CURRICULUM

IN CARDIOLOGY

Cholesterol embolism: clinical entity Anil Om, MD, MS, Samer Ellahham, Richnond,

An underdiagnosed

MD, and German0 DiSciascio, MD

Va.

Cholesterol embolization is a disorder that is caused by showers of cholesterol crystals from atheromatous large arteries, which block the small arteries (100 to 300 pm) and cause distal ischemia, gangrene, and necrosis. The disorder is also called atheroembolic disease, microembolic disease, or cholesterol crystal embolization. This condition is probably underdiagnosed for three reasons: (1) there is a myth that cholesterol embolization is seen after difficult, “nonsmooth” invasive procedures and angiographers therefore are very reluctant to make this diagnosis; (2) the symptoms may be atypical, are often not reported by the patient, and may be missed by the physician; and (3) the only reliable means of establishing this diagnosis is by biopsy, which is most often not performed and even when done, does not always reveal the characteristic clefts of cholesterol embolization. Obstruction of small arteries by cholesterol particles was first observed by Panuml in 1862, but its description was first detailed by Flory’ in 1945. Since then, a number of case reports and small studies have described this disorder in detail. However, no prospective, large-scale study has evaluated the incidence of cholesterol embolization after invasive procedures. INCIDENCE

Drost et a1.3 reported cholesterol embolism in only 7 of 4587 (0.15 % ) patients who were undergoing cardiac catheterization. Similarly, low incidence was reported by Rosansky and Deschamps4 in 9 of 11,402 (0.08%’ ) patients who were undergoing angiography and in 0.7956 of subjects in an autopsy series by

From the Division of Cardiology, ical College of Virginia, Virginia Received

for publication

Reprint requests: 23298-0281. 4/l/40454

Mar.

Department of Internal Medicine, MedCommonwealth University, Richmond. 9, 1992; accepted

Apr.

Anil Om, MD, MS, Box 281, MCV

28, 1992.

Station,

Richmond,

VA

Kealy.5 However, Ramirez et a1.6 demonstrated the presence of cholesterol emboli in the spleen and kidneys of 30 ‘% of patients after aortography and 25.5 f’, of patients after cardiac catheterization who died within 6 months of the procedure. A much higher percent of patients (77 % ) who had undergone aortic manipulation was shown to have renal emboli at autopsy by Thurbeck and Castleman. The reported incidence may therefore be low because clinical suspicion of cholesterol embolization is high only when cutaneous manifestations are evident. The absence of such manifestations may prevent many cases of visceral embolization from being detected. PRECIPITATING

EVENTS

Cholesterol embolization is most commonly seen after invasive procedures that involve manipulation of the aorta. The typical patient is over the age of 60 and has extensive atherosclerotic disease. Atherosclerotic plaques are found most commonly in the lower abdominal aorta, the coronary arteries, the popliteal arteries, the descending thoracic aorta, and the internal carotid arteries (in descending order of severity).8 Cholesterol embolization has been documented after angiography,4* 6~g, lo cardiac catheterization, percutaneous transluminal coronary angioplasty,3> 11-13 and cardiovascular surgery that involved aortic manipulation.7, 14,I5 Because the vessels of the upper extremities are rarely involved in atherosclerosis, it was expected that the incidence of cholesterol embolization would be higher with the use of femoral approach for angiography16v l7 as compared with the brachial artery approach. The coronary artery surgery (CASS) trial,l* however, did not prove this. This large prospective trial revealed arterial embolization in 0.17% of patients when the brachial route of catheterization was used and in 0.08% of patients when the femoral route was used. Cholesterol embolization is not only seen after invasive procedures with prolonged manipulation but has been documented after very smooth procedureslg 1321

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Om, Ellahham, and DiSciascio

Table

I. Manifestations

of cholesterol embolization

System Skin

Renal

Nervous Miscellaneous

Manifestations Livedo reticularis, gangrene, cyanosis, ulceration, nodules, purpura Nonoliguric renal failure, new-onset hypertension or worsening of preexisting hypertension Transient ischemic attacks, amaurosis fugax, paralysis Bowel ischemia, gangrene, infarction, or obstruction; pancreatitis, adrenal insuf ficiency

and can also occur spontaneously.“0-22 Few case reports of cholesterol embolization after the use of tissue plasminogen activator23 and streptokinase24-26 for treatment of acute myocardial infarction have been reported. Most of these patients had simultaneous angiography performed, and therefore the role of lytic therapy could not be precisely delineated. The role of anticoagulation in cholesterol embolization has been controversial: “purple toe” syndrome as a result of anticoagulation has been well known, but its exact etiology has been debated in the past.27, 28 Initially it was thought to be secondary to warfarin’s toxic effect on the capillaries,2g> 3o but Hyman et a1.31 and Colt et al.lg clearly demonstrated that cholesterol embolization that is secondary to anticoagulation therapy was the cause of “purple toe” or “blue toe” syndrome. CLINICAL

MANIFESTATION

Cholesterol embolization has varied clinical manifestations because of multiple organ system involvement (Table I). The organs affected depend on the site of origin of the shower of atheroma: when it comes from the proximal part of the aorta, the central nervous system, the abdominal organs, and the extremities are involved. Only the extremities would be involved if the aorta below the renal arteries is the site of origin of atheromas. The various manifestations of cholesterol emboli include: (1) ischemia and necrosis of the lower extremities32-34; (2) focal central neurologic disorders 21s35,36; (3) nonoliguric renal failure with or without hypertensionlO,il; (4) coronary insufficiency with or without myocardial infarction37; (5) peripheral palsies as a result of spinal cord infarction38; and (6) abdominal pain, nausea, gastrointestinal bleeding,3g pancreatitis40 and splenic infarct.

American

November 1992 Heart Journal

Cutaneous manifestations. Cutaneous manifestations are the most common signs of cholesterol embolization and are seen in approximately 35 “; of pa. tients. Livedo reticularis is the most common type (49%), followed by gangrene (35?C ), cyanosis (28’, ). ulceration (17 0; ), nodules (104’0 ), and purpura (9 @&).41 Livedo reticularis, which is most commonly seen over the lower extremities, is a purple-bluish discoloration network that is most likely due to obstruction of small arteries in the deep dermis. Presence of cyanosis in cholesterol embolism is characterized by well-preserved peripheral puIses,3gT 42 and this finding should suggest cholesterol embolization as the cause of cyanosis in the clinical setting. Subcutanous nodules appear as a result of an inflammatory reaction surrounding cholesterol crystals. Renal manifestations. Acute nonoliguric renal failure after invasive procedures has been the common presentation of cholesterol embolism t,o kidneys.‘O, ” Usually there is rise in creatinine a few weeks rather than a few days after the procedure, and there may be a plateau phase before a further rise in creatinine occurs. Diagnostic suspicion is enhanced by associated cutaneous manifestations, in the absence of which only renal biopsy will establish the diagnosis. Differentiation from acute dye-induced nephropathy is very important. It seems likely that a small, nonsignificant cholesterol embolism could occur in kidneys and be clinically silent. Ramirez et al.6 found autopsy evidence of cholesterol embolism in the kidneys and spleens of 30”; of subjects at 6 months after aortography. Most often there is associated hypertension or worsening of previously existing hypertension,““. 44 the mechanism of which is likely due to activation of the renin-angiotensin system43; therefore, a significant increase in plasma renin activity as compared with the preprocedure level may suggest the diagnosis. Nervous system manifestations. Showers of cholesterol embolism to cranial and ocular arteries can produce various symptoms including transient ischemic attacks, amaurosis fugax, and paralysis3”r x A cholesterol embolism could arise from the proximal part of the aorta or more commonly from the carotid vessels. Diagnosis may be obvious by the presence of Hollenhorst plaques in the retina, which are bright and shiny yellow spots at the retinal arteriolar bifurcation45, 46 (Fig. 1). Involvement of the spinal cord artery could lead to lower-extremity paralysis.“8 There is sufficient collateral circulation to the spinal cord, and this may reduce the incidence of clinical paralysis. In spite of the lower incidence of paralysis, a significant number of cholesterol crystals were

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Cholesterol

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Fig. 1. Fundoscopic view of the retina, revealing a cholesterol crystal (Hollenhorst plaque) at the bifurcation of retinal arteriole (arrow).

found in the anterior spinal and sacral cord arteries in autopsy studies.47 Other manifestations. Showers of cholesterol crystals to mesenteric arteries can lead to bowel ischemia, gangrene, and infarction48; and the fibrosis that is secondary to gangrene can lead to intestinal stricture.4g Pancreatitis40 and adrenal insufficiency50 are some of the other rare manifestations of cholesterol embolism. A case of acute myocardial infarction that was secondary t.o cholesterol embolism has also been most cases of cholesterol reported. 37 Surprisingly, embolism have been reported to occur in white patients41j 51; whether some of the subtle cutaneous lesions are missed in more darkly pigmented patients is not known. DIAGNOSIS A high degree of suspicion is required to detect early subtle cutaneous changes and confirm the diagnosis with the use of a properly selected site for biopsy. A triad of leg and foot pain, livedo reticularis, and intact peripheral pulses is pathognomonic. Diagnosis of cholesterol embolism without cutaneous manifestations is usually difficult. A temporal relation between the invasive procedure and the onset of symptoms usually favors the diagnosis of cholesterol embolism. Therefore the diagnosis of spontaneous cholesterol embolism is also difficult to make. Early and precise diagnosis is important for further plan-

Table II. Laboratory findings associated with cholesterol embolization Leukocytosis Eosinophilia Elevated sedimentation rate Hypocomplementemia

ning, even though cholesterol embolism is not a curable disorder. Discontinuation of anticoagulation therapy has been shown to slow down and also decrease symptoms.52 Various laboratory tests help to establish the diagnosis of cholesterol embolism (Table II). Leukocytosis, eosinophilia, 53,54 elevated sedimentation rate, and decreased complement leve155 are often observed. However, precise and confirmatory diagnosis is only made by means of biopsy. Frozen or wet formalin-fixed sections will reveal doubly refractile cholesterol crystals, and with the Schultz histochemical stain these crystals are stained blue-green. More precise chemical analysis and x-ray crystallography can be performed for proper identification.12 In the paraffin-fixed sections the cholesterol crystals are dissolved and leave needle-like clefts (Fig. 2). If there is no definite area over the toes or foot that is suitable for biopsy, random biopsy specimens of gastrocnemius or quadriceps muscles have been shown to provide a reliable diagnosis. 32j56 On one occasion the di-

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and DiSciascio

American

November 1992 Heart Journal

2. Photomicrograph of a paraffin-fixed section of the anterior spinal artery, revealing needle-like clefts, which are diagnostic of cholesterol emboli. (Magnification x300.)

Fig.

Table

III. Differential diagnosis of cholesterol embolization Dye-induced nephropathy Subacute bacterial endocarditis Vasculitis Thrombotic embolism

agnosis was established by bone marrow biopsy.j7 Antemortem diagnosis of cholesterol embolism is not often made,58 and so far the majority of cases were detected at autopsy.5g DIFFERENTIAL

DIAGNOSIS

A number of clinical entities can simulate cholesterol embolization (Table III). In the immediate phase after an invasive procedure in which dye has been used, differentiation from dye-induced nephropathy is important. Usually in the latter situation, there is an increase in creatinine a few days after the procedure, with a peak at 7 to 10 days and a return to baseline within 2 to 3 weeks. In contrast, in cholesterol embolism the rise in creatinine is late (1 to 2 weeks) and usually leads to progressive and often irreversible deterioration of renal function, which often requires dialysis. Subacute bacterial endocarditis have neurologic, ophthalmic, renal, and cutaneous manifestations that are similar to those of cholesterol embolism, but the diagnosis can be confirmed by

blood cultures. Spontaneous cholesterol embolism should be differentiated from vasculitis.5g Both may present as visceral infarctions, leukocytosis, eosinophilia, hypocomplementemia, and elevated sedimentation rate. Biopsy of the involved tissue can help differentiate the diagnosis of these two clinical entities.60 MANAGEMENT

Aim of treatment is to halt the progression of tissue ischemia and prevent such events in the future. At present there is no ideal treatment for cholesterol embolism. Because of embolic phenomena, anticoagulation has been attempted. It has been shown to worsen the condition,61, 62 and its discontinuation has been shown to decrease symptoms.52 A number of antiplatelet drugs have been tried without success.3* 30,44 Inflammatory reaction around the cholesterol embolus can further block the arterioles, and therefore steroid therapy has been used to treat this condition with limited63 or no effect.42 Likewise, lowmolecular-weight dextran and pentoxyfylline have been of no proven benefit. Lumbar sympathectomy may relieve symptoms transiently64, 65 but not for long.@ A number of other surgical approaches have been used (e.g., resection of the atheroma site67, 68 and the aneurysm6gv 7o) with often disappointing results.71, 72 Cholesterol-lowering agents have been

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tried73 with the hope that regression of atheroma may prevent future attacks. Management of hypertension that is secondary to cholesterol embolism has been controversial. Because of renin-angiotensin activation, an angiotensin converting enzyme inhibitor may be the drug of choice with or without minoxidil, a potent vasodilator, to increase renal flow. Prognosis for patients with cholesterol embolism remains poor. The mortality rate ranges from 72% 41 to 80 o,G.58

Cholesterol

12 13

14

15.

16. 17

CONCLUSIONS

Cholesterol embolism is most commonly an iatrogenie problem, which is very much underdiagnosed. An increasing number of cardiac catheterization, percutaneous transluminal coronary angioplasty, and peripheral angioplasty procedures are being performed, and therefore clinicians should be aware of this rare but potentially fatal problem. A high degree of clinical suspicion and a biopsy specimen that is obtained from a properly selected site can confirm the diagnosis. Its differentiation from dye-induced nephropathy and other types of vasculitis is important,. Although no cure exists at present, search for newer agents should continue. A number of questions remain to be answered. What initiates the process of cholesterol crystal showers, which continues to occur for many weeks after the invasive procedure? Is this an immunologic process? Is it a race-related phenomenon? What is the best drug of choice for management of cholesterol-embolism-induced hypertension? It is hoped that many of these questions will be answered in the near future. REFERENCES

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