Eye (1989) 3, 240-250 Lipid Deposition at the Limbus S. M. CRISPIN Bristol Summary Lipid 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 cornea 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 lipoprotein 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 lipoproteins 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 (cholesterol 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 atherosclerosis. 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 Lipids 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 blood 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