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Vitamin A Deficiency
Vitamin A Deficiency
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