Corneal arcus as coronary artery disease risk factor

Atherosclerosis 193 (2007) 235–240

Review

Corneal arcus as coronary artery disease risk factor Antonio Fern´andez a , Alexey Sorokin a,b , Paul D. Thompson a,b,∗ b

a University of Connecticut, Farmington, CT, United States The Henry Low Heart Center, Cardiology Division, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, United States

Received 8 April 2006; received in revised form 25 August 2006; accepted 28 August 2006 Available online 17 October 2006

Abstract Corneal arcus is a lipid-rich and predominantly extracellular deposit that forms at the corneoscleral limbus. It represents the most common peripheral corneal opacity and is not associated with tissue breakdown but rather with the deposition of lipids. The deposition of cholesterol in the peripheral cornea and arterial wall are similar in that both are accelerated by elevated serum levels of atherogenic lipoproteins, such as low-density lipoproteins (LDL). Corneal arcus is more prevalent in men than in women and in Blacks than in Whites. Its prevalence increases with advancing age. It has been associated with hypercholesterolemia, xanthelasmas, alcohol, blood pressure, cigarette smoking, diabetes, age, and coronary heart disease. Nevertheless, it is not clear whether or not corneal arcus is an independent risk factor for coronary heart disease (CHD). The present systematic review examines the relationship of corneal arcus and CHD to determine if corneal arcus is an independent CHD risk factor. We conclude that there is no consensus that corneal arcus is an independent risk factor. The presence of corneal arcus in a young person should prompt a search for lipid abnormalities. Also, because corneal arcus represents physical evidence of early lipid deposition, its presence suggests the need for aggressive lipid therapy. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Corneal arcus; Atherosclerosis; Coronary heart disease; Hypercholesterolemia

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Definition of corneal arcus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Pathophysiology of corneal arcus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Composition of the corneal arcus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Prevalence of corneal arcus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Relationship with plasma lipids and hyperlipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Relationship between corneal arcus and familial hypercholesterolemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. Plasma lipid disorders and other corneal opacities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.8. Association between corneal arcus and cardiovascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.9. Clinical implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

236 236 236 236 236 237 237 237 238 238 239 239 239

∗ Corresponding author at: The Henry Low Heart Center, Cardiology Division, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, United States. Tel.: +1 860 545 2899; fax: +1 860 545 2882. E-mail address: [email protected] (P.D. Thompson).

0021-9150/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2006.08.060

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1. Introduction Estimates of individual atherosclerotic cardiovascular disease (ASCVD) risk are based on historical or physical examination findings of atherosclerosis as well as measurements of atherosclerotic risk factors, such as serum lipids, blood pressure, and cigarette use [1]. Such estimates are not exact and have prompted the use of nontraditional risk factors, such as lipoprotein particle size, high sensitivity C-reactive protein [2], lipoprotein a, and coronary artery calcification scoring [3] to assess ASCVD risk more accurately. Corneal arcus was first suggested as a cardiac risk factor by Virchow in 1852 [4], and has been supported by several subsequent studies. The present report presents a systematic review of corneal arcus as a coronary heart disease (CHD) risk factor.

2. Methods We performed a systematic literature search of articles published in English with Pub Med through July 2005 using the search terms “corneal arcus” alone and in combination with “coronary heart disease”, “hypercholesterolemia” or “atherosclerosis”. Abstracts and the retrieved articles relevant to corneal arcus, atherosclerotic disease and hypercholesterolemia were reviewed in detail. Older references from these articles were also reviewed. Studies based on small number of patients were not excluded, as most series are comparatively small. Abstracts were reviewed and appropriate articles retrieved and examined in detail. Selected citations from these articles were also reviewed. 2.1. Definition of corneal arcus Corneal arcus is a grey-white or yellowish opacity, 1–1.5 mm wide, located near the periphery of the cornea but separated from the limbic margin by a clear corneal zone 0.3–1mm wide [5,6] called the lucid interval of Vogt [7] (Fig. 1).

Fig. 1. Corneal Arcus in a 55-year-old woman with hyperlipidemia and CHD.

Corneal arcus is the most common corneal peripheral opacity [8] and is variably referred to as: gerontoxon, arcus lipidalis, arcus lipoides corneae. Corneal arcus must be distinguished from a congenital opacity of the peripheral cornea, embryontoxon, a feature of osteogenesis imperfecta, in which a peripheral lipid arc or ring extends to the corneal edge. 2.2. Pathophysiology of corneal arcus Corneal arcus consists of lipid deposits within the corneal stroma [8]. It is frequently associated with abnormal serum lipid levels, but may occur without any predisposing factors. Corneal arcus has also been associated with alcohol intake [9], diabetes mellitus [10,9], smoking [11], blood pressure [9,12,13], BMI [14], obesity [9], age [15] and Dupuytren’s contracture [16]. The term “corneal arcus” is used instead of “corneal ring” because the lipid deposition initially forms arcs at the inferior, then superior poles of the cornea. These separate arcs may ultimately join to form a ring or circle approximately 1 mm in width [17,18]. The greatest deposit of lipid occurs in the peripheral cornea and this may reflect the fact that the peripheral cornea receives the most perfusion from the limbic vasculature [19]. Lipid filtration from the limbic vessels in the corneal stroma may lead to arcus formation in the absence of any underlying degenerative change suggesting that arcus is more than just senile degeneration [20]. Corneal arcus is almost always bilateral [21]. Unilateral arcus is rare; but does occur on the contralateral side of unilateral carotid artery occlusions. This observation supports the role of limbic blood supply in arcus formation [22,23]. Unilateral corneal opacities can also be seen following surgery or trauma possibly secondary to vascular congestion or increased vascular permeability [8]. Corneal arcus has no local consequences and does not threaten sight [12]. 2.3. Composition of the corneal arcus As early as 1850, Canton [24] demonstrated that the corneal deposit was insoluble in water and acetic acid but soluble in ether, suggesting that it was lipid. Numerous subsequent studies confirmed this report [25,20,26–28] and demonstrated that the deposits are composed of cholesteryl ester-rich lipid particles, primarily from low-density lipoproteins (LDL), phospholipids and triglycerides [29]. Most of these particles are 40–200 nm in diameter and thus similar in size to some of the cholesteryl ester-rich particles that accumulate in atherosclerotic lesions [28]. The adult human cornea normally lacks macrophages and foam cells [20], possibly explaining why corneal arcus does not injure corneal tissue. Evidence suggests that LDL is a major source of the cholesteryl ester that accumulates in the cornea. Corneal arcus formation is accelerated by high plasma LDL levels [30]. Apo B, the major LDL apoprotein is present in the corneal arcus, although the lipid particles in the arcus are of lower density and larger diameter than plasma LDL. These

A. Fern´andez et al. / Atherosclerosis 193 (2007) 235–240

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Table 1 Composition of human plasma lipoproteins and human corneal arcus [29,60]

Density (g/ml) Size of the particles Unesterified cholesterol Esterified cholesterol Phospholipid Apo A-I Apo A-II Apo B Apo E Apo C-I Apo C-II Apo C-III Apo D

Lipid composition of corneal arcus

VLDL

LDL

HDL

<1.02 40–200 † † † † – † † – – – –

0.95–1.006 28–70 † † † – – † † † † † –

1.006–1.063 20–25 † † † – – † – – – – –

1.063–1.210 8.0–11.0 † – † † † – † † † † †

†, Present; –, absent.

larger particles may be selectively trapped in the extracellular matrix. These particles also contain apolipoprotein E attesting to their origin from very low-density lipoprotein catabolism [28] (Table 1). 2.4. Prevalence of corneal arcus The prevalence of corneal arcus increases with age [5,15,31,32] from approximately 14% in the 4th decade to 75% in the 7th decade of life (Table 2). The prevalence is lower in women at each decade [15]. Corneal arcus is almost ubiquitous in men over the age of 80 years old [32]. There are also racial differences in the prevalence of corneal arcus. It occurs more frequently and at an earlier age in Blacks than Whites [13,25,33,34]. Canadian Indians and Eskimos reportedly have no [35] or a low [5] incidence of corneal arcus even in advanced age, although some studies suggest a higher incidence in American Indians than in Caucasians [24].

The width and circumference extension of corneal arcus correlates directly with plasma LDL-cholesterol concentrations in some studies [12,40]. Arcus has also been associated with low concentrations of high-density lipoproteincholesterol (HDL-C), and LDL-C:HDL-C ratios > 5 [41,42]. Corneal arcus is related to the extent (serum level) and duration (age) of the elevated LDL levels. Corneal arcus can be seen in patients as young as 13 years of age in the presence of severe familial hypercholesterolemia (FH) [12]. Some authors have estimated that a patient with arcus has approximately an 88% chance of having a cholesterol level above 200 mg/dl [43]. However, the high proportion of patients with corneal arcus, in some series, who are normolipidemic leads to the possibility that this lesion constitutes an independent risk factor for atherosclerosis [39,40,44]. Regression of corneal arcus has been demonstrated in hyperlipidemic animal models following the cessation of diet-induced hyperlipidemia [45], but regression of corneal arcus with lipid-lowering therapy has not to our knowledge been demonstrated in humans.

2.5. Relationship with plasma lipids and hyperlipidemia The relationship of corneal arcus to serum lipid levels is supported by the lipid nature of the corneal deposit, an increased arcus frequency in familial hyperlipidemia and a variety of association studies [5,36,37,21,38,9,39,12,14].

2.6. Relationship between corneal arcus and familial hypercholesterolemia Familial hypercholesterolemia produces marked elevations in LDL levels due to mutations in genes affecting

Table 2 Prevalence (%) of corneal arcus in healthy men/women Decade (years)

20–29 30–39 40–49 50–59 60–69 70–79 80–89

Rifkin (1965)

Hickey (1970)

Men

Women

8 30 41 67

14 47 71 75

Men

22 40 34

Forsius (1954) Women

Lindholm (1960)

Men

Women

0 2 8 30 53 70

0 3 6 25 33 61

Men

Women

4 13 29 55 57 69

0 14 35 44 35 68

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the LDL receptor and related proteins resulting in delayed catabolism and increased production of LDL [46]. Heterozygote forms of the disease are common and frequently seen in routine clinical encounters. Patients with FH demonstrate corneal arcus, tendon xanthomas, and cutaneous xanthelasmas, as well as ASCVD at an early age. Multiple mutations in genes affecting LDL clearance have been identified [47], and the degree of LDL receptor dysfunction correlates directly with the severity of hypercholesterolemia and inversely with the age of presentation of ASCVD [48]. The prevalence of arcus in patients with FH increases with age and is greater than in the general population [49–51]. Persistently high serum cholesterol levels since birth contribute to the high frequency of corneal arcus in familial hypercholesterolemia [52]. This differs from patients with secondary hypercholesterolemia due to such conditions as hyperthyroidism and nephrotic syndrome because of the shorter duration of the hyperlipidemia in these conditions. Segal et al. used the North American Lipid Research Clinics data base to study 8998 hyperlipidemic patients of both genders and found that corneal arcus was more prevalent than xanthelasmas and that individuals with either arcus or xanthelasma had a two to three-fold increased chance of having Fredrickson Type IIa hyperlipidemia [51]. Winder et al. examined 154 untreated individuals aged 16–76 with heterozygous FH. They observed some degree of corneal arcus in 50% of the patients between 31 and 35 years of age and estimated that arcus occurred approximately 10 years earlier than in the controls from the general population. A complete ring was found in 50% of FH patients by the age of 50, but in only 5% of the controls. The authors concluded that arcus presence before age 35 or a completely ringed arcus by age 50 were manifestations of FH. Not surprisingly given the small sample and the selected nature of this population, early corneal arcus was not an independent predictor of CHD in this specific high risk patient population [49]. Treatment with modern lipid lowering agents or LDL apheresis markedly reduces lipid levels in heterozygous FH patients, but we are unaware of studies documenting reversal of corneal arcus with this treatment. 2.7. Plasma lipid disorders and other corneal opacities Diffuse corneal opacities associated with other lipid disorders, such as Tangier disease, familial lecithin cholesterol acyltransferase (LCAT) deficiency (complete LCAT deficiency), and Fish eye disease (partial LCAT deficiency), may be the initial manifestation of these disorders [8]. The deposition in these conditions tends to be in the central cornea and only homozygotes manifest corneal deposits [10]. In Tangier disease the cornea may be cloudy on naked eye examination and widespread stromal involvement in the form of random soft densities or a flocculent infiltrate has

been described. The corneal opacity is pronounced and can be annular shaped near the limbus resembling a well-defined corneal arcus [8,54]. Familial LCAT deficiency causes corneal arcus and a fine, central, stromal corneal haze [55]. Fish eye disease is a partial LCAT deficiency that causes corneal opacities similar to the eyes of a boiled fish. The corneal opacities of LCAT deficiency are the only corneal deposits associated with lipid disorders that can severely impair vision at an early age [56]. This particular corneal opacity does affect vision to the point that, in occasions, corneal transplantation is required for restoration of the vision. Schnyder’s crystalline stromal dystrophy is a rare corneal pathology, in which corneal arcus, along with a central corneal opacity, occur bilaterally due to the abnormal accumulation of HDL apolipoproteins, including apo A-I, apo A-II, and apo E. It can lead to decrease in daylight vision [53]. Other uncommon conditions that can present with peripheral corneal opacities include limbal dermoid, a benign congenital tumor that appears most commonly in the inferior temporal quadrant of the corneal limbus and juvenile xanthogranuloma, a self limited dermatologic disorder that often curses with ocular involvement affecting the cornea and limbal tissue [8]. 2.8. Association between corneal arcus and cardiovascular disease Virchow in 1852 first suggested that corneal arcus was useful in the diagnosis of heart disease [10,4]. At least nine researchers have subsequently examined the relationship of corneal arcus to CHD [15,57,9,39,13,58,51,59,14]. Rifkind and Dickson in 1965 studied 435 Scottish men and women and reported a higher prevalence of arcus in men between 40 and 49 years old with a history of myocardial infarction (n = 113) than in young healthy men (n = 51). Corneal arcus patients also had higher serum cholesterol levels, but newer CHD risk factors, such as highdensity lipoprotein (HDL) cholesterol were not measured [15]. McAndrew and Ogston in 1965 compared the incidence of arcus in healthy men and women age 20–69 years (n = 250) and in men post-myocardial infarction men age 40–69 years (n = 100). There was no significant difference in the incidence of arcus in the post-myocardial infarction men compared to 100 aged and gender matched controls. Both the control and the post-myocardial infarction groups had a similar increase in the incidence of arcus with age suggesting that arcus was not a reliable indicator of cardiac risk. However, statistical details were not specified in the final report [57]. Rosenman et al., in a 1974 retrospective analysis of the Western Collaborative Study reported that the incidence of myocardial infarction was increased in subjects with corneal arcus, but only in young men aged 39–49. The average annual

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incidence of symptomatic myocardial infarction in this age group was 6.8 per 1000 subjects with, versus 3.2 per 1000 without, corneal arcus p < 0.001. The odds ratio of the association for CHD between subjects aged 39–49 years with and without corneal arcus was 1.57 after adjusting for age, serum cholesterol and smoking [39]. Such results suggest that arcus may be independent of lipid levels in its ability to predict CHD. Klein et al. in 1975 used data from 2530 Caucasian patients of both genders in the Evans County Cardiovascular Study and observed a higher 7-year incidence of CHD in White men with corneal arcus than in men without arcus. However, after adjusting the incidence rate for age, corneal arcus was no longer predictive of CHD events in any ethnic group or gender [13]. Cooke in 1981 reported a cross sectional analysis of 1150 patients admitted to the General Infirmary in Leeds, England. These authors observed a higher prevalence of CHD in men aged 30–39 (n = 60) with corneal arcus (p < 0.01), but not in any other age group [59]. Halfon et al. in 1984, also using the Evans County population, prospectively followed 947 men and 972 women over age 40 for 20 years. CHD mortality was higher in subjects with baseline corneal arcus, but only in White men aged 40–59 (p < 0.05). The authors concluded that there was a lack of significant association between arcus and CHD mortality, that the mechanism of association between arcus and CHD was unclear, and that if corneal arcus is to be used for prognostic purposes other examination procedures should be performed [58]. Chambless et al., in 1990, using The Lipid Research Clinics Mortality Follow-up Study data concluded that corneal arcus was a predictor of CHD, independent of total cholesterol, serum HDL-cholesterol and smoking, among hyperlipidemic men aged 30–49 years (estimated relative risk of 6.7). For normolipidemic men in the same age group, the presence of corneal arcus did not appear to have the same strength of association (estimated relative risk 3.4). The sample consisted of exclusively Caucasian individuals. There were too few women with corneal arcus at baseline and too few CHD events in women to analyze the relationship of arcus to CHD in women. Above age 50, corneal arcus did not appear to be positively related to subsequent CHD events [14]. 2.9. Clinical implications Corneal arcus is clearly associated with hyperlipidemia and CHD. It is not clear, however, from available studies whether or not corneal arcus and its relationship to CHD is independent of hyperlipidemia. We suggest that corneal arcus in a young person be used as a sign to look for lipid abnormalities. In addition, among normolipidemic individuals, corneal arcus may indicate an increased susceptibility to CHD because the formation of corneal arcus and atherosclerotic vascular lesions share some physiological similarities.

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3. Summary Corneal arcus is a recognized sign of hyperlipidemia. It has been associated with CHD since Virchow’s initial observation in 1852, but despite the length of this association, it is still not clear whether corneal arcus’ association with CHD is statistically independent of other risk factors, primarily hyperlipidemia. We suggest that physicians use the presence of corneal arcus to search for hyperlipidemia. In addition, given the association of arcus and CHD, normolipidemic patients with corneal arcus may be at increased risk of CHD events and should be considered for CHD risk reduction despite their apparent low risk based on lipid levels alone. Firm recommendations in managing low CHD risk individuals with corneal arcus, however, must wait further evaluations of arcus as an independent CHD risk factor.

References [1] Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486–97. [2] Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 2001;285:2481–5. [3] Huang PH, Chen LC, Leu HB, et al. Enhanced coronary calcification determined by electron beam CT is strongly related to endothelial dysfunction in patients with suspected coronary artery disease. Chest 2005;128(2):810–5. [4] Virchow VR. Uber parenchymatose entzundun. Virchows Arch Pathol Anat 1852;4:261. [5] Forsius H. Arcus senilia corneae—its clinical development and relationship to serum lipids, proteins and lipoproteins. Acta Ophtalmol 1954;42(Suppl.):1–72. [6] Newell FW. The Cornea. In: Ophthalmology principles and concepts. 8th ed. St. Louis, MO: CV Mosby Co.; 1986. p. 221. [7] Vogt A. Textbook and atlas of slit lamp microscopy of the living eye. Bonn: Wayenborgh Editions; 1981. [8] Waring III G, Mbekeani JN. Corneal degeneration. In: Howard M, Leibowitz, George O, Waring III, editors. Corneal disorders clinical diagnosis and management. 2nd ed. Saunders; 1998. p. 296–303. [9] Hickey N, Maurrer B, Mulcahy R. Arcus senilia: its relation to certain attributes and risk factors in patients with coronary artery disease. Br Med J 1970;32:449–52. [10] Barchiesi BJ, Eckel RH, Ellis PP. The cornea and disorders of lipid metabolism. Surv Ophthalmol 1991;36(1):1–22. [11] Chua BE, Mitchell P, Wang J, Rochtchina E. Corneal arcus and hyperlipidemia: findings from an older population. Am J Ophthalmol 2004;137(2):363–5. [12] Pe’er J, Vidurri J, Halfon ST, Eisenberg S, Zauberman H. Association between corneal arcus and some of the risk factors for coronary artery disease. Br J Ophthalmol 1983;67:795–8. [13] Klein B, Klein R, Haseman J, Maready J, Hames C. Corneal arcus and cardiovascular disease in Evans County, Georgia. Arch Intern Med 1975;135:509–11. [14] Chambless LE, Fuchs FD, Linn S, et al. The Association of corneal arcus with coronary heart disease and cardiovascular disease mortality in the lipid research clinics mortality follow-up study. AJPH 1990;80:1200–4.

240

A. Fern´andez et al. / Atherosclerosis 193 (2007) 235–240

[15] Rifkind BM, Dickson C. The incidence of arcus senilis in ischemic heart disease, its relation to serum-lipid levels. Lancet 1965;1:312–4. [16] Caroli A, Marcuzzi A, Pasquali-Ronchetti I, Guerra D, Zanasi S. Correlation between Dupuytren’s disease and arcus senilis: is dislipidemia a common etiopathological factor? Ann Chir Main Membr Super 1992;11(4):314–9. [17] Degowin R. Degowin & DeGowin’s diagnostic examination. 6th ed. McGraw Hill; 1994. p. 105. [18] Sugar Allan. Cornea and conjunctival degenerations. In: Kaufman HE, Barron BA, McDonald MB, editors. The cornea. 2nd ed. C. Boston: Butterworth-Heinemann; 1998. p. 486–7. [19] Phillips CI, Tsukahara S, Gore SM. Corneal arcus: some morphology and applied pathophysiology. Jpn J Ophthalmol 1990;34:442–9. [20] Cogan D, Kuwabara T. Arcus Senilis. Its pathology and histochemistry. Arch Ophthalmol 1959;61:553–60. [21] Rifkind BM. Corneal arcus and hyperlipoproteinemia. Surv Ophthalmol 1972;16:295–304. [22] Sugimura G. Unilateral corneal arcus. Arch Ophthalmol 1990;108:780. [23] Lawton-Smith J, Susac JO. Unilateral arcus senilis: sign of occlusive disease of the carotid artery. JAMA 1973;226(6):676. [24] Canton E. Observations on the arcus senilis or fatty degeneration of the cornea. Lancet 1850;1:560–2. [25] Takayasu M. Beitrage zur Pathologischen anatomie des arcus senilis. Arch Augenheik 1901;43:154–62. [26] Tchetter RD. Lipid analysis of the human cornea with and without arcus senilis. Arch Ophthalmol 1966;76:403–5. [27] Paananen K, Saarinen J, Annila A, Kovanen PT. Proteolysis and fusion of low density lipoprotein particles strengthen their binding to human aortic proteoglycans. J Biol Chem 1995;270:12257–62. [28] Gaynor PM, Zhang W, Salehizadeh B, Pettiford B, Kruth HS. Cholesterol accumulation in human cornea: evidence that extracellular cholesteryl ester-rich lipid particles deposit independently of foam cells. J Lipid Res 1996;37:1849–61. [29] Andrews JS. The lipids of arcus senilis. Arch Ophthalmol 1962;68:264. [30] Wissler RW. Update on the pathogenesis of atherosclerosis. Am J Med 1991;91(1B):3S–9S. [31] Lindhol H. Arcus lipoids corneae and arteriosclerosis. Acta Med Scand 1960;168:45–9. [32] Friedlander MH, Smolin G. Corneal degenerations. Ann Ophthalmol 1979;10:1485. [33] Klintworth G. Degenerations, depositions, and miscellaneous reactions of the cornea, conjunctiva, and sclera. In: Garner A, Klintworth G, editors. Pathobiology of ocular disease. New York: Marcel Dekker; 1982. p. 1431. [34] Macaraeg PVJ, Lasagna L. Arcus not so senilis. Ann Intern Med 1968;68(2):345–54. [35] Sinclair HM. In: Rodger FC, Sinclair HM, editors. Metabolic and nutritional eye diseases. Springfield, IL: CC Thomas; 1969. p. 135. [36] Pomerantz HZ. The relationship between coronary heart disease and the presence of certain physical characteristics. Can Med Assoc J 1962;86:57. [37] Shanoff HM, Little JA. Studies of male survivors of myocardial infarction due to “essential” atherosclerosis. III. Corneal arcus: incidence and relation to serum lipids and lipoproteins. Can Med Assoc J 1964;91:835–9. [38] Bersohn L, Politzer W, Blusohn D. Arcus senilis cornea: its relationship to serum lipids in the South African Bantu. S Afr Med J 1959;43:1025–9. [39] Rosenman RH, Bradn RJ, Sholtz RI, Jenkins CD. Relation of corneal arcus to cardiovascular risk factors and the incidence of coronary disease. N Engl J Med 1974;291:1322–4.

[40] Varnek L, Schnohr P, Jensen G. Presenile corneal arcus in healthy persons. A possible cardiovascular risk indicator in younger adults. Acta Ophthalmol 1979;57(5):755–65. [41] Lertchavanakul A, et al. Corneal arcus associated with dislipidemia. J Med Assoc Thai 2002;85(1):S231–5. [42] Meyer D, et al. Serum lipid parameters and the prevalence of corneal arcus in a dyslipidaemic patient population. Cardiovasc J S Afr 2004;15(4):166–9. [43] Nishimoto JH, Townsend JC, Selvin GJ, De Land PN. Corneal arcus as an indicator of hypercholesterolemia. J Am Optom Assoc 1990;61:44–9. [44] Gofman JW, Rubin L, McGinley JP, Jones HB. Hyperlipoproteinemia. Am J Med 1954;17:514. [45] Crispin SM, Barnett KC. Arcus lipoides secondary to hypothyroidism in the Alsatian. J Small Anim Pract 1978;19:127–42. [46] Hoeg JM, Demosky SJ, Schaefer EJ, Starzl TE, Brewer Jr HB. Characterization of hepatic low density lipoprotein binding and cholesterol metabolism in normal and homozygous familial hypercholesterolemic subjects. J Clin Invest 1984;73:429–36. [47] Hobba HH, Brown MS, Goldstein JL. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1992;1:445–6. [48] Sprecher DL, Hoeg JM, Schaefer EJ, et al. The association of LDL receptor activity, LDL cholesterol level. And clinical course in homozygous familial hypercholesterolemia. Metabolism 1985;34: 294–9. [49] Winder AF, Jolleys JCW, Day LB, Butowski PF. Corneal arcus, case finding and definition of individual clinical risk in heterozygous familial. Hypercholesterolaemia 1998;54:497–502. [50] Winder AF. Relationship between corneal arcus and hyperlipidaemia is clarified by studies in familial hypercholesterolaemia. Br J Ophtahlmol 1983;67:789–94. [51] Segal P, Insull W, Chambless LE, Stinnett S. The association of dyslipoproteinemia with corneal arcus and xanthelasma. The lipid research clinics program prevalence study. Circulation 1986;73(1): 1–108. [52] Kwiterovich PO, Fredrickson DS, Levy RI. Familial hypercholesterolemia (one form of familial type II hyperlipoproteinemia). A study of its biochemical, genetic and clinical presentation in childhood. J Clin Invest 1974;53:1237–9. [53] Gaynor PM, Zhang WY, Weiss JS, et al. Accumulation of HDL apolipoproteins accompanies abnormal cholesterol accumulation in Schnyder’s corneal dystrophy. Arterioscler Thromb Vasc Biol 1996;16:992–9. [54] Fredeickson DS, Gotto AM, Levy RI. Familial lipoprotein deficiency. In: Stanburry JB, Wygaarden JB, Fredeickson DS, editors. The metabolic bases of inherited disease. 3rd ed. New York: McGraw-Hill; 1972. p. 493. [55] Horven I, Egge K, Gjone E. Corneal and fundus changes in familial LCAT deficiency. Acta Ophthalmol 1974;52:201. [56] Klachko DM, Talavera F, Wehmeier K, Cooper M. LecithinCholesterolAcyltransferase Deficiency. Emedicine web site. Available at: http://www.imedicine.com. Accessed June 25, 2005. [57] McAndrew GM, Ogston D. Arcus senilis and coronary artery disease. Am Heart J 1965;70(6):838–40. [58] Halfon ST, Hames CG, Heyden S. Corneal arcus and coronary heart disease mortality. Br J Ophtahlmol 1984;68:603–4. [59] Cooke NT. Significance of arcus senilia in Caucasians. JR Soc Med 1981;74:201–4. [60] Nelson DL, Michael MC. Lipid biosynthesis. In: Lehninger principles of biochemistry. 4th ed. New York, NY: WH Freeman; 2005. p. 821-23.