Eye (1989) 3, 240-250

Lipid Deposition at the Limbus

S. M. CRISPIN Bristol

Summary deposition at the limbus is a feature of familial and non-familial dyslipopro­ teinemias and can also occur without apparent accompanying systemic abnormality. Hyperlipoproteinemia, most notably type II hyperlipoproteinemia, is frequently associated with bilateral corneal arcus, with less common association in types III, IV and V. Diffuse bilateral opacification of the with accentuation towards the limbus is a feature of HDL deficiency syndromes and LCAT deficiency. Whereas the lipid accumulation of hyperlipoproteinemia may be representative of excessive insudation of from plasma into the cornea that of hypoliproteinemia is more likely to be a consequence of defective lipid clearance. The situation is yet further complicated by the modifying influences of secondary factors. both local and systemic.

Lipid may be deposited at the limbus in a so. Both local and systemic factors can influ­ variety of situations; most commonly it ence lipid deposition in this region and their accumulates as a consequence of excessive inter-relationships are complex and often lipid entry or defective lipid clearance over a poorly understood. Some of the local factors long period of time, but this is not invariably which have been investigated include normal and abnormal structure and function; the effects of temperature and vasculature; and the modifying influences of certain ocular disorders. LIVER Local lipoprotein metabolism of cornea and limbus has received little study but there is a wealth of information available concerning systemic plasma in health and disease and a number of dyslipoproteinemias VLDLI LDL have been reported in which corneal lipid deposition is one of the clinical features. In view of this association, it is important to examine briefly some aspects of lipoprotein metabolism; further information can be LDL obtained from recent reviews. 1.2 PERIPHERAL CELL Lipoprotein Metabolism Fig. 1. Outline of central pathways of lipoprotein Normal human lipoprotein metabolism is metabolism.

Correspondence to: Dr. S. M. Crispin, School of Veterinary Science, University of Bristol, Langford House, Langford, Bristol 8S187DU. LIPID DEPOSITION ATTHE LIMBUS 241 summarised very simply in Figure 1. Lipopro­ ( linoleate) to CIS: 1 (cholesterol teins consist of a hydrophobic core of cho­ oleate) ratios. lesteral esters and triglycerides surrounded by High density lipoproteins (HDL) form a very a membrane-like shell of free cholesterol, heterogeneous group. They are derived from phospholipid and apolipoproteins. The the catabolism of both VLDL and apolipoproteins increase in relative propor­ chylomicrons as well as by direct synthesis tion as the size of the lipoprotein diminishes from the liver and small intestine. The newly and concomitant with this there is progressive synthesised (nascent) HDL is disc shaped and decrease in lipid content. contains no esterifiedcholesterol. Production of mature spherical particles of HDL (diam­ Triglyceride rich lipoproteins are secreted 3 eter 7 nm) and HDLz (diameter 10 nm) is from the small intestine as large (>75 nm) dependent on the plasma cholesterol esterify­ chylomicrons which contain apoliprotein ing enzyme lecithin cholesterol acyl trans­ B-4S (apo BAS). The triglyceride of ferase (LCAT) or, more specifically, alpha­ chylomicrons undergoes lipolysis through the LCAT as beta-LCAT is associated with action of apo C-ll activated lipoprotein lipase esterification of LDL and VLDL cholesterol. (LPL) in peripheral capillaries and the result­ Phospholipid is the more abundant lipid com­ ing chylomicron remnants are rapidly cleared ponent of most HDL. followed by cholesterol by receptor mediated hepatic uptake. ester. Apo A-I (a co-factor for LCAT) and The liver also secretes triglyceride-rich par­ apo A-ll (a structural protein) are the major ticles called very low density lipoproteins HDL apolipoproteins, with B, C and E as (VLDL) of some 30-90 nm diameter which minor components. contain apo B-100, as well as apo C and E, and HDL appears to be involved in reverse cho­ these too are degraded by LPL. Some VLDL lesterol transport from the peripheral tissues remnants are removed by the liver and others to the liver; by removing cholesterol from are converted to low density lipoprotein these sites it can be said to have anti-athero­ (LDL) via intermediate density lipoprotein genic activity. It is therefore particularly sig­ (IDL). nificant that HDL rather than LDL is the Low density lipoprotein is the major cho­ major transporter of plasma cholesterol in the lesterol transporter in man, it is of some dog, a species known to be highly resistant to 20-25nm diameter and rich in apo-B. LDL is naturally occurring . Whether removed from the circulation by specific cell or not these innate differences of cholesterol surface receptors which recognise both apo transport make any difference to the patho­ B-100 and apo E (B/E receptors). B/E recep­ genesis of corneal stromal lipid deposition is a tors are found on peripheral cells like fibro­ matter of conjecture. blasts. smooth muscle cells and endothelial cells as well as in the liver. By a well defined Local Factors and Lipid Deposition at the pathwayO LDL is taken into the cell and free Limbus cholesterol and amino acids are liberated by and lipoproteins probably reach the lysosomal hydrolysis. The free cholesterol corneal stroma from the limbal vessels. Distri­ supresses the activity of 3-hydroxy 3 methyl­ bution within the stroma depends upon local glutaryl coenzyme A reductase (HMO Co A vessels, local temperature effects, the reductase) which controls the rate deter­ size and properties of the lipids and lipopro­ mining step in cholesterol biosynthesis, it also teins, the potential for interaction with other down regulates production of LDL receptors plasma constituents and corneo-limbal com­ and stimulates its own re-esterification by ponents, and the organisation of the corneal activating acyl-COA: cholesterol acyl­ stroma. transferase (ACAT). The overall effect of re-esterificationis to shift the balance of fatty Blood vessels acids in the cholesterol esters from a polyun­ Lipid can migrate right across the vessel wall saturated to a more saturated form, most in capillaries4 and normal endothelium is per­ readily appreciated by examination of C1S : 2 meable to plasma macromolecules.5 Lipid 242 S. M. CRISPIN transport is more rapid in newly formed cell necrosis in progressive lesions, affecting vessels and in inflamedor damaged vessels,6J,S particularly lipid-filled fibroblasts (ker­ increased temperature may also increase local atocytes) rich in esterified cholesterol; cell capillary permeability.9 death results in the deposition of extracellular No enzyme degradative system for cho­ crystalline and non-crystalline material, lesterol exists in the blood vessel wall whereas mainly free and esterified cholesterol and phospholipids and triglycerides can be influ­ varying quantities of phospholipid, 11,13 enced by phospholipases and triglyceride In humans lipid keratopathy is much com­ lipases respectively,1O There have been no moner in women than men, a review of the studies of enzyme degradation in the limbal existing literature revealed a ratio of approxi­ blood vessels but it is possible that lipids and mately 70: 30 per cent. \3 Few studies have lipoproteins delivered to the stroma are modi­ examined the lipoprotein profile in detail in fiedon arrival. Corneal lipid deposition can be humans which is odd in view of the-reported dramatic when peri-limbal blood vessels are similarity to atherosclerotic plaques,II.l5 In inflamed or if corneal neovascularisation has studies of dogs with naturally occurring lipid occurred, whether as ghost vessels in quiet keratopathy raised cholesterol-enriched plas­ eyes or as part of active inflammation.11 ,12,13 ma HDL was the commonest finding13 and Lipid keratopathy, a vascularised form of lipid keratopathy is the usual sequel to inges­ lipid deposition, is perhaps a consequence of tion of high fat diets rich in cholesterol in the unmodified lipid deposition, For inflamed or rabbit. The predominantly peripheral distri­ new vessels, especially in the presence of cor­ bution of lipid in hypercholesterolemic rab­ neal damage, will allow access by lipoproteins bits bears a superficialresemblance to human of all sizes, The most marked depositions arcus; however there is no lucid interval of occur if the human or animal is also Vogt, the lesion is vascularised and there are hyperiipoproteinemic, usually hyperchol­ abundant quantities of acicular birefringent esterolemic, when neovascularisation oc­ crystals in addition to numerous fat-filled curs. 13,14 The lipid keratopathy varies in cells. 14 extent, position and depth according to cause It is possible to produce regression of some (Figs, 2-5), lipid keratopathies in dogs, humans and rab­ Lipid keratopathy is typified by extensive bits,1 3,16,17 In dogs this situation is achieved by restoration of normolipoproteinemia and local effects within the cornea, Effective cor­ neal vascularisation permits lipid clearance by haematogenous macrophages and multi­ nucleate giant cells, other compensatory devices such as increased phospholipid syn­ thesis and liposome formation play a lesser role, Whilst blood vessels may be crucial in delivering lipid to the cornea they may also be instrumental in making possible its clearance,

Temperature Blood flowand corneal temperature are inter­ related in that a rise in temperature is associ­ ated with a corresponding increase in the cap­ illary filtration coefficient.18 Regional temperature differences may be relevant to long term corneal lipid deposition such as human arcus in which it has been demon­ strated that arcus commences in the warmer Fig. 2. Jack Russell Terrier (f emale), Lipid kera­ topathy left eye following cat scratch 9 months earlier. regions of the cornea and that if a unilateral Mild increase in HDL cholesterol, arcus is present it is the warmer eye which is LIPID DEPOSITION AT THE LIMBUS 243

Fig. 3. Golden Retriever (castrated male). Lipid kera­ Fig. 4. Labrador (castrated male). Diffuse and cir­ topathy right eye-following diffuse . Mild cumscribed lipid deposition left eye-following scle­ and . ritis. Mild hypercholesterolemia and hypertriglyceridemia. affected.19,20 Arcus can also be deflected by ticularly obvious in areas below body core conditions which modify local blood temperature like the tonsils and medial and flOWIl.13,20,21 (Fig. 6) and it is possible to have lateral quadrants of the cornea.24 It is possible both arcus and lipid keratopathy in the same that the cooler regions provide a critical tem­ cornea. perature difference which slows melting of the Arcus senilis is a normal feature of human cholesterol ester liquid crystals and impedes ageing (Fig. 7) but its incidence shows marked their utilisation. individual and racial variation22 and there is an inconsistent relationship between arcus and Physical and Chemical Modifications to hyperlipoproteinemia23 which will be con­ Lipoprotein and Lipids sidered when systemic factors are discussed. This is a complex subject which has been little In dogs there are interesting breed variations studied in the cornea. There are, however, in susceptibility to corneal lipid deposition. some excellent reviews concerned with Whilst warmth can encourage lipid and atherosclerosis which are relevant to corneal lipoprotein deposition the converse is also lipid deposition in relation to both the lipids true and remobilisation of deposited lipid may and lipoproteins,25.26.27 and the corneal fibro­ be more difficult in cooler areas. In Tangier blasts and intercellular matrix.3•28 disease, for example, cholesterol ester-rich The normal human cornea has a very lipid accumulates in several sites and is par- orderly arrangement of collagen fibrils

Fig. 5. Afghan Hound (female). Right and left eye; lipid deposition occurred in apparently normal cornea, affecting the left eye before the right. Intermittent mild hypercholesterolemia and marked hypertriglyceridemia; repeated blood samples indicated normolipoproteinemia on most occasions. 244 s. M. CRISPIN

bound by collagen, GAGS and proteo­ glycans.28 In relation to arcus, Fielder and others20 showed that intact LD L is an inconsistent con­ stituent of arcus and no evidence for per­ sistence of GAG-lipoprotein complexes was found in arcus material examined,30 so it is possible that GAG-lipoprotein interactions do not occur in the cornea or are concerned only with initial localisation. This is a slightly different situation from that of atherosclerosis where apo B-IOO segments with positively charged side chains have been shown to medi­ ate the action of LDL with chondroitin J<'ig. 6. German Shepherd Dog (neutered female). sulphate.31 Corneal arcus left eye at the edge of a limbal melanoma. Other important interactions which may NormolijJOproteinemia. occur are between the lipoproteins them­ selves, between the lipids of cell membranes centrally, whereas at the limbus there are and between the lipoproteins and corneal fewer fibrils of more diverse diameter spaced fibroblasts. Whether these interactions occur further apart. The organisation of collagen between intact lipoproteins with minor com­ fibrils is directly related to the acidic positional changes, or whether between dis­ glycosaminoglycan content which is highest sociated lipoprotein constituents, is poorly centrally. The small, negatively charged, ker­ understood. However it is clear that lipopro­ at an sulphate molecules on the surface of the teins and lipids deposited at the limbus do proteoglycan subunits, which coat the col­ undergo both chemical and physical modifica­ lagen fibrils, create a negatively charged field tions. Evidence for chemical modification comes from studies of corneal arcus and lipid around each collagen fibril.which maintains keratopathy. Two profilestudies on precise spacing of the fibrils by mutual repul­ corneae with arcus, analysing total lipids32 or sion. The greater spacing found at the peri­ the cholesterol ester fraction?) both indicate a phery is probably due to the larger size of the lower Iinoleate and higher saturated fatty acid negatively charged chondroitin sulphate mol­ content than would be expected from ecules which are absent from central cornea. 29 unmodifiedLDL which is rich in linoleic acid. Maurice30 suggested that the largest mole­ In lipid keratopathy fibroblastinvolvement cule capable of diffusing across unswollen is an early feature of naturally occurring cases human cornea would be of approximately 12 nm diameter. The size of intact lipopro­ teins is such that only free fatty acid-albumin complexes and HDL will be theoretically capable of such diffusion. Other lipoproteins (LDL, VLDL and chylomicrons) are too large to make free diffusion of intact lipoprotein a practical possibility in normal cornea. In addition to the potential for free diffu­ sion there are, however, other mechanisms to be considered; for example the liproproteins may dissociate, the glycosaminoglycans (GAG) might act as a molecular sieve and there is the possibility of specific ionic com­ Fig. 7. Human (male}-Corneal arcus (bilateral). plex formation. There is some evidence from Normolipoproteinemia. (With acknowledgement to work on atherosclerosis that lipids can be Professor A. F Winder.) LIPID DEPOSITION AT THE LIMBUS 245

in dogs and humans and experimental lesions alphalipoproteinemia although the corneal in rabbits. \3 Once lipoproteins have been appearance was not described.34 In patients chemically modified within the cornea physi­ with corneal opacification apo A-I, A-li, cal alterations may follow. Mobility is related C111 and E were elevated and there was to the physical state of the lipid (liquid drop­ defective net transfer of cholesterol ester from let, liquid crystal, solid crystal) and properties HDL and decreased hepatic lipase activity. such as solubility, chain length and saturation HDL particles were markedly enlarged and are relevant. It is of interest that the lipids LDL particles were small and polydispersed. which accumulate in atherosclerosis and lipid keratopathy (cholesterol, cholesterol esters Hyperlipoproteinemia and Corneal Arcus and phospholipids) are water insoluble and in The World Health Organisation study group35 this context it is worth remembering that the classifiedhyperlipoproteinemia into six types; presence of predominantly crystalline, high the divisions are somewhat arbitrary as they melting point lipids, does not necessarily indi­ are based on the patterns of lipoprotein eleva­ cate their exclusive production, but rather the tion rather than knowledge of the specific more rapid removal of non-crystalline, lower defect involved. There are common clinical melting point, lipids. Central cornea is some features between some of the types and exten­ 3.6 degrees C below body temperature in sive modification can also occur because of humans whilst the limbus is approximately treatment. 1 degree C warmer than the centre. Cho­ Peripheral lipid deposition is a feature of lesterol esters can undergo reversible thermal types II, III, IV and V, notably as xanthomata transitions at around body temperature asso­ and corneal arcus. Corneal arcus is common ciated with a liquid crystalline order-disorder in type II, less so in type IV and develops phase change. In intact LDL, for example, the occasionally in types III and IV, it is probably amount of triglyceride present can influence a visible manifestation of excessive insudation the fluidityof the cholesterol esters." Increas­ of plasma lipoprotein. ing the amount of triglyceride lowers the tem­ perature at which the liquid to smectic liquid Type IIa Hyperlipoproteinemia crystalline transition occurs. There is, how­ Inherited type IIa hyperlipoproteincmia (FH) ever, individual variation, so that although is due to a qualitative or quantitative defect in the peak transition temperature is appro x­ LDL receptors. Hence LDL and apo-B levels imatley 30 degrees C some individuals will are increased as mechanisms for cellular have a fraction of LDL cholesterol esters in a uptake of LDL and consequent supression of smectic-like state at body temperature. In intracellular cholesterol synthesis are addition, patients with homozygous familial defective. In FH homozygotes the resulting hypercholesterolemia (FH) have less tri­ hypercholesterolemia is such that survival glyceride in LDL compared to normals. These beyond twenty years is rare and death usually findings are therefore of significance with occurs because of premature atherosclerotic regard to peripheral lipid deposition in both heart disease. Heterozygotes develop vari­ normolipoproteinemic and hyperlipopro­ able degrees of the same clinical manifesta­ teinemic individuals. tions as homozygotes at a slower rate.36.37 Premature arcus is common (Fig. 8) usually Systemic Factors and Lipid Deposition at the before 10 years of age in homozygotes.36 Limbus In secondary type lla hyper- Hyperlipoproteinemia cholesterolemia it is also possible that recep­ Raised lipoprotein levels are found in both tor mediated catabolism of LDL is abnormal, primary inherited types of hyperlipopro­ possibly influencedby factors such as diet and teinemia and secondary non-inherited types. hormones. The defect can be reversed by appropriate therapy, for example thyroxine Hyperalphalipoproteinemia administration for hypothyroidism.38 Corneal opacification has been reported in The inconsistent relationship between association with some cases of hyper- arcus and hyperlipoproteinemia was clarified 246 s. M. CRISPIN

upper and lower lids as in man, but also in the region of the third (Figs. 9-12). The lack of senile arcus formation in dogs may be indicative of more effective scavenger mecha­ nisms at the limbus, perhaps connected with the high levels of HDL which are concerned with cholesterol transport in this species.

Type lIb Hyperliproproteinemia In type lIb hyperlipoproteinemia the underly­ ing defect may be related to increased synthesis of apo B which results in over­ Fig. 8. Human (female)-Corneal arcus (bilateral). Patient heterozygous for FH. (With acknowledgement production of VLDL particles coupled with to Professor A. F. Winder.) decreased catabolism of LDL. The clinical course is rather less severe than for type IIa by Winder23 in a study of patients with homo­ but clinical findings are similar. zygous and heterozygous FH in which it was shown that arcus development correlated with Type III Hyperlipoproteinemia age and thus to the duration of hyperlipopro­ Corneal arcus is an occasional finding in type teinemia, rather than extent or pattern of III hyperlipoproteinemia (broad beta disease) hyperlipoproteinemia. which is characterised by the presence of Arcus Iipoides corneae is a very rare finding abnormal, and large, cholesterol-rich beta­ in dogs and is always associated with hyper­ VLDL. The accumulation of beta VLDL in Iipoproteinemia.39 In affected animals it is plasma is due to defective apo E mediated usually secondary to primary acquired removal of chylomicron remnants. hypothyroidism with raised plasma HDL (as cholesterol enriched HDLe alphaz lipopro­ tein) LDL (beta) and VLDL (pre-beta) as the Type IV Hyperlipoproteinemia commonest laboratory findings. Initially it Type IV hyperlipoproteinemia is charac­ resembles human arcus.40 In both there is fine, terised by raised VLDL. The arcus which extracellular, granular sudanophilia of the forms is more diffuse than that seen with stroma, and in Descemet's membrane a hypercholesterolemia and excess of LDL, marked sudanophilia with characteristic perhaps reflecting some differences in the hyaline quality. In man there is a similar mechanisms of lipid accumulation within the hyaline type of sudanophilia in Bowman's cornea.4' membrane; in the dog, which lacks Bowman's layer, this lipid deposits immediatley beneath the basal lamina of the corneal epithelium in Type V Hyperlipoproteinemia the subepithelial zone. As the canine arcus Type V hyperlipoproteinemia is associated becomes denser it becomes vascularised, the with chylomicronemia and hyper­ lucid interval of Vogt is usually absent and triglyceridemia. It bears some resemblance to scintillating crystals can be observed with the type I hypertriglyceridemia in which biomicroscope. Microscopy of chylomicronemia is the predominant finding. affected demonstrates intracellular Type V is due to apo C-ll deficiencywhereas involvement with cell death and necrosis con­ type I is a result of defective, or absent, apo tributing to the crystalline appearance. C-ll or LPL. There are no specific ocular Appropriate treatment with thyroxine features with either type although corneal reduces the density and extent of the corneal arcus may develop in type V. Reports of lipid arcus in a proportion of cases. It is of interest keratopathy associated with type 142 did not that the arcus forms preferentially in the contain sufficient information to discern warmest regions of the cornea; beneath the whether the association was coincidental. LIPID DEPOSITION AT THE LIMBUS 247

Fig. 9. German Shepherd Dog (male). Corneal arcus Fig. 10. German Shepherd Dog (male). The left eye (arcus lipoides corneae) associated with primary of the dog shown in Figure 9. The left cornea is more acquired hypothyroidism. Marked hyper­ opaque and has been affected for longer. Fine blood cholesterolemia and hypertriglyceridemia. The right vessels are present in the densest parts of the opacity. eye is shown.

Fig. 11. Human (female). Right eye showing typical Fig. 12. Human (female). The left eye of the patient corneal arcus. Normolipoproteinemia. (With acknowl­ shown in Figure 11. The reason for this dense arcus was edgement to Professor C. J. Phillips.) not clear. Fine blood vessels are apparent in the ventral opacity. (With acknowledgement to Professor C. 1. Phillips. )

Crystalline Stromal Dystrophy (Schnyder's both classical LCAT deficiency and alpha Crystalline ) LCAT deficiency (Fish ). This inherited disorder has been reported to occur in conjunction with hyperlipopro­ H D L Deficiency Syndromes teinemia in humans43 and dogs44 and in both Apo A-I deficiencyis common to all the HDL species it is possible that crystalline stromal deficiency syndromes in which corneal dystrophy is due to a genetically-determined opacificationhas been reported.4 6 The corneal local metabolic defect in the cornea and that opacity takes the form of a finegranular stro­ the morphological features may be modified mal haze which may be missed unless the cor­ by coexisting plasma lipoprotein abnor­ nea is examined with a slit lamp malities.45 biomicroscope. This panstromal lipid deposit has been described in familial apo A-I and Hypolipoproteinemia apo C-III deficiency, and Panstromal lipid deposition has been HDL deficiency with planar . In described in a number of familial HDL defi­ these disorders there is probably defective ciency syndromes and in LCAT deficiency; clearance of lipid from the cornea.47 248 S. M. CRISPIN

In Tangier disease opacities are more con­ with alteration in the character of the centrated in the periphery and the peripheral accumulating lipid by active local metabolism. density, circumferential with and approxi­ mately 0.5 mm on the corneal side of the lim­ Fish Eye Disease bus, is most apparent at 3 and 90'clock.24 In this condition there is a mosaic pattern of Patients with this condition usually have diffuse dot like opacities throughout the cor­ reduced levels of total cholesterol and LDL nea, but accentuated towards the limbus with mild elevation of triglyceride. The mor­ (Fig. 14). Material from two affected corneas phology of the ultracentrifugal HDL fraction indicated cholesterol and phospholipid from the plasma of homozygous Tangier enrichment in the stroma and Bowman's patients examined with the electron micro­ membrane. Numerous vacuoles were present scope indicates two distinct populations of between the collagen fibrils, those of Bow­ particles; one of 15-21 nm diameter and the man's membrane being smaller and more other of less than 5 nm diameter. 4S SO the trace numerous than those of the stroma. The fibro­ amounts of HDL in Tangier plasma differ blasts were not apparently involved.54 qualitatively and quantitatively from normal Plasma lipoprotein abnormalities include HDL.49 The intracellular lipid droplets which hypertriglyceridemia, raised VLDL and accumulate in macrophages in sites such as liver and spleen have been identified as cho­ lesterol esters. mainly in the smectic liquid crystalline state, at 37 degrees C.511

LCAT Deficiency In LCAT Deficiency Disease there is almost total absence of cholesterol esterification so that unesterified cholesterol and phos­ pholipids accumulate in the kidney, liver, spleen and cornea. HDL' are present in reduced quantities They are rich in phos­ pholipid (lecithin) and unesterified cho­ lesterol and thev malllly resemble 'nascent' Fig. 13. Human (female). LCA T deficiency, bilateral involvement. (With acknowledgement to Professor A. HDL, mature HDL particles are absent. F Winder.) There may he moderate increases in plasma total cholesterol and triglyceride and VLDL levels are often high. The corneal appearance is of numerous minute grey. microscopically visible dots which produce corneal haziness and a rather diffuse and soft edged arcus encircling the cornea5l (Fig. 13). Anterior and posterior crocodile shagreen has also been reported.52 Examination of an affected cornea53 indicated multilaminated accumulation of excess lipid, mainly as phospholipid and cholesterol with a reduced ester content. Cholesterol linoleate was the predominant residue in the cho­ lesterol ester fatty acid fraction, with a C18: 1/18: 2 ratio of 1 : 6.5. This ratio differs Fig. 14. Human (female). Fish Eye Disease (bilateral from that in normal cornea, and also from that involvement). A and B are the eyes of two sisters, Cis the eye of an affected unrelated female and D is a in plasma and other tissue deposits in LCAT normal eye for comparison. (With acknowledgement to deficiency. The corneal findingsare consistent Professor L. A. Carlson. ) LIPID DEPOSITION AT THE LIMBUS 249 reduced concentrations of HDL.55 Carlson experimental hypercholesterolemia. Arch and Holmquist56 demonstrated that the Ophthalmol 1959,61: 219-25. changes are due to a deficiency of plasma 15 Meesman A: Anatomischer befund eines auges mit massenhafter ablagerung von cho­ alpha-LCAT, (which has HDL as its preferred lesterinkristallen im vorderen kammer und substrate) in the presenc of normal beta­ sekundarer atheromatose der hornhaut. Arch f LCAT (which esterifies the cholesterol of Augenheilk 1924, 94: 56-72. LDL and VLDL). Ib Zeeman WPC and Groen J: Lipidosis corneae. Gen­ eeskundije bladen uit klinick en laboratorium voor de praktijk 1947, 41: 375-411. I am grateful to Dr. C. H. Bolton, Mr. A. J. Bron, 17 Rodger FC: A study of the ultrastructure and Professors L. A. Carlson, A. Garner, C. I. Phillips and cytochemistry of lipid accumulation and clear­ A. F. Winder for allowing me to use some of their ance in cholesterol-fed rabbit cornea. Exp Eye material. I am particularly indebted to Professor A. F. Res 1971, 14: S8-93. Winder for his help and guidance. My thanks to Mrs. IS Landis EM and Pappenheimer JR: Circulation. In M. Hughes for typing the manuscript and to Mr. J. Hamilton WF, Dow Peds. Handbook of Physiol­ Connibear and Mr. M. Parsons for some of the ogy, Washington DC: American Physiological photography. Society 1963: Volume 11, Section 2: 961-1034. 19 Fielder AR, Winder AF, Cooke DE Bowcock SA: Arcus senilis and corneal temperature in man. In References Trevor-Roper P ed. Proc Eur Congr Ophthalmol, I Grundy SM: Pathogenesis of hyperlipoproteinemia. London: Royal Society of Medicine, 1981: 1015- J Lipid Res 1984,25: 1611-18. 20. 2 Bolton CH: Lipid disorders. In Holton JB ed. The 20 Fielder AR, Winder AF, Sheraidah GAK, Cooke inherited metabolic diseases, London. Churchill ED: Problems with corneal arcus. Trans Livingstone 19S7: 358-83. ophthalmol Soc UK 1981, 101: 22-6. 'Brown MS and Goldstein JL: Receptor mediated 21 Forsius H and Eriksson A: and its rela­ control of cholesterol metabolism. Science 1976, tion to arcus senilis, and other similar 191: 150-4. conditions. Acta Ophthalmol1962, 40, 402-10. 4 Courtice FC and Garlick DG: Thc permeability of 22 Macaraeg PVJ Jr, Lasagna L, Snyder B: Arcus not the capillary wall to the different plasma lipopro­ so senilis. Ann Intern Med 1968,68: 345-54. teins of the hypcrcholesterolemic rabbit in rela­ 23 Winder AF: Relationship between corneal arcus and tion to their size. Quart J exp Physiol 1962, 47: is clarified by studies in familial 221-7. hypercholesterolemia. BrJ Ophthalmol1981, 67: 5 Bell FP, Adamson IL, Schwartz CJ: Aortic endo­ 789-94. thelial permeability to albumin: focal and 24 Spaeth GL: Ocular manifestations of the lipidoses In regional patterns of uptake and transmural distri­ Tasman Wed. Retinal diseases in children, New bution of 1131 albumin in the young pig. Exp Mol York: Harper and Row 1971: 127-206. Patho11974, 20: 57-68. 25 Small DM and Shipley GG: Physical-chemical basis "Friedman M and Byers SO: Some local factors of lipid deposition in atherosclerosis. Science affecting iridic lipid infiltration in hyper­ 1974,185: 222-9. cholesterolemic rabbits. Am J Physiol1959, 197: 26 Smith EB: Molecular interactions in human athe­ S42-9. rosclerotic plaques. Am J Pathol 1977,86: 665- 7 Friedman M and Byers SO: Excess lipid leakage: a 74. property of very young vascular endothelium. Br 27 Small DM: Progression and regression of athe­ J exp Path 1962,43: 363-72. rosclerotic lesions. Arteriosclerosis 1988, 8: 103- H Walton KW: The role of altered vascular per­ 29. meability in the induction of experimental 2" Camejo G: The interaction of lipids and lipoproteins xanthomata. Nutr Metab 1973, IS: 59-67. with the intercellular matrix of arterial tissue; its Y Rippe B, Kamiya A, Folkow B: Transcapillary pas­ possible role in atherogeneis. 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