Vitamin A is a fat-soluble vitamin found in liver, egg yolks, and dairy products. It may also be obtained in the form of carotenoid precursors, which are present in carrots, green leafy vegetables, yellow fruits, and red palm oil [1]. Vitamin A deficiency occurs when there is poor dietary intake, insufficient absorption or storage, or rapid loss of the vitamin from the body [2]. In its early stages, vitamin A deficiency is most commonly expressed as night blindness. Prolonged deficiency, however, can induce significant pathological changes to the eye in the form of xerosis and keratomalacia, which may lead to total and irreversible blindness [3].

The ocular manifestations of vitamin A deficiency have long been recognized and described. Ancient Egyptians observed that night blindness could be treated with liver extracts [4]. Throughout the eighteenth and nineteenth centuries, night blindness was commonly reported and various cures were utilized including the administration of cod liver oil [5]. Hubbenet [6] and Bitot [7] independently reported the association between night blindness and white foamy lesions on the outer conjunctiva, now known as “Bitot’s spots .” Cases of advanced xerophthalmia were seen with more severe deficiency, often in children who were near death from malnutrition [8].

Systemic animal experiments in the early twentieth century identified the specific fat-soluble vitamin essential for normal growth and integrity of the eye [9, 10]. By the 1930s, the cause and clinical features of vitamin A deficiency had been elucidated [11]. While the incidence of vitamin A deficiency fell dramatically in wealthy countries with a concurrent rise in nutritional status, it continued to be a leading cause of blindness and death in the developing world. A number of randomized field-based trials conducted in rural Asia and Africa, showing a reduction in mortality with vitamin A supplementation, were instrumental in the development of global vitamin A fortification programs [12–14]. Since then, many countries have adopted WHO’s guidelines to implement universal distribution of vitamin A for their preschool-age populations.

Vitamin A deficiency is associated with increased morbidity and mortality in preschool-age children in developing countries [12, 15]. WHO reports that between 1995 and 2005, vitamin A deficiency was a moderate to severe public health problem in 122 countries—mostly in Africa and Southeast Asia—where economical and social deprivation was prevalent [16]. Annually, five to ten million children develop xerophthalmia , the most direct manifestation of vitamin A deficiency [17]. Furthermore, vitamin A-deficient children are more susceptible to respiratory and intestinal infections such as measles or diarrhea, which may exacerbate the poor intake of vitamin A and contribute to the increased risk of mortality [18, 19]. WHO estimates that between 250,000 and 500,000 children with vitamin A deficiency lose their sight every year, half of whom die within a year of going blind. Vitamin A supplementation in high-risk areas has shown to be effective in preventing childhood morbidity and mortality, reducing the overall risk of death by 24 % [20].

Vitamin A deficiency also occurs in developed nations, most often due to malabsorption or underutilization of vitamin A. Gastrointestinal or liver diseases , such as cystic fibrosis, cirrhosis, ulcerative colitis, celiac syndrome, short bowel syndrome and hepatitis, can interfere with proper absorption and storage of vitamin A [21–24]. Additionally, patients who undergo bariatric surgery , including gastric bypass and biliopancreatic diversion, may develop ocular symptoms caused by vitamin A deficiency [25–27].

In addition to its role in ocular health, vitamin A has important systemic functions. First, it is required for proper differentiation of mucosal epithelium in various organs. In vitamin A deficiency, mucous membranes lining the respiratory, gastrointestinal, and genitourinary tracts undergo keratinization, thereby compromising local resistance to bacterial infection [28–30]. This damage to the epithelial integrity is thought to be partially responsible for the increased risk of respiratory infections, chronic dry cough, and pyuria observed in severely deficient children [28, 29]. Keratinizing metaplasia also occurs in the skin, resulting in dry, scaly skin and follicular hyperkeratosis [2].

Another systemic manifestation of vitamin A deficiency is growth retardation. The fat-soluble compound was first identified by animal studies in which vitamin-deprived rats failed to grow as rapidly as their normal counterparts [9, 10]. The effect of vitamin A on human growth was later confirmed; moderate-to-severe deficiency marked by xerophthalmia was shown to impair normal physical growth in Nepalese children [31]. Vitamin A deficiency is also thought to play a role in the pathogenesis of anemia, although the exact biological mechanism remains unclear [16, 32].

Vitamin A plays three essential roles in ocular metabolism . First, it serves as a precursor for the visual photosensitive pigment rhodopsin, which initiates neural impulses from photoreceptors to enable vision. Second, vitamin A is involved in rod outer segment turnover as well as phagocytosis of the outer segment material. Third, vitamin A is necessary for maintaining the structural and functional integrity of corneal epithelial cells [3].

In the body, vitamin A exists in four forms: retinol, retinal, retinoic acid, and retinyl ester. Approximately 50–90 % of ingested vitamin A is absorbed in the small intestine and transported to the liver, where it is stored as retinyl ester [17]. From the liver, it is transported to the eye as retinol in combination with retinol-binding protein. In the eye, vitamin A compounds reside in the outer segment of photoreceptors and retinal pigment epithelium (RPE) . Vitamin A is required for the synthesis of rod rhodopsin and cone iodopsin, which consist of 11-cis-retinal covalently bound to opsin and photopsin, respectively. When rhodopsin is exposed to light, isomerization of 11-cis-retinal to all-trans-retinal occurs, inducing a conformational change in the protein and release of the retinal. This process, known as bleaching , initiates a neural impulse and is responsible for phototransduction [33].

Xerophthalmia is the most specific ocular manifestation of vitamin A deficiency and is also the leading cause of childhood blindness in developing countries. The term ‘xerophthalmia’ encompasses a spectrum of ocular manifestations ranging from night blindness to keratomalacia , as classified by WHO (Table 22.2). Because of vitamin A’s essential role in photoreceptor function, night blindness is the primary and most common expression of vitamin A deficiency . Children with night blindness have impaired adaptation to darkness, often unable to move about in dim light or after sunset. Cone dysfunction occurs more slowly and less completely than rod dysfunction, explaining the relative preservation of visual acuity in the presence of night blindness [34]. At early stages, night blindness is reversible and responds rapidly to vitamin A replacement [17].

With prolonged deficiency, the conjunctival epithelium undergoes pathological changes, from the normal stratified columnar type to the stratified squamous type. These changes cause a loss of mucous-secreting goblet cells, formation of a granular cell layer, and keratinization of the conjunctival epithelium, resulting in conjunctival xerosis. Clinical features of conjunctival xerosis include dryness, wrinkling, loss of luster, thickening, and roughening of the bulbar conjunctiva, characterized by fine droplets or bubbles on the surface [17]. In some cases, white triangular foamy plaques known as Bitot’s spots can occur temporally on the bulbar conjunctiva. These lesions result from the accumulation of keratinized debris and saprophytic bacilli on the xerotic surface [17]. Although Bitot’s spots are easily recognized, they may not serve as an adequate indicator of disease states. Bitot’s spots sometimes persist in the absence of active vitamin A deficiency, representing generalized malnutrition or a previous episode of deficiency [35]. Conjunctival xerosis and Bitot’s spots typically begin to resolve within 2–5 days of vitamin A therapy, with most dissipating by 2 weeks [17].

More severe deficiency can lead to corneal xerosis, ulceration , and keratomalacia . Initially, the cornea loses its normal luster and develops a hazy, opaque, and dry appearance (xerosis) near the inferior limbus, as seen in Fig. 22.1. Keratinized patches resembling Bitot’s spots may also form on the corneal surface, most commonly in the interpalpebral zone. As the disease progresses, corneal ulceration, perforation, and keratomalacia may develop. Ulceration and necrosis are often caused not by vitamin A deficiency alone, but by infections or trauma occurring in a vitamin-deficient state [36]. Ulceration or keratomalacia covering less than a third of the corneal surface generally leaves the central pupillary zone intact, and some useful vision may be preserved with immediate treatment . More widespread keratomalacia tends to result in perforation, extrusion of intraocular contents, and loss of the globe [17]. Children with untreated keratomalacia have a mortality rate of 90 % [37].

Vitamin A levels are used as the biochemical indicator of vitamin A deficiency. Serum retinol concentrations lower than 0.7 μmol/l and 0.35 μmol/l represent deficiency and severe deficiency, respectively [16]. Clinical diagnosis can also be made by examining the eyes for signs of xerophthalmia. Conjunctival impression cytology, in which a conjunctival specimen is collected, fixated, and stained, is a method for detecting preclinical and clinical xerophthalmia [36], although the validity of this technique has been debated [38–41]. Dark adaptation tests , which assess a patient’s response to dim light, may serve as a helpful complement to the diagnosis. Whenever possible, diagnosis should be made based on multiple indicators to accurately assess the vitamin A deficiency state.

Xerophthalmia should be recognized as a medical emergency and be treated immediately with vitamin A supplementation. Prompt therapy is usually successful in reversing early stages of vitamin A deficiency, including night blindness , conjunctival xerosis and Bitot’s spots , but more advanced corneal damage may persist after therapy. For treatment of xerophthalmia, WHO recommends immediate oral supplementation of vitamin A for two consecutive days (100,000 IU for children <1 year of age and 200,000 IU for children >1 year of age), with the same dosage repeated 2 weeks later (Table 22.3) [42]. In settings where vitamin A deficiency is of public health concern, a high-dose supplementation regimen (Table 22.3) is proven to be safe and effective in preventing childhood xerophthalmia and death [43]. Acute side effects such as headache, nausea, vomiting, and diarrhea may occur in a small percentage of children receiving 100,000–200,000 IU of vitamin A. However, these symptoms are transitory and generally disappear within a day of dosing [44].

In addition to systemic therapy, topical lubrication with retinoic acid may accelerate corneal healing in children with corneal xerophthalmia [45]. An antibiotic eye ointment such as tetracycline or chloramphenicol is recommended for treatment and prevention of secondary infections; however, steroid-containing ophthalmic ointments should never be used in these instances [42]. Corneal surgery may be indicated for complications of keratomalacia [2].

Of additional interest, vitamin A supplementation has been shown to slow the progression of retinal degeneration in patients with retinitis pigmentosa (RP) [46]. The essential role that vitamin A plays in photoreceptor cell function may explain its efficacy in treating RP, which is characterized by a gradual loss of rods and cones. A daily dose of 15,000 IU of vitamin A palmitate is recommended for treatment of adults with typical forms of RP [47].

Vitamin B complex consists of several water-soluble compounds —thiamine (B₁), riboflavin (B₂), niacin or nicotinic acid (B₃), pantothenic acid (B₅), pyridoxine (B₆), biotin (B₇), folic acid (B₉), and cyanocobalamin (B₁₂). The B vitamins generally act as coenzymes in metabolic processes, often working synergistically with one another. Food sources of vitamin B complex include whole grains, dried beans, green leafy vegetables, legumes, dairy products, liver, and meat. Water-soluble vitamins, including the B vitamins, must be consumed daily, because any excess amounts are readily excreted in the urine. Vitamin B₁₂ is the only B vitamin that can be stored in large concentrations in the liver. Deficiency of vitamin B complex can result in ocular symptoms in addition to a multitude of systemic disorders , including beriberi and Wernicke-Korsakoff syndrome (thiamine deficiency), pellagra (niacin deficiency), and pernicious anemia (vitamin B₁₂ deficiency).

While disorders of vitamin B deficiency had been recognized and described for centuries, the individual vitamins responsible for these disorders were not identified until the twentieth century [48]. As the functions of B vitamins became clearer, many countries have mandated adding these vitamins to polished rice, flour, cereal, etc. to replace the micronutrients that are removed during the refining process. In the United States, white flour and other refined grains have been enriched with thiamine, riboflavin , and niacin since the 1940s; folic acid fortification of grain products was mandated in 1998 [48, 49].

Although the occurrence of vitamin B-related disease has declined, sub-clinical manifestations of vitamin B complex deficiency are still widespread in populations under various stress situations [50]. In developing countries where diets are not fortified with micronutrients, vitamin B deficiency results mainly from inadequate intake. In wealthy countries, vitamin B deficiency is primarily seen in people with self-imposed dietary restrictions, malabsorption syndromes, or chronic alcoholism. Thiamine deficiency , for example, occurs most often in chronic alcoholics, who have impaired gastrointestinal absorption and utilization of thiamine. Thiamine deficiency has also been observed relatively frequently in patients who have undergone bariatric surgery [51, 52]. Vegetarians and vegans are at particular risk for developing a deficiency of vitamin B₁₂ , which is only available from meat and dairy products. Breast-fed infants of mothers who adhere to a strict vegan diet may develop symptoms related to vitamin B₁₂ deficiency . Autoimmune disease is also associated with vitamin B₁₂ deficiency, due to impaired absorption.

Thiamine functions as an essential coenzyme in carbohydrate metabolism and energy utilization. Thus, its deficiency is particularly deleterious to the nervous system, which harnesses energy largely from glucose oxidation [3]. The classic systemic manifestation of thiamine deficiency is beriberi. In dry beriberi , the peripheral nervous system undergoes damage, leading to neuropathy, ataxia, loss of muscle strength, and eventually paralysis. In wet beriberi , the cardiovascular system is affected and congestive heart failure can occur. Cerebral beriberi , also known as Wernicke’s encephalopathy , affects the central nervous system; symptoms include mental disturbance and ataxia, and if left untreated, Korsakoff syndrome may develop. Infantile beriberi can occur in babies breast-fed by mothers who are alcoholic or malnourished [53]. Infants with acute beriberi develop a loss of appetite, irritability, vomiting of milk, edema and hoarseness, and often die within a few days of onset if not treated promptly [54, 55].

Riboflavin is the precursor for two essential redox cofactors involved in energy production, FMN and FAD. Deficiency of riboflavin results in “ariboflavinosis ,” which refers to the clinical symptoms of glossitis, anemia, sore throat, seborrheic dermatitis, angular stomatitis, and cheilosis.

Niacin is the precursor for two other cofactors critical in energy metabolism —NAD and NADP. Niacin deficiency causes pellagra , a disease that is characterized by diarrhea, dermatitis, and dementia. Symptoms of pellagra in infants and children include irritability, anxiety, apathy, and anorexia. Young patients with pellagra may also present with dry, scaly skin and sore tongues and lips.

Pyridoxine serves as a cofactor in amino acid, carbohydrate, and lipid metabolism as well as in hemoglobin synthesis. Vitamin B₆ deficiency most often occurs in combination with other vitamin B deficiencies; deficiency of pyridoxine alone is rare [56]. In infants and children, symptoms of vitamin B₆ deficiency include seizures, anemia, dermatitis, and hyperirritability. Because the need for vitamin B₆ is closely linked to protein intake, the symptoms may worsen as more protein is consumed.

Folate is involved in one-carbon transfers of methylation reactions and nucleic acid synthesis, and is therefore essential for cell division and growth. Folic acid deficiency in pregnant women has been linked to neural tube defects in early embryo development. Severe and prolonged deficiency may result in megaloblastic anemia and neuropathy [57].

Vitamin B₁₂ is the largest of the B vitamins , consisting of a porphyrin-like ring with a cobalt atom at the center. Vitamin B₁₂ is critical for the normal functioning of the nervous system, and its deficiency can lead to neurologic symptoms including peripheral neuropathy, sensory or motor defects, and wide-based gait. In infants, low levels of vitamin B₁₂ can disrupt myelination of the brain, thereby interfering with early brain development [58]. The most common cause of vitamin B₁₂ deficiency is pernicious anemia, an autoimmune disease that destroys parietal cells of the stomach. Parietal cells are responsible for secreting intrinsic factor, which is needed for normal absorption of vitamin B₁₂; a lack of intrinsic factor causes malabsorption and deficiency of vitamin B₁₂. Furthermore, because vitamin B₁₂ is necessary for erythrocyte production in the bone marrow, its deficiency can in turn result in pernicious anemia. Vitamin B₁₂ deficiency is also associated with long-standing vegan diets, i.e. when the diet contains no animal source foods. Although there typically are extensive hepatic stores of the vitamin, these can be depleted over time, particularly over the course of a reproductive cycle including both pregnancy and lactation.

Optic nerve degeneration is the primary ocular manifestation of vitamin B deficiency. In particular, deficiency of vitamin B₁₂ can cause an optic neuropathy in which the vision loss is bilateral, symmetric, gradual, and painless. The optic nerve appears normal during the early stages of disease, while visual field testing generally reveals central and cecocentral scotomas [36]. The optic neuropathy resulting from vitamin B₁₂ deficiency clinically resembles Leber’s hereditary optic neuropathy (LHON) . One study suggests that in patients carrying a primary LHON mtDNA mutation, optic neuropathy may be precipitated by vitamin B₁₂ deficiency [59].

Deficiencies of thiamine, riboflavin, niacin, pyridoxine, and folic acid have also been associated with optic neuropathy ; however, the causal role of these vitamins remains controversial [60–63]. In one study, vitamin B complex deficiency in school children was negatively associated with visual acuity, which improved following vitamin B supplementation [64].

Eye movement disorders such as nystagmus, diplopia, and ophthalmoplegia has been shown to occur with thiamine deficiency , particularly in patients with Wernicke’s encephalopathy [33, 54]. Blepharoptosis is commonly seen associated with infantile beriberi [55]. Rarely, eye movement disorders can be caused by vitamin B₁₂ deficiency; cases of ophthalmoplegia, downbeat nystagmus, and upward gaze palsy have been described [65].

Vitamin B₁₂ deficiency has also been directly linked to vascular changes in the retina. Retinal hemorrhages, edema, and dilatation have been observed with megaloblastic anemia [3]. The hemorrhages usually occur at the posterior pole of the eye and rarely interfere with central vision.

In addition to the optic nerve and retina, the anterior segment of the eye can be affected by vitamin B deficiency. Peripheral corneal vascularization and superficial keratitis with thin opacities in the center of the cornea have been reported to occur with riboflavin deficiency [66]. Although the biochemical role of riboflavin in the cornea is unclear, a decrease in oxygen uptake by the corneal epithelium has been noted [67, 68]. Thiamine, riboflavin, and pyridoxine deficiencies can also result in angular conjunctivitis and blepharoconjunctivitis [66, 69].

Because the clinical symptoms of vitamin B deficiency can be nonspecific, diagnosis is typically made on the basis of serum vitamin levels or urinary excretion [50]. The specific diagnostic tools used for each vitamin are listed in Table 22.4. The Schilling test may be used as a confirmatory test to identify vitamin B₁₂ deficiency and pernicious anemia, and is helpful for determining the root cause of deficiency.

Treatment of vitamin B complex deficiency is achieved by individual vitamin supplementation, as listed in Table 22.4. Because the metabolic pathways of the B vitamins are closely interrelated, diverse clinical manifestations resulting from multiple deficiencies may be seen in one individual. Therefore, a patient presenting with a specific vitamin B deficiency is generally treated with the entire group of B-complex vitamins. While vitamin B replacement therapy will resolve most symptoms, any damage to the nerve may be permanent.

Vitamin C, also known as ascorbic acid , is a water-soluble vitamin involved in various enzymatic reactions in the body. It is found in fresh vegetables and fruits, including tomatoes, spinach, cabbage, green pepper, and citrus fruits. Vitamin C is an essential cofactor in the synthesis of collagen, which is necessary for the integrity of vascular basement membranes . Its deficiency results in a systemic disease known as scurvy , which includes several hemorrhagic manifestations.