Ординатура / Офтальмология / Английские материалы / Handbook of Nutrition and Ophthalmology_Semba_2007

Fig. 8. Corneal xerosis. (Courtesy of Task Force Sight and Life.)

Fig. 9. Corneal xerosis with desquamated epithelium. (Courtesy of Task Force Sight and Life.)

greatest in the inferonasal part of the cornea (283). Corneal xerosis may be more apparent in the inferior portion of the cornea, and there may be underlying stromal edema that is detectable on slit lamp examination (285). In more severe disease, the cornea has a peau d’orange appearance, and there may be accumulations desquamated, cornified epithelium that may slough off or form large xerotic plaques on the cornea (285) (Fig. 9). Foreign body sensation, photophobia, and irritation have been described in patients with corneal xerosis (285).

Fig. 10. Corneal ulcer. (Courtesy of Task Force Sight and Life.)

In the vitamin A-deficient rat, keratinization occurs in the corneal epithelium with thickening of the stroma (286). The changes occur without any evidence of a preinflammatory lesion or bacterial infection (286). Pathological changes in the cornea of vitamin A-deficient mice included keratinizing epithelium with loosened outer layers and keratohyalin granules in cells of the intermediate and superficial regions, variegated, invaginated nuclei and mitochondria of the basal cells, and occasional free and phagocytized bacteria on the loosened outer layers of the keratinized epithelium (287). In vitamin A- deficient guinea pigs, punctate corneal irregularities were common, and scanning electron microscopy showed extensive areas of surface epithelial cells lifting off the cornea and large, mound-like irregular projections distributed sparsely over the plasmalemma, in comparison to primary microvilli and no evidence of plasmalemmal disruption in vitamin A-sufficient control animals (273). Studies in vitamin A-deficient rabbits showed multiple punctate epithelial erosions that progressed with a peau d’orange appearance and later with development of polycystic microbullae in the central region of the cornea with underlying stromal edema (288). In more severe deficiency, necrotizing stromal infiltrates developed beneath keratinized plaques, with eventually ulceration of the corneal stroma (288). Vitamin A deficiency also affects glycoprotein synthesis in the rat corneal epithelium (289).

4.1.5. CORNEAL ULCER

Corneal ulceration may follow corneal xerosis, and the typical corneal ulcer associated with vitamin A deficiency is round or oval with a relatively clean, punched-out appearance, as if the cornea had been altered with a small trephine (Fig. 10). With fullthickness ulceration, the iris may prolapse through the ulcer. Secondary infection may occur. In a large series of 100 patients with vitamin A deficiency and xerophthalmia in the Philippines, among those with corneal ulceration or perforation, the most common isolates were Pseudomonas aeruginosa, Streptococcus pneumoniae, and Moraxella spp.,

with P. aeruginosa cultured from 35% of cases that had a corneal perforation (290). Most of the subjects had concurrent infections such as gastroenteritis, bronchopneumonia, and upper respiratory infection, and about one-third had severe malnutrition.

Experimental animal studies show that the healing process is impaired after various traumatic injuries to the cornea in vitamin A deficiency. After epithelial abrasions of the cornea, vitamin A-deficient rats progressed to extensive epithelial defects and stromal ulceration, often with an intense inflammatory reaction and bacterial infection (291). Impaired wound healing was also observed in vitamin A-deficient rabbits (292). Recovery from thermal burns to the cornea was slower in vitamin A-deficient compared with control rats (293), and polymorphonuclear leukocytes appear to play a role in the worsening of ulcerative lesions (294). Vitamin A deficiency appears to be associated with impaired epithelial migration and impaired production of fibronectin, a glycoprotein that plays a role in adhesion, chemotaxis, and tissue repair (295). The plasminogen activatorplasmin system has been implicated in corneal ulceration (296), but lack of tissue plasminogen activator has been found in the center of induced corneal wounds in vitamin A-deficient rats (297). After mechanical abrasion of the cornea in vitamin A-deficient rats, infiltrates of polymorphonuclear leukocytes were observed, but reepithelialization occurred without severe stromal degradation (298). In contrast, stromal incision in vitamin A-deficient rats resulted in marked stromal degradation, which suggested that stromal injury was more important than polymorphonuclear leukocytes in the pathogenesis of corneal ulceration in vitamin A deficiency (298). Vitamin A-deficient rabbits in the late stages of xerophthalmia were more susceptible to experimental infection with P. aeruginosa than animals in the early stages of xerophthalmia or control animals (299). Following induced trauma, P. aeruginosa infection and ulceration were worse in vitamin A-deficient compared with control rats (300). The production of collagen in rabbit corneal keratocytes is modulated by retinoids, which suggests an additional mechanism for vitamin A in the maintenance of cornea integrity (301).

Matrix metalloproteinases, collectively known as matrixins, are proteinases that are involved in degradation of the extracellular matrix, and these include collagenases, gelatinases, stromelysins, and matrilysins (302). Corneal ulceration in vitamin A deficiency is influenced by the production of proteinases, which can be produced by the cornea (303– 308), inflammatory cells (309), and bacteria (310). The expression of different proteinases in the cornea may vary during vitamin A deficiency and might explain conditions that occur with differences in proteolysis. Under conditions of vitamin A deficiency, with decreased proteolysis, epithelial cells may not exfoliate properly, and with increased proteolysis, superficial punctate keratopathy and increased corneal keratocyte loss may occur (311). Cathepsin D, an aspartic proteinase, was increased threefold in the corneas of vitamin A-deficient rabbits compared with pair-fed control rabbits (311). The production of collagenase in the cornea is increased in vitamin A-deficient rats compared with control rats (293,305).

Retinoids modulate the expression of numerous proteins such as matrix metalloproteinases and plasminogen activator through alteration of gene transcription and through interaction of retinoic acid receptors with transcription factors such as c-Jun and c-Fos at the activator protein (AP)-1 site (312). The promoter region of the collagenase gene contains an AP-1 responsive element that is repressed by retinoic acid (313). RARs do not appear to bind directly to the AP-1 site but appear to bind with c-Jun to form an inactive

Fig. 11. Keratomalacia. (Courtesy of Task Force Sight and Life.)

complex that does not upregulate collagenase expression (313–315). Interleukin (IL)-1, a potent mediator of inflammation, shows increased activity in the cornea of vitamin A- deficient rats after mechanical injury in comparison to corneas of control rats (316). IL- 1 stimulates and retinoic acid inhibits collagenase transcription through inhibition of c-Fos (317). The combination of increased IL-1 activity and deficiency in retinoic acid may both potentially contribute to the increased expression of collagenase in corneal ulceration and keratomalacia associated with vitamin A deficiency.

4.1.6. KERATOMALACIA

Keratomalacia is characterized by melting of the cornea (Fig. 11). In the late 19th century, keratomalacia was not uncommon in Europe and was noted primarily among young infants. Albrecht von Graefe (1828–1870) noted: “although the illness concerned here is not exactly a frequent one, hardly a semester passes when I do not see an incidence of it, and at times I have seen three or four cases within a month. The general picture offered, with some variation of details, is uniform to such an extent that I always held to the idea that a constant general affection must be present in the organism” (318). Von Graefe found that the illness usually occurred within a few weeks of birth, especially among infants with pale appearance, loss of tone, poor nutrition, decline in appetite, and diarrhea (318). Von Graefe recognized that the condition began with a lesion of the bulbar conjunctiva that was “dull, dry, covered with fine scales and raised in appearance with perpendicular wrinkles” and “depleted of its natural moisture,” and that this “acute xerosis” was connected to the corneal destruction that followed. Von Graefe attributed the corneal ulceration to encephalitis, since autopsy findings had suggested brain inflammation among

infants who had died with keratomalacia. Julius Hirschberg (1843-1925), a disciple of Von Graefe, described how apparently healthy infants developed anorexia, diarrhea, marasmus, and then rapidly progressed with xerophthalmia in both eyes (319). Intestinal helminthiasis increases the risk of keratomalacia in children (320,321). Keratomalacia was described in a child with familial hypo-retinol-binding proteinemia (322) and also has been described in acrodermatitis enteropathica (323).

Keratomalacia has also been described among adults, usually in association with severe diarrheal disease (324–326), and sometimes in association with unusual dietary practices, alcoholism, and severe cachexia (see Subheading 5.3.10.). The ocular pathology of keratomalacia has been described in a few reports (327,328), including a 27-yr-old woman who followed a “cult” vegetable and grain diet, developed night blindness, keratomalacia, and died (328). Bilateral corneal melting was noted with minimal inflammatory reaction, despite a large corneal perforation. Keratomalacia has been produced in vitamin A-defi- cient animals (329). A discussion of the biological mechanisms that have been implicated in the pathogenesis of corneal ulceration and keratomalacia was discussed under Subheading 4.1.5. Secondary infection may play a role in keratomalacia (330) but does not appear to be the initiating event (331). Some investigators believe that protein malnutrition is an important contributing factor to keratomalacia because of keratomalacia is more common among individuals with protein energy malnutrition (332,333).

4.1.7. XEROPHTHALMIC FUNDUS

Xerophthalmic fundus (fundus xerophthalmicus) is a condition characterized by fine white, cream-colored, or greyish dot-like, oval, or linear opacities in the retina. It usually occurs among individuals with night blindness, conjunctival xerosis and/or Bitot spots. In 1894 in Freiburg, Karl Baas (1866–1944) described a 15-yr-old field hand with night blindness, conjunctival xerosis, and a large amount of small white dots located in the retina (334). The condition was associated with liver disease and called “ophthalmia hepatitica.” Otmar Purtscher (1852–1927) described more cases of “ophthalmia hepatitica” in Klagenfurt, Austria in 1900 (335). In 1915, Sanroku (or Saroku) Mikamo described

a12-yr-old boy from Fukuoka, Japan who had night blindness (336). The boy worked for

arice dealer and was known to have been healthy all his life. He began to bump into furniture at night and had dropped a rice bowl, and even after scolding, he continued to have difficulty making his way around when it became dark. One evening he was pouring water into a tub to take a bath, and his friends were astonished to see him pouring the water onto the ground, as he could not see well and had missed the tub completely. The following day he was taken to the eye hospital, where it was noted that he had Bitot spots and small white dots in the equatorial zone of the fundus of both eyes. The fundus findings were depicted (Fig. 12) (336). The patient was noted to have a narrowed visual field, and laboratory investigations revealed that the boy had hookworm infection. During treatment with cod-liver oil, the night blindness and Bitot spots disappeared after a few days, but it took several weeks for all the white dots in the fundus to disappear (336).

In 1922, Robert E. Wright described “a mid-peripheral belt of discreet white spots” in the fundus of patients with night blindness and keratomalacia in Madras, India (337). Misao Uyemura reported two cases of xerophthalmic fundus in 1928 seen at the eye clinic of Keio University in Tokyo (338), and the condition became known later as Uyemura’s syndrome (339). Adalbert Fuchs (1887–1973) described another case while he was a

Fig. 12. Fundus xerophthalmicus. (From ref. 336.)

visiting professor at Peking Union Medical College (340), and additional cases were described in Japan (339,341,342), China (343,344), Italy (345,346), and Germany (347). The retinal lesions are located most commonly in the peripheral retina and are usually found in both eyes. As noted by Teng Khoen Hing: “It is striking that in the flourishing cases, where it looks as if they have been scattered lavishly over the surface of the fundus, the granules are glaringly white like sugared caraway seeds. In these cases, we see many ‘sugared caraway seeds’ grow together to ramify like a clover-leaf, or we see them in a row along the vessels, so that the vessels look as if they get a shell in their course in some places” (348). The whitish lesions are located deeper in the retina than the retinal blood vessels. In 1933, Yatsutake described bilateral visual field constriction in a patient with xerophthalmic fundus (342).

Although xerophthalmic fundus is often described as a rare condition, most individuals who are encountered in the field with Bitot spots and/or night blindness do not generally receive a dilated fundus examination and the condition may be overlooked. In the largest published cases series, Teng Khoen Hing examined hundreds of outpatients seen at the Cicendo Eye Hospital in Bandung, Indonesia who had xerophthalmia in a period from about 1956 to 1961 (349). Of 190 subjects with night blindness, 23.7% had xerophthalmic fundus, and of 600 subjects with conjunctival xerosis, Bitot spots, corneal xerosis, or keratomalacia, 35% had xerophthalmic fundus. The highest prevalence of xerophthalmic fundus was found among children aged 5–14 yr. Of 321 cases of xerophthalmic fundus that were reported, 93% had night blindness, conjunctival xerosis, or both (349, 350). An additional case of xerophthalmic fundus was described from Cicendo Eye Hospital in 1978 (351). The severity of xerophthalmic fundus appears to correlate with more longstanding vitamin A deficiency and lower serum vitamin A concentrations (352,353). The highest risk group for xerophthalmic fundus appears to be those in the age group from 5 to 14 yr (350). Xerophthalmic fundus can usually be differentiated from other fundus conditions with white dots, such as retinitis punctata albescens and fundus albipunctatus,

Fig. 13. Rat model, changes in outer segments after vitamin A-deficient diet for 23 wk. (Reprinted from ref. 360, with permission of Investigative Ophthalmology and Visual Science.)

because xerophthalmic fundus is often associated with other signs of vitamin A deficiency (conjunctival xerosis, Bitot spots, corneal xerosis, and so on), and the white lesions resolve after treatment with vitamin A (350).

Vitamin A deficiency has been shown to induce histopathological changes in the rod photoreceptors of the retina in experimental animal models (354–360). These changes consist of degeneration of rod outer segments, the external limiting membrane, the retinal pigment epithelium, the outer molecular layer and the inner nuclear layer (356,357). The pathological changes in rod outer segments with prolonged vitamin A deficiency in the rat model includes distention or dispersion of disc into vesicles, and the appearance of vesicles in the pigment epithelium and between processes of the pigment epithelium (Fig. 13). In contrast, normal rod outer segments show regular organization of outer

Fig. 14. Corneal scar. (Courtesy of Task Force Sight and Life.)

segment discs and close contact with processes of the pigment epithelium (360). Autoradiographic studies show that the rate of rod outer segment renewal and removal is impaired by vitamin A deficiency (361). Vitamin A-deficient rats with degeneration of the rod photoreceptors may recover to almost normal appearance after refeeding with vitamin A over 10 to 18 wk (357). Refeeding of deficient animals is associated with an increase in rod outer-segment density (362).

Xerophthalmic fundus has been described in a 20-yr-old man who stopped consuming food sources of vitamin A for about 5.5 yr because he thought it would reduce his epileptic seizures (363,364). His serum retinol concentrations were as low as 0.14 μmol/L when he was seen as an outpatient (363). The patient refused any treatment with vitamin A and later developed bilateral corneal xerosis. He was eventually admitted on an emergency basis to the hospital with fever, anorexia, abdominal pain, and corneal ulceration. After treatment with daily vitamin A therapy for 3 mo, the yellowish dots in the fundus decreased in size and disappeared (365). A hereditary defect in the gene for serum RBP, a heterozygous missense mutation Ile41Asn and Gly75Asp, is associated with xerophthalmic fundus (366). Fundus examination of two siblings with the condition showed small dots representing focal loss of retinal pigment epithelium (366). The white dots characteristic of xerophthalmic fundus appear as window defects in the retinal pigment epithelium in fluorescein angiograms (351).

4.1.8. CORNEAL SCAR

The sequelae to corneal ulcer and keratomalacia include the formation of a corneal scar or leucoma (Fig. 14). Corneal scarring can arise from causes other than vitamin A deficiency, such as following trauma and infectious keratitis unrelated to vitamin A, thus, the interpretation of corneal scarring must be made with caution in surveys. The corneal scarring that occurs with measles and vitamin A deficiency cannot be distinguished from corneal scarring from vitamin A deficiency without measles. Many surveys of the causes

of blindness in schools for the blind may simply classify the corneal scarring as due to “vitamin A deficiency/measles.” The prevalence of vitamin A deficiency as ascertained by institutional surveys should be considered extremely conservative estimates, since corneal ulceration and keratomalacia are associated with high mortality rates. In Hyderabad, India, a longitudinal study of 32 children who had been hospitalized for keratomalacia revealed that nearly one-third died within 3 to 4 mo after discharge from the hospital (367).

4.1.9. OTHER

Widely dilated pupils have been described since at least the seventeenth century among individuals with night blindness, and often the pupils constrict weakly or not at all when a light source such as candlelight is used to illuminate the eyes. Pupillary dilation has formed the basis for a test of vitamin A deficiency (see Subheading 6.2.6.).

4.2. Immune Suppression and Inflammation

Vitamin A modulates many different aspects of immune function, both nonspecific (innate) immunity (i.e., maintenance of mucosal surfaces, natural killer (NK) cell activity, and phagocytosis) and specific (adaptive) immunity (i.e., generation of antibody responses). Some aspects of immunity are not affected by vitamin A deficiency. Much of our knowledge of vitamin A and immune function is based on experimental animal studies involving mice, rats, and chickens, and from in vitro studies involving modulation of specific cell lines with retinoids. The effects of vitamin A deficiency on immune function are summarized in Table 4.

4.2.1. MUCOSAL IMMUNITY

The mucosal surfaces of the body include the respiratory, gastrointestinal, and genitourinary tracts as well as the cornea and conjunctiva. There are at least seven known mechanisms by which vitamin A deficiency impairs mucosal immunity: (1) loss of cilia in the

respiratory tract, (2) loss of microvilli in the gastointestinal tract, (3) loss of mucin and goblet cells in the respiratory, gastrointestinal, and genitourinary tracts, (4) squamous metaplasia with abnormal keratinization in the respiratory tract, (5) alterations in anti- gen-specific secretory immunoglobulin (Ig)A concentrations, (6) impairment of alveolar monocyte/macrophage function, and (7) decreased integrity of the gut. In early studies of vitamin A deficiency in autopsy studies of humans and experimental animals, the findings included widespread pathological alterations in the respiratory, gastrointestinal, and genitourinary tracts (87,368,369). During vitamin A deficiency, there is loss of mucin and goblet cells from the conjunctiva and squamous metaplasia of the conjunctiva and cornea (285,370) and impaired wound healing (298). Vitamin A is involved in the expression of both mucins (248,371) and keratins (249,372,373). Lactoferrin, an iron-binding glycoprotein involved in immunity to bacteria, viruses, and fungi, appears to be modulated in the tear film of children by vitamin A supplementation (374). Loss of mucin and alterations in keratins in vitamin A deficiency may increase susceptibility to experimental ocular infection with pathogens such as Herpes simplex virus (375) and Pseudomonas (299,300). Other corneal alterations in experimental vitamin A deficiency include structural abnormalities of the epithelial basement membrane complex (376).

In the respiratory tract, pathogens are constantly trapped and removed by the mucociliary elevator in the normal tracheobronchial tree. Vitamin A-deficient animals show loss of ciliated epithelial cells and mucus and replacement by stratified, keratinized epithelium (377–379). The terminal differentiation of keratins is modulated by vitamin A (380,381) and mucin gene expression is regulated by all-trans retinoic acid (382,383). Such broad pathological changes in the tracheobronchial tree may be reflected in the observation that vitamin A-deficient mice are more susceptible to ozone-induced lung inflammation (384).

Vitamin A deficiency is associated with morphological and function alterations in the gut that may predispose individuals to more severe diarrheal disease. Vitamin A deficiency in rats is associated with a large reduction in goblet cells in duodenal crypts (385) and impaired biliary secretion of total secretory IgA (386). Reduced villus height was observed in the jejunum of vitamin A-deficient rats that were not challenged with any gastrointestinal pathogens (387). Vitamin A-deficient mice were more susceptible to the destruction of duodenal villi following experimental challenge with rotavirus (388). The genitourinary tract is also adversely affected by vitamin A deficiency, with replacement of normal transitional epithelium with stratified squamous epithelium and expression of distinct types of keratins (389). Changes in the genitourinary epithelia may contribute to increased urinary tract infections in vitamin A-deficient children (390).

Vitamin A deficiency may affect both the concentrations of secretory IgA on mucosal surfaces and specific IgA responses in the gut. In vitamin A-deficient chickens, the concentrations of total IgA were lower in the gut than in control animals (391). Vitamin A- deficient BALB/c mice that were challenged with influenza A had a lower influenzaspecific IgA response than control mice (392). Vitamin A-deficient mice had significantly lower serum antibody responses against epizootic diarrhea of infant mice (EDIM) rotavirus infection compared with pair-fed control mice (393). An impaired ability to respond with IgA antibodies to oral cholera vaccine was demonstrated in vitamin A-deficient rats (394). Vitamin A treatment prevented the decline in IgA in the intestinal mucosa of pro- tein-malnourished mice (395). Recent studies in IL-5 receptor-knockout mice suggest