Bahan Kramer

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Chapter 62 – Nutritional Disorders

Deval R. Paranjpe,

Christopher J. Newton,

Andrew A.E. Pyott,

Colin M. Kirkness

All tissues throughout the body depend on adequate levels of nutrition, and the cornea is no

exception. Deficiency or excess of various substances can lead to altered cornealmetabolism but, with few exceptions, only one is of clinical importance. This striking

example is given by inadequate levels of vitamin A.

It is estimated that as many as 140 million children worldwide are vitamin A deficient,[1]

making it the second most prevalent nutritional disorder after protein calorie malnutrition.

Of these, 4.4 million are xerophthalmic.[2] Between 250 000 and 500 000 xerophthalmic children become blind annually, and up to half will die within 1 year of losing their vision.[1] Improving the vitamin A status of all deficient children could prevent between 1 and 3

million deaths,

[3]

with the cost of 2 days of supplementation being about 10 US cents per child.[4] If the scale of the problem is impressive, so too is the behavior of an individual

cornea, which, when faced with a sudden decompensation of vitamin A levels, can undergocomplete colliquative necrosis within a matter of hours.

While this tragedy is largely borne by the impoverished of developing countries, it is

occasionally encountered in so-called developed nations. Thus, clinical xerophthalmia has

been observed in food fadists,[5] psychiatric patients,[6–8] and alcoholics.[9],[10] Particularlyimportant is the recognition that conditions that can lead to fat malabsorption, such as

cystic fibrosis[11],[12] or surgical procedures involving jejunoileal bypass,[13] can lead to

xerophthalmia and that ocular problems can be overlooked for many years because the

diagnosis is not entertained.

[14]

Metabolism of Vitamin A

The storage capacity of the human body is greater for fat-soluble than for water-soluble

vitamins and, accordingly, under normal conditions the liver can maintain a 1 to 2 years’

supply of vitamin A. Thus, when intake exceeds 300 to 1200 µg/day of retinol or itsequivalent, stores are laid down. When intake falls below this level, liver stores are drained

to maintain serum retinol levels above 0.7 µmol/L.[15] Vitamin A is found in animal foods

and dairy products, usually esterified as retinyl palmitate. After ingestion, hydrolysisoccurs in the small intestine, producing retinol, which is then incorporated into mixed

micelles and absorbed into mucosal cells.

[16]

Carotene is a naturally occurring progenitor of vitamin A produced by plants. However, the efficiency of carotenoid conversion variesamong individuals,[17] and only 50 or 60 of the 400 known carotenoids have provitamin

activity.[18] The most important of these is beta-carotene, which is present in dark green

leafy vegetables and certain colored fruits. Carotene, when absorbed into mucosal cells, issplit into two molecules of retinaldehyde, which are then reduced to retinol. Retinol travels

to the liver largely in the re-esterified form. Retinol is a highly active, membrane-toxic

molecule. It is released from the liver in combination with a specific transport protein

belongs to: Dhia Ulhaq, young-MD 1



called apo-RBP (retinol-binding protein). The complex of apo-RBP and retinol is known as

holo-RBP16 (Fig. 62.1). Associated deficiencies of fat or protein can interfere with the

metabolism of both carotene and vitamin A. However, these deficiencies seem to play arelatively minor role compared with actual vitamin A deficiency, In areas prone to

kwashiorkor, even the small amounts of carotene in bananas and other produce can prevent

the development of xerophthalmia.[19]

Xerophthalmia is particularly prevalent in areas suchas Southeast Asia where rice is the staple food.[20] In all areas of endemic xerophthalmia,

the diet is deficient in sources of the preformed vitamin, such as milk, eggs, and meat, and

reliance is on limited amounts of the provitamin.[19]

Historical Considerations




Xerophthalmia is one of the oldest recorded medical afflictions, and both nyctalopia (night

blindness) and keratomalacia were recognized by the ancient Egyptians and Greeks.

Interestingly, their treatments for these conditions frequently involved the use of animallivers.[21] The celebrated Scottish ophthalmologist William Mackenzie was familiar with the

disease, and in 1830 he published A Practical Treatise on the Diseases of the Eye, where he

refers to ‘conjunctiva arida.’ He also elaborated on the beautifully descriptive termmyiocephalon (head of a fly) to describe the prolapse of the iris through a softened cornea.[22]

Probably the first person to produce xerophthalmia experimentally was the French

physiologist Magendie. In 1816, he fed dogs a restrictive diet of wheat gluten, starch, andolive oil, and he mentions the development of corneal ulcers.[23] Such animal experiments

have since often been repeated. Only in 1925 in the work of Wolbach and Howe, using

selectively vitamin A-deficient diets in rats, was the primacy of the vitamin's role in thedevelopment of keratomalacia established.[24] It was, however, a European epidemic of

keratomalacia and painstaking observations by the Danish physician Bloch that confirmed

the parallels in humans.

[25],[26]

Classification and Clinical Manifestations of Xerophthalmia

Vitamin A deficiency results in changes in mucosal surfaces throughout the body, and theresulting keratinizing metaplasia in the lining epithelia of the lungs and intestines is

responsible for the respiratory and gastrointestinal symptoms of severely depleted children.

It is in the eye that the classic signs of vitamin A deficiency can be readily observed.Because of the importance of being able to screen and evaluate treatment regimens in

communities at risk, considerable care has been taken to draw up a classification of the

different stages of the disease (Box 62.1).[27] This classification scheme remains the

standard for assessment of xerophthalmia to date.

Night blindness (XN)

Retinol is essential for the production by the rod photoreceptors of the visual pigment

rhodopsin. In mild cases, nyctalopia or ‘night blindness’ is apparent only after photic stress, but all patients respond rapidly to therapy with vitamin A, usually within 48 hours.[15]




Conjunctival xerosis (X1A) and Bitot's spots (X1B)

Conjunctival xerosis and Bitot's spots should be considered together. The diagnosis of

‘Bitot's spots’ is dogged with controversy. The first description was by Hubbenet (1860) [28]

but Bitot (1863)[29] made the observation of dry scaly patches on the bulb of the eye and

their association with nyctalopia and lack of ‘corneal luster.’ The observation that someBitot's spots appear in isolation (without coexisting clinical or biochemical evidence) and

fail to respond to vitamin A therapy has led some to claim that they bear no relationship tovitamin A deficiency at all.[30],[31]

Histologically, xerosis represents metaplasia of the conjunctival epithelium from its normal

columnar to a stratified squamous type. A prominent granular layer is apparent, but mostsignificant is the loss of goblet cells and the formation of a metaplastic, keratinized surface.[16] In inverse relationship with the depletion of goblet cells is an increase in the mitotic rate

of the epithelial cells, although, unlike ocular cicatricial pemphigoid where this also occurs,

there is no subepithelial scarring.[32] As an example of the extreme lengths to which the

keratinizing effect can occur, there is a documented case of a calf born to a vitamin A-deficient cow that had a thick patch of hair in the center of its cornea. [33]

Histologically, Bitot's spots are tangles of keratin admixed with saprophytic bacteria and

sometimes fungi.[16] Often Corynebacterium xerosis is present, and it is suggested that sincethis is a gas-forming organism, it is responsible for the typical ‘foamy’ appearance of other

spots.[31] The material can be easily scraped off. The base, however, remains xerotic and the

‘spot’ will recur within a few days. The deposit can be very extensive, involving the corneaas well as the conjunctiva.[19]

The real confusion regarding the significance of Bitot's spots has arisen because sometimes

they are observed in individuals who have no supportive evidence of vitamin A deficiency,nor do they always disappear with supplemental vitamin therapy. Sommer [16] has carriedout a careful investigation comparing lesions responsive and those unresponsive to retinol.

While numerically far less prevalent, nasally situated lesions are a more reliable sign of

active deficiency. They are always less prominent than temporal lesions.

A far more significant indicator is the age of the patient. Sommer found that in those under 6 years of age, 97% of lesions disappeared rapidly; xerosis resolves within 2 to 5 days, and

most spots resolve in 2 weeks. In children over 10 years of age, 60% were unresponsive.

The general principle applies that in a child under 6, especially when a history of night blindness can be established, a Bitot's spot should be regarded as evidence of vitamin A

deficiency. In older children it is evidence of past or chronic suboptimal levels of retinol.

From a practical point of view, given the tendency for clustering of vitamin A deficiency,[34] when an older child is found with Bitot's spots, it is probably the younger siblings who

are in greater need of examination and treatment.

The development and persistence of Bitot's spots are almost certainly related to exposure.[35] Although histologic evidence is widespread early in the disease, clinically obviousxerosis is seen just on the temporal conjunctiva (Fig. 62.2), then nasally, then inferiorly,




and finally superiorly. If excised, lesions do not recur, providing an adequate diet is

maintained.[36]

Fig. 62.2 Typical ‘foamy’ Bitot's spot.

In adults, the presence of thickening, wrinkling, and pigmentation of the conjunctiva can be

caused by chronic ultraviolet (UV) exposure, smoke, dust, and eye infections and shouldnot be seen as pathognomonic of vitamin A deficiency. [19] In children, however, dryness of

the conjunctiva is always significant. While it is usual for conjunctival xerosis to precedeor coexist with more severe ocular involvement, it should not be regarded as a sine quanon. Inflammation may mask (or possibly even reverse) conjunctival xerosis. In general,

however, when 180 degrees of the conjunctiva is involved, then there is either established

or incipient corneal disease.[37]

Corneal xerosis (X2)




Careful slit lamp examination may reveal superficial punctate, fluorescein-staining lesions

in eyes that otherwise have no obvious clinical evidence of conjunctival xerosis. Initially,

these lesions are seen inferonasally, but later they progress to involve the entire cornealsurface. Sometimes nonstaining, water-repellant microcysts are seen. They respond readily

to vitamin A therapy, often being replaced by fluorescein-positive punctate defects. [15] In

more established disease, it is possible to use a penlight to detect localized or generalizededema with a typical dry, ‘lackluster’ appearance (Fig. 62.3). Later, the cornea may

develop a ‘peau d’orange’ appearance from keratinization (Fig. 62.4). Sometimes,

fluorescein staining reveals pooling between plaques of keratinized epithelium, giving riseto a tree-bark appearance.[16] Accumulated keratin debris and bacteria resembling Bitot's

spots may form; these peel off with treatment, often leaving a small superficial erosion that

heals rapidly.[15] Many of the early changes of corneal xerosis resemble localized exposure

and dellen formation.[38] Vitamin A deficiency has been shown to reduce aqueous tear production.[39] Loss of mucus-producing goblet cells leads to localized drying and epithelial

loss.[40] Furthermore, vitamin A deficiency has been shown to alter both the expression of

mucin genes in rat ocular surface epithelium[41] and the balance of rat corneal matrix

metalloproteinases.

[42]




Fig. 62.3 Corneal xerosis. (A) Dry lusterless appearance of corneal xerosis (X2). (B)Appearance of cornea from Figure 62.3A after vitamin A supplementation.




Fig. 62.4 Marked keratinization of the inferior cornea.

Corneal ulceration/keratomalacia (X3A/X3B)

Uncomplicated corneal ulcers typically have very sharp margins, as if they have been cut

with a trephine. Superficial ulcers may result from the rupture of subepithelial bullae, but

their depth can vary. They tend to form in the lower half of the cornea and may be multiple.Smaller ones tend to be peripheral and, if both eyes are involved, are frequently

symmetrical.[43] Uninvolved cornea, although xerotic, is clear and lacks the gray infiltration

typical of bacterial keratitis. Superficial ulcers frequently heal with remarkably littlescarring. Deeper ulcers may perforate, often with the anterior chamber being maintained by

a plug of iris. This will obviously result in a dense peripheral leukoma. Eyes with ulcers

frequently have a hypopyon.[16] In more severe lesions there is frank necrosis or sloughingof the corneal stroma, and these deserve the term keratomalacia. The lesions may be gray

or yellow and vary in size from 2 mm to involvement of almost the entire cornea. The

lesions may appear elevated but with treatment may collapse to reveal an area of stromal

loss with sharp boundaries. Occasionally, the borders so produced are much smaller thanotherwise anticipated, which may indicate that a central area of necrosis is bounded by a

region of potential reversibility.[16] Deep stromal loss results in the production of

descemetoceles. With minimal pressure, these can rupture, resulting in loss of the ocular contents, although frequently they scar and form anterior staphylomata. Prompt treatment




when ulceration or keratomalacia involves less than one-third of the corneal surface (X3A)

often restores useful vision, since the visual axis may be uninvolved (Fig. 62.5). When

corneal involvement is more extensive (X3B) (Figs 62.6–62.9), treatment may not only prevent loss of the globe but, more importantly, may preserve useful vision in the fellow

eye as well as the life of the child.




Fig. 62.5 Corneal ulceration/keratomalacia. (A) Corneal xerosis progressing to a small

ulcer involving less than one-third of the cornea (X3A). (B) Same patient after three dosesof 200 000 IU vitamin A, 5 days later.




Fig. 62.6 Keratomalacia involving the whole corneal surface (X3B).




Fig. 62.7 Keratomalacia progressing to descemetocele formation (X3B).




Fig. 62.8 Gross pathologic specimen illustrating descemetocele complicating

keratomalacia.




Fig. 62.9 Histologic section illustrating a heavily keratinized epithelial surface in a

xerophthalmic patient.

Pathogenesis of corneal ulceration

Although the role of vitamin A deficiency in xerophthalmia is undoubted, the mechanisms

by which this occurs are not clear. Vitamin A is involved in corneal metabolism,[44] and

specific retinol-binding proteins are present in the epithelium, keratocytes, andendothelium.[45] Vitamin A is merely a necessary but not sufficient factor. Additional

components in the pathogenesis of vitamin A deficiency keratopathy are trauma and

infection. Sloughing of cornified epithelium by lid action could remove a deep epithelial plug,[43] and animal studies suggest that this might be caused by a reduction in

hemidesmosomes.[46] Inflammatory cells, particularly polymorphonuclear leukocytes

(PMNs), are visibly involved in keratomalacic corneas and release destructive proteases




such as collagenase.[47–49] Collagenase may also be released by regenerating epithelium.[50]

Elevated levels of chemoattractant factors for PMNs, such as interleukin-1, have been

identified in rat models of corneal injury in vitamin A deficiency. [50] Sommer notes therelative lack of inflammatory change in humans when compared with animal models. [43]

Furthermore, rat studies showed that despite heavy PMN infiltration provoked by corneal

abrasion, it took stromal injury to produce frank keratomalacia.[51]

However, a more recentstudy demonstrated keratomalacia after epithelial scraping alone and correlated its

development with the degree of xerosis at the time of injury.[52] In addition, clinical reports

suggest that xerophthalmic dissolution can proceed beneath an intact epithelium.[53]

Infection complicates many cases. One study suggested that nearly 90% of xerophthalmiceyes harbored either pathogenic ( Pseudomonas, Pneumococcus, Moraxella) or potentially

pathogenic (Streptococcus viridans, Staphylococcus aureus) organisms.[54] Other studies

have shown that the cultures of organisms from ulcerated and nonulcerated xerophthalmiceyes are very similar.[55] Although eyes may harbor organisms such as Pseudomonas

without corneal ulceration,[56] a breach in epithelial integrity can produce a devastating

result. Experiments with the germ-free rat in which corneal liquefaction fails to occur arguefor a central role of infection.[57] Others, particularly Sommer,[51] maintain that metabolic

derangement of the cornea caused by vitamin A deficiency can by itself lead to the rapid

colliquative process. This is supported by demonstration that prompt dosing with vitamin A

can bring about dramatic reversal in a way that is not achievable with antibiotics alone.

Interactions with Other Factors

Vitamin A deficiency rarely occurs in isolation; it usually occurs with generalized protein

energy malnutrition (PEM). Approximately 43%, or 230 million children under 5 years of

age in the developing world, have stunted growth due to PEM. [58] Due to the frequent

coexistence of these two conditions, there has been confusion as to which is the moreimportant factor in corneal disease.[55,59,60] Vitamin A deficiency and PEM are clearly

interrelated. The malabsorption that accompanies PEM may reduce retinol levels bothdirectly and by impaired conversion of beta-carotene, while reduced protein synthesis (and,

in particular, reduced synthesis of RBP) prevents release of vitamin A from the liver.[61–63]

Protein status may also in some way influence the metabolism of vitamin A at the level of

the target cell.[64] Attempts have been made to control for the influence of PEM by usingserum albumin and transferrin as indices of protein status, along with basic weight-for-

height measurements.[64] Furthermore, the observation that massive dosing with vitamin A

can sometimes promote some healing of xerophthalmic corneas even in the presence of severe PEM would argue for the primacy of vitamin A.[65],[66]

Vitamin E and zinc have also been investigated in regards to potential interactions with

vitamin A. The administration of intraperitoneal vitamin E yielded a significant protective

effect against corneal changes observed in rats fed a vitamin A deficient diet. Thesechanges specifically included decreased microvilli and clear cells in the superficial corneal

epithelium and conjunctiva, fewer secretory granules in goblet cells, and keratinization of

the corneal surface.[67] Similarly, zinc may be a factor in corneal epithelial health. A recentin vivo rat study demonstrated a synergistic interaction between zinc and vitamin A by




showing amelioration of effects caused by deficiency of one nutrient via supplementation

with the other. Effects caused by deficiency of either nutrient included changes in corneal

epithelial microvilli, conjunctival goblet cells, and keratinization.[68]

Infectious processes may interact with vitamin A in a number of ways. Vitamin A

deficiency is a well-recognized risk factor for severe measles infection associated withincreased morbidity and mortality,[69],[70] as well as an increased rate of maternal–fetal HIV

transmission.[71] Vitamin A deficiency may reduce normal cellular immunity by causing analteration in T-cell subsets and, in particular, by reducing CD4 cell numbers. This is

reversible when retinol levels are restored.[72] Fever from any cause can depress vitamin A

levels by reducing the hepatic synthesis of RBP, and prolonged anorexia may diminishabsorption.[19]

The disease most closely associated with vitamin A deficiency is rubeola (measles). [73],[74]

Corneal involvement after measles keratoconjunctivitis was a significant problem in

Europe until the mid-twentieth century.[75] However, general improvement in nutrition,

immunization, and a possible decrease in the virulence of the organism has led to only rarereports of late.[76] The same is not true in developing countries, where several studies

highlight the devastating effect of postmeasles xerophthalmia.[77–79] A mildkeratoconjunctivitis is an almost universal finding in patients with rubeola. Punctate

superficial keratopathy occurs, resulting from direct viral involvement in the cornea and

causing lacrimation and photophobia.[80],[81] This usually resolves as the skin rash fades,leaving no scarring sequelae. On occasion, areas of punctate involvement may become

confluent, leading to a central epithelial defect.[82] Generally, these heal readily, but can

become secondarily infected.

Response to early Pseudomonas infection can be compromised by vitamin A deficiency.

Vitamin A deficient corneas developed pseudomonal ulcers in the presence of normallysubthreshold bacterial loads, and demonstrated inflammatory cells with unusual

characteristics and increased concentrations of cysteine protease inhibitors. Other major alterations to the corneal response to Pseudomonas aeruginosa infection included

decreased tear film, epithelial keratinization, impaired corneal wound healing, and changes

in polymorphonuclear leukocyte function.[83]

A further infection that can affect children with measles and/or malnutrition involvesherpes simplex virus (HSV). Probably, these children are rendered more susceptible by

suppression of their cell-mediated immunity.[82],[84] Foster and Sommer found vitamin A

deficiency to be responsible for half of the measles-associated corneal ulcers, HSV for a

fifth, and PEM for about 17%.[82] The longer the duration between onset of measles and thedevelopment of the ulcer, the more likely the ulcer was hypovitaminosis-related. HSV

infection was associated with features of immunosuppression, with 50% of the ulcers being

geographic and nearly a quarter bilateral. In general, bilaterality was more suggestive of vitamin A deficiency. Figure 62.10 illustrates how the various factors mentioned can

conspire to result in keratomalacia.




Epidemiology

The vitamin A reserves of the neonate are limited,[85] and initially the child depends on

vitamin A supplied by mother's milk. Except for colostrum (which has a higher concentration), vitamin A in breast milk is equivalent to plasma levels (40 µg/100mL),

although this tends to drop with the progression of breastfeeding.[86] If the mother herself is

deficient, the situation becomes precarious; examples exist of xerophthalmic childrenwhose mother's milk contained no vitamin A at all.[87] Currently, it is estimated that 7.2

million pregnant women are vitamin A deficient, and an additional 13.5 million have

reduced vitamin A levels.[2] Annually, over six million pregnant women develop night blindness, usually during the third trimester when maternal and fetal demands are greatest.

Southeast and South Asia account for over 60% of all maternal night blindness, with three-

fourths of this number located in India.




Despite these figures and the previously mentioned decrease in breast milk vitamin A

levels over time, studies have demonstrated reduced risk of xerophthalmia resulting from

delayed weaning and prolonged breastfeeding.[88],[89] The age group most at risk of blindingcorneal disease (X2, X3) is between 6 months and 3 years of age. These children are often

severely malnourished and, as mentioned, there is frequently a precipitating illness. Both

sexes are at equal risk. Conversely, conjunctival disease (X1A, X1B) is more common inolder children (between 3 and 6 years) and reflects a chronic nutritional problem. Signs of

PEM are milder, and a precipitating illness is less likely. In males, the metabolism of

vitamin A is less efficient; night blindness and Bitot's spots are, therefore, encounteredmore frequently in boys.[15] Xerophthalmia is most frequently a problem among the poorest,

most disadvantaged groups within a society with limited access to medical services. To

assist health administrators in assessing which communities are most at risk, the World

Health Organization (WHO) has established prevalence criteria of the various stages of xerophthalmia (Table 62.1).

Table 62.1 -- Criteria for assessing the public health significance of xerophthalmia

and vitamin A deficiency, based on the prevalence among children less than 6 yearsold (1982 revision)

Criterion Minimum prevalence

Clinical

Night blindness (XN) 1%

Bitot's spots 0.5%

Corneal xerosis and/or ulceration/keratomalacia (X2 + X3A + X3B) 0.01%

Xerophthalmic-related corneal scars (XS) 0.05%

Biochemical

Serum retinol level less than 100 µg/L (0.35 µg/L) 5.0%

From Control of vitamin A deficiency and xerophthalmia. Report of a joint

WHO/USAID/UNICEF/HKI/IVACG meeting, (WHO Technical Report Series, No. 672),Geneva, 1982, World Health Organization.

Xerophthalmia can also be found among more affluent patient subsets, especially in the

developed world. Malabsorption related to gastric bypass procedures for bariatric surgery isa notable cause of iatrogenic hypovitaminosis A. Xerophthalmia, nyctalopia, and corneal

scarring have been described in the setting of inadequate vitamin A supplementation in a

post-gastric bypass patient. Psychiatrically induced severe self-imposed dietary restrictionshave been associated with keratomalacia, and bilateral corneal ulcers and melting. Chronic

alcoholics are also vulnerable to hypovitaminosis A and its ocular complications via

nutritional deficiency.

Attempts have been made to improve the detection of conjunctival xerosis using vital dyessuch as lissamine green; however, they have not been found to be particularly specific. [90]

Much more encouraging is the use of impression cytology (IC).[91–96] The technique




involves application of a strip of cellulose acetate filter paper to the ocular surface to

remove the superficial layers of the conjunctival epithelium. Active deficiency is evident

by loss of goblet cells and both enlargement and partial keratinization of epithelial cells.Abnormal cytology is a sensitive marker of early disease, and the reliability of the test has

been improved by the use of a specific ‘disk applicator.’[94] IC is a noninvasive test, which

is well tolerated, and most significantly does not require the large population samples of clinical or biochemical surveys, since 50% abnormal cytology is proposed as a marker of

significant risk.[92] A recent IC study revealed abnormal cytology results in children aged 6

months to 10 years with subclinical vitamin A deficiency based on serum retinol levels.These children were retested after supplementary vitamin A and reversal of the

abnormalities was seen.[97] Results should be interpreted carefully, since the specificity will

be compromised by coexisting conjunctival disease such as trachoma.[91] The presence of

PMNs in a sample is more likely to lead to its being read as abnormal. Presumably, thePMNs and accompanying mucin tend to lie as a surface layer, which is lifted by the

cellulose paper, leaving the epithelium behind.[94]

Treatment

The diagnosis of xerophthalmia constitutes a medical emergency, and prompt treatmentwith massive supplementation of vitamin A is required. World Health Organization

standard doses vary with the age of the patient. In children over 12 months of age and in all

women of childbearing age with severe xerophthalmia, this should be given orally, either as 110 mg of retinol palmitate or as 66 mg retinol acetate (200 000 IU vitamin A)

immediately and again the following day. An additional dose should be given 2 weeks later

to boost liver reserves. Oil-miscible injections should not be given because they are poorly

absorbed, but if parenteral replacement is essential, 55 mg of water-miscible retinol palmitate (100 000 IU) can replace the first oral dose.[15] Parenteral administration is

indicated in children with severe anorexia, edematous malnutrition, septic shock, or inability to take oral supplementation. For children aged 6 to 12 months, half dosage isappropriate, while for children less than 6 months of age quarter dosage is recommended.

While this regimen can result in swift corneal healing, protein-deficient children do not

handle massive vitamin A dosages adequately, and holo-RBP levels may decline rapidlywith return of corneal lesions within 1 to 3 weeks.[98] This is especially likely to occur if

only a single dose is given, rather than two doses. It is apparent, therefore, that adequate

treatment includes correction of PEM. Until this has been achieved, vitamin Asupplementation should continue every 1 or 2 weeks.[98] Women of reproductive age with

night blindness or Bitot's spots should receive 5000–10 000 IU daily for 4 weeks, not

exceeding 10 000 IU daily. A weekly dose of 25 000 IU is acceptable. Figure 62.3A,B

illustrates the dramatic response of xerophthalmia to vitamin A therapy.

Some studies suggest a link between vitamin A supplementation and an increased

prevalence of acute lower respiratory tract infections.[99],[100] Several animal studies have

suggested that vitamin A excess can have an immunosuppressive effect. [101],[102] Vitamin A

overdosage can be toxic,[18] and 4% of patients developed transient diarrhea and vomitingon a 300 000 IU dosing regimen.[103] This discouraged community support, so the lower

dose of 200 000 IU is recommended. These factors are important because our concern is




not only to treat individuals but also whole communities that are at risk. Children at highest

risk should receive repeated dosing at 4–6-month intervals. Studies suggest that priming

doses 1 week before the full dose can extend the protection conferred by suchsupplementation.[104] Vitamin E deficiency can impair the absorption and storage of vitamin

A,[19] and combined supplementation with vitamin E may have the additional benefit of

reducing the toxicity of hypervitaminosis A.[105]

To avoid the risk of teratogenesis,[18]

supplementation should be avoided in pregnancy but should be given to the mother at

childbirth (400 000 IU) to augment milk vitamin A levels.

Vitamin A supplementation programs have been undertaken in numerous developing

nations and have been shown to be effective in reducing the incidence of xerophthalmia.Vehicles for supplementation include capsules given out during national immunization

days, fortified beverages, as well as other food products. [106],[107]

Such supplementation regimens usually form part of a general mother and child health

program and are short-term solutions to the problems of vitamin A deficiency and

xerophthalmia. Certain risk factors can be removed by measures such as measlesimmunization and the prevention of diarrhea. Undoubtedly, the most effective measure is

education about adequate nutrition and the benefits of foods rich in vitamin A andcarotenoids. While vitamin A capsules are inexpensive, distribution systems may be

suboptimal; dietary vitamin A has been shown superior to supplementation programs in

reducing rates of xerophthalmia.[108]

Topical retinoic acid is of benefit in the treatment of xerophthalmic animals, [109],[110] andlimited trials in humans have suggested that it might induce more rapid healing. In vivo

rabbit studies have suggested that topical application of a 0.05% all-trans retinoic acid

emulsion shortens healing time after corneal abrasion.[111] The role of retinoic acid in

corneal wound healing is likely complex. Retinoic acid has been shown to inhibitcollagenase.[112] In vitro studies have demonstrated that retinoic acid is instrumental in

stimulating the normal differentiation of limbal stem cells and also inhibits abnormalterminal differentiation.[113]

Fibronectin has been found to aid in corneal epithelial wound healing in vitamin A

deficient rats when applied topically.[114] No human studies using only fibronectin in this

situation have been reported to date.

Surgery has only a limited role in the management of xerophthalmia and none at all whencomplete corneal necrosis is present. Ben-Sira et al. reported the successful use of

‘covering grafts’ in restoring anterior chambers.[115] However, Sommer [16] questions

whether this represents a great advance, as medical therapy often results in a similar reformed anterior chamber, albeit with a corneal defect plugged by iris. Singh and Malik [116]

claim restoration of useful vision by penetrating keratoplasty, but no mention is made of

the follow-up period. Of necessity, the trephines were large, which even in lesscompromised situations carries with it the risk of postoperative problems. In a 2003 study

involving 29 young children, Vajpayee et al. agree with the conclusion that keratoplasty for

keratomalacia is associated with poor visual outcome even in the unlikely instance when




the graft survives.[117] Amniotic membrane transplantation for corneal perforation in

xerophthalmia has been described as a reasonable option in conjunction with oral vitamin

A supplementation as an alternative to primary corneal grafting.[118]

Vitamin A DeficiencyVitamin A is a fat-soluble vitamin essential in the photoreceptor visual pigment rhodopsin,as well as in the differentiation of basal cells into mucous epithelium, which includes

the conjunctiva. It is absorbed by the small intestine, transported to the liver, where it is

stored, then redistributed to target organs, including the RPE. Malnutrition, malabsorption,

liver disease, and zinc deficiency (zinc is a cofactor in the conversion of retinol to

I I -cis-retinal) contribute to vitamin A defiCiency. Manifestations of deficiency include

xerosis, conjunctival Bitot spots, keratomalacia, nyctalopia, peripheral visual field loss,

and sometimes central visual loss. Ancillary test ing reveals marked rod dysfunction (on

ERG) and elevated thresholds of rods and cones (on dark adaptation). Patients often show

dramatic recovery with treatment, which includes vitamin A supplementation and treatment

of any underlying systemic disorder.

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