Ocular Pathologic Features of Arteriohepatic Dysplasia (Alagille's Syndrome) Bruce 1. Johnson, M.D. Arteriohepatic dysplasia (Alagille's syndrome), an autosomal dominant condition involving jaundice caused by a developmental scarcity of intrahepatic bile ducts, has characteristic cardiovascular, skeletal, facial, and ocular features that distinguish it from extrahepatic biliary atresia and an array of other neonatal intrahepatic cholestatic disorders. Two children who died of this syndrome had prominent Schwalbe's rings with attached iris strands characteristic ofAxenfeld's syndrome. Additional histologic findings of iris atrophy and stromal nodules, however, made the designation Axenfeld-Reiger's syndrome more appropriate. Pigmentary retinopathy, degeneration of Bruch's membrane, and prominent lipofuscin deposition in the ciliary muscle noted in one of the patients were not regarded as primary changes of Alagille's syndrome, but were believed to be secondary to acquired deficiency of the fat-soluble vitamins A and E. Early recognition of the ocular changes in arteriohepatic dysplasia is helpful in establishing the proper diagnosis to avoid unnecessary abdominal surgery and institute vitamin therapy. IN 1973, WATSON AND MILLER! reported the association of congenital cholestasis with nearly absent development of interlobular intrahepatic bile ducts and familial pulmonary artery stenosis. Alagille and associates- in 1975 emphasized the association of intrahepatic ductal hypoplasia with other systemic findings, which
Published in honor of Lorenz E. Zimmerman, M.D. From the Department of Pathology, University of Pittsburgh School of Medicine, and the Eye Pathology Laboratory, Eye and Ear Hospital of Pittsburgh, Pittsburgh, Pennsylvania. This study was supported in part by the Pathology Education and Research Foundation, Department of Pathology, University of Pittsburgh School of Medicine. Reprint requests to Bruce L. Johnson, M.D., Eye and Ear Institute, 203 Lothrop St., Pittsburgh, PA 15213.
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included deep set eyes, hypertelorism and pointed chin, vertebral (butterfly) malformations, and retarded physical, mental, and sexual development. Ophthalmic findings helped to establish the proper category of cholestasis.t" The most frequently documented clinical change is posterior embryotoxon in which a thickened axially displaced Schwalbe's ring is visible in the peripheral cornea. Frequently, strands of peripheral iris tissue extend to it, and then the term Axenfelds syndrome is applicable. In one series," posterior embryotoxon was noted in 55 of 62 patients (89%) with Alagille's syndrome compared with an estimated 8% to 15% in the normal population. Retinal pigmentary abnormalities are a second frequent finding. The light and electron microscopic findings of the ocular changes in two patients who had this disorder are reported.
Case Reports Case 1 A 6-year-old boy was noted at 3 days of age to have jaundice and a cardiac murmur consistent with pulmonic stenosis. At 3 weeks of age, an intraoperative cholangiogram showed only a few intrahepatic bile ducts, and no extrahepatic bile duct was visualized at the time of laparotomy. A cholecystoportohepatostomy (modified Kasal operation)" was performed. Jaundice was persistent, and between 4 and 5 years of age, hospitalizations were necessary for bowel obstruction secondary to peritoneal adhesions, anasarca, and streptococcal sepsis. The patient's health declined, and jaundice, ascites, and respiratory distress persisted. Cardiac catheterization showed increased right ventricular pressure with severe pulmonic valvular stenosis and pulmonary artery branch stenosis. A percutaneous balloon valvuloplasty was performed with some improvement of the respiratory symptoms. Pertinent laboratory values obtained at the time of examination for possible
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liver transplantation were as follows: total bilirubin, 26.4 mgl dl with a direct bilirubin of 17.6 mgl dl; alkaline phosphatase, 564 U I dl; serum glutamic oxaloacetic transaminase, 373 U Iml; serum glutamic pyruvic transaminase, 190 U/ ml; total protein, 8.0 g/dl; albumin, 3.8 g/dl; cholesterol, 372 mg Zdl: and triglycerides. 193 mgydl, Serum vitamin E was 0.7 IJ.g/ml (normal, 5 to 10 IJ.g/ml) and vitamin D was less than 2 ng/ml (normal, 10 to 55 ng Zml). Lack of fusion of the anterior arches of several thoracic vertebrae (butterfly deformity) was noted radiologically. The patient had the dysmorphic facies (deep set eyes, hypertelorism, straight nose, small pointed chin) seen frequently in cases of Alagille's syndrome. Ophthalmic examination was limited because the patient was not cooperative. There was prominent conjunctival icterus. The corneas were of normal dimension and had small concentric white rings slightly internal to the corneoscleral limbus, consistent with posterior embryotoxon. No iris or lens changes were noted. Gonioscopic and adequate ophthalmoscopic examinations could not be performed. The posterior pole and optic disks were, however, visualized briefly and no pigmentary changes or glaucomatous cupping were seen. At 6 years of age, the patient underwent hepatic allograft transplantation. Twelve hours later, he developed sudden ventricular tachycardia and hypotension, which did not respond to therapy, and he died. His liver, removed at the time of orthotopic hepatic transplantation, showed atresia of the hepatic duct with a paucity of intrahepatic bile ducts. Autopsy findings of note were pulmonic valvular stenosis, hypoplasia of the left pulmonary artery, and right ventricular hypertrophy. There was pronounced lipofuscin deposition in lymph nodes, spleen, and smooth muscles of the esophagus, gastrointestinal tract, and urinary bladder, which were related to the severe, chronic vitamin E deficiency. Lipofuscin deposition associated with advanced neuroaxonal dystrophy in the gracile and cuneate nuclei was also noted. There were xanthomas of the spinal cord dura mater and arteriosclerosis of the thoracic aorta and main pulmonary artery. Severe growth retardation was noted. Both eyes obtained at autopsy were similar, and pertinent macroscopic findings were limited to the anterior segment and retina. The cornea showed a prominent, centrally displaced Schwalbe's ring. Fine, filmy strands extended to it from the iris root. Tiny gray nodules
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were seen on the anterior surface of the iris. Extensive retinal pigmentary change was noted. This consisted of a broad circumferential zone extending from the ora to the central retina of fine, star-shaped and dendritic, hyperpigmented, black, intraretinal deposits with circular, lobulated, and often confluent, lightly depigmented underlying lesions at the level of the retinal pigment epithelium (Fig. 1). The posterior limits of the pigmentary change lay approximately 4 mm posterior to the equator, had a fairly distinct demarcation line, and spared the central retina. The choroid was thin and grossly unremarkable. The disk and optic nerve were normal. Histologically, the cornea had an enlarged and centrally displaced Schwalbe's line with attached iris strands. Temporally, the chamber angle was closed by short anterior synechiae. There was prominent thinning of the iris root stroma. Near the pupil, aggregates of small, nonpigmented cells were noted, which had poorly defined cytoplasmic borders and small, uniform, round nuclei (Fig. 2). The ciliary muscle contained numerous periodic acid-Schiff stain-positive, finely granular, and coarsely clumped deposits. There was prominent alteration of the outer layers of the sensory retina and retinal pigment epithelium, which extended from the ora serrata to well behind the equator (Fig. 3). The outer plexiform layer was inapparent, and the outer nuclear layer was reduced to
Fig. 1 (Johnson). Case 1. Gross photograph of the opened right eye showing the retinal pigmentary change that extends from near the ora to the central retina (XS).
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Fig. 2 (Johnson). Case 1. Nodule on anterior iris surface composed of closely packed, small, uniform, round, and spindle-shaped cells (hematoxylin and eosin, x 500).
Throughout this zone, there was extensive atrophy and focal hyperplasia of the retinal pigment epithelium. Some remaining pigment epithelial cells contained decreased amounts of melanin, whereas others were distended with
one layer in thickness. Melanin pigment deposits were numerous within the inner nuclear layer with fewer granules seen in the nerve fiber layer. The inner and outer segments of the photoreceptors were disrupted extensively.
Fig. 3 (Johnson). Case 1. The retina shows degeneration of the photoreceptors, pronounced atrophy of the outer nuclear layer, and dispersed melanin pigment at all levels. Most retinal pigment epithelial cells (open arrowheads) appear distended and contain decreased amounts of melanin (I-um plastic, toluidine blue, x 450).
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Fig. 4 (Johnson). Case 1. Electron micrograph of retinal pigment epithelial cell shows numerous lipofuscin granules (open arrowheads) of moderate density and only a few dense melanin granules. Clumped electrondense material (arrow) is present between the plasmalemma of the retinal pigment epithelium and its basement membrane. Vesicular bodies and crystalline material are present in the inner collagenous portion (B) of Bruch's membrane (X 4,300).
PAS-positive granular material. Bruch's membrane appeared unremarkable. The choroid and sclera were normal. There was mild disk edema; the optic nerve was unremarkable. Ultrastructurally, the retinal pigment epithelial cells of the involved peripheral and equatorial zone contained large numbers of lipofuscin granules within their cytoplasm (Fig. 4). These far outnumbered the more dense melanin granules, which were confined to the apical portions of the cell. In many, only few peripherally displaced melanin granules were noted with a lipofuscin:melanin ratio of approximately 4: 1. Compound melanin and lipofuscin bodies were also common. Lamellar structures and residual bodies that represented engulfed outer segment photoreceptor material were noted. Autolytic change within the sensory retina precluded satisfactory interpretation. Abundant finely fibrillar structures that contained clumped electron-dense material were interposed between
the retinal pigment epithelium plasmalemma and its basement membrane. Numerous vesicular bodies, as well as fibrillar and dense crystalline material, was deposited in the widened inner collagenous portion of Bruch's membrane. The elastica was thickened. Few vesicular bodies were scattered throughout the outer collagenous portion. The ciliary body disclosed numerous rounded and irregularly shaped homogenous or finely granular lipofuscin deposits of a slight to moderate density, which distended the cytoplasm of many smooth muscle cells and occasionally indented their nuclei (Fig. 5). Case 2 A 4Y2-month-old girl was a full-term delivery by cesarean section for breech presentation. At 12 hours of life, the patient was noted to be jaundiced and had hepatomegaly, cyanosis, and persistent vomiting. Total bilirubin level
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Fig. 5 (Johnson). Case 1. Electron micrograph of ciliary body shows smooth muscle cell that contains numerous cytoplasmic lipofuscin deposits that indent its nucleus (x 12,100).
was 14.4 mgjdl with a direct bilirubin level of 3 mgjdl. By 3 weeks of age the jaundice had decreased, but six weeks later recurrent jaundice was noted. The results of a physical examination at that time disclosed dysmorphic facies and posterior embryotoxon. A butterfly deformity of the thoracic vertebrae was apparent on radiologic examination. The results of an exploratory laparotomy with cholangiogram and liver biopsy showed hypoplastic intrahepatic bile ducts. Two months later, the patient was again hospitalized because of repeated apneic episodes and irregular respirations. Prothrombin and partial thromboplastin times were more than 120 seconds. A computed tomographic scan showed a large, right, cerebral hemispheric hemorrhage with edema and subfalcial herniation. The patient was determined to be brain dead and life support was discontinued. At autopsy, pertinent systemic findings included jaundice with intrahepatic and extrahepatic bile duct hypoplasia. There was right ventricular cardiac hypertrophy with peripher-
al pulmonary artery stenosis. Butterfly thoracic vertebrae were noted. The kidneys had medullary cysts. The lungs showed pulmonary edema and mild interstitial pneumonitis. Death resulted from massive intracerebral hemorrhage with cerebellar tonsillar herniation. Similar findings were noted in both eyes obtained at autopsy. The sclera was icteric. The cornea showed a prominent centrally displaced Schwalbe's line. The anterior chamber angle appeared to be open. A few iris strands extended across the angle. The lens and vitreous were unremarkable. The retina had a prominent peripheral Lange fold. No retinal pigmentary changes were seen in the artifactually opacified retina. Numerous bright red, flat and slightly raised, generally round hemorrhages were noted within and on the peripapillary retina. The optic disk margin appeared slightly elevated, and a small physiologic cup remained. Bright red hemorrhage was noted in the attached optic nerve meninges, especially in the subarachnoid space. Histologically, the pertinent findings were
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Fig. 6 (Johnson). Case 2. There is an enlarged centrally displaced Schwalbe's line. Marked thinning of the iris root stroma is present (hematoxylin and eosin, x 80).
limited to the anterior segment. There was an enlarged centrally displaced Schwalbe's ring (Fig. 6). Fine strands extended from it to the iris root slightly central to the trabecular meshwork. No synechiae were present. There was conspicuous segmental thinning of the iris root stroma. Near the pupil, moundlike elevations were noted on the anterior iris surface that were composed of closely packed nonpigmented cells and had small round or ovoid uniform nuclei and scant cytoplasm with poorly defined cell borders (Fig. 7). The cells within the iris nodules resembled those seen within some of the iris root strands at their attachments to Schwalbe's ring. The retina had no visible alterations of the outer layers or retinal pigment epithelium. Numerous, recent hemorrhages involved the nerve fiber, inner nuclear, and plexiform layers, as well as the subhyaloid space. Additional hemorrhages were noted within the edematous optic disk and subarachnoid space of the optic nerve.
Discussion
Alagille's syndrome is an autosomal dominant condition" that initially occurs as persis-
tent neonatal intrahepatic cholestasis associated with a paucity of interlobular bile ducts.P In a series of 80 cases, cardiovascular involvement in the form of peripheral pulmonary stenosis, isolated or at multiple sites, was noted in 68 patients (85%).7 In the same study, skeletal abnormalities were an equally regular feature with the most common finding being butterfly vertebral arch defects seen in 70 of 80 patients (87%). Supposedly characteristic facies that include prominent forehead, deep set eyes with mild hypertelorism, straight nose, and small pointed chin have been reported as a feature of this condition.v'v" Sokol, Heubi, and Balistreri" believe the facial findings are characteristic of congenital intrahepatic cholestasis, whatever its cause, and are not specific for Alagilles syndrome. At least six other syndromes with familial intrahepatic cholestasis have been recognized. None of these have associated ocular findings." Axenfeld's syndrome and retinal pigmentary abnormalities have, however, been regarded as important markers for Alagille's syndrome. Of 13 patients reported in four published articles.i" 12 (92 %) had posterior embryotoxon and ten (77%) also had associated iris strands. The second most frequent finding was a retinal pigmentary abnormality seen in nine of 13 patients (69%).
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Fig. 7 (Johnson). Case 2, Several small hypercellular nodules are present on the anterior iris surface (hematoxylin and eosin, x 450).
Both patients in the present study had prominent axially displaced Schwalbe's rings with fine attached iris strands clinically characteristic ofAxenfeld's syndrome. Additionally, both had striking peripheral iridic stromal atrophy and nodular aggregates of cells on the anterior border layer (Figs. 2 and 7). These possibly represent cellular islands derived developmentally from the monolayer of neural crest ectoderm, which is also responsible for producing the peripheral iris strands. These cellular aggregates may be the histologic correlate of anomalous hypopigmented anterior iris tissue clumps described clinically in some of the reports.!- Additional iris abnormalities reported on slit-lamp examination include corectopia.v' rudimentary coloboma." and thick iris root vessels." These clinical and histologic features are those noted in the classic description by Rieger of mesodermal dysgenesis." I agree with Shields" that the variety of changes designated separately as Axenfeld's and Rieger's syndromes are a spectrum of alterations representing different manifestations of the same developmental disorder. Shields" proposes that the collective term Axenfeld-Rieger syndrome best describes this condition. I believe that careful slit-lamp examination in patients with Alagille's syndrome will often show these additional iris findings. Pigmentary retinopathy is a feature documented in more than half of the patients with this syndrome and is probably an acquired
change, as it has not been seen in infants; it has been found only in patients who have survived with the cholestasis for some years. There are at least 40 diverse conditions" with a retinal pigmentary degeneration and, in most, the responsible genetic or metabolic defect remains uncertain. Evidence suggests that failure of absorption of fat-soluble vitamins plays a major role in the evolution of the retinopathy in Alagille's syndrome." In this patient, there was a diffuse peripheral retinal pigment epithelial change composed of fine, reticulated, pale yellow, flat lesions with well-defined borders. Fine, branching, often star-shaped, black pigment deposits were noted in the overlying sensory retina. Similar lesions affecting the retinal pigment epithelium have been noted in otherwise healthy individuals with vitamin A defici en cy l 8-2o and in experimentally induced vitamin A or E deficiencies in primates.v" Both of these vitamins are believed to be important in maintaining the integrity of the photoreceptor outer segments. Vitamin A depletion results in uniform loss of the visual pigments rhodopsin and iodopsin, which interfere with the electrophysical requirements of vision and later with structural dismantling of the outer segments." The mechanism of the visual role of vitamin E is less clear, but it is believed to have an important protective function as a lipid antioxidant for the extremely high concentration of polyunsaturated fatty acids found in the outer segments. 21-24
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Ultrastructurally, the retinal pigment epithelium in Case 1 resembled that seen in animals experimentally deprived of vitamin A or E. Robison, Kuwabara, and Bieri" noted a fivefold increase in the number of lipofuscin granules in the retinal pigment epithelial cytoplasm of vitamin E deficient rats. In the 6-year-old patient (Case I), massive lipofuscin accumulation was greater than that seen in normal elderly individuals and, in this sense, resembled premature senescence." Bruch's membrane also reflected this excessive accumulation. Normally, decades of daily diurnal photoreceptor disk membrane phagocytosis by the retinal pigment epithelium with incomplete lysosomal enzymatic degradation and cytoplasmic lipofuscin accumulation are required before these phospholipid membrane products are eventually deposited in Bruch's membrane. This usually occurs after the fourth decade with deposition of these products extracellularly in the innermost collagenous portion of Bruch's membrane." In Case 1, what normally takes decades has been contracted into a few years by this apparent accelerated outer segment damage and turnover. Vesicular bodies, fibrillar deposits, and crystalline material were noted in the widened inner collagenous layer of Bruch's membrane. Additionally, abnormal basement membrane material, including widespaced collagen, was noted between the plasmalemma and basement membrane of the retinal pigment epithelium. This was similar in appearance to the diffuse drusen or basal laminar deposits seen in agerelated maculopathy." Other factors, still poorly understood, may additionally be operative in pigmentary degeneration associated with Alagille's syndrome. It has been assumed that the vitamin E deficiency seen in this syndrome was the result of inadequate intestinal intraluminal concentration of bile salts necessary for solubilization and absorption of fat-soluble vitamins and dietary Iipids." In Alagille's syndrome, a scarcity of intrahepatic interlobular bile ducts occurs. Ahdab-Barmada, Hashida, and Yunis" compared seven cases of Alagille's syndrome obtained by autopsy with 14 children (age and disease length matched) who died of extrahepatic biliary atresia. The extent of neuroaxonal dystrophy and lipofuscin storage was less severe in the latter group, and none of these had retinal pigmentary abnormalities. They concluded that chronic cholestasis by itself does not explain the mechanism of vitamin E malabsorption or the deficient blood concentrations
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seen in Alagille's syndrome. They did note, however, high levels of cholesterol in the children with Alagille's syndrome. They speculated that the marked hypercholesterolemia or an associated basic chemical defect in the metabolism of liposoluble vitamins might explain the severity of the pigmentary degeneration in arteriohepatic dysplasia. Patients with the retinal pigmentary degeneration of Bassen-Kornzweig syndrome are also usually markedly hyperchoIesterolernic." Altered lipid metabolism or defects in the metabolism of liposoluble vitamins may, therefore, be of fundamental importance in the understanding of some secondary forms of retinal pigmentary degeneration. Prompt recognition of this syndromic form of neonatal cholestasis with its ophthalmic markers is crucial so that these children can be considered for early institution of therapy in the form of injectable fat-soluble vitamins to prevent or delay the subsequent evolution of the pigmentary retinopathy. Additionally, proper diagnosis of this condition as a predominantly intrahepatic bile duct developmental problem avoids confusion with extrahepatic biliary atresia so that unnecessary anastomotic portoenterostomy surgery is avoided.
References 1. Watson, G. H., and Miller, V.: Arteriohepatic dysplasia. Familial pulmonary arterial stenosis with neonatal liver disease. Arch. Dis. Child. 48:459, 1973.
2. Alagille, D., Odievre, M., Gautier, M., and Dommergues, J. P.: Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental and sexual development, and cardiac murmur. J. Pediatr. 86:63, 1975. 3. Puklin, J. E., Riely, C. A., Simon, R. M., and Cotlier, E.: Anterior segment and retinal pigmentary abnormalities in arteriohepatic dysplasia. Ophthalmology 88:337, 1981. 4. Romanchuk, K. G., [udisch, G. F., and LaBrecque, D. R.: Ocular findings in arteriohepatic dysplasia (Alagille's syndrome). Can. J. Ophthalmol. 16:94,1981. 5. Mayer, V., and Grosse, K.-P.: Zur klinik und vererbung der augensymptome bei arteriohepat-
ischer dysplasie. 180:290, 1982.
Klin. Monatsbl. Augenheilkd.
6. Raymond, W. R., Kearney, J. J., and Parmley, V. C.'; Ocular findings in arteriohepatic dysplasia (Alagille's syndrome). Arch. Ophthalmol. 107:1077, 1989.
7. Alagille, D., Estrada, A., Hadchouel, M., Gau-
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tier, M., Odievre, M., and Dornmergues. ]. P.: Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia). Review of 80 cases. J. Pediatr. 110:195, 1987. 8. Karrer, F. M., and Raffensperger, J. G.: Biliary atresia. In Raffensperger, J. G. (ed.): Swenson's Pediatric Surgery, ed. 5. Norwalk, Connecticut, Appleton and Lange, 1990, pp. 649-660. 9. LaBrecque, D. R., Mitres, F. A., Nathan, R. J., Romanchuk, K. G., [udisch. G. F., and EI-Khoury, G. H.: Four generations of arteriohepatic dysplasia. Hepatology 2:467, 1982. 10. Riely, C. A., Cotlier, E., Jensen, P.S., and Klatskin, G.: Arteriohepatic dysplasia. A benign syndrome of intrahepatic cholestasis with multiple organ involvement. Ann. Intern. Med. 91 :520, 1979. 11. Mueller, R. F.: The Alagille syndrome (arteriohepatic dysplasia). J. Med. Genet. 24:621, 1987. 12. Shulman, S. A., Hyams, J. 5., Gunta, R., Greenstein, R. M., and Cassidy, S. B.: Arteriohepatic dysplasia (Alagille syndrome). Extreme variability among affected family members. Am. J. Med. Genet. 19:325,1984. 13. Sokol, R. J., Heubi, J. E., and Balistreri, W. F.: Intrahepatic "cholestasis facies." Is it specific for Alagille syndrome? J. Pediatr. 103:205, 1983. 14. Rieger, H.: Beitrage zur kenntnis seltener missbildungen der Iris. Uber Hypoplasie des Irisvorderblatter mit verlagerung und entrundung der pupillae. Graefes Arch. Clin. Exp. OphthalmoI. 133:602, 1935. 15. Shields, M. B.: Axenfeld-Rieger syndrome. A theory of mechanism and distinctions from the iridocorneal endothelial syndrome. Trans. Am. Ophthalmol. Soc. 81:736, 1983. 16. Green, W. R.: Retina. In Spencer, W. H. (ed.): Ophthalmic Pathology. An Atlas and Textbook, ed. 3. Philadelphia, W. B. Saunders, 1985, pp. 1220-1221. 17. Rosenblum, J. L., Keating, J. P., Prensky, A. L., and Nelson, J. 5.: A progressive neurologic syndrome in children with chronic liver disease. N. Engl. J. Med. 304:503, 1981. 18. Fells, P., and Bors, F.: Ocular complications of self-induced vitamin A deficiency. Trans. Ophthal-
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mol. Soc. U.K. 89:221, 1969. 19. Bors, F., and Fells, P.: Reversal of the complications of self-induced vitamin A deficiency. Br. J. Ophthalmol. 55:210, 1971. 20. Sommer, A., Tjakrasudjatma, S., Djunaedi, E., and Green, R.: Vitamin A-responsive panocular xerophthalmia in a healthy adult. Arch. Ophthalmol. 96:1630,1978. 21. Robison, W. G., Kuwabara, T., and Bieri, J. G.: Vitamin E deficiency and the retina. Photoreceptor and pigment epithelial changes. Invest. Ophthalmol. Vis. Sci. 18:683, 1979. 22. Hayes, K. c.: Retinal degeneration in monkeys induced by deficiencies of vitamin E or A. Invest. Ophthalmol. Vis. Sci. 13:499, 1974. 23. Katz, M. L., Stone, W. L., and Dratz, E. A.: Fluorescent pigment accumulation in retinal pigment epithelium of antioxidant-deficient rats. Invest. Ophthalmol. Vis. Sci. 7:1049, 1978. 24. Feeney-Burns, L., Berman, E. R., and Rothman, H.: Lipofuscin of human retinal pigment epithelium. Am. J. Ophthalmol. 90:783, 1980. 25. Marshall, J.: Editorial. Cellular debris. A key to the aging macula. Br. J. Ophthalmol. 73:161, 1989. 26. Hogan, M. J., Alvarado, J. A., and Weddell, J. E.: Histology of the Human Eye. An Atlas and Textbook, ed. 1. Philadelphia, W. B. Saunders, 1971, pp. 344-363. 27. Green, W. R., McDonnell, P. J., and Yeo, J. H.: Pathologic features of senile macular degeneration. Ophthalmology 92:615,1985. 28. Muller, D. P., Harries, J. T., and Lloyd, J. K.: The relative importance of the factors involved in the absorption of vitamin E in children. Gut 15:966, 1974. 29. Ahdab-Barrnada, M., Hashida, Y., and Yunis, E.: Axonal dystrophy and neuronal pigmentary degeneration in Alagille's syndrome (abstract). J. Neuropathol. Exp. Neurol. 48:349, 1989. 30. Muller, D. P., and Lloyd, J. K.: Effect of large oral doses of vitamin E on the neurological sequelae of patients with abetalipoproteinemia. Ann. N.Y. Acad. Sci. 393: 133, 1982.
Published in honor of Lorenz E. Zimmerman, M.D. From the Department of Pathology, University of Pittsburgh School of Medicine, and the Eye Pathology Laboratory, Eye and Ear Hospital of Pittsburgh, Pittsburgh, Pennsylvania. This study was supported in part by the Pathology Education and Research Foundation, Department of Pathology, University of Pittsburgh School of Medicine. Reprint requests to Bruce L. Johnson, M.D., Eye and Ear Institute, 203 Lothrop St., Pittsburgh, PA 15213.
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included deep set eyes, hypertelorism and pointed chin, vertebral (butterfly) malformations, and retarded physical, mental, and sexual development. Ophthalmic findings helped to establish the proper category of cholestasis.t" The most frequently documented clinical change is posterior embryotoxon in which a thickened axially displaced Schwalbe's ring is visible in the peripheral cornea. Frequently, strands of peripheral iris tissue extend to it, and then the term Axenfelds syndrome is applicable. In one series," posterior embryotoxon was noted in 55 of 62 patients (89%) with Alagille's syndrome compared with an estimated 8% to 15% in the normal population. Retinal pigmentary abnormalities are a second frequent finding. The light and electron microscopic findings of the ocular changes in two patients who had this disorder are reported.
Case Reports Case 1 A 6-year-old boy was noted at 3 days of age to have jaundice and a cardiac murmur consistent with pulmonic stenosis. At 3 weeks of age, an intraoperative cholangiogram showed only a few intrahepatic bile ducts, and no extrahepatic bile duct was visualized at the time of laparotomy. A cholecystoportohepatostomy (modified Kasal operation)" was performed. Jaundice was persistent, and between 4 and 5 years of age, hospitalizations were necessary for bowel obstruction secondary to peritoneal adhesions, anasarca, and streptococcal sepsis. The patient's health declined, and jaundice, ascites, and respiratory distress persisted. Cardiac catheterization showed increased right ventricular pressure with severe pulmonic valvular stenosis and pulmonary artery branch stenosis. A percutaneous balloon valvuloplasty was performed with some improvement of the respiratory symptoms. Pertinent laboratory values obtained at the time of examination for possible
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liver transplantation were as follows: total bilirubin, 26.4 mgl dl with a direct bilirubin of 17.6 mgl dl; alkaline phosphatase, 564 U I dl; serum glutamic oxaloacetic transaminase, 373 U Iml; serum glutamic pyruvic transaminase, 190 U/ ml; total protein, 8.0 g/dl; albumin, 3.8 g/dl; cholesterol, 372 mg Zdl: and triglycerides. 193 mgydl, Serum vitamin E was 0.7 IJ.g/ml (normal, 5 to 10 IJ.g/ml) and vitamin D was less than 2 ng/ml (normal, 10 to 55 ng Zml). Lack of fusion of the anterior arches of several thoracic vertebrae (butterfly deformity) was noted radiologically. The patient had the dysmorphic facies (deep set eyes, hypertelorism, straight nose, small pointed chin) seen frequently in cases of Alagille's syndrome. Ophthalmic examination was limited because the patient was not cooperative. There was prominent conjunctival icterus. The corneas were of normal dimension and had small concentric white rings slightly internal to the corneoscleral limbus, consistent with posterior embryotoxon. No iris or lens changes were noted. Gonioscopic and adequate ophthalmoscopic examinations could not be performed. The posterior pole and optic disks were, however, visualized briefly and no pigmentary changes or glaucomatous cupping were seen. At 6 years of age, the patient underwent hepatic allograft transplantation. Twelve hours later, he developed sudden ventricular tachycardia and hypotension, which did not respond to therapy, and he died. His liver, removed at the time of orthotopic hepatic transplantation, showed atresia of the hepatic duct with a paucity of intrahepatic bile ducts. Autopsy findings of note were pulmonic valvular stenosis, hypoplasia of the left pulmonary artery, and right ventricular hypertrophy. There was pronounced lipofuscin deposition in lymph nodes, spleen, and smooth muscles of the esophagus, gastrointestinal tract, and urinary bladder, which were related to the severe, chronic vitamin E deficiency. Lipofuscin deposition associated with advanced neuroaxonal dystrophy in the gracile and cuneate nuclei was also noted. There were xanthomas of the spinal cord dura mater and arteriosclerosis of the thoracic aorta and main pulmonary artery. Severe growth retardation was noted. Both eyes obtained at autopsy were similar, and pertinent macroscopic findings were limited to the anterior segment and retina. The cornea showed a prominent, centrally displaced Schwalbe's ring. Fine, filmy strands extended to it from the iris root. Tiny gray nodules
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were seen on the anterior surface of the iris. Extensive retinal pigmentary change was noted. This consisted of a broad circumferential zone extending from the ora to the central retina of fine, star-shaped and dendritic, hyperpigmented, black, intraretinal deposits with circular, lobulated, and often confluent, lightly depigmented underlying lesions at the level of the retinal pigment epithelium (Fig. 1). The posterior limits of the pigmentary change lay approximately 4 mm posterior to the equator, had a fairly distinct demarcation line, and spared the central retina. The choroid was thin and grossly unremarkable. The disk and optic nerve were normal. Histologically, the cornea had an enlarged and centrally displaced Schwalbe's line with attached iris strands. Temporally, the chamber angle was closed by short anterior synechiae. There was prominent thinning of the iris root stroma. Near the pupil, aggregates of small, nonpigmented cells were noted, which had poorly defined cytoplasmic borders and small, uniform, round nuclei (Fig. 2). The ciliary muscle contained numerous periodic acid-Schiff stain-positive, finely granular, and coarsely clumped deposits. There was prominent alteration of the outer layers of the sensory retina and retinal pigment epithelium, which extended from the ora serrata to well behind the equator (Fig. 3). The outer plexiform layer was inapparent, and the outer nuclear layer was reduced to
Fig. 1 (Johnson). Case 1. Gross photograph of the opened right eye showing the retinal pigmentary change that extends from near the ora to the central retina (XS).
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Fig. 2 (Johnson). Case 1. Nodule on anterior iris surface composed of closely packed, small, uniform, round, and spindle-shaped cells (hematoxylin and eosin, x 500).
Throughout this zone, there was extensive atrophy and focal hyperplasia of the retinal pigment epithelium. Some remaining pigment epithelial cells contained decreased amounts of melanin, whereas others were distended with
one layer in thickness. Melanin pigment deposits were numerous within the inner nuclear layer with fewer granules seen in the nerve fiber layer. The inner and outer segments of the photoreceptors were disrupted extensively.
Fig. 3 (Johnson). Case 1. The retina shows degeneration of the photoreceptors, pronounced atrophy of the outer nuclear layer, and dispersed melanin pigment at all levels. Most retinal pigment epithelial cells (open arrowheads) appear distended and contain decreased amounts of melanin (I-um plastic, toluidine blue, x 450).
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Fig. 4 (Johnson). Case 1. Electron micrograph of retinal pigment epithelial cell shows numerous lipofuscin granules (open arrowheads) of moderate density and only a few dense melanin granules. Clumped electrondense material (arrow) is present between the plasmalemma of the retinal pigment epithelium and its basement membrane. Vesicular bodies and crystalline material are present in the inner collagenous portion (B) of Bruch's membrane (X 4,300).
PAS-positive granular material. Bruch's membrane appeared unremarkable. The choroid and sclera were normal. There was mild disk edema; the optic nerve was unremarkable. Ultrastructurally, the retinal pigment epithelial cells of the involved peripheral and equatorial zone contained large numbers of lipofuscin granules within their cytoplasm (Fig. 4). These far outnumbered the more dense melanin granules, which were confined to the apical portions of the cell. In many, only few peripherally displaced melanin granules were noted with a lipofuscin:melanin ratio of approximately 4: 1. Compound melanin and lipofuscin bodies were also common. Lamellar structures and residual bodies that represented engulfed outer segment photoreceptor material were noted. Autolytic change within the sensory retina precluded satisfactory interpretation. Abundant finely fibrillar structures that contained clumped electron-dense material were interposed between
the retinal pigment epithelium plasmalemma and its basement membrane. Numerous vesicular bodies, as well as fibrillar and dense crystalline material, was deposited in the widened inner collagenous portion of Bruch's membrane. The elastica was thickened. Few vesicular bodies were scattered throughout the outer collagenous portion. The ciliary body disclosed numerous rounded and irregularly shaped homogenous or finely granular lipofuscin deposits of a slight to moderate density, which distended the cytoplasm of many smooth muscle cells and occasionally indented their nuclei (Fig. 5). Case 2 A 4Y2-month-old girl was a full-term delivery by cesarean section for breech presentation. At 12 hours of life, the patient was noted to be jaundiced and had hepatomegaly, cyanosis, and persistent vomiting. Total bilirubin level
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Fig. 5 (Johnson). Case 1. Electron micrograph of ciliary body shows smooth muscle cell that contains numerous cytoplasmic lipofuscin deposits that indent its nucleus (x 12,100).
was 14.4 mgjdl with a direct bilirubin level of 3 mgjdl. By 3 weeks of age the jaundice had decreased, but six weeks later recurrent jaundice was noted. The results of a physical examination at that time disclosed dysmorphic facies and posterior embryotoxon. A butterfly deformity of the thoracic vertebrae was apparent on radiologic examination. The results of an exploratory laparotomy with cholangiogram and liver biopsy showed hypoplastic intrahepatic bile ducts. Two months later, the patient was again hospitalized because of repeated apneic episodes and irregular respirations. Prothrombin and partial thromboplastin times were more than 120 seconds. A computed tomographic scan showed a large, right, cerebral hemispheric hemorrhage with edema and subfalcial herniation. The patient was determined to be brain dead and life support was discontinued. At autopsy, pertinent systemic findings included jaundice with intrahepatic and extrahepatic bile duct hypoplasia. There was right ventricular cardiac hypertrophy with peripher-
al pulmonary artery stenosis. Butterfly thoracic vertebrae were noted. The kidneys had medullary cysts. The lungs showed pulmonary edema and mild interstitial pneumonitis. Death resulted from massive intracerebral hemorrhage with cerebellar tonsillar herniation. Similar findings were noted in both eyes obtained at autopsy. The sclera was icteric. The cornea showed a prominent centrally displaced Schwalbe's line. The anterior chamber angle appeared to be open. A few iris strands extended across the angle. The lens and vitreous were unremarkable. The retina had a prominent peripheral Lange fold. No retinal pigmentary changes were seen in the artifactually opacified retina. Numerous bright red, flat and slightly raised, generally round hemorrhages were noted within and on the peripapillary retina. The optic disk margin appeared slightly elevated, and a small physiologic cup remained. Bright red hemorrhage was noted in the attached optic nerve meninges, especially in the subarachnoid space. Histologically, the pertinent findings were
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Fig. 6 (Johnson). Case 2. There is an enlarged centrally displaced Schwalbe's line. Marked thinning of the iris root stroma is present (hematoxylin and eosin, x 80).
limited to the anterior segment. There was an enlarged centrally displaced Schwalbe's ring (Fig. 6). Fine strands extended from it to the iris root slightly central to the trabecular meshwork. No synechiae were present. There was conspicuous segmental thinning of the iris root stroma. Near the pupil, moundlike elevations were noted on the anterior iris surface that were composed of closely packed nonpigmented cells and had small round or ovoid uniform nuclei and scant cytoplasm with poorly defined cell borders (Fig. 7). The cells within the iris nodules resembled those seen within some of the iris root strands at their attachments to Schwalbe's ring. The retina had no visible alterations of the outer layers or retinal pigment epithelium. Numerous, recent hemorrhages involved the nerve fiber, inner nuclear, and plexiform layers, as well as the subhyaloid space. Additional hemorrhages were noted within the edematous optic disk and subarachnoid space of the optic nerve.
Discussion
Alagille's syndrome is an autosomal dominant condition" that initially occurs as persis-
tent neonatal intrahepatic cholestasis associated with a paucity of interlobular bile ducts.P In a series of 80 cases, cardiovascular involvement in the form of peripheral pulmonary stenosis, isolated or at multiple sites, was noted in 68 patients (85%).7 In the same study, skeletal abnormalities were an equally regular feature with the most common finding being butterfly vertebral arch defects seen in 70 of 80 patients (87%). Supposedly characteristic facies that include prominent forehead, deep set eyes with mild hypertelorism, straight nose, and small pointed chin have been reported as a feature of this condition.v'v" Sokol, Heubi, and Balistreri" believe the facial findings are characteristic of congenital intrahepatic cholestasis, whatever its cause, and are not specific for Alagilles syndrome. At least six other syndromes with familial intrahepatic cholestasis have been recognized. None of these have associated ocular findings." Axenfeld's syndrome and retinal pigmentary abnormalities have, however, been regarded as important markers for Alagille's syndrome. Of 13 patients reported in four published articles.i" 12 (92 %) had posterior embryotoxon and ten (77%) also had associated iris strands. The second most frequent finding was a retinal pigmentary abnormality seen in nine of 13 patients (69%).
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Fig. 7 (Johnson). Case 2, Several small hypercellular nodules are present on the anterior iris surface (hematoxylin and eosin, x 450).
Both patients in the present study had prominent axially displaced Schwalbe's rings with fine attached iris strands clinically characteristic ofAxenfeld's syndrome. Additionally, both had striking peripheral iridic stromal atrophy and nodular aggregates of cells on the anterior border layer (Figs. 2 and 7). These possibly represent cellular islands derived developmentally from the monolayer of neural crest ectoderm, which is also responsible for producing the peripheral iris strands. These cellular aggregates may be the histologic correlate of anomalous hypopigmented anterior iris tissue clumps described clinically in some of the reports.!- Additional iris abnormalities reported on slit-lamp examination include corectopia.v' rudimentary coloboma." and thick iris root vessels." These clinical and histologic features are those noted in the classic description by Rieger of mesodermal dysgenesis." I agree with Shields" that the variety of changes designated separately as Axenfeld's and Rieger's syndromes are a spectrum of alterations representing different manifestations of the same developmental disorder. Shields" proposes that the collective term Axenfeld-Rieger syndrome best describes this condition. I believe that careful slit-lamp examination in patients with Alagille's syndrome will often show these additional iris findings. Pigmentary retinopathy is a feature documented in more than half of the patients with this syndrome and is probably an acquired
change, as it has not been seen in infants; it has been found only in patients who have survived with the cholestasis for some years. There are at least 40 diverse conditions" with a retinal pigmentary degeneration and, in most, the responsible genetic or metabolic defect remains uncertain. Evidence suggests that failure of absorption of fat-soluble vitamins plays a major role in the evolution of the retinopathy in Alagille's syndrome." In this patient, there was a diffuse peripheral retinal pigment epithelial change composed of fine, reticulated, pale yellow, flat lesions with well-defined borders. Fine, branching, often star-shaped, black pigment deposits were noted in the overlying sensory retina. Similar lesions affecting the retinal pigment epithelium have been noted in otherwise healthy individuals with vitamin A defici en cy l 8-2o and in experimentally induced vitamin A or E deficiencies in primates.v" Both of these vitamins are believed to be important in maintaining the integrity of the photoreceptor outer segments. Vitamin A depletion results in uniform loss of the visual pigments rhodopsin and iodopsin, which interfere with the electrophysical requirements of vision and later with structural dismantling of the outer segments." The mechanism of the visual role of vitamin E is less clear, but it is believed to have an important protective function as a lipid antioxidant for the extremely high concentration of polyunsaturated fatty acids found in the outer segments. 21-24
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Ultrastructurally, the retinal pigment epithelium in Case 1 resembled that seen in animals experimentally deprived of vitamin A or E. Robison, Kuwabara, and Bieri" noted a fivefold increase in the number of lipofuscin granules in the retinal pigment epithelial cytoplasm of vitamin E deficient rats. In the 6-year-old patient (Case I), massive lipofuscin accumulation was greater than that seen in normal elderly individuals and, in this sense, resembled premature senescence." Bruch's membrane also reflected this excessive accumulation. Normally, decades of daily diurnal photoreceptor disk membrane phagocytosis by the retinal pigment epithelium with incomplete lysosomal enzymatic degradation and cytoplasmic lipofuscin accumulation are required before these phospholipid membrane products are eventually deposited in Bruch's membrane. This usually occurs after the fourth decade with deposition of these products extracellularly in the innermost collagenous portion of Bruch's membrane." In Case 1, what normally takes decades has been contracted into a few years by this apparent accelerated outer segment damage and turnover. Vesicular bodies, fibrillar deposits, and crystalline material were noted in the widened inner collagenous layer of Bruch's membrane. Additionally, abnormal basement membrane material, including widespaced collagen, was noted between the plasmalemma and basement membrane of the retinal pigment epithelium. This was similar in appearance to the diffuse drusen or basal laminar deposits seen in agerelated maculopathy." Other factors, still poorly understood, may additionally be operative in pigmentary degeneration associated with Alagille's syndrome. It has been assumed that the vitamin E deficiency seen in this syndrome was the result of inadequate intestinal intraluminal concentration of bile salts necessary for solubilization and absorption of fat-soluble vitamins and dietary Iipids." In Alagille's syndrome, a scarcity of intrahepatic interlobular bile ducts occurs. Ahdab-Barmada, Hashida, and Yunis" compared seven cases of Alagille's syndrome obtained by autopsy with 14 children (age and disease length matched) who died of extrahepatic biliary atresia. The extent of neuroaxonal dystrophy and lipofuscin storage was less severe in the latter group, and none of these had retinal pigmentary abnormalities. They concluded that chronic cholestasis by itself does not explain the mechanism of vitamin E malabsorption or the deficient blood concentrations
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seen in Alagille's syndrome. They did note, however, high levels of cholesterol in the children with Alagille's syndrome. They speculated that the marked hypercholesterolemia or an associated basic chemical defect in the metabolism of liposoluble vitamins might explain the severity of the pigmentary degeneration in arteriohepatic dysplasia. Patients with the retinal pigmentary degeneration of Bassen-Kornzweig syndrome are also usually markedly hyperchoIesterolernic." Altered lipid metabolism or defects in the metabolism of liposoluble vitamins may, therefore, be of fundamental importance in the understanding of some secondary forms of retinal pigmentary degeneration. Prompt recognition of this syndromic form of neonatal cholestasis with its ophthalmic markers is crucial so that these children can be considered for early institution of therapy in the form of injectable fat-soluble vitamins to prevent or delay the subsequent evolution of the pigmentary retinopathy. Additionally, proper diagnosis of this condition as a predominantly intrahepatic bile duct developmental problem avoids confusion with extrahepatic biliary atresia so that unnecessary anastomotic portoenterostomy surgery is avoided.
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7. Alagille, D., Estrada, A., Hadchouel, M., Gau-
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tier, M., Odievre, M., and Dornmergues. ]. P.: Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia). Review of 80 cases. J. Pediatr. 110:195, 1987. 8. Karrer, F. M., and Raffensperger, J. G.: Biliary atresia. In Raffensperger, J. G. (ed.): Swenson's Pediatric Surgery, ed. 5. Norwalk, Connecticut, Appleton and Lange, 1990, pp. 649-660. 9. LaBrecque, D. R., Mitres, F. A., Nathan, R. J., Romanchuk, K. G., [udisch. G. F., and EI-Khoury, G. H.: Four generations of arteriohepatic dysplasia. Hepatology 2:467, 1982. 10. Riely, C. A., Cotlier, E., Jensen, P.S., and Klatskin, G.: Arteriohepatic dysplasia. A benign syndrome of intrahepatic cholestasis with multiple organ involvement. Ann. Intern. Med. 91 :520, 1979. 11. Mueller, R. F.: The Alagille syndrome (arteriohepatic dysplasia). J. Med. Genet. 24:621, 1987. 12. Shulman, S. A., Hyams, J. 5., Gunta, R., Greenstein, R. M., and Cassidy, S. B.: Arteriohepatic dysplasia (Alagille syndrome). Extreme variability among affected family members. Am. J. Med. Genet. 19:325,1984. 13. Sokol, R. J., Heubi, J. E., and Balistreri, W. F.: Intrahepatic "cholestasis facies." Is it specific for Alagille syndrome? J. Pediatr. 103:205, 1983. 14. Rieger, H.: Beitrage zur kenntnis seltener missbildungen der Iris. Uber Hypoplasie des Irisvorderblatter mit verlagerung und entrundung der pupillae. Graefes Arch. Clin. Exp. OphthalmoI. 133:602, 1935. 15. Shields, M. B.: Axenfeld-Rieger syndrome. A theory of mechanism and distinctions from the iridocorneal endothelial syndrome. Trans. Am. Ophthalmol. Soc. 81:736, 1983. 16. Green, W. R.: Retina. In Spencer, W. H. (ed.): Ophthalmic Pathology. An Atlas and Textbook, ed. 3. Philadelphia, W. B. Saunders, 1985, pp. 1220-1221. 17. Rosenblum, J. L., Keating, J. P., Prensky, A. L., and Nelson, J. 5.: A progressive neurologic syndrome in children with chronic liver disease. N. Engl. J. Med. 304:503, 1981. 18. Fells, P., and Bors, F.: Ocular complications of self-induced vitamin A deficiency. Trans. Ophthal-
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mol. Soc. U.K. 89:221, 1969. 19. Bors, F., and Fells, P.: Reversal of the complications of self-induced vitamin A deficiency. Br. J. Ophthalmol. 55:210, 1971. 20. Sommer, A., Tjakrasudjatma, S., Djunaedi, E., and Green, R.: Vitamin A-responsive panocular xerophthalmia in a healthy adult. Arch. Ophthalmol. 96:1630,1978. 21. Robison, W. G., Kuwabara, T., and Bieri, J. G.: Vitamin E deficiency and the retina. Photoreceptor and pigment epithelial changes. Invest. Ophthalmol. Vis. Sci. 18:683, 1979. 22. Hayes, K. c.: Retinal degeneration in monkeys induced by deficiencies of vitamin E or A. Invest. Ophthalmol. Vis. Sci. 13:499, 1974. 23. Katz, M. L., Stone, W. L., and Dratz, E. A.: Fluorescent pigment accumulation in retinal pigment epithelium of antioxidant-deficient rats. Invest. Ophthalmol. Vis. Sci. 7:1049, 1978. 24. Feeney-Burns, L., Berman, E. R., and Rothman, H.: Lipofuscin of human retinal pigment epithelium. Am. J. Ophthalmol. 90:783, 1980. 25. Marshall, J.: Editorial. Cellular debris. A key to the aging macula. Br. J. Ophthalmol. 73:161, 1989. 26. Hogan, M. J., Alvarado, J. A., and Weddell, J. E.: Histology of the Human Eye. An Atlas and Textbook, ed. 1. Philadelphia, W. B. Saunders, 1971, pp. 344-363. 27. Green, W. R., McDonnell, P. J., and Yeo, J. H.: Pathologic features of senile macular degeneration. Ophthalmology 92:615,1985. 28. Muller, D. P., Harries, J. T., and Lloyd, J. K.: The relative importance of the factors involved in the absorption of vitamin E in children. Gut 15:966, 1974. 29. Ahdab-Barrnada, M., Hashida, Y., and Yunis, E.: Axonal dystrophy and neuronal pigmentary degeneration in Alagille's syndrome (abstract). J. Neuropathol. Exp. Neurol. 48:349, 1989. 30. Muller, D. P., and Lloyd, J. K.: Effect of large oral doses of vitamin E on the neurological sequelae of patients with abetalipoproteinemia. Ann. N.Y. Acad. Sci. 393: 133, 1982.
