Vitamin A Deficiency Disorders

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Vitamin A is essential for maintaining normal retinal function and differentiation of rapidly dividing, bipotential cells. These regulatory roles give rise to specific manifestations of hypovitaminosis A, such as poor photoreceptor function leading to night blindness, metaplasia, and keratinization of mucosal epithelial surfaces leading to clinical abnormalities of conjunctival and corneal xerosis as well as epidermoid metaplasia and other epithelial defects throughout the respiratory, genitourinary, and gastrointestinal tracts and glandular ducts. Deficiency can also impair development or functioning of multiple arms of the immune system that can weaken host defenses against infection. Collectively, all pathophysiological consequences attributed in varying degrees to VA depletion are termed 'vitamin A deficiency disorders (VADD) (Figure 1).

Keratomalacia/ Corneal Ulceration (X3)

Night Blindness (XN)

Chronic Dietary Deficit

Keratomalacia/ Corneal Ulceration (X3)

Night Blindness (XN)

Metaplasia, Impaired Immunity, Morbidity, Anemia, Poor Growth

Chronic Dietary Deficit

Figure 1 Concept of vitamin A deficiency disorders (VADD), due primarily to underlying chronic dietary deficit in preformed vitamin A and provitamin A carotenoids. From West KP Jr (2002) Extent of vitamin A deficiency among preschool children and women of reproductive age. Journal of Nutrition 132: 2857S-2866S.

and intake adequacy of breast-fed infants, stable isotopic dilution to assess the total body vitamin A pool, impression cytology that detects early or mild metaplasia on the bulbar conjunctiva, and clinical stages of xerophthalmia.

Xerophthalmia

Conjunctival and corneal epithelium deprived of vitamin A undergoes keratinizing metaplasia. Columnar epithelial cells become squamous and mucus-producing goblet cells disappear, providing the histopathologic mechanisms for deficiency-induced xerotic (drying) changes to the ocular surfaces. VA deficiency is also required for rod vision in dim light. VA deficiency-induced night blindness often occurs with histopathologic changes on the ocular surface. Thus, night blindness and clinical eye signs are both listed under one xerophthalmia classification scheme (Table 1).

Night blindness Vitamin A, as retinaldehyde, is an essential cofactor in the generation of rhodopsin. This is a photosensitive pigment in rod photorecep-tors of the retina that responds to light (it is 'bleached') by releasing vitamin A and initiating neural impulses to the brain that permit vision under conditions of low illumination. The utilization and recycling of vitamin A in this process is known as the 'visual cycle.' Hypovitaminosis A restricts rhodopsin production, which in turn raises the scotopic (low light) visual threshold. Gradually, a

Table 1 WHO and IVACG classification and minimum prevalence criteria for xerophthalmia and vitamin A deficiency as a public health problem

Definition (code)

Children 1-5 years of age

Night blindness (XN) Conjunctival xerosis (XIA) Bitot's spots (X1B) Cornea xerosis (X2)/corneal ulceration (X3A)/keratomalacia (X3B)

Xerophthalmic corneal scar (XS) Deficient serum retinol

(<0.70 mmol/l) Pregnant/lactating women

Night blindness (XN) during most recent pregnancy Low serum retinol (<1.05 mmol/l)

Minimum Highest risk prevalence period (%)

0.01 1-3 years

1-5 years

5.0 3rd trimester

20.0

Adapted from Sommer A and Davidson FR (2002) Assessment and control of vitamin A deficiency: The Annecy Accords. Journal of Nutrition. 132: 28455-28505.

perceptive threshold is reached that leads to recognition of night blindness (XN), the earliest symptom of xerophthalmia. It is marked by an inability to move about in the dark. Children between 1 and 5 years of age and pregnant women appear to be at greatest risk of XN. Where endemic, there is often a local term for XN that translates into 'evening' or 'twilight' blindness or 'chicken eyes' (lacking rod cells, chickens cannot see at night), making the condition readily detectable by history. Typically, gesta-tional night blindness resolves spontaneously with child birth and expulsion of the placenta, likely relieving maternal metabolic demands for vitamin A.

Conjunctival xerosis and Bitot's spots Early xerosis of the conjunctiva can be detected subclini-cally by filter paper impression cytology, showing distorted, enlarged, and noncontiguous sheaths of epithelial cells and the disappearance of goblet cells. In advanced vitamin A deficiency, xerosis appears clinically as a dry, unwetable surface of the bulbar conjunctiva (X1A). The affected areas are usually overlaid with superficial white, cheesy, or foamy patches of triangular or oval shape that consist of desquamated keratin and bacteria (often the xerosis bacillus). These are known as Bitot's spots (X1B). They are nearly always bilateral, found temporal (and, in more advanced cases, also nasal) to the corneal limbus, and more reliably diagnosed than X1A. Bitot's spots are not blinding but are reflective of chronic moderate to severe systemic depletion of vitamin A.

Corneal xerophthalmia Corneal xerophthalmia is manifested in increasingly severe stages. The earliest corneal lesions appear as superficial punctate defects, evident with a slit lamp, that with advanced deficiency become more numerous and concentrated. The cornea is considered xerotic (X2) when punctate keratopathy covers large areas of the surface, rendering a hazy, nonwetable, lusterless, and irregular appearance on handlight examination. Stromal edema may be present. In more severe cases, thick, elevated xerotic plaques may form. Usually, both eyes are affected. Corneal ulcers (X3A) can be sharply demarcated, round or oval defects that are usually shallow but may also perforate the cornea. Healed ulcers form a leukoma (scar) or adherent leukoma if the iris has plugged the perforated ulcer. Most ulcers occur peripheral to the visual axis and thus may not threaten central vision if treated promptly. Keratoma-lacia (X3B) refers to a full-thickness softening and necrosis of the corneal stroma that can cause protruding, opaque, yellow to gray lesions to form (Figure 2). These tend to collapse or slough off, leaving a

Corneal Scar Detetction
Figure 2 Keratomalacia. From Sommer A (1995) Vitamin A deficiency and its consequences. A Field Guild to detection and control. 3rd ed. Geneva, WHO.

descemetocele following VA treatment. Keratomala-cia usually impairs vision in the involved eye, although the degree of visual loss depends on the location, thickness, and extent of corneal necrosis and resultant scar. Due to the generally malnourished and ill state of children with corneal xerophthalmia, the mortality rate of hospitalized cases is 4-25%.

Other VADD

Infection A bidirectional relationship exists between hypovitaminosis A and infection, each exacerbating the other, representing a classic 'vicious cycle.' Thus, infection may be considered both a cause of VA deficiency and, in terms of severity and sequellae, a 'disorder' as well. Cross-sectionally, xerophthalmia or severe hyporetinolemia has been consistently associated with higher frequencies of diarrhea, fever, and other infections, although directionality is difficult to parse from such evidence.

VA deficiency raises the risk of infection presumably due to compromised 'barrier' epithelial function and impaired innate, cell-mediated, and humoral immune mechanisms. VA-deficient Southeast Asian preschoolers (i.e., with mild xerophthalmia) were twice as likely to develop acute respiratory infection and (in Indonesia) three times more likely to develop diarrhea over subsequent 3- to 6-month periods. Deficient children are also more likely to die. This was so among Indonesian preschool children, whose risk of mortality increased with increased severity of mild eye signs (Figure 3). In Nepal, siblings of patients were more likely to develop the eye lesions but were also at a twofold higher risk of dying than children living in unaffected households, reflecting a clustering of child mortality risk within VA-deficient households.

Data from children and animals support the plausibility of these findings. VA-deficient children show increased bacterial adherence to respiratory epithelium, low lymphocyte counts and T helper to cytotoxic/suppressor cell ratios, and a weaker delayed-type hypersensitivity response compared to nonxerophthalmic children. In animals, VA deficiency produces keratinizing metaplasia of epithelial linings that may affect 'barrier' defenses. It also compromises acquired immunity, indicated by lymphoid atrophy, reduced numbers of circulating lymphocytes, impaired blast transformation responses to antigen, T cell-dependent antibody responses, and natural killer cell activity, and a greatly increased risk of infection and death.

Anemia and Poor Growth Children with xe-rophthalmia and night blind mothers tend to be anemic relative to peers without eye disease. VA-supplemented trials often show improvement in indicators of iron status, including reductions in anemia. Mechanisms involved in this interaction are not clear but may involve enhanced iron absorption, storage,

Normal

XN XIB

Ocular status

Figure 3 Risk of mortality among ~3500 Indonesian preschool children by ocular status at the outset of each 3-month interval. RR, relative risk of mortality. Adapted from Sommer A et al. (1983) Increased mortality in children with mild vitamin A deficiency. Lancet 2: 585-588.

Normal

XN XIB

Ocular status

Figure 3 Risk of mortality among ~3500 Indonesian preschool children by ocular status at the outset of each 3-month interval. RR, relative risk of mortality. Adapted from Sommer A et al. (1983) Increased mortality in children with mild vitamin A deficiency. Lancet 2: 585-588.

and transport as well as direct effects on hematopoi-esis in the presence of adequate iron stores.

VA deficiency decelerates growth in animals and has been associated with both stunting and wasting malnutrition in children, possibly reflecting roles for the vitamin in osteogenesis and protein metabolism. Trials, however, have shown inconsistent effects of VA supplementation on child growth, possibly due to variations in the extent of infection, season-ality in dietary protein and energy adequacy, exclusion criteria, and levels of VA status among study children. It appears that VA supplementation can influence ponderal and linear growth, as well as body composition, in children for whom VA deficiency is a 'growth limiting' nutritional deficit.

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