Absorption, Transport, Metabolism, Storage

The body acquires vitamin A either as preformed vitamin A (usually as esters) or as provitamin-A carotenoids. In the USA, grains and vegetables supply approximately 55% and dairy and meat products supply approximately 30% of vitamin A intake from food. Vitamin A and the provitamins-A are fat-soluble, and their absorption depends on the presence of adequate lipid and protein within the meal. Chronic intestinal disorders or lipid malabsorption syndromes can result in vitamin A deficiency. Ingested and absorbed provitamins-A are bioconverted to vitamin A molecules in the small intestine by the carotene cleavage enzyme dioxygenase; β-carotene provides twice the vitamin A activity of the other provitamins-A. Further processing in the enterocyte involves the esterification of vitamin A to retinyl palmitate for incorporation into chylomicrons, which are released into lymph and transported via the circulation to the liver for storage or to other tissues. The vitamin A content in the liver is low at birth, but it increases 60-fold during the first 6 mo of life. If the growing child has a well-balanced diet and obtains vitamin A from foods that are rich in vitamin A or provitamin-A (see Table 45-1), the risk of vitamin A deficiency is small. However, even subclinical vitamin A deficiency can have serious consequences.

Stored vitamin A is released from the liver into the circulation as retinol bound to its specific transport protein, retinol-binding protein (RBP), which binds to the thyroid hormone transport protein, transthyretin; this complex delivers retinol (as well as the thyroid hormone) to tissues. Normal plasma levels of retinol are 20-50 µg/dL in infants and 30-225 µg/dL in older children and adults. Uncleaved provitamin-A carotenoids in the intestine are also incorporated into chylomicrons and delivered to various tissues. Malnutrition, particularly protein deficiency, can cause vitamin A deficiency by the impaired synthesis of retinol transport protein. However, if dietary vitamin A is provided in the absence of RBP, vitamin A is transported to the tissues via chylomicrons and almost completely alleviates the symptoms of vitamin A deficiency. In developing countries, subclinical or clinical zinc deficiency can increase the risk of vitamin A deficiency. There is also some evidence of marginal zinc intakes in children in the USA.

Function and Mechanism of Action

Vitamin A is required throughout the life cycle, beginning with embryogenesis. Except for its role in vision, the pleiotropic actions of this micronutrient include many systemic functions that are mediated at the gene level by all-trans-retinoic acid (RA), which is a ligand for specific nuclear transcription factors, the retinoid receptors: RARs and RXRs. When an RAR is activated by the presence of RA, it combines with an RXR, and the resulting heterodimer binds to target genes that have specific recognition sites. Thus, vitamin A, via its active form, retinoic acid, regulates many genes that are involved in the fundamental biologic activities of cells, such as cell division, cell death, and cell differentiation.

Retinoic acid is among the most important signaling molecules in vertebrate ontogenesis. It affects many physiologic processes, including reproduction, growth, embryonic and fetal development, and bone development, in addition to respiratory, gastrointestinal, hematopoietic, and immune functions. The role of vitamin A in immune function and host defense is particularly important in developing countries, where vitamin A supplementation or therapy reduces the morbidity and mortality rates of various diseases, such as measles (Chapter 238).

The best understood function of vitamin A is its nongenomic role in vision. The human retina has two distinct photoreceptor systems: the rods, containing rhodopsin, which can detect low-intensity light, and the cones, containing iodopsin, which can detect different colors. The aldehyde form of 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 vitamin A molecule to photoisomerize (change shape when exposed to light). Thus, in the dark, low-intensity light isomerizes the rhodopsin prosthetic group, 11-cis retinal, to all-trans-retinal, generating an electrical signal that is transmitted via the optic nerve to the brain and results in visual sensation.

Clinical Manifestations

The most obvious symptoms of vitamin A deficiency are associated with the requirement of this vitamin for the maintenance of epithelial functions. In the intestines, a normal mucus-secreting epithelium is an effective barrier against a pathogenic attack that can cause diarrhea. Similarly, in the respiratory tract, a mucus-secreting epithelium is essential for the disposal of inhaled pathogens and toxicants. Epithelial changes in the respiratory system can result in bronchial obstruction. Characteristic changes due to vitamin A deficiency in the epithelia include a proliferation of basal cells, hyperkeratosis, and formation of stratified cornified squamous epithelium. Squamous metaplasia of the renal pelves, ureters, vaginal epithelium, and the pancreatic and salivary ducts can lead to increased infections in these areas. In the urinary bladder, loss of epithelial integrity can result in pyuria and hematuria. Epithelial changes in the skin due to vitamin A deficiency are manifested as dry, scaly, hyperkeratotic patches, commonly on the arms, legs, shoulders, and buttocks. The combination of defective epithelial barriers to infection, low immune response, and lowered response to inflammatory stress, all due to insufficient vitamin A, can cause poor growth and serious health problems in children.

The most characteristic and specific signs of vitamin A deficiency are eye lesions. Lesions due to vitamin A deficiency develop insidiously and rarely occur before 2 yr of age. An early symptom is delayed adaptation to the dark; later when vitamin A deficiency is more advanced, it leads to night blindness due to the absence of retinal in the visual pigment, rhodopsin, of the retina. Photophobia is a common symptom. As vitamin A deficiency progresses, the epithelial tissues of the eye become severely altered.

The cornea protects the eye from the environment and is also important in light refraction. In early vitamin A deficiency, the cornea keratinizes, becomes opaque, is susceptible to infection, and forms dry, scaly layers of cells (xerophthalmia). In later stages, infection occurs, lymphocytes infiltrate, and the cornea becomes wrinkled; it degenerates irreversibly (keratomalacia), resulting in blindness. The conjunctiva keratinizes and develops plaques (Bitot spots [Fig. 45-1]). The pigment epithelium is the structural element of the retina and keratinizes. When the pigment epithelium degenerates, the rods and cones have no support and eventually break down, resulting in blindness. Advanced xerophthalmia is shown in Figure 45-2, and xerophthalmia with permanent damage to the eye is shown in Figure 45-3. These eye lesions are primarily diseases of the young and are a major cause of blindness in developing countries.

Figure 45-1 Bitot spots with hyperpigmentation seen in a 10 mo old Indonesian boy.

(From Oomen HAPC: Vitamin A deficiency, xerophthalmia and blindness, Nutr Rev 6:161–166, 1974.)

Figure 45-2 Advanced xerophthalmia with an opaque, dull cornea and some damage to the iris in a 1 yr old boy.

(From Oomen HAPC: Vitamin A deficiency, xerophthalmia and blindness, Nutr Rev 6:161–166, 1974.)

Figure 45-3 Recovery from xerophthalmia, showing a permanent eye lesion.

(From Bloch CE: Blindness and other disease arising from deficient nutrition [lack of fat soluble A factor], Am J Dis Child 27:139, 1924.)

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 due to bone overgrowth causing pressure on the optic nerve.

Diagnosis

Dark adaptation tests can be used to assess early-stage vitamin A deficiency. Although Bitot spots develop early, those related to active vitamin A deficiency are usually confined to preschool-aged children. Xerophthalmia is a very characteristic lesion of vitamin A deficiency. Caution must be exercised to exclude other, similar eye abnormalities from those associated with vitamin A deficiency. To detect marginal vitamin A status, there are 3 useful indicators: conjunctival impression cytology, relative dose response, and modified relative dose response. There is a relatively high prevalence of marginal vitamin A state among pregnant and lactating women. The plasma retinol level is not an accurate indicator of vitamin A status unless the deficiency is severe and liver stores are depleted. The range of normal vitamin A levels is 20-60 µg/dL; a level <20 µg/dL occurs in deficiency.

Prevention

The daily recommended dietary allowance (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). The RAE for infants 0-1 yr of age is 400-500 µg; for children 3 yr of age is 300 µg; for children 4-8 yr of age is 400 µg; for children 9-13 yr of age is 600 µg; for boys 14-18 yr of age and men is 900 µg; and for girls 14-18 of age and women is 700 µg (also see Table 41-8). 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 breast-feeding. A daily tolerable upper level of vitamin A for adults is 3,000 µg of preformed vitamin A. Approximately 80% of dietary vitamin A is absorbed as long as the meal contains some fat (>10 g). Low-fat diets may need to be supplemented with vitamin A. In disorders with poor fat absorption or increased excretion of vitamin A, water-miscible preparations should be administered in amounts higher than the RDAs. Premature infants have poor lipid absorption and thus should receive water-miscible vitamin A and be monitored closely.

Epidemiology and Public Health Issues

Vitamin A deficiency and xerophthalmia occur throughout much of the developing world and are linked to undernourishment and complicated by illness. More than 350,000 cases of childhood blindness are reported annually due to severe vitamin A deficiency. Because maternal vitamin A status is reflected in the vitamin A content of breast milk, intervention trials are ongoing with mothers of breast-fed infants living in regions where vitamin A deficiency is common. In these trials, 2 doses of 200,000 IU (60 mg) each of vitamin A are given to the mother immediately after delivery, and the infant is given 3 doses of 25,000 IU (7.5 mg) each of vitamin A at 1-3 mo of age (1 IU = 0.3 µg retinol).

Treatment

The safety and efficacy of vitamin A supplementation depend on the patient’s state of health and the regimens of other treatments. A daily supplement of 1,500 µg of vitamin A is sufficient for treating latent vitamin A deficiency. In children without overt vitamin A deficiency, morbidity and mortality rates from viral infections such as measles can be lowered by daily administration of 1,500-3,000 µg of vitamin A, under careful monitoring to avoid toxicity associated with excess vitamin A. Xerophthalmia is treated by giving 1,500 µg/kg body weight orally for 5 days followed by intramuscular injection of 7,500 µg of vitamin A in oil, until recovery.