of vitamin A, or higher doses of 30-60 mg of retinol (100,000- supplements, or food faddism resulting in excessive intakes of organ
200,000 IU) given once or twice, under careful monitoring to avoid meats. Toxicity can be induced in adults and children with chronic
toxicity associated with excess vitamin A. Xerophthalmia is treated by daily intakes of 15,000 µg and 6,000 µg, respectively. As there is no
giving 1,500 µg/kg body weight orally for 5 days followed by intramus- antidote for hypervitaminosis A, the prevention of this condition is
cular injection of 7,500 µg of vitamin A in oil, until recovery. most important. Symptoms may subside rapidly on withdrawal of the
Vitamin A is also used in preterm infants for improvement of respi- vitamin, but the rate of improvement depends on the amount of
ratory function and prevention of the development of chronic lung vitamin A that has built up in tissues. In extreme cases, hypervitamin-
disease. An analysis of 9 randomized controlled trials of vitamin A osis A can be fatal. Signs of subacute or chronic toxicity can include
found that vitamin A appears to be beneficial in reducing death or headache; vomiting; anorexia; dry, itchy desquamating skin; seborrheic
oxygen requirement with no differences in neurodevelopmental cutaneous lesions; fissuring at the corners of the mouth; alopecia and/
outcomes. or coarsening of the hair; bone abnormalities; swelling of the bones;
enlargement of the liver and spleen; diplopia; increased intracranial
HYPERVITAMINOSIS A pressure; irritability; stupor; limited motion; and dryness of the mucous
Chronic hypervitaminosis A results from excessive ingestion of pre- membranes; desquamation of the palms and the soles of the feet.
formed vitamin A (retinol or retinyl ester), generally for several weeks Radiographs may show hyperostosis affecting several long bones, espe-
or months. The cause is often excessive use of vitamin A–containing cially in the middle of the shafts (Fig. 48-5). Serum levels of vitamin
A are elevated, mostly as retinyl ester contained in lipoproteins, which
may contribute to membrane damage and symptoms, including release
of liver enzymes into plasma. Hypercalcemia and/or liver cirrhosis may
be present. Hypervitaminosis A is distinct from cortical hyperostosis
(see Chapter 700).
In young children, toxicity is associated with vomiting and bulging
fontanels. An affected child has anorexia, pruritus, and a lack of weight
gain. Acute hypervitaminosis A, such as after consumption of a single
large (30-60 mg dose) of vitamin A may include nausea, vomiting, and
drowsiness; less-common symptoms include diplopia, papilledema,
cranial nerve palsies, and other symptoms suggesting pseudotumor
cerebri.
A syndrome of severe congenital malformations may occur in
infants of mothers who have consumed therapeutic doses (0.5-1.5 mg/
kg) of oral 13-cis-retinoic acid (e.g., Accutane), generally taken for the
treatment of acne or cancer, during the 1st trimester of pregnancy.
These malformations result in a high incidence (>20%) of spontaneous
abortions and birth defects including characteristic craniofacial abnor-
malities. The U.S. Food and Drug Administration has increased the
stringency of prescription of such drugs in women of childbearing age
to attempt to reduce these birth defects.
Excessive intake of carotenoids is not associated with toxicity but
can cause yellow coloration of the skin (carotenodermia) and serum
(carotenemia) that disappears when intake is reduced. Children with
liver disease, diabetes mellitus, or hypothyroidism are more suscepti-
ble. Food faddism including an excessive consumption of carotene-rich
foods may be a cause of this condition.

Bibliography is available at Expert Consult.