Vitamin metabolism and therapy in ophthalmology

SURVEY OF OPHTHALMOLOGY

VOLUME 24

THERAPEUTIC

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NUMBER 3

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NOVEMBER-DECEMBER

1979

REVIEW

STEVEN G. KRAMER, EDITOR

Vitamin

Metabolism

and Therapy

in

Ophthalmology

CREIG

S. HOYT III, M.D. Department of Ophthalmology, cisco, California

University of California Medical Center, San Fran-

Abstract. Vitamin deficiency states are important in the genesis of many ocular disorders. Deficiencies may be due to poor dietary intake, or to alterations in metabolism produced by some commonly prescribed medications or by certain diseases. Furthermore, some vitamins may exert important pharmacologic effects on the normal eye. The ocular effects of deficiencies and excesses of specific vitamins, and the therapeutic uses of each vitamin, are reviewed. (Surv Opbthalmol 24:177-190, 1979) Key words. cataract cornea1 vascularization hemorrhage optic nerve disorders metabolism night blindness pseudotumor cerebri vitamin metabolism vitamin therapy xerophthalmia l

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of vitamin deficiencies in many ophthalmic disorders is well recognized.17sg’ Xerophthalmia is still a significant sight-threatening disorder in many

parts of the world. The role of various nutrients in normal optic nerve metabolism suggests that a wide range of optic nerve disorders may be caused by nutritional deficiencies. Interest continues to be directed toward the problem of cataract formation and the possibility that dietary disturbances might play a part in the cataractogenic process. In this report I shall review the ocular consequences of each vitamin deficiency state and the indications for vitamin therapy in various ocular disorders. Inherited metabolic disorders which respond to supraphysiologi-

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cal amounts of a single vitamin*2e will also be noted. These vitamin-responsive inborn errors of metabolism will certainly become increasingly important to ophthalmologists interested in genetics and pediatric ophthalmology.

Vitamin A Disturbances of vitamin A metabolism are most significant because of the extensive pathological changes in the eye which they cause. Even today, vitamin A deficiency is recognized as a leading cause of blindness in many underdeveloped countries.s8-‘0’ Several of these countries have inaugurated nationwide distribution of massive doses of

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\~tamin A for their preschool-age population.7s The ocular manifestations of vitamin A deficiency have long been recognized, although it was not until 1913 that animal experiments established the existence of a fat-soluble vitamin necessary for the growth and integrity of the eyes.ee Vitamin A plays two essential roles in normal ocular metabolism. First, it helps to maintain the normal structural and functional characteristics of epithelial cells, and second, it acts as an essential precursor for synthesis of visual photosensitive pigments. The term, xerophthalmia, has been adopted to describe the changes in cornea and conjunctiva which are a result of vitamin A deficiency. Experimentally, xerophthalmia was probably first produced in dogs by Magendie in 18 16.8eInitially, one sees an area of dryness on the conjunctiva in the area of t’le palpebral fissure, the Bitot spot. A lesion similar to a Bitot spot may occur very rarely in Reiger’s anomaly, but this lesion does not respond to vitamin A administration.12 J,erosis may lead to dryness of the entire conjunctiva and cornea, hyperpigmentation of tile conjunctiva, meibomianitis, and keratoI lalacia. Keratomalacia, softening of the cor:a, usually results from cornea1 xerosis and ccondary bacterial infection. It carries an ; nfavorable prognosis for survival of the Tatient.‘O* The common early pathological hange in xerophthalmia is keratinization of rle columnar epithelium of the conjunctiva, the cornea, and the lacrimal and meibomian glands.8@ Even early reports of xerophthalmia noted that infections and poor general nutrition aggravated the basic vitamin deficiency.s4 In a recent study of 100 patients with xerophthalmia, 86% of the patients harbored frankly pathogenic, or potentially pathogenic bacteria on the conjunctiva or cornea.lg* The many ocular secondary bacterial infections, even in the early stages of xerophthalmia, probably play a major role in cornea1 ulceration and perforation. Similarly, the importance of hypoproteinemia in xerophthalmia has been emphasized.l16’ It has been documented that xerophthalmia can develop ;n the presence of near normal serum vitamin .\ levels if hypoproteinemia is present concurrently.’ It has been suggested that hypoproteinemia leads to fatty infiltration of the liver with a resultant impairment of 4tamin A absorption and storage. Treatment

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of hypovitaminosis A with protein supplements in addition to vitamin A is recommended.lzs The anterior and posterior segments of the eye are equally affected by hypovitaminosis A; the destruction of either or both may cause blindness. Vitamin A exists in two forms, retinol or vitamin A, and 3-dehydroretinol or vitamin A,. The aldehydes of these compounds are bound to two types of opsin. Thus, the four main types of photosensitive pigments are the result of the combination of two forms of vitamin A and two forms of opsin. Vitamin A deficiency leads to a deficiency of photosensitive pigments. Moreover, the rates of rod outer segment turnover,6e and pigment epithelial phagocytosis of outer segment material are effected by vitamin A deficienCY.~~Night blindness, or hemeralopia, is the primary visual symptom of vitamin A deficiency. It may, or may not be associated with xerophthalmia. Vitamin A deficiencyinduced night blindness often occurs in association with increased pigmentation of the conjunctiva in dark-skinned individuals.118 Replacement of vitamin A, in large doses, can result in improvement of night adaptation within a few hours. As in the case of zerophthalmia, the importance of adequate protein intake and vitamin A supplementation in the treatment of night blindness has been documented.ls Ophthalmoscopic examination of patients suffering from hypovitaminosis A will occasionally reveal yellow spots in the equatorial and peripheral portions of the retina.116J9e However, these resolve completely with adequate vitamin A replacement.20 The daily requirement of retinol in an average adult man is 750 mg. In young children the requirement is around 300 mg,ls Vitamin A deficiency may occur as the result of poor dietary intake, malabsorption secondary to gastrointestinal disease, or inadequate hepatic transformation of dietary carotenes. Clinically significant vitamin A deficiency occurs primarily in children under four years of age.lgOThe ingestion of 60 mg of retinol every 3-6 months should provide adequate vitamin A stores if generalized malnutrition does not coexist. Another potential threat to visual function which may arise from vitamin A deficiency has been described in dogs and calves. In these growing young animals, a vitamin A

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deficiency may result in severe constriction of the optic foramen.se This constriction can lead to optic nerve necrosis with severe visual impairments. The postulated etiology of the bony constriction is a failure of the mesenchymal cell to differentiate beyond the osteoblast to the osteoclast.60 No comparable abnormality of the optic foramen has been attributed to vitamin A deficiency in man. Despite the vital role of vitamin A in normal retinal metabolism, the search for degenerative retinal diseases resulting from vitamin A deficiency has been singularly unfruitful. In rats, a fundus picture and electroretinographic findings suggesting retinitis pigmentosa have been produced as a result of vitamin A deficiency. 88 However, vitamin A levels in retinitis pigmentosa patients have been found to be normal.78+‘4Recent studies have suggested that it might be a deficiency of the vitamin A transport protein, and not primarily vitamin A, which leads to pigmentary retinal degeneration.‘*’ Other authorities have not found any evidence that in retinitis pigmentosa, prealbumin-retinal-binding protein complex differs from that seen in unaffected patients.88*8e Studies of patients with fundus albipunctatus have also failed to implicate vitamin A or retinol-binding protein deficiencies as a causative factor.2sJ’2 Vitamin A therapy has been reported to reverse partially the dark adaptation and ERG abnormalities of the retinopathy seen in abetalipoproteinemia, although the long-term value of this therapy has been questioned.” Not only is hypovitaminosis A important to the ophthalmologist, but so is hypervitaminosis A. In experimental animals fed massive doses of vitamin A, weight loss, spastic contractures of the extremities, and exophthalmos were described.= A similar condition has been reported in humans taking at least 50,000 units of vitamin A daily.‘*’ A more important ophthalmic result of vitamin A intoxication has been the development of pseudotumor cerebri.‘O* The mechanism whereby excessive vitamin A produces pseudotumor cerebri has not been established. However, this syndrome has been reported more frequently, as a result of the increasing experimentation with self-prescribed megadose vitamin therapy. In the case of vitamin A, large doses have been consumed for the treatment of common skin disorders, in particular, acne.

Thiamine (B,) Thiamine is essential as a coenzyme in the decarboxylation of keto acids. If the diet is deficient in thiamine, pyruvate metabolism is radically altered. Thiamine also is an essential coenzyme in the pentose shunt during transketolation. Thus, thiamine occupies two independent and essential positions in glucose oxidation. It would seem only logical to assume that an organ (like the brain) which is solely dependent upon glucose oxidation for energy might be damaged by thiamine deficiency. This is the case in WernickeKorsakoff encephalopathy where the primary role of thiamine deficiency seems well established.“O However, significant optic nerve dysfunction is not a common feature of this disorder. Moreover, whether thiamine deficiency alone can cause optic nerve dysfunction has been questioned.140 In the rat, degenerative changes in the optic nerve can be produced when the animals are fed a diet deficient only in thiamine.lP6 The pathological changes become evident more quickly and severely if the diet is also deficient in riboflavin. This study has been criticized by Victor because the weights of the test animals were less than those of pair-fed contr0ls.14o It has been argued that the test animals may have suffered from general starvation, as well as thiamine deficiency. In the disorder referred to as alcohol amblyopia, the causative role of thiamine deficiency seems likely, but it remains controversial.a9 Pathological studies of the optic nerve in cases of alcohol amblyopia demonstrate changes quite similar to those seen in the rats fed a low thiamine diet.“’ Moreover, treatment of these patients with thiamine alone is equally effective as treatment with yeast or B-complex supplementation.*’ Improvement may occur even in the face of continued alcohol consumption. Measurements of serum transketolase (thiamine-dependent transferase) levels in patients with alcohol amblyopia are low, thus supporting the thesis that thiamine deficiency is the central causative factor in this disorder.‘O A significant thiamine deficiency has been documented in over 50% of chronic alcoholics studied in one German center.O’ The nutritional optic neuropathy seen in allied prisoners during World War II was probably secondary to multiple dietary deficienciesa However, there were reports

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that treatment with thiamine alone halted the progression of this disorder.lg*loZ A recent report has documented an optic neuropathy following prolonged restriction of carbohydrate intake with a resultant thiamine deficiency.61 A similar thiamine deficiency optic neuropathy has been seen in children treated with ketogenic diets as part of anticonvulsant therapy.68 There have been reports suggesting that thiamine deficiency plays a role in tabetic optic atrophya or in the optic nerve dysfunction chloramphenicol longterm seen after therapy.se It has also been reported that thiamine is effective in the treatment of traumatic optic nerve injuries.2s However, all these reports require further evaluation. Of particular interest is the current debate surrounding the question of what role thiamine in megadoses may play in the treatment of subacute necrotizing encephalomyelopathy, or Leigh’s disease. Histologically, this disease appears quite similar to Wernicke’s encephalopathy with some differences in the topographic distribution of the lesions.‘O’ Optic atrophy is a prominent feature of Leigh’s disease. Pincus and coworkers118 have shown that blood, urine and cerebrospinal fluid inhibit a yet to be purified thiamine-dependent enzyme. Thus, thiamine intake and stores appear to be adequate, but they are ineffectively utilized. It has been recommended that treatment with thiamine 1-3 gms/day may saturate the enzymeinhibited system and lead to clinical impr0vement.l17 This is one of the inherited metabolic diseases that may respond to supraphysiological amounts of a single vitamin. Beriberi is the classic systemic disease resulting from thiamine deficiency. In pigeons suffering from beriberi, dryness of the conjunctiva has been described.?’ Epithelial changes in the cornea have been documented in some patients with beriberi,6 and these cornea1 changes may be the direct result of cornea1 nerve dysfunction.80 However, anterior segment involvement is not common, nor striking, in the thiamine deficiency states in humans. It is optic nerve dysfunction which is the primary ocular insult seen in all thiamine-poor animals and also in humans. The daily adult requirement of thiamine is about 1 mg. Thiamine is heat labile, so that a great deal of it is destroyed during cooking.

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Prior to the introduction of enriched breads and cereal foods the average American diet probably provided thiamine at a level near, or below, minimum daily requirements.ls In most disease conditions where thiamine deficiency is implicated, the recommended therapy is at least 50 mg/day in order to restore body stores as quickly as possible.

Riboflavin Most of the research documenting ocular changes due to riboflavin deficiency has centered on the anterior segment. Most controversial have been the reports of cataracts resulting from riboflavin deficiency in experimental animals.a1-8s~100 It has been postulated that it is a disturbance in trypotophan metabolism which results from riboflavin deficiency and thus leads to cataract formation.@’ Researchers studying cataract formation in riboflavin-deficient animals have also noted cornea1 and conjunctival changes. Cornea1 vascularization is the most consistent finding in these studies.10*50 The exact nature of the biochemical defects in the cornea in riboflavin deficiency is not known, but it has been noted that the oxygen uptake of cornea1 epithelium is diminished.‘s*8’ In the Tsugaru district of Japan a disease entity, “shibi-gatchaki,” has been described. The main clinical features include roughness of skin, scrotal and vulva1 dermatitis, angular blepharoconjunctivitis, keratitis, and optic nerve atrophyF6 Riboflavin blood levels and urinary excretion after a loading dose are very low in these cases. Yet, it is likely that this disorder is not due to an isolated riboflavin deficiency, but rather to a vitamin B complex deficiency. Nicotinic acid blood levels are also low in this disease. The primary features of “shibi-gatchaki” seem to be similar to those of pellagra and riboflavin deficiency combined. A report identifying riboflavin deficiency as a cause of the common symptom complex of itching and burning of the eyes created some excitement among ophthalmologists.181 However, treatment of this common complaint with riboflavin supplements has not produced noteworthy results.86 It has also been suggested that ariboflavinosis may play a role in some cases of keratoconjunctivitis sicca.66 A disturbance in riboflavin metabolism has been reported in some cases of Behcet’s disease, but no conclusions were drawn as to whether this was a cause or effect

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THERAPEUTIC REVIEW

in this disease entity.‘* The acceleration of thiamine deficiency optic neuropathy when simultaneous riboflavin deficiency exists has already been noted.‘16 However, an isolated riboflavin deficiency state has not been correlated with optic nerve dysfunction. Likewise, although riboflavin is found in high concentrations in some animals’ retinae, Applemans’ and Bietti” have demonstrated conclusively that pure riboflavin deficiency is not a cause of night blindness. Pyridoxine ( BB) Pyridoxine is primarily involved in the metabolism of tryptophan and sulfurcontaining amino acids; it is a coenzyme in decarboxylation, transamination, and deamination of these amino acids. A clinically significant deficiency of pyridoxine is rarely produced, even by severe dietary deprivation. However, ingestion of certann drugs (hydralazine, isonazid, and penicillamine) may lead to deficiency states of clinical importance.‘** In man, a pyridoxine deficiency state has been experimentally produced by the administration of the pyridoxine antagonist, desoxypyridoxine.14z The features of this state include anorexia, nausea, listlessness, seborrheic dermatitis, cheilosis, conjunctivitis, glossitis, and polyneuritis. In children, one of the major manifestations of the pyridoxine deficiency state is convulsions6’ Optic neuropathies have been reported to result from treatment with isonazid,76J24 apresoline,61 penicillamine,18’ and pheniprazine.‘* It is recommended that these drugs be discontinued if any evidence of optic nerve dysfunction appears. Pyridoxine supplements have been recommended as prophylactic therapy whenever this agent is prescribed for longterm usage. However, this complication is infrequent considering the widespread clinical acceptance of these agents, and it seems that pyridoxine deficiency is only rarely responsible for optic nerve disorders. In rats deficient in pyridoxine, slight degenerative changes of the retinal ganglion cells have been reported.‘* In this same study, cornea1 vascularization was documented as a result of the pyridoxine deficiency state.‘* More severe lesions consisting of keratitis, cornea1 ulceration, and abscess formation were noted by other investigators who fed rats a diet deficient in pyridoxine.lo6 Some

workers have produced angular blepharoconjunctivitis in rabbits fed a pyridoxine poor diet.“g It has been suggested that treatment of angular blepharo-conjunctivitis with pyridoxine supplementation is effective even without therapy.8* antimicrobial concomitant Pyridoxine deficiency may be a cause of some cases of angular blepharo-conjunctivitis. However, as in the other clinical conditions related to deficiency states of the vitamin B several simultaneous vitamin complex, deficiencies may be implicated in the pathologic process. At least six inherited metabolic disorders have been shown to by pyridoxine responsive.“* None has been associated with any evidence of pyridoxine deficiency, and all require 5-50 times the usual physiological dose of pyridoxine for biochemical and/or clinical improvement. One of these disorders, homocystinuria, is important because of its prominent ocular feature, dislocation of the lenses. Although pyridoxine therapy has been shown to improve the mental disorder in homocystinuria, there is no evidence that it prevents or delays the lens dislocation process.69*104There is a tendency for intravascular thrombosis formation in patients with homocystinuria which can precipitate serious complications, particularly after surgery. It is noteworthy that this tendency does not seem to be pyridoxine responsive.6a Nicotinic Acid The disease, pellagra, is thought to be primarily the result of low intake of nicotinic acid or its percursor, tryptophan. However, it may occur as a consequence of multiple vitamin deficiencies, or as the result of gastrointestinal infections. The symptoms of pellagra include headaches, weakness, dizziness, diarrhea, dryness of the skin, increased pigmentation of the skin, dementia, and a polyneuropathy. Optic neuropathy has been reported in patients suffering from pellagra,‘@ but it is not a common or prominent finding. One wonders if the optic neuropathy does not arise because of a simultaneous deficiency in one of the other B vitamins, and is unrelated to nicotinic acid metabolism. Degeneration of retinal ganglion cells have been noted in rabbits fed a diet deficient in nicotinic acid?O In the anterior segment of the eye nicotinic acid is thought to be important in normal and cornea1 metabolism. conjunctival

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Cornea1 vascularization, pigmentation at the limbus, and separation of the basal cell layer of the conjunctiva have been documented in rabbits fed a diet deficient in nicotinic acid.16’ Enhanced cornea1 wound healing was described in healthy rabbits fed supplemental amounts of nicotinic acid.’ Recently, excessive nicotinic acid ingestion has been implicated as a potential cause of a serious ocular disturbance. The use of nicotinic acid in high doses of 3-6 grams/day has become a widely accepted treatment for lowering serum lipids.’ A newly recognized toxic maculopathy has been described in three patients who lost central vision while on this therapeutic regimens2 An atypical form of cystoid macular edema without perifoveal retinal capillary leakage was observed. These macular changes improved, or disappeared completely, after nicotinic acid ingestion was halted. It is interesting that in the case reports of acute nicotinic acid intoxication caused by ingestion of meats dusted with nicotinic acid, this macular disorder was not observed.l?o It would seem that this maculopathy only occurs with chronic excessive intake of nicotinic acid.

Vitamin B,, and Folic Acid Ophthalmic interest in these two vitamins has focused primarily on their role in optic nerve metabolism. A deficiency of vitamin B,, may occur either because of poor intake or the inability to absorb the vitamin from the gastrointestinal tract (usually as the result of achylorhydria). Pernicious anemia is a systemic disease that may result from a vitamin B,, deficiency state. Although damage to the central and peripheral nervous system is common in this disorder, optic nerve dysfunction is only rarely a consequence of pernicious anemia.g*68 Optic neuropathy may be associated with vitamin B,, deficiency of other origins, including veganism,66 tapeworm infestation,“’ and ileal resections.“* Nonetheless, it is extremely difficult to induce a deficiency of vitamin B,, severe enough to produce optic nerve damage.¶ Optic nerve involvement appears to be more common in patients with vitamin B,, deficiency who smoke.61 Furthermore, tobacco smokers have been found to have impairment of intestinal absorption of this vitamin.“’ These observations coupled with

HOYT

the fact that vitamin B,, is required for the normal detoxification of cyanide has led some authors to postulate that cyanide is the causative factor in some optic neuropathies.U This theory is countered by the fact that sublethal acute cyanide toxic doses rarely lead to optic nerve degeneration,6* and that cyanide is not a cumulative poison.l” Nevertheless, clinical reports have documented improvement in optic nerve function in tobacco amblyopia patients given supplemental hydroxycobalamin.” Recently, it has been suggested that simultaneous deficiencies of vitamin B,, and sulfur-containing amino acids are responsible for the optic nerve lesions in tobacco amblyopia.l16 Considerable controversy still exists in this regard, but it is well established that normal cyanide detoxification requires sulfur-containing amino acids for conjugation, and vitamin B,, which is an essential coenzyme in the elaboration of methionine from homocysteine.46 The interrelationship of cyanide detoxification, vitamin B12, and sulfur-containing amino acids seems to be the essential metabolic problem area in the ataxic neuropathy syndrome reported in Western Nigeria,lw and in Jamaican amblyopia.“’ In both these conditions, optic nerve dysfunction is a cardinal feature.ll*JM In the case of the Nigerian neuropathy, it has been documented that one of the major staples in the diet, cassava, contains a high level of cyanide, and very low levels of vitamin B,* and sulfurcontaining amino acids.“’ However, attempts to treat Nigerian patients with the appropriate vitamins and nutritional supplements have been woefuily unsuccessful; this may be because the dietary intake of cyanide continued. 110 It seems clear that nuances of normal cyanide metabolism and its relationship to dietary deficiencies will become a vital concern to the medical communities of the food-starved nations which are seeking inexpensive protein alternatives. Attempts have been made to invoke the cyanide-vitamin B,, relationship as a causative factor in Leber’s optic neuropathy. lMIt has been argued that Leber’s optic neuropathy is an inborn error of cyanide metabolism, exacerbated by smoking and/or vitamin BIP deficiency. However, clinical trials of hydroxycobalamin in patients with Leber’s optic neuropathy have been disappointing in their failure to halt the progres-

TWRRAPRUTIC REVIRW

sion of the disorder, let alone improve it.148At the present time, the full extent to which deficiencies of vitamin B,, may precipitate optic nerve dysfunction has not been established. Vitamin B,, deficiency has been directly implicated in vascular changes of the retina. It has been noted that retinal hemorrhages, edema, and dilatation of retinal veins may occur in patients with megaloblastic anemia.la5 In a recent matched study of patients with megaloblastic anemias and patients with iron deficiency anemias of equal severity, the incidence and severity of retinal hemorrhages were much greater in the group with megaloblastic anemias.e1 Pure folic acid deficiencies are said not to result in any neurologic features of B,, deficiency pernicious anemia. It has been pointed out that vitamin B1*is selectively excluded from the spinal fluid, whereas, folate is concentrated there. Folic acid may play an active, although indirect, role in producing optic neuropathy in patients with pernicious anemia by’ mobilizing the remaining vitamin B,, storeslo On the other hand, a recent study has documented that folic acid deficiency without vitamin Blz deficiency can cause neurological symptoms; however, optic nerve dysfunction was not recognized in the reported patients.M A careful study of patients with laennac’s cirrhosis indicates that folate deficiency may be correlated with impaired color vision.lzT These patients were preselected by eliminating those with any ocular defects other than Whether folic acid dedyschromatopsia. ficiency affects primarily the rods and cones, or the retinal ganglion cells, has not been documented. Three children with a volateresponsive form of homocystinuria have been described, but no comment was made concerning the effect of this therapy on stability of the lenses.‘O

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conjunctiva, anterior chamber, and retina. In infantile scurvy the most dramatic event is proptosis which results from subperiosteal hemorrhage in the orbital bones4’ However, this occurs in no more than 10% of infantile scurvy victims, and rarely occurs in adults. Although much attention has been directed toward investigation of vitamin C and its role in normal metabolism of the eye, no other clinical ocular entity has been proven to result from vitamin C deficiency. It has been suggested that vitamin C deficiency may be a causative factor in the diabetic retinal hemorrhages, recurrent vitreous hemorrhages, and cataract formation, but no conclusive evidence supports any of these theories at the present time. The ascorbic acid level in aqueous humor and lens may exceed the plasma level by as much as 50-fold in some species. It has been shown that vitamin C concentration in the aqueous of cataractous eyes is much less than that in normal eyes. l6 The complete role of vitamin C in normal lens metabolism remains to be detailed. The importance of aqueous vitamin C levels for proper cornea1 wound healing has been emphasized. p4 However, in studies of guinea pigs the high concentration of vitamin C in the aqueous is maintained even in scorbutic animals.128 This selective maintenance of vitamin C levels in the aqueous would seem to protect the collagen of the cornea from the more severe effects of vitamin C deprivation seen in the collagen of other tissues. In some animals the concentration of vitamin C in the aqueous is probably maintained by synthesis within the lensgl However, this does not seem to be true in humans. Early reports of the clinical features of scurvy reported night blindness as a feature of this disorder.M However, it appears that these cases involved concomitant vitamin A and C deficiencies. It should also be noted that retinal levels of vitamin C are several hundred Vitamin C times the plasma levels.” In the rat it has A deficiency of vitamin C in humans, other been demonstrated that ascorbic acid is primates, and guinea pigs, results in the dis- transported into the retina by an energyease known as scurvy. Most other animals are dependent, sodium-sensitive active transport capable of synthesizing vitamin C from car- mechanism.“’ The active maintenance of high bohydrate precursors. The clinical features of retinal levels of ascorbic acid has been inthe scorbutic state include bleeding gums, in- voked to explain the infrequency of retinal tracranial bleeding, subperiosteal hemor- hemorrhages in scurvy. Retinal vitamin C rhages, hematuria, heart failure, and purpural levels have been correlated with alterations of bleeding. Ocular involvement is primarily due visual field size for green targets,” and im. _ _._ However. definite . to hemorrhages which may occur in the lids, ,moved dark adantation.‘”

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evidence of vitamin C function in normal retinal physiology is not positively documented at present. Large doses of vitamin C (0.5 G/Kg) have been used to lower intraocular pressure.“‘*“’ The effect is most pronounced in patients with chronic simple glaucoma, but the large doses were associated with diarrhea and other gastrointestinal symptoms. The ability of vitamin C to penetrate easily into the anterior chamber has prompted the suggestion that vitamin C might be an effective vehicle for drugs with poor cornea1 penetration.“* No ocular complications resulting from excessive vitamin C ingestion have been reported despite the current pandemic of megadose vitamin C usage. Systemic toxic effects from ingestion of large amounts of vitamin C include acidosis, gastrointestinal complaints, glycosuria, or sensitivity reactions; these effects are insignificant or rare.’ However, there have been a few reports of effects which are not so negligible. Especially threatening is the possibility of systemic conditioning, particularly in infants born of women receiving ascorbate during pregnancy. The possibility of increasing serum cholesterol levels in atherosclerotic patients and of destruction of vitamin Blz requires further documentation.

Vitamin D Vitamin D is actually a group of steroid compounds essential for the maintenance of normal calcium and phosphate metabolism. Vitamin D deficiency causes rickets in the growing young animal, and osteomalacia in adults. There is very little evidence to suggest that the eye is primarily involved in vitamin D deficiency states. Zonular cataracts may be seen in tetany and rickets. However, it has been demonstrated in rats that the cataractogenie process is correlated with the decreased calcium levels and not primarily with the vitamin D deficiency.6 Some old reports suggested that proptosis may occur in rickets due to orbital hemorrhage. The mechanism whereby vitamin D deficiency might cause hemorrhage seems obscure. It would appear most likely that the cases described were cases of combined scurvy and rickets. Some investigators have coined the term, “Scleral rickets,” for the condition of weakening and stretching of the sclera which they postulate results from vitamin D deliciency.18 These

authors proposed that progressive myopia and/or keratoconus may be improved by vitamin D administration. However, other researchers have failed to substantiate this. Excessive ingestion of vitamin D may cause a lethal syndrome characterized by anorexia, loss of weight, nausea, pain, diarrhea, weakness, polydipsia, multiple fractures, and renal damage. 18*The alterations in calcium and phosphate levels may lead to cornea1 and conjunctival calcification.28*64 However, it should be emphasized that it is the elevated serum calcium level, not the actual vitamin D level, which is directly responsible for these ocular changes.

Vitamin E Vitamin E, or alpha tocopherol, is found in high concentration in wheat germ oil, green vegetables, and nuts. However, it is nearly ubiguitous in foods, and experimental vitamin E deficient diets are difficult to construct and maintain. No disease state in man has been proven to arise as a result of a deficiency in vitamin E. In experimental animals the most severe ocular changes have been reported as a result of in utero, rather than post-natal, deprivation of vitamin E. In the embryos of turkey hens fed a low vitamin E diet, ocular defects included corneal bulging, intraocular hemorrhages, and lens epithelial proliferation with cataract formation. Recently, it has been demonstrated that lenticular opacities are more common in infant rats if the maternal diet during gestation and lactation was deficient in both vitamin E and tryptophan.2g Although retrolental fibroplasia has been clearly linked with neonatal arterial hyperoxemia, effective prevention of this retinopathy is not always possible even with the most fastidious oxygen monitoring. Because of the antioxidant property of vitamin E, several studies have been undertaken to ascertain its effectiveness in preventing the retinopathy of These studies appear prematurity. 71~113~1s14 promising, and longterm clinical trials are currently in progress. In a recent experiment in rabbits, an oxygen-induced visual cell degeneration was described.** Pretreatment with vitamin E supplements did not prevent this visual cell damage. However, in a clinical study of glaucoma patients, the addition of vitamin E to the regular antiglaucomatous medication

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TABLE 1 Summary Vitamin

Tissues Requiring Vitamin

of Vitamin Requirements Effects of Deficiency

in Ophthalmology Effects of Excess

Therapeutic Uses

Vitamin A

Epithelial cells Visual pigments

Xerophthalmia, xerosis, Bitot’s spot, ulceration, secondary infection Night blindness

Pseudotumor cerebri

Xerophthalmia Night blindness

Thiamine (B,)

Optic nerve ? Cornea

Optic neuropathy, Wernicke’s encephalopathy Cornea1 epithelial damage

None

Optic neuropathy secondary to alcoholism or low carbohydrate diet Leigh’s disease

Riboflavin (B2)

Optic nerve ? Cornea1 epithelium

Cornea1 vascularization Cataract (in animals) ? Blepharitis

None

Probably none

Pyridoxine (Be)

Optic nerve Cornea

Optic neuropathy in patients taking hydralazine, isonazid or penicillamine

None

Optic neuropathy due to hydralazinc, isonazid, or penicillamine

Nicotinic acid

Optic nerve Conjunctiva, cornea

Optic neuropathy Cornea1 vascularization

Atypical cystoid maculopathy

? Cornea1 wound healing

Vitamin B,,

Optic nerve

Optic neuropathy due to pernicious anemia, tobacco, tropical neuropathies

None

Optic neuropathy due to pernicious anemia, tobacco, tropical neuropathies

Vitamin C

Blood vessels

Hemorrhages in lids, conjuctivae, anterior chamber, retina

None

Bleeding ? Lower intraocular pressure

Vitamin D

None in the eye

Cataracts secondary to tetany

Renal damage

None in ophthalmology

Vitamin E

Not certain

No deficiency state known

None

? Retrolental tibroplasia ? Glaucoma

Vitamin K

None in the eye

Bleeding disorder

None

? Retinal hemorrhages in neonates

was reported to result in improved visual fields in 68% of patients.*l Further research is required to elucidate the role of vitamin E in both normal and pathological retinal and optic nerve metabolism. Impressive changes were reported to occur in the eyes of rats fed a diet deficient in vitamin E; these included keratoconjunctivitis, keratoconus, iridocyclitis, cataract, and serous retinal exudates.a6 However, these changes have not been reported by other investigators and the details of the diet in this study have not been

published. Most researchers in this field doubt that any significant ocular changes occur in adult animals whose diet is deficient solely in vitamin E.

Vitamin K Vitamin K was discovered after it was noted that chicks fed a diet poor in fats developed a hemorrhagic disease.80 This observation led to the discovery of the fat soluble nature of the vitamin. In most mammals, a deficiency state does not occur primarily as the result of dietary insuffcien-

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cy, because the normal intestinal flora synthesize vitamin K. Thus, vitamin K deficiency in humans evolves either as a result of insufficient bile to absorb the formed vitamin K, or as a consequence of some disturbance of the normal intestinal flora. In experimental animals no ocular manifestations have been documented as a result of vitamin K deficiency. Similarly, in experiments in guinea pigs, where massive doses of vitamin K were given, no toxic ocular lesions were seen.1ze This is remarkable, in that many of these animals developed severe degenerative changes in the liver, kidneys, and adrenals. Ophthalmologists have centered their interest in vitamin K on any potential role that deficiency states might play in causing retinal hemorrhages (particularly in the newborn). Prenatal administration of vitamin K to expectant mothers has been reported to reduce significantly the incidence of retinal hemorrhages in the newborn.80J1e Furthermore, it has been demonstrated that neonatal retinal hemorrhages, although fundamentally of mechanical origin, are more frequent when there is a concomitant coagulapathy.” However, at the present time, vitamin K supplementation for expectant mothers is not a common medical practice in this country. Furthermore, there is very little interest in creating an experimental mode of infantile retinal hemorrhages. Both of these facts can be explained in light of the essentially benign nature of, and good visual prognosis in, the syndrome of infantile retinal hemorrhages.

Summary Vitamin deficiency states are important in the genesis of many ocular disorders. Although vitamin deficiencies resulting from poor dietary intake are unusual in most developed nations, they are still a major health problem in many underdeveloped nations. In underdeveloped countries a significant proportion of ophthalmic problems are either directly caused by or aggravated by poor vitamin intake. Many of the resulting ocular conditions are potentially sight-threatening. In develaped nations the role of normal vitamin metabolism in the eye is important for several ‘reasons. Some commonly prescribed medications produce their side-effects by interfering with normal vitamin metabolism. In addition, the possibility that some vitamins might exert im-

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portant pharmacologic effects on the normal eye has been a topic of renewed research interest. Several inherited and acquired diseases interfere with the absorption and/or metabolism of individual vitamins. Knowledge of the specific vitamin involved allows the clinician to initiate treatment with the appropriate supplements. Finally, it is remarkable that, in this era of megadose vitamin usage by a large segment of the population in the United States, few serious systemic or ocular complications of this fad have been reported.

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Reprint requests should be addressed to Creig S. Hoyt III, M.D., Department of Ophthalmology, Room 490-U, University of California Medical Center, San Francisco, California 94143.