Vitamin A deficiency is the leading cause of childhood blindness worldwide. It is most common in developing countries, where the WHO estimates that there are approximately 200.8 million children with moderate to moderate deficiency. The population most at risk is malnourished children born to vitamin A-deficient mothers, especially if they also have other diseases such as diarrhea or measles. Although relatively uncommon in the United States, vitamin A deficiency occurs as a result of inadequate dietary intake, liver disease, and gastrointestinal malabsorption.
A group of ophthalmic disorders caused by vitamin A deficiency are collectively known as xerophthalmia. Ocular pathologies include dryness of the conjunctiva and cornea (Xerosis), corneal ulceration and melting (kerotomalacia), night blindness (nyctalopia) and retinopathy. In addition to being very important for eye function, vitamin A is necessary for the soundness of the immune system. Vitamin A deficiency can lead to considerable morbidity and mortality, as the affected child is susceptible to intestinal and respiratory infections.
Pathophysiology
Vitamin A is a fat-soluble vitamin obtained through the diet in two forms: animal foods containing retinol such as milk, fish, animal liver and eggs, and plant foods such as green leafy vegetables, yellow fruits, and the vitamin precursor carotene contained in red olive oil. It is mainly absorbed by the small intestine. In the mucosal cells of the small intestine, carotenoids are converted into retinol, which, together with the directly absorbed retinol, is esterified and converted to palmitic acid [10]. Retinyl palmitate is transported via the lymphatic system to the liver for storage. When metabolism requires the involvement of vitamin A, retinyl palmitate is hydrated and re-produced as retinol, which reaches the tissues through the blood circulation, attached to retinol binding protein (RBP). Adequate stores of zinc and protein in the body are necessary for the synthesis of RBP, without which vitamin A cannot be transported to reach the target tissues [11].
Vitamin A is involved in ocular metabolism in two ways. First, in the retina, vitamin A is involved in the initiation of nerve impulses in the optic sensory cells as a precursor substance for light-sensitive visual pigments. Secondly, it is necessary for the synthesis of RNA and glycated proteins in the conjunctival epithelium and helps to maintain the integrity of the conjunctival mucosa and corneal stroma.
The retina contains two types of photosensitive cells, rod cells and cone cells. The rod cells are responsible for vision in dim light and the cone cells are responsible for color vision and vision in bright light. Vitamin A is the main component of the optic pigment in the cone rod cells, with the main difference being the type of protein bound. In the optic rods, aldehydes of vitamin A bind to the optoprotein to form the retinoid, which is the photoreceptor pigment. When light strikes the optic rods, the pigment is isomerizes and generates nerve impulses that produce visual signals. The pigment breaks down into the all-trans stereoisomeric structure of retin and retinol.
Regeneration of the normal geometric structure of retinol requires re-binding of retinoids. However, this process results in the loss of some retinol and requires vitamin A supplementation to form enough retinol to maintain normal function of the optic rod cells. Cone rod cells have the same mechanism of stimulating catabolic regeneration. The exact mechanism remains unclear, but the vitamin is necessary for the differentiation of the epithelial surface of the body. Deficiency leads to degenerative changes in the normal mucosal surface, including loss of cup cells and squamous epithelial metaplasia of the epithelium. In addition to this, the stromal layer of the cornea breaks down and liquefies leading to corneal flaccidity.
Epidemiology
Ocular dryness is a condition that arises from a combination of vitamin A and protein deficiency. It is rare in developed countries. However, it is a massive problem worldwide, especially in the less developed regions of Asia, where the diet includes only small amounts of rice. In most of Latin America and the Caribbean, the disease is well controlled, except in Haiti, where the incidence is as high as in some Asian countries. The prevalence of xerophthalmia has been reported to be as high in some parts of Africa as in Asia, except in some parts of West Africa where the disease has been spared because of the use of vitamin A-rich red palm oil for cooking [19]. In endemic countries, the disease is mostly acquired by low-income groups because of food deficiencies.
Ocular dryness can affect any age group, but is common in children aged 1-6 years, and blinding complications often involve children aged 6 months to 3 years. The high prevalence in children is due to the fact that infants are born with low vitamin A reserves and receive less from breast milk, and that children grow rapidly, require more nutrients, are susceptible to infectious diseases, and consume more nutrients.
Eye manifestations
Night blindness
Because of the important role of vitamin A involved in visual function, night blindness is the earliest and most common symptom to occur. Even in the subclinical state, electroretinography and dark adaptation tests can reveal reduced retinal function. Night blindness usually responds rapidly to systemic vitamin A treatment (24-48hrs).
Conjunctival manifestations
X1A describes the manifestations of dryness. Vitamin A deficiency leads to a decrease in mucus-secreting cupped cells and eventually squamous epithelial metaplasia of the conjunctival epithelium. Conjunctival dryness occurs mainly in the temporal bulbar conjunctiva at the lid fissure. The characteristic presentation is a dry granular patch with thickened, wrinkled, depigmented and opaque conjunctiva. Rosacea staining is strongly positive.
Bitot’s spot (X1B) refers to a triangular, grayish-white elevation at the corneal limbus covering a degenerated keratotic conjunctiva in the dry part of the conjunctiva. It is sometimes seen in malnourished patients with normal vitamin A levels. It often disappears on its own if vitamin A returns to normal.
Corneal manifestations.
The earliest corneal manifestation of ocular dryness may be instability of the tear film, with a lusterless corneal appearance and light punctate staining when stained. Most patients with night blindness and Bitot’s spots have this manifestation. Untreated, corneal lesions can progress to epithelial defects, stromal edema, and keratinization of the lid fissure. The lesions usually develop simultaneously in both eyes. If treated promptly, complete healing occurs within approximately 1 week.
The corneal epithelial defect progresses to a corneal ulcer. The characteristic corneal ulcer is small, located on the nasal periphery of the cornea, and has a clear border. It may be a partial or total corneal layer. Ulcer progression can block the center of the pupil, secondary to bacterial infection. Corneal chondromalacia is a liquefied necrosis of the entire cornea. Clinically, the lesion is well defined and becomes opaque grayish-yellow in appearance. The stromal layer becomes thin, or the posterior elastic layer bulges, and in severe cases, the anterior chamber of the cornea perforates and disappears. Adjunctive treatment with vitamin A may accelerate healing. Corneal flaccidity may not be caused by vitamin A deficiency alone and is rare in vitamin-deficient animals. It is often associated with systemic diseases such as measles, diarrhea, or respiratory infections, or with concomitant protein-deficient malnutrition.
XerophthalmicFundus (dry corneal fundus) is uncommon and presents as a yellowish-white dotted lesion in the peripheral fundus. Sodium fluorescein staining shows a focal retinal pigment epithelial defect. Patients less commonly present with visual field defects associated with retinopathy. With vitamin A treatment, this lesion can disappear within 1-2 weeks and the retinal damage tapers off within 1-4 months.
Diagnosis
The diagnosis of ocular dryness is mainly clinical and requires a high degree of suspicion. The simplest, inexpensive and practical diagnosis is treatment. Blood tests can be done, but they are of limited value and require special testing equipment. However, physicians should be aware that there are tests that can be done [26].
Serum vitamin A levels
The biochemical definition of vitamin A is a serum level less than or equal to 35 umol/dl. Many methods can be used, but high-pressure liquid chromatography is the most reliable. The important factor is that serum vitamin A levels can be reduced if protein deficiency is present, despite normal vitamin A intake and reserves [27].
Whole RBP test
Total RBP is a vitamin A and RBP complex that correlates with serum vitamin A levels. It may be reduced in protein deficiency.
Conjunctival blot cytology
Useful for examining preclinical ocular dryness. Non-invasive method to obtain a conjunctival sample to assess the histological appearance of the superficial conjunctiva. Squamous epithelial metaplasia typically presents as irregularly enlarged keratinized epithelial cells with reduced cupped cells. The results correlate with serum vitamin A levels [30].
Treatment
The aim of treatment is to restore vitamin A stores. The oral dose is 200,000 IU of vitamin A oil, repeated on alternate days. Treatment should be repeated every two weeks in children with severe protein deficiency knowing that protein levels are raised to normal. If there is severe corneal disease or malabsorption, 100,000 IU of vitamin A can be administered intramuscularly.
Topical treatment is primarily used to prevent and treat bacterial infections secondary to corneal ulcers. Because of the time lag between oral supplementation therapy and healing, topical supplementation with 0,1% retinoic acid therapy may be used to promote healing. However, be aware of the thick vascularized scarring that may result and use with caution if the ulcer is above the median visual axis of the cornea.
Surgery is of little use. Superficial corneal ulcers that heal with a small amount of scarring will not affect vision. Full corneal softening involving the entire cornea is inoperable and the patient is in extremely poor health and cannot tolerate anesthesia. A small number of patients with scarring involving the visual axis can undergo corneal transplantation. However, the reason for the poor outcome is not only that amblyopia has already occurred, but also that the survival of the implant is unlikely due to their social and economic conditions.
Prevention
Increasing vitamin A levels can reduce the risk of childhood mortality and blindness. Prevention is achieved by maintaining adequate vitamin A stores, either through dietary supplementation or regular vitamin A. Newborns should receive 50,000 IU of vitamin A every 4-6 months, children under one year of age should receive 100,000 IU of vitamin A, adults or children over one year of age should receive 200,000 IU of vitamin A, and those who are pregnant or breastfeeding should receive 20,000 IU per week of Vitamin A.
Public health programs studying vitamin A deficiency are investigating the most effective ways to distribute supplements, either tied to immunization programs or fortified with common food intake (e.g., iodized salt). They are also working on nutrition education to increase the consumption of red-yellow and green leafy vegetables in populations in endemic areas. Scientific research is now also using the latest technology to eliminate such problems as golden rice, a genetically modified food rich in iron and carotenoids. In addition, the treatment of other diseases such as protein malnutrition, measles and diarrhea has a crucial role to play in controlling the onset of vitamin A deficiency.