Xanthelasmas and xanthomas — cutaneous clues to systemic lipid disorders

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Clinical Eye and Vision Care 7 (1995)117-128

Clinical review

Xanthelasmas and xanthomas - cutaneous clues to systemic lipid disorders Richard M. Frankel* , Robert Capone The New England College of Optometry, 424 Beacon Street Boston, Boston, MA 02115. USA

Received November 1994; revision received February 1995: accepted April 1995

Abstract

Xanthelasmas and xanthomas are fatty skin lesions which are important clinical signs of underlying systemic lipid disorders. They consist of clusters of lipid-laden macrophages and are present in a variety of conditions: inherited disorders of lipid metabolism, systemic diseases in which lipid disorders arise, or in states without significant detectable lipid abnormalities. Xanthomas tend to appear in specific locations in the body, usually in the dermis or within tendons. They occur in a variety of forms: flat or nodular, localized or disseminated. Patterns of both location and form suggest single specific lipid disorders or a narrow field of disorders. Recognition of xanthomas should prompt the alert clinician to perform an appropriate history. physical examination and laboratory investigation. An early diagnosis of significant underlying systemic diseases can be obtained. This can have a significant impact on general health, cardiovascular status as well as ocular health Keywords:

Xanthelasma; Xanthoma; Lipoprotein; Dyslipoproteinemias

1. Introduction

Cardiovascular disease remains the primary cause of mortality in the Western world [l]. It is therefore critical to prevent or modify the course of cardiovascular disease.Early detection of those patients predisposed to atherosclerosis and its pathologic sequelae can be life-saving. Examiners eliciting pertinent history and identifying relevant physical findings can establish a diagnosis of underlying lipid disorders. Among the physical findings suggesting an underlying predisposition to cardiovascular disease are lipid infiltrates in the dermis of the skin or in tendons, usually observable as yellow lesions. The most well known of these is the xanthelasma, appearing at the medial canthi of the eyelids (Fig. 1). It is the best known of the xanthomas because it is most common, and is readily observable on exposed skin. However, xanthelasma is only part of a large family of lipid

*Corresponding author.

lesions occurring in less easily inspected parts of the body. Identification of these less common xanthomas can also be beneficial in the identification and management of those at risk for cardiovascular disease. Deposition of excesslipid in skin suggestselevated lipid ingestion or production in the body, or insufficient breakdown or excretion [2]. Xanthomas often arise when accumulated plasma lipids leak from vessels into the surrounding superficial dermis. Lipidgulping macrophages gather around the fat, forming nodular and plaque-like masses recognizable as xanthomas (Figs. 2 and 3). They may be observed in different clinical conditions and situations which may be divided into three groups: 1. Xanthomas arising in patients with no underlying lipid disorder 2. Xanthomas arising in an inherited or primary lipid disorder 3. Xanthomas arising in patients with a lipid disorder secondary to another systemic condition involving disordered lipid metabolism

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Atherogenic lipid profiles in patients with primary lipid disorders may be exacerbated by concomitant secondary systemic disorders leading to more serious sequelae[2]. Therefore, clinicians must first diagnose and treat those systemic diseases.This results in two benefits: diagnosis of the exacerbating systemic disease will contribute to control of the overall disorder of lipid metabolism. In addition, a major systemic diseasewith its own set of potential complications can be uncovered and brought under control. To illustrate: an acquired, systemic disease such as diabetes may exacerbate the lipid profile in a patient with an inherited lipid disorder. Xanthomas may occur in this situation and may be the first clue to diagnosis of both diseases.The clinician knowlegeable in the detection of xanthomas provides a double benefit to his patients. By the same token, systemic diseaseswhich remain undetected when xanthomas are overlooked become a double-barreled threat. 1.1. Xanthomas in patients with no underlying lipid disorder Xanthelasmas are the most common representative of this category, and the most commonly occurring xanthoma [3,4]. When xanthelasmas are observed in patients, 50% paradoxically show normal lipoprotein levels [S]. It has been suggestedthat paroxysmal increases in intracapillary pressure in the palpebral dermis during blinking plays a major role in the extravasation of lipid into the eyelids [6]. 1.2.Xanthomas arising in patients with an inheritedor a primary lipid disorder Xanthelasmas signal an abnormal lipid disorder only 50% of the time, giving it the lowest predictive value in the xanthoma family [4]. This may be considered a low predictive value when compared to other xanthomas; but it would be negligent to dismiss the presenceof xanthelasma,becauseassociatedlipid disorders feature elevated LDL-cholesterol levels, which are atherogenic [7]. Elevated LDL levels are often due to a condition known as Familial Hypercholesterolemia or to polygenic hypercholesterolemia (discussed below) [8]. It is not surprising that the

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clusters of macrophages found in xanthelasmas are heavy with engulfed cholesterol 191. Xanthelasmas have been associated with an increased incidence of cardiovascular disease in those patients with normal cholesterol and triglyceride levels [lo]. But most of these patients have also been found to have decreased levels of high density lipoprotein (HDL) [Ill. Because HDL promotes removal of cholesterol from the circulation. decreased levels of HDL predisposesa patient to coronary heart disease 112,131.This is particularly true for postmenopausal women, for whom HDL level is a more accurate predictor of cardiovascular mortality than either LDL-cholesterol or triglycerides [ 141.For these reasons, the clinician must be certain to order HDL levels in those patients presenting with xanthelasma. Tendonxanthomas. Tendon xanthomas result from accumulation of lipid-consuming macrophagesaround blood vessels within the substance of tendons 1151. They appear as firm nodules of varying sizes under the skin, which maintains its normal color [4]. (Fig. 41 The tendons most frequently involved are the achilles tendon and the extensor tendons of the hands, elbows and knees. With these tendons located in areas exposed to physical strain and trauma, small vessels within them leak lipids into the fibrous connective tissue of the tendon [16]. The appearanceof tendon xanthomas is highly consistent with lipid disorder, since only an occasional patient has tendon xanthomas with a normal lipid profile [17,18]. A recent study showed that tendon xanthomas and associatedarthritis (stemming from the deposition of cholesterol crystals) preceded the diagnosis of lipid disorder in 62 % of a series of 39 patients [19]. A positive history of achilles tendonitis can be useful in the diagnosis of dyslipidemia. Eruptive xanthomus. Eruptive Xanthomas have se\era1 distinguishing features. They are the smallest ot the xanthoma family, only l-4 mm in diameter. (Fig. 5) They tend to be yellow-brown in color with a red rim, which corresponds to a peripheral inflammatory cellular component of the lesion. They characteristically appear suddenly, in multiple lesions, with a tendency to erupt over the buttocks and thighs: they

Fig. 1. Xanthelasmata palpebrarum Fig. 2. Low power micrograph of a skin nodule formed by an infiltrate of macrophages in the dermis. From ‘Gross an1 Macroscopic Skin Pathology Slide Set’, courtesy of the Dermatopathology Foundation, Canton, Mass. Fig. 3. High magnification shows macrophages filled with lipid, lending a pale, foamy appearance. From ‘Gross and Microscopic Skin Pathology Slide Set’, courtesy of the Dermatopathology Foundation, Canton, Mass. Fig. 4.Tendon xanthomas on the hands. From Fitzpatrick, TB, Color Atlas and Synopsis of Clinical Pathology, ft. 593, courtesy of McGraw-Hill, Inc. Health Professions DivisionFig. 5. Eruptive xanthomas on knees. From Gross and Microscopic Skin Pathology Slide Set’. courtesy of the Dermatopathology Foundation, Canton, Mass. Fig. 6. Tuberous xanthomas on the knee. From ‘Gross and Microscopic Skin Pathology Slide Set’, courtesy of the Dermatopathology Foundation, Canton, Massachusetts. Fig. 7. Xanthoma striata palmaris appearing as yellow streaks on the palms. From Fitzpatrick, TB, Color Atlas and Synopsis of Clinical Pathology, p. 593, courtesy of McGraw-Hill, Inc. Health Professions Division.

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Table 1 Summary of typical clinical findings associatedwith primary and secondarylipid disorders __Clinical Sign Primary Disorder Xanthelasma

Comeal Arcus

Lipemia Retinalis Eruptive Xanthoma

Tuberous Xanthoma Tendinous Xanthoma Palmar Crease Xanthoma

Polygenic Hypercholesterolemia Familial Hypercholesterolemia Familial Dysbetalipoproteinemia Polygenic Hypercholesterolemia FamilialHypercholesterolemia FamihaIDysbetalipoproteinemia Familial Hypertriglyceridemia Hyperchylomicronemia Familial Hypertriglycridemia Hyperchylomicronemia

Familial Familial Familial Familial

Hypercholesterolemia Dysbetalipoproteinemia Hypercholesterolemia dysbetalipoproteinemia

may also appear over the extensor surfaces of the arms, in axillary folds and oral mucosa [3,20-221. Triglycerides are greatly elevated in these patients [21]. This is consistent with the finding that eruptive xanthomas contain more triglycerides than any other member of the xanthoma family [9]. Treatment of the underlying lipid disorder by diet and drugs results in a dramatic disappearanceof these xanthomas and may be a life-saving measure [22]. Tuberous xanthomas. Tuberous xanthomas are slowly developing,yellow nodules favoring the elbows and knees, but also appearing over the knuckles, toe joints, axillary and inguinal folds, and the face [3,22]. (Fig. 6) They are seen in a variety of disorders which feature elevated cholesterol and triglyceride levels, particularly in dysbetalipoproteinemia, discussed below [4,20]. Xanthoma striata palmaris. These xanthomas occur as yellow streaks of lipid infiltrating around the creases of the palms and fingers (Fig. 7). These may be flat or elevated. These occur almost exclusively in a hereditary lipid disorder known as dysbetalipoproteinemia,a disorder which will be discussedlater [23]. 1.3. Xanthomas arising in patients with a lipid disorder secondaly to another systemic condition involving abnormal lipid metabolism

A variety of systemic diseases may give rise to secondary hyperlipoproteinemias.These include diabetes, some forms of renal disease, hypothyroidism, cholestatic liver disease, obesity and iatrogenic diseaseinduced by drugs. These conditions produce signs which overlap with those of the genetic lipid disorders. They may generate similar lipid profiles that can induce xanthoma formation [21]. Therefore, when a xanthoma associatedwith an abnormal lipid profile is found, the possibility of a lipid disorder secondary

SecondaryDisorder Hypothyroidism Nephrotic Syndrome Plasma Cell Neoplasia

Diabetes Mellitus Alcoholism Diabetes Mellitus Alcoholism Oral Contraceptives Obesity Nephrotic Syndrome Obstructive Biliary Disease Obstructive Biliary Disease Plasma Cell Neoplasia Nephrotic Syndrome Obstructive Bihary Disease

to a systemicdisorder should be explored. In addition, since the secondary lipid disorder often exacerbates the lipid profile of the concomitantly occurring primary disorder, the managementof both is necessary to appropriately address the disorder of lipid metabolism and its potential for life-threatening disease. It is not possible to correlate each form of xanthoma with a specific underlying primary or secondary disorder, since the same form of xanthoma may occur in a variety of primary or secondary diseases.Also, more than one type of xanthoma can occur in each disease[21]. There are, however, some useful associations of xanthoma types with secondarylipid disorders which can guide one in the laboratory diagnosis of these illnesses: Tendon xanthomas occur in obstructive liver disease,hypothyroidism and diabetes in addition to their association with hypercholesterolemia [21]. Eruptive xanthomas may develop in diabetes, hypothyroidism, nephrotic syndromeand a number of primary lipid disorders 13,201. Xanthoma striatum palmare are typical of obstructive biliary disease, diabetes and familial dyslipidemia [3,21]. Xanthomas serve as important clinical evidence of a potentially life-threatening lipid disorder. Since observation of specific forms of xanthomas can suggest particular disorders, a selective diagnostic pathway and rational therapy is afforded. An understanding of the diagnostic pathway and therapy can be assistedby a review of lipoprotein metabolism. 2. Lipoproteins and lipid metabolism Storage of lipid deposits in the dermis of the skin may m irror a similar process occurring in the intima of major arteries. This reflects an unfortunate routing of body lipids into lifelines of the body, eventually

R.M. Frankel, R. Capone / Clinical Eye and Vision Care 7 (1 WSl I 17 1.3

choking off blood supply to vital tissues. To understand how this detour comes about, it is necessaryto review the current road map that lipids normally follow (see Fig. 8, the Lipoprotein Highway). Lipid globules floating in broth remind us of the insoluble state of lipids in blood. In Go, it is critical that lipids be made soluble in blood to allow for cell to cell transport, for use as substrates for cell membrane or steroid production, or to be stored for later use. To make lipids soluble in plasma, a piece of protein, ‘apoprotein’, is added by the cell processes. The plasma-soluble aggregateof lipid and protein is known as a lipoprotein. In this package, lipids course through the blood from intestines and liver to other tissues for use and storage. Specific portions of the apoprotein dangle from the lipoprotein to link up with cell receptor sites to allow entry of the lipoprotein into tissues. Other portions activate enzymesthat cleave lipid from lipoprotein, leaving it within the cell [ 161. Abnormalities in an apoprotein owing to genetic

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error could thereby prevent entry to and utilization of lipid by cells, resulting in an increase in lipid levels in the plasma. Receptor abnormalities on the cells give the same result: excessiveplasma lipids occurring as an inherited lipid disorder. Excess liptd may then deposit in arteries as atherosclerotic plaque and extravasate from venules into the dermis or tendons as xanthomas. 2.1. Lipoprotein clusses Lipoproteins occur as aggregatesof protein carrier and varying types and proportions of ipid load. A lipoprotein in which the lipid core is almost all triglyceride is known as a chylomicron. Ingested triglycerides (Fig. g-step 1) are taken up into cells lining the intestines and packagedinto chylomicrons with bits of cholesterol, protein and bile acids (Fig. ‘i-step 2) [24]. These large particles scatter light in the plasma. Abnormally heavy concentrations ot triglyceriderich chylomicrons lend a milky appearance to plasma

-

TRIGLYCERIDES FATTY ACIDS

Fig. 8. The lipoprotein highway

ARTERIAL WALLS AND OTHER TISSUES 11

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1241.When such triglyceride-rich particles reach retinal vessels, lipemia retinalis is observed [16]. Some triglycerides are removed from chylomicrons and converted to fatty acids by lipoprotein lipase (Fig. g-step 3) for use by cells as an energy source or for storage in adipose tissue and muscle (Fig. g-step 4). The remainder is known as a chylomicron remnant (Fig. g-step 5) [24]. The chylomicron remnants are then taken up by the liver (Fig. g-step 6). A second class of lipoprotein particle containing somewhat less triglyceride and somewhat more cholesterol is produced in the liver, and is known as very low density lipoprotein, or VLDL (Fig. g-step 7). Almost all triglycerides from VLDL are removed by lipoprotein lipase (Fig. g-step 8) leaving a triglyceride poor but cholesterol rich particle classified as low density lipoprotein, LDL (Fig. g-step 9). Most cholesterol in plasma is transported within low density lipoprotein. Some LDL cholesterol binds to receptors of hepatocytes in the liver (Fig. g-step 10) and is endocytosedfor storage or transfer to other lipoproteins. Unfortunately, some of the cholesterol is deposited in arterial walls (Fig. g-step 11). A fourth class of lipoproteins, produced mainly by the liver is known as high density lipoprotein, or HDL. These have a relatively dense coat of protein containing moderate amounts of cholesterol (Fig. g-step 12). Cholesterol in HDL is contributed from arterial walls and other tissues. The cholesterol thus accumulated in HDL is then transferred from HDL to other lipoproteins (Fig. g-dotted line) like VLDL and LDL (Fig. g-steps7 and 91, which return it to the liver, where it is largely excreted as part of bile into the intestine [24]. Much cholesterol leaves the body in this way rather than entering blood vessels.High HDL levels are therefore protective, while low HDL levels increase the risk for cardiovascular disease [25]. The ratio of total cholesterol to HDL-cholesterol is generally considered to be a reliable indicator of risk for coronary heart disease

[261. Spinning plasma in a centrifuge tube will arrange these lipids in layers according to their buoyant density, with chylomicrons at the top. The rest of the lipoproteins are named according to their layered arrangement determined by their densities: layered below chylomicrons are very low density lipoproteins, followed by low density lipoprotein, and high density lipoprotein. When cholesterol and triglyceride levels in plasma are determined, they are removed from lipoproteins by organic solvents [24]. Lipoprotein and apoprotein levels are determined separately. 2.2.Abnomal lipid and lipoproteinlevelsand the diagnosisof lipid disorders The primary care practitioner who recognizes a xanthoma should evaluate the patient’s predisposition

for vascular disease. This includes determination of the presence of major risk factors, as well as the diagnosis of disorders giving rise to abnormal lipid levels. If any risk factors exist which can be controlled by diet, lifestyle changes or a drug regimen, these must be explained to the patient. These include the major risk factors, such as high blood pressure,smoking, diabetes, sedentary life style and hyperlipidemia. Hyperlipidemia denotes elevated levels of cholesterol or triglyceride. Cholesterol has been implicated by numerous epidemiologic studies, as well as by its role in the genesis of the atherosclerotic plaque [27,28]. Elevated triglyceride levels play a somewhat lesser role in the pathogenesisof vascular disease,but can promote pancreatitis, a life-threatening condition [29,30].As discussedbelow, the practitioner’s observation of a xanthoma can lead to a finding of hypertriglyceridemia allowing treatment and reduction of a patient’s risk for pancreatitis [31]. From the discussion of lipoprotein components, it is evident that the patient with a solitary elevation of plasma cholesterol will virtually always have an increased level of LDL, which carries 75% of the body’s cholesterol. A solitary elevation in triglyceride level would also show increased levels of chylomicrons or VLDL, lipoproteins carrying a significant triglyceride load. When both cholesterol and triglycerides are elevated, chylomicrons or VLDL may be elevated, particularly if the triglyceride level is at least five times greater than the cholesterol level. When the triglyceride is less than five times that of the cholesterol level, LDL and VLDL levels may be raised [2]. Any abnormality in the lipid profile, (including decreasedlevels of HDL and other abnormal levels of lipid, lipoprotein or apoprotein) is referred to by the more encompassing term, dyslipidemia. These could arise from a primary or secondarydisorder. Having reviewed the major risk factors, and determined cholesterol and triglyceride levels, the practitioner should pursue further diagnostic studies leading to a diagnosis of a secondary disorder. Having ruled out a secondarydisorder, he or she should then attempt to pinpoint a primary disorder. Secondarydisorders loom large in the diagnosis of dyslipidemias because they are, in aggregate, very common. One of them, diabetes, has for some time been recognized as a major risk factor. Additionally, the presence of a secondary condition such as diabetes, hypothyroidism, or even pregnancy can aggravate the lipid profile in a patient with a concomitant primary lipid disorder [32]. The presenceof kidney or liver disease must be taken into account when drug therapy is considered.Therefore, proper management of a primary lipid disorder is not possible until secondary disorders are ruled out. In addition, the benefit of diagnosinga serious systemic diseasespeaks for

R.M. Frankel, R. Capone /Clinical

itself. The discovery of a xanthoma may be the first indication that such an underlying systemic disease exists [21]. 3. Secondary or acquired dyslipidemias

A variety of disorders may cause disturbances of lipid handling resulting in clinically significant increases in cholesterol, triglycerides or both, with or without a decreasedHDL level. These can hasten the advent of cardiovascular disease and, in disturbances which result in severe triglyceridemia, raise the spectre of life threatening pancreatitis. Clinicians should be alert for the possibility of a secondary lipid disorder in those patients with a xanthoma or abnormal lipid profile, or both, without a family history of premature cardiovascular disease or dyslipidemia. They should consider that a secondary disorder may be developing in a patient with a primary lipid disorder with a worsening lipid profile with no changein diet or therapy. They should also suspect that a secondarydisorder may be present in a patient unresponsive to treatment for a primary lipid disorder. Finally, they should be watchful for the exacerbation of a mild hypertriglyceridemia by a secondary disorder which precipitates severe hyperlipidemia and acute pancreatitis [32]. Abnormal lipid profiles may result from a diet choked with cholesterol and saturated fat; secondary to drugs, as in corticosteroid therapy; with endocrine disorders, such as diabetes and hypothyroidism, and during other diseases, such as nephrotic syndrome and obstructive liver disease [32]. In all cases, treatment must be directed first at the underlying disease. 3.1. Diabetes

In about one-third of diabetics, a secondary lipid disorder develops [21]. In both insulin dependent and non-insulin dependent diabetes mellitus, triglyceride levels can be greatly increased, especially in undiagnosed or poorly controlled patients. Primarily in insulin dependent diabetics, high plasma glucose levels provide abundant fuel for triglyceride synthesis in the liver. The triglycerides released into the bloodstream are then sluggishly removed. Breakdown of triglycerides as well as chylomicrons is slowed because the enzyme responsible, lipoprotein lipase, functions poorly in insulin deficiency. (Fig. 8-steps3 and 4). The most dangerouslevels of triglyceride are produced in patients who have both a genetic lipid disorder and diabetes. High triglyceride levels can lead to acute pancreatitis in a process which is still obscure [33]. Eruptive xanthomas can occur in patients with diabetes [21]. Detection of xanthomas may lead to the early diagnosis of non-insulin dependent diabetes, in which half of the cases remain undiagnosed until a

Eye and Viiion Care 7 (IY95i 117-128

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vascular event occurs [34]. Lipemia retinalis may also occur as a sign of poorly controlled diabetes 121.In some cases, with exceeding high glucose levels, lacy vacuolization of the iris will occur. By this time, however, manifestations of acute ketoacidosis will be obvious. Diabetic control can help to normalize lipid levels, reduce the risk of pancreatitis, and decelerate the development of the vascular sequelae associated with diabetes 121,331. 3.2. Use of oral contraceptives

The estrogensin birth control pills raise triglyceride levels, and in concert with a primary triglyceride disorder, can predisposeto acute pancreatitis [32]. Eruptive xanthomas may assist one in the diagnosis of contraceptive-induced dyslipidemia [2Q]. The risk of dyslipidemia varies directly with the level of estrogens in the contraceptive. 3.3. Other medications

A number of medications can induce or accentuate dyslipidemias. These include glucocorticoids, which increase triglyceride levels; anabolic steroids and retinoids, both of which increase LDL to HDL ratios; thiazide diuretics, which promote hyperlipidemia; beta blockers, which raise triglycerides and depress HDL levels; and cyclosporine, which elevates LDL. 3.4. Hea y alcohol consumption

In a subset of people, steady alcohol intake can markedly increase triglyceride levels, partly owing to enhanced fatty acid synthesis in the liver. Aside from producing an enlarged, fatty liver, triglycerides can seep into the dermis producing eruptive xanthomas, flood retinal vessels causing lipemia retinalis, and in some unknown fashion, stimulate inflammation of the pancreas [2,35]. Both may serve as warnings of impending disaster for the alcohol abuser. 3.5. Obesity The prevalence of obesity in this country has been rising steadily, with obesity being defined as a body mass index (weight in kilograms/height in meters squared)of more than 27 [36]. By this criterion, about one third of adults over age 20 are obese. The metabolic consequencesof obesity can be harsh. Significant elevations in triglycerides as well as glucose intolerance, diabetes mellitus, hypertension, decreased HDL-cholesterol and increased LDLcholesterol levels may occur [24]. A tendency to accumulate fat in the abdominal pannus has been particularly associated with the development of these risk factors [36]. Xanthomas may erupt, but are accessory manifestations to the obese state which itself is a major risk factor for cardiovascular morbidity and mortality [241.

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3.6. Hypothyroidism

Hypothyroidism is characterized by a slowing down of metabolic processes. The sluggish catabolism of low density lipoproteins in hypothyroid patients results in elevated cholesterol levels. Also, reduced activity of lipoprotein lipase, causing reduced breakdown of VLDL, results in elevated levels of triglyceride. (7, Fig. 8) Xanthelasmas and xanthomas appear commonly in hypothyroidism [20]. Thus, thyroid deficiency may underlie the hyperlipidemic state. Any person presenting with a xanthelasma or xanthoma who has an elevated lipid level should be investigated for decreasedlevels of thyroxine (T4) and increased levels of thyroid stimulating hormone (TSH). Levels of TSH are necessary to detect cases of subclinical hypothyroidism missed by thyroxine levels alone [32]. 3.7. The nephrotic syndrome

The nephrotic syndrome is a systemic condition produced by greatly increased glomerular permeability to protein and other macromolecules [37]. Proteinuria may be heavy. This results in a significant loss of albumin from the blood. The body responds by producing increased amounts of low density lipoprotein. Elevated levels of plasma cholesterol and often elevated levels of triglycerides occur [32]. The severity of the hyperlipidemia in the nephrotic syndrome has been found to be inversely proportional to the severity of the hypoalbuminemia [38]. The elevated levels of cholesterol and triglyceride may lead to xanthelasmas, xanthomas of tendons, and eruptive xanthomas as well as predispose to accelerated atherosclerosis [21,321. 3.8. Chronic renal failure

Individuals with chronic renal failure, whether or not on dialysis, may show increased levels of triglycerides and decreased levels of high density lipoproteins [2,32]. Dyslipidemia and xanthomas may therefore occur, but less often than in the nephrotic syndrome [21]. 3.9. Liver disease

Obstruction of the biliary tract, as seen in biliary cirrhosis, can result in hypercholesterolemia. The patient will be jaundiced, will show scleral icterus, and demonstrate malabsorption due to obstruction of bile flow to the intestine [39]. 3.10. Plasma cell neoplasia

Xanthomas have been known to arise over a decade before the diagnosis of multiple myeloma [24]. In this and related dysglobulinemias (including the plasma cell myelomas and B cell lymphomas), dyslipidemia is thought to arise when abnormally produced antibodies bind to and inhibit enzymes, (like lipoprotein lipase), which break down lipids [21,24]. The clinician

Eye and Vision Care 7 (1995) I1 7-128

who observesdisseminated, flat, yellow xanthomas of the head, neck and trunk should request a hematocrit, leukocyte count, serum and urine immunoelectrophoresis, chest X ray, and, in the proper clinical setting, a bone marrow biopsy. This may allow for early diagnosis and intervention in the neoplastic disease process [21]. In considering secondary lipid disorders, the clinician should obtain a good history of dietary habits, including alcohol intake, and a medication history. For detection of both secondary and primary lipid disorders, the clinician should scrutinize the skin for xanthomas. The presence of a xanthelasma should encourage the clinician to look for cornea1 arcus, Hollenhorst plaques, lipemia retinalis or venous occlusive disease. Moving from eyes to fingers, elbows, knees and ankles, the clinician will search for xanthomas, for they are always reliable sentinels for a variety of dyslipidemias [21]. The presence of carotid bruits should be determined by auscultation. Laboratory values for fasting plasma glucose for diabetes, T4 and TSH for hypothyroidism, and creatinine for renal function are useful in the diagnosis of some of the more common forms of secondary lipid disorder [24]. Having ruled out the secondarylipid disorders, which are common and can exacerbatea primary dyslipidemia, the clinician should turn to an investigation of these less common, hereditary disorders. 4. The primary lipid disorders Of those who sustain a myocardial infarction, about 20 percent show an underlying primary dyslipidemia [40]. The first useful diagnostic classification of the primary dyslipidemias was developed 20 years ago. It grouped patients according to the pattern of excess lipoproteins isolated from their plasma by electrophoresis [41]. There were six groups, given roman numerals. This reliance on the outward manifestations of a disease,known as phenotyping, reflects how little was known at the time of the molecular origin of the lipid disorders. The elucidation of the genetic and biochemical defects underlying many of these disorders demonstrated that individuals with the same lipoprotein phenotype did not represent a homogeneous group, but rather a heterogeneousgroup with a variety of genetic and biochemical abnormalities. In addition, a number of secondary lipid disorders can mimic the lipoprotein phenotypes of primary disorders. In too many cases, the lipoprotein profiles of the phenotypes correspondedneither to one primary or one secondary disorder. The original roman numeral classification was therefore de-emphasized but still appearsas a form of clinical shorthand [2,24]. Current and evolving classification of primary disorders arrange them according to genetic disorders

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and their primary biochemical defects. Most of these disorders arise from single gene mutations [2]. Gene therapy may provide alternate treatment modalities in the future. Xanthomas may be the first signs of a variety of underlying molecular abnormalities resulting in one of the inherited or primary dyslipidemias [42]. These skin manifestations, combined with a family history of hyperlipidemia or premature atherosclerotic vascular disease,suggesta primary lipid disorder. By this time, risk factors, particularly those with a hereditary component such as hypertension and diabetes, will have been evaluated. Total cholesterol, LDL, HDL and triglyceride levels, if not determined as part of a screening, can be useful in the diagnosis of a number of primary or genetic disorders: 4.1. A disorder showing elevated LDL-cholesterol levels, familial hypercholesterolemia

This is a rather common autosomal dominant disorder [2]. It results from a genetic mutation in the LDL receptor, resulting in a decline in LDL uptake by the liver and an increase in plasma LDL [23]. Most of these patients are heterozygotes,receiving only one mutant gene. Those with heterozygousfamilial hypercholesterolemia occur in one out of every 500 individuals. They account for about five percent of survivors of myocardial infarction younger than 60 years of age 1431. Heterozygotes show plasma cholesterol in the 300-400 range. They show xanthomas which form particularly within the achilles tendons and on extensor tendons on the dorsum of the hand. Cornea1arcus and xanthelasma may be present by age 20 [3,44]. Rarely, retinal, choroidal and conjunctival xanthomas may be found [44]. Premature atherosclerosis and myocardial infarctions are common by age [40]. Dietary and drug therapy designed to stimulate the production of LDL receptors have been useful in slowing the progression of this disease[2]. Both mutant genes are received in homozygotes, who constitute about one in a million individuals [2]. Homozygotes show plasma cholesterol levels which are at least twice has high as in heterozygotes.Xanthomas appear within a few years after birth, characteristically in the webs of the fingers and at sites of trauma over the knees and elbows [21]. Cornea1arcus and xanthelasmas are also characteristic [3]. Myocardial infarctions occur in the first and second decades of life. Homozygotes usually suffer a fatal infarction by age 20 E21.Therapy is usually ineffective. LDL-cholesterol levels are elevated in an ill-defined category of polygenic hypercholesterolemia.This category has been arbitrarily defined as the top five percent of LDL levels in the entire population. A pathogenesisinvolving a complex interplay of numerous genes and environmental factors is suspected[2].

Eye and Vision Care 7 (I 995) I 17-128

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Xanthelasmas and tuberous xanthomas frequently occur in polygenic hypercholesterolemia. along with cornea1 arcus [45,46]. Some patients respond to dietary therapy, others to drug therapy [2! 4.2. A disorder showing increased levels of tri@ycetides - familial hypertriglyceridemia

This is a common autosomal dominant disorder suggestinga single gene mutation, the nature of which is currently unknown. An inability to degrade the triglycerides in VLDL occurs (7, Fig, 8) leading to hypertriglyceridemia [2]. Eruptive xanthomas and lipemia retinalis are observed, particularly with triglyceride levels over 3000 mg/ dl (normal range. 50-150 mg/dl, fasting). The milky appearanceof the plasma is seen most readily in slim peripheral vessels of the retina, where red cells are massed less, and only minimally obscure the view [44]. These individuals also tend to be hypertensive and have low HDL levels. Possessinga constellation of potent risk factors. these indivividuals are at great risk for adverse vascular events. In some studies, approximately 15% of those with coronary heart disease manifested this dyslipidemia [46]. At lower levels of hypertriglyceridemia. xanthomas are infrequent. However, excessivealcohol intake and oral contraceptive use, poorly controlled diabetes, or the development of hypothyroidism can cause the triglyceride level to rise drastically [3]. This may lead to pancreatitis [2]. The clinician is forewarned of potential disaster by the earlier appearanceof erup-tive xanthomas, including those appearingon the lids. Lipemia retinalis will also appear, and with eruptive xanthomas, urges intervention to lower triglyceride levels [44]. Action is directed toward controlling all factors which increase the triglyceride levels, including low calorie diet, avoidance of alcohol and oral contraceptives and tight managementof diabete+[:I. 4.3. A primaly disorder showing increased levels cholesterol and triglycerides - ~familiai dysbetalipoproteinimia

of both

In this inherited disease,the apoprotein present on very low density lipoproteins and chylomicron remnants is defective (Fig. g-steps 5 and 7). This occurs because of a mutation of the gene r,esponsiblc for producing the apoprotein. Because the apoprotein (arbitrarily named apoprotein E) is defective, very low density lipoprotein and chylomicron remnants cannot enter cells and therefore accumulate in the bloodstream [47]. Since the low density lipoprotein particles are relatively rich in cholesterol and the chylomicron remnants are relatively rich in triglycerides, the level of all of these compounds rises in the plasma. Because several types of mutations can produce this disease and environmental factors arc thought to sti.

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mulate its expression, it is inherited in multiple patterns [48]. Patients have nearly pathognomonic yellow, fatty infiltrates in the creases of the palms (xanthoma striata palmaris) [3]. They also show tuberous or tuboeruptive xanthomas of the elbows, knees and buttocks 13,211.Xanthelasmas may occur and cornea1 arcus may be seen at an early age [2,44]. Patients with dysbetalipoproteinemia are often obese, diabetic, hypothyroid and hypertensive [45]. They suffer from accelerated and widespreadatherosclerosis and its sequelae: premature myocardial infarction, strokes, and pain and gangreneof the lower extremities [2]. Early diagnosis of this disease with observation of palmar lesions can allow for early intervention. Diet and drug therapy, including treatment of hypertension and secondary lipid disorders, can result in major reduction in abnormal lipid levels and risk for cardiovascular disease[2,42]. 4.4. Disorders showing increased levels of chylomicrons - the hyperchylomicronemias

These are uncommon autosomal recessive disorders characterized by severe hypertriglyceridemia and accompanied by markedly elevated levels of chylomicrons in the blood. They stem from single mutations in genes responsible for the production of lipoprotein lipase (Fig. 8-step 3), or of an apoprotein necessary for the proper functioning of the enzyme [49]. This results in inadequate catabolism of triglycerides present in chylomicrons [50]. Patients will characteristically show eruptive xanthomas on the elbows, knees, back and buttocks at pressure points [3]. Eruptive xanthomas of the lids are commonly found. Rarely, iris and retinal xanthomas are observed.In the presenceof this heavy accumulation of chylomicrons, the patient’s plasma, if left standing in the refrigerator overnight, will show a creamy layer at the top in the morning [51]. With triglyceride levels over 3000 mg/dl, retinal vesselswill appear milky white, and the fundus will have a pale appearance.All of these in vitro and in vivo manifestations occur due to the light scattering properties of the chylomicrons. The lipemia retinalis may cause visual impairment if involving the macula, but is reversible with lowering of the chylomicron levels by dietary fat restriction. Treatment also decreasesthe chance of a lipid exudate forming due to leakage of chylomicrons from the microvasculature [ 161. More serious is the tendency of these patients to develop retinal vascular occlusions and acute and recurrent pancreatitis [16,50]. Pancreatitis is the major lifethreatening condition brought on by the hyperchylomicronemias. Patients with this disorder do not appear to be predisposedto accelerated atherosclerosis and its sequelae.

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4.5. Uncommon disorders of high density lipoprotein deficiency

A group of seven rare disorders of high density lipoprotein deficiency feature diffuse cornea1opacification, occasional xanthomas, and premature coronary artery disease. Cornea1opacification which can reduce vision occurs as a diffuse, extracellular, granular lipid deposition in the cornea1stroma. Xanthomas occur on the lids as flat lesions, but do not favor the medial canthi as in common xanthelasmas. Xanthomas may also occur on the neck, chest, arms, back and legs. These clusters of lipid laden macrophages may also appear in the tonsils, liver, spleen and lymph nodes, enlarging these lymphoid organs and presenting as clinical signs. The most severe cases of cornea1opacification and visual impairment occurs in one of these disorders: Fish-Eye disease.The slit lamp will show small greyyellow dot-like opacities in a mosaic pattern in the stroma and Bowman’s layer. Cornea1transplantation may become necessary.For unexplained reasons,premature coronary artery disease is not a feature of Fish-Eye Disease [45]. 5. Approaches to the treatment of lipid disorders 1361 5.1. First line approach -

diet and exercise

Prevention of atherosclerotic cardiovasculardisease before disease sequelae arise is called primary prevention. It should rely on dietary and exercise therapy first, barring patients with severe dyslipidemias. The diet should emphasizea nutritionally balanced diet of fruits, vegetables,grains, fish, poultry, lean meats and low fat dairy products. Should this fai1, drug therapy can be considered, particularly in middle-aged and older patients with LDL cholesterol levels above 190 mg/dl or when over 160 mg/dl with several cardiovascular risk factors [36]. Secondaryprevention for patients already manifesting some form of atherosclerotic cardiovascular disease requires a target goal of LDL cholesterol reduction to 100 mg/dl or lower. Should dietary therapy fail to approach this goal, drug therapy should be considered, particularly in patients who cannot lower their LDL-cholesterol to below 129 mg/dl with intensive dietary therapy. 5.2. Second line approach -

drag therapy

The major classes of drugs used in treatment of lipid disorders are; . l l

the bile acid sequestrants nicotinic acid HMG CoA reductase inhibitors

R.M. Frankel, R. Capone /Clinical

The bile acid sequestrants, including cholestyramine and colestipol, are resins which bind cholesterol-derived, bile acids in the intestinal lumen (Fig. 8-step 1). This interrupts the enterohepatic circulation of bile acids, and promotes their elimination in the feces. Bile acid sequestrants are thus particularly effective in lowering LDL-cholesterol levels. Nicotinic acid, also known as niacin, is a B vitamin. It appearsto act by reducing the production of VLDL by the liver (Fig. g-step 7). Since LDL is derived from VLDL, LDL-cholesterol levels are also reduced. Nicotinic acid in some fashion also decreasestriglyceride levels and raises HDL-cholesterol levels [52]. HMG CoA reductase inhibitors, including lovastatin, pravastatin, and simvistatin, act to lower LDLcholesterol levels. They do so by inhibiting HMG CoA reductase, a rate-limiting enzyme in cholesterol synthesis in hepatocytes. Hepatocytes respond by increasing the production of LDL receptors, which accelerates clearance of LDL cholesterol from the bloodstream (Fig. 8-step 10). HMG CoA reductase inhibitors infrequently cause skeletal muscle breakdown, myoglobinuria and renal toxicity. Therefore, patients with dyslipidemia secondary to renal disease are at increased risk. Some HMG CoA reductase inhibitors have been known to be hepatotoxic and are contraindicated in those with liver disease.It is therefore necessaryto ascertain the presence of lipid disorders secondary to kidney or liver disease before initiating drug therapy. 6. Conclusion

Xanthelasmas are part of a large family of fatty lesions (xanthomas),which are easily observablesigns of life-threatening serum lipid abnormalities. The detection of the most common of these, the xanthelasma, should prompt a search for other members of the xanthoma family, for the xanthelasma is the least reliable indicator of serum lipid disorder. With few exceptions, related xanthomas found in skin and tendons mirror fatty deposits in arterial walls which endangerblood flow to vital organs in the body. The clinician who finds xanthomas should pursue a diagnosis of dyslipidemia by appropriate history, physical examination and laboratory testing so that treatment can be promptly initiated towards normalization of lipid levels. Diagnosis and treatment should then be directed at secondary or acquired disorders which can, by themselves, produce abnormal lipid profiles, and which can exacerbate lipid abnormalities in a primary disorder. The less common primary disorders are then sought. In this investigation, the presenceof significant risk factors, including a family history of cardiovascular events and physical signs, including

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cornea1arcus and lipemia retinalis, are useful, related findings. Xanthomas are thus a significant clinical finding and may be the first clue to the diagnosis of a variety of systemic diseases such as diabetes and hypothyroidism, as well as the inherited lipid disorders. Management of these disorders can spare the patient needless suffering from disseminated atherosclerotic vascular diseaseas well as potentially fatal pancreatitis [53]. The primary care optometrist who is acquainted with the portrait of xanthelasmas and their relatives is in a position to determine the significance of xanthomas in their patients. The knowledgeable practitioner can modify the profile of risk for each individual for a variety of serious disorders and make a profound impact in the well-being of his or her patients, References [II Boring CC, Squires TS, Tong T, Montgomery S. Cancer Statistics 1994 in CA. Cancer J Clin 1994;44:?2h.

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