AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Cholesterol embolism (CE), also known as atheroembolization, refers to the occlusion of small- and medium-caliber arteries (100-200 µm in diameter) by cholesterol crystals. Panum first reported this disease entity in 1862 in his autopsy report of the famous Danish sculptor Thorwaldsen. In 1945, Flory proved the embolic origin of the cholesterol crystals and stimulated new interest in this disorder. Fine et al documented the presence of characteristic skin findings in 35% of cases, thereby making the clinical diagnosis of CE readily possible. With publication of a successful treatment strategy by Belenfant et al, in 1999, the medical necessity of making this diagnosis became apparent. The purpose of this article is to define the cardinal clinical features of CE and relate these to the pathophysiology of this condition.

CE can be a difficult clinical diagnosis. While many patients with CE present with leg pain and livedo reticularis or blue toes in the presence of good peripheral pulses, a high index of suspicion is needed because the symptoms often are atypical, not temporally correlated with the onset of physical findings, or not reported by the patient. Additionally, laboratory test results are not specific for CE. Biopsy results demonstrating the needle-shaped cholesterol clefts in intravascular microthrombi are the most specific findings to make a definitive diagnosis of CE.

Pathophysiology

Atherosclerosis is a necessary prerequisite for CE, although it is not always sufficient. CE is often triggered by an invasive vascular radiographic or vascular surgical procedure, administration of anticoagulants, local or systemic thrombolytic therapy, or trauma. These cause rupture of atheromatous plaques in proximal major arteries releasing cholesterol crystals into the bloodstream. The crystals migrate distally until they lodge in small arterioles, where they provoke an acute inflammatory response, causing intravascular thrombus formation, endothelial proliferation, and finally fibrosis of the vessel. These processes can lead to ischemia, infarction, and necrosis of the organs supplied by the affected vessels.

In any given patient, the precise clinical syndrome depends on the location of the source of cholesterol crystals and the pattern and distribution of their flow downstream. The most common sites for severe atheromatous disease are in the abdominal aorta and the iliac and femoral arteries; accordingly, signs and symptoms more commonly result from embolism to the lower half of the body. Patients with CE frequently present with lower limb ischemia (blue toe syndrome), abdominal pain, melena, and a stepwise decline in creatinine clearance levels resulting from focal underperfusion of the intestine and the kidneys. When the source of crystals is in the aortic arch, additional important and diagnostic signs and symptoms of embolization may occur in the eyes and the CNS.

Clinical signs and symptoms may take from 1 day to several months to evolve after the inciting event. A 1999 study by Belenfant et al of patients with cholesterol emboli found that the likely precipitating event occurred an average of 2 months before their admittance to the ICU for acute renal failure (ARF).

Frequency

International

The incidence of CE is unknown. Published estimates range from 1.9-77%, in part due to populations studied and whether biopsy or autopsy data were analyzed.

Thurlman and Castleman report an incidence of 25-77% in a population at high risk for the disease. Klein et al report that a study of a small Wisconsin town populated primarily with white people (n = 4926) found a 10-year rate of retinal emboli of 1.5%. Moolenaar and Lamers completed the largest descriptive epidemiologic study of CE using the Dutch National Pathology Information System. Cholesterol crystal embolization was found in 0.007% of 8.5 million premortem histology specimens and in 0.31% of 89,000 autopsy reports. The estimated annual incidence of CE increased through 1985, with stabilization thereafter (6-7 cases per 1 million population). Explanations for the discrepancy between the Dutch and previous studies probably are related to selection bias; however, the prevalence of underlying risk factors (eg, atherosclerosis, rate of invasive vascular procedures) may be lower in the Netherlands than in North America.

Mortality/Morbidity

CE is regarded as a marker of severe atherosclerosis, and its morbidity and mortality reflect this. Mortality rates are reported up to 65-87% within 1 year of diagnosis in some studies. The leading causes of death include acute myocardial infarction, ruptured aortic aneurysm, gastrointestinal infarction, congestive heart failure, sepsis, and cachexia.

• Markers for higher mortality rates include hypertension, decreased creatinine clearance, and a short delay between the occurrence of symptoms and the development of skin findings.
• Patients with visceral involvement (half of whom also had peripheral manifestations) had 50% and 65% mortality rates within 6 and 12 months, respectively.
• The presence of cutaneous manifestations does not appear to predict survival. Patients with only peripheral manifestations had a 38% mortality rate within 15 months.
• Morbidity includes chronic renal insufficiency requiring hemodialysis, stroke resulting in paraplegia, unstable angina, amputation of the affected extremity, (5-15% of patients), and malnutrition or significant weight loss (70% of patients).

Race

CE is more commonly found in whites than in other racial groups, with a ratio of 32:1 in whites compared to blacks. This observation may be related to ascertainment bias and the difficulty of detecting the subtle cutaneous findings in darkly pigmented skin.

Sex

CE occurs more often in males than in females, with a male-to-female ratio of approximately 3.4:1. The risk factors for atherosclerosis as identified by the Framingham Heart Study included male gender, smoking, hypertension, diabetes, hyperlipidemia, and family history. Because CE can be considered a complication of atherosclerosis, these same risk factors offer some explanation for the increased risk in males.

Age

The reported age range for CE is 26-90 years; the mean age is 66-72 years.

CLINICAL

Section 3 of 11  

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• Clinical
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• Follow-up
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History

Once termed the great masquerader for its clinical similarity to several other important systemic diseases (eg, polyarteritis nodosa), CE syndrome is often unrecognized or misdiagnosed. Thus, a high suspicion is needed, especially in the setting of a history of preexisting atherosclerotic cardiovascular disease and specific precipitating events. The classic triad of lower extremity pain, livedo reticularis, and good peripheral pulses in a person older than 50 years should be considered to be due to cholesterol embolization until proven otherwise

Physical

The onset of physical findings may be delayed by days to months once precipitating events have occurred. Cutaneous manifestations are the most common physical findings in patients with CE (35% of patients) and the most helpful in establishing a diagnosis. Premortem diagnosis was made in 60% of patients with dermatologic findings, compared with less than 20% in patients without skin findings. The following percentages represent all skin lesions found in CE in multiple studies; the total exceeds 100% because more than one manifestation is usually present in an individual.

• Livedo reticularis is the most common dermatologic manifestation of CE, comprising approximately 50% of CE-related skin lesions. This blue-red mottling of the skin in a netlike pattern usually affects the feet, the legs, the buttocks, and the thighs and can extend to the trunk and the upper extremities. Livedo reticularis may be noted only while the patient is standing; therefore, examining patients in both the supine position and the standing position is important. To distinguish livedo reticularis from cutis marmorata, perform the following 2 maneuvers:
• • Raise the extremity. In livedo reticularis, the netlike pattern disappears after several minutes.
  • Warm the extremity by covering it with blankets for 1 hour. Cutis marmorata disappears with warming of the extremity, while livedo reticularis persists.
• Gangrene (35%) is the loss of tissue due to a lack of blood supply. In CE, it may supervene from acrocyanosis or livedo reticularis. Gangrene is almost always confined to the toes (bilaterally in 50% of patients) but rarely involves the scrotal area. The gangrene is dry and demarcates after a few weeks and eventually requires surgical debridement.
• Acrocyanosis or blue toe syndrome (28%) is a characteristic blue-black or violaceous discoloration of the toes, the feet, and (on occasion) upper extremities. The lesions are painful, and the color change is secondary to decreased blood supply. Blue toe syndrome, a term coined by Karmody et al, refers to acute digital ischemia caused by microembolism from the distal aorta or the iliac or femoral arteries.
• Ulceration (17%) is typically unilateral and located on the toes and the feet. Unusual presentations of cutaneous ulcerations ultimately shown to be related to CE have also been reported. These have included refractory or recurrent ulcers of the digits and the lower extremities.
• Nodules or indurated papules (10%) are firm, violaceous, and painful. They can appear on the legs, the thighs, the toes, or the feet as a result of an inflammatory reaction surrounding cholesterol crystals.
• Purpura (9%) is most commonly seen on the legs and the feet. The lesions resemble those of vasculitis, but they typically spare the toes.
• Petechiae (4%) are small, pinpoint, purpuric spots that rarely may appear in CE.
• Other unusual clinical presentations include the following:
• • Balanitis (necrosis of the penile foreskin, perineal area, and scrotum) has been reported with CE, reflecting a distal aortic or iliofemoral source.
  • Isolated case reports exist where cholesterol clefts have been demonstrated in solitary lesions in unusual locations (eg, a nodule on an ear, red and painful swelling on the chest) with microscopic findings of hemorrhagic panniculitis.
  • Violaceous subcutaneous nodules on the calves of one patient thought to have erythema induratum of Bazin was ultimately shown to have CE.
  • Punctiform subungual hemorrhages occur along with other cutaneous signs after left heart catheterization.
  • Full-thickness cutaneous infarcts mimicking heparin necrosis have been reported.
• Extracutaneous manifestations of CE include constitutional symptoms, such as fever and weight loss, as well as the following:
• • Pulses: Pedal pulses are palpable in 60% of patients, bilaterally decreased in approximately 40%, and absent on the side of the cutaneous lesions in fewer than 5% of patients. The relative normality of pulse findings in patients with CE at risk for atherosclerotic peripheral vascular disease occurs because the emboli and microthrombi occur in the most distal vessels
  • Renal manifestations (34%): Renal CE is the best marker for visceral involvement because the kidneys have a large blood supply distal to atherosclerotic lesions in the abdominal aorta. While the skin is extensively collateralized, the blood supply to the renal cortex consists of end-arterioles. Therefore, embolic events in the kidneys often result in an irreversible loss of some glomerular function. The clinical diagnosis of CE can be made when stepwise loss of glomerular function is accompanied by other manifestations of CE. The 2 most common renal manifestations of CE are hypertension and loss of glomerular function.
  • • Hypertension resulting from CE can be difficult to control and is associated with high plasma renin and angiotensin levels. Renin is released by the juxtaglomerular cells in the afferent arterioles of each glomerulus in response to decreased blood flow, in this case caused by cholesterol emboli.
    • ARF is common in CE, and one study estimated it to account for 5-10% of all cases of ARF. Loss of glomerular function in CE is a progressive process, occurring over 4-6 weeks. It results from periodic showering of emboli and causes renal insufficiency in approximately 30-50% of patients. A delay of as long as 2-6 weeks may occur between precipitating events and the onset of renal dysfunction. This pattern is in contrast to radiographic dye–induced renal failure, which typically occurs immediately following the procedure and usually resolves within 10-14 days.
    • Other features of renal CE may include flank or back pain, gross or microscopic hematuria, pyuria, and/or urinary casts.
    • A multivariate analysis in 2003 found a history of intermittent claudication as a predictor of poor kidney recovery. The exact nature of the reversible component to the ARF is unknown, but the functional recovery rate is higher with CE than with other vascular causes of renal failure.
    • Visualization of cholesterol crystal clefts in a renal biopsy specimen is pathognomonic for CE. The crystals embolize in the arcuate and interlobular arteries of the kidneys, producing an acute inflammatory reaction with endothelial proliferation and occlusion of the lumen, leading to infarction and forming a wedge-shaped scar in the kidney.
  • GI manifestations (30%): CE causes abdominal pain and melena by ischemia or infarction of the small or large bowel. Patients with CE to the bowel frequently have cholesterol emboli to other GI organs, including the spleen (57%), the liver (15%), and the gallbladder (8%). Of patients with GI involvement, 10-30% have hemorrhage, which was found to be the cause of death in at least 1% of patients with fatal CE.
  • Ophthalmic manifestations (6%): Retinal cholesterol crystals (Hollenhorst plaques) are bright yellow, glittering intravascular plaques situated at the bifurcation of retinal arterioles. They can occasionally be found on funduscopic examination. Patients may be asymptomatic, or they may report intermittent monocular blindness, amaurosis fugax (transient blindness), or retinal infarction resulting from complete occlusion. Patients with carotid or vertebrobasilar atherosclerosis who undergo endarterectomy are at high risk.
  • Musculoskeletal manifestations: CE to arterioles in muscles can cause intense myalgia at rest or, with exertion, muscle tenderness and/or weakness. Involvement of lower extremity muscles with upper limb sparing is characteristic in CE.
  • CNS manifestations: CNS CE can occur after vascular procedures such as carotid angiography or endarterectomy or, more rarely, spontaneously. The most frequent sources of emboli are the carotid arteries, the thoracic aorta, or the aortic trunk. Manifestations can include transient ischemic attack and stroke from involvement of the cerebral arteries and spinal cord symptoms from involvement of the anterior spinal artery. Case reports have described of delirium and dementia attributable to CE.
  • Pulmonary manifestations: Alveolar hemorrhage, presumably resulting from CE, was reported in one patient with severe atherosclerosis, hemoptysis, renal failure, and purpura after vascular surgery. Another case report documented pulmonary-renal syndrome in a patient with hemoptysis, respiratory distress, and radiographic alveolar shadowing. Renal and skin biopsies revealed CE.
• Endocrine manifestations: One study reported the presumed death of a patient with visceral CE resulting from necrosis of the adrenal glands.

Causes

CE occurs spontaneously in patients with atherosclerosis, but a trigger is usually required for full expression of CE syndrome. A history of antecedent therapy with anticoagulants is present in 35% of patients; various surgical or radiologic vascular procedures were performed before the onset of CE in 30-50% of patients. Precipitating factors include the following:

• Anticoagulation and thrombolytic therapy: These therapies strip away the layer of fibrin isolating the subintimal deposits of cholesterol from the bloodstream. While multiple case reports describe CE after thrombolysis, a small, prospective study to assess the incidence of CE after thrombolytic therapy for acute myocardial infarction was published in 1995 by Blankenship et al. They found no significant difference in the incidence of CE between patients who had received thrombolytic therapy and those who had not.
• Interventional vascular techniques: The introduction of a foreign object into the vessel can cause intimal trauma, exposing the underlying cholesterol-rich extracellular matrix to the arterial circulation. This risk is increased with increased sheath size of the catheter. Additional risk factors for developing CE after cardiac catheterization include hypertension, a history of smoking, and elevated preprocedural C-reactive protein levels.
• Trauma, including cardiopulmonary resuscitation or sudden deceleration injury

DIFFERENTIALS

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Other Problems to be Considered

Systemic vasculitis (eg, Polyarteritis Nodosa, Buerger Disease [Thromboangiitis Obliterans])
Collagen-vascular disease (eg, Systemic Lupus Erythematosus, Rheumatoid Arthritis , Scleroderma, Sjogren Syndrome, Polymyositis)
Cryoglobulinemic vasculitis
Warfarin necrosis
Heparin-induced thrombocytopenia
Chronic pernio
Symmetric peripheral gangrene
Emboli of cardiac origin (eg, subacute bacterial endocarditis, Atrial Myxoma, mural or atrial thrombi, marantic endocarditis, Libman-Sacks Endocarditis)
Acquired hypercoagulability disorders (eg, Trousseau syndrome, anticardiolipin antibody syndrome, drug-induced anticardiolipin antibodies)
Immune complex disease

WORKUP

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Lab Studies

• Laboratory abnormalities in CE are nonspecific. However, the basic metabolic panel, a complete blood cell count with differential, a urinalysis with microscopic evaluation of the sediment, an erythrocyte sedimentation rate, and a C-reactive protein level can all be helpful in making the diagnosis of CE. Select other laboratory studies based on the patient's underlying disease and the clinical picture.
• • Anemia and leukocytosis are found in 50% of patients.
  • Eosinophilia (>300 cells/µL or 3-18% total WBCs) developed within 3 days of embolization in 70-80% of patients and remained elevated for up to 1 month after the diagnosis of CE was made. Cholesterol crystals in tissue initiate a cascade of reactions, including increased interleukin 5 levels. Interleukin 5 is the most specific cytokine in eosinophil differentiation.
  • Eosinophiluria may indicate CE when identified in patients with other findings of CE. One study found that 8 of 9 patients with biopsy-proven CE had positive Hansel staining for eosinophiluria. When looking for eosinophiluria, note that it cannot be identified with the use of Wright stain and is commonly seen in persons with acute interstitial nephritis.
  • The presence of elevated blood urea nitrogen levels, creatinine levels, proteinuria, pyuria, hematuria, and various urinary casts (in order of descending frequency: granular, hyaline, white cell, red cell, and oval fat bodies) are further indications that glomerular damage is occurring.
  • The erythrocyte sedimentation rate is often elevated (>30 mm/h) in persons with CE.
  • Elevated plasma levels of preprocedural C-reactive protein are associated with subsequent CE in patients who undergo vascular procedures, according to Fukumoto et al.
  • Hypocomplementemia and antineutrophil cytoplasmic antibody positivity are also reported in persons with CE.
  • If the patient has abdominal pain, measure serum transaminase and amylase levels, and test for fecal occult blood. Elevated levels of serum amylase and transaminases suggest embolization to the pancreas or the liver, respectively. If levels are elevated, perform abdominal ultrasonography or CT scanning. The presence of occult fecal blood should prompt further tests to discover the source of bleeding.

Imaging Studies

• Establishing the source of cholesterol emboli remains a formidable challenge, especially in patients with diffuse atherosclerotic disease. Perform noninvasive procedures first. If a resectable or reconstructible lesion is found, perform invasive procedures only if committed to surgical intervention.
• • A transthoracic echocardiogram can help exclude an intracardiac source of emboli.
  • Transesophageal studies are required to exclude very small valvular thrombi, which are present in marantic endocarditis, and occasionally cannot be resolved with transthoracic ultrasonography.
  • Use Doppler ultrasonography of the aorta to exclude aortic aneurysm.
  • Magnetic resonance imaging and CT scanning offer alternative means to effectively evaluate thoracic and abdominal aortic sources of embolism. Media File 10 shows a CT scan of the abdomen, demonstrating the infrarenal aorta with an aneurysm and a mural thrombus.
  • Angiography is necessary in most patients before surgical intervention can be performed, despite the risk of exacerbating CE by mechanical trauma. Peripheral angiography is the definitive test for establishing a diagnosis of atheroembolism involving the abdominal aorta and the lower extremity arteries.

Procedures

• Definitive diagnosis of CE is made by performing a biopsy on affected tissue.
• • Skin and muscle are the most accessible sites for obtaining a biopsy specimen and offer excellent sensitivity (approximately 90%), especially in the subgroup of patients with cutaneous findings and predisposing factors. The unexpectedly high sensitivity claimed in a report by Falanga et al may be due in part to selection bias.
  • Include symptomatic skin or muscle in the biopsy site whenever possible, but even asymptomatic extremities in patients with visceral disease may yield positive biopsy results.
  • Make the biopsy incision as deep as possible (including some subcutaneous fat) to sample the small vessels in which CE commonly occurs.
  • Instruct the laboratory to cut sections at multiple levels through the tissue block because changes can be present in only short segments of affected arteries. In one instructive case report, premortem diagnosis of CE was missed when the first sections of a muscle biopsy were interpreted as being consistent with vasculitis. No further sectioning of the specimen was performed. Cholesterol clefts were found in the tissue at the postmortem examination, and further sectioning of the original muscle biopsy sample revealed cholesterol crystals amid the vasculitis lesions.
  • In evaluating a patient with suspected CE, the consulting dermatologist is often faced with the prospect of performing a skin biopsy on an already compromised extremity and creating a nonhealing wound. In an attempt to define the situations in which skin biopsy materially contributes to the diagnosis, tissue samples (skin or GI tract) are obtained only if 1 or more of 3 clinical criteria used to diagnose CE were lacking. Use of the clinical criteria may allow selective use of the biopsy, thus avoiding serious complications in some patients. The criteria are (1) history of exposure to a known CE-precipitating factor or factors in a patient with documented diffuse atherosclerosis, (2) ARF with an increase in creatinine levels more than 150% of the baseline, and (3) characteristic cutaneous lesions or retinal embolism.

Histologic Findings

CE is defined by the presence of birefringent cholesterol crystals, visualized by special techniques, or biconvex needle-shaped clefts within the arterial lumen corresponding to cholesterol crystals dissolved during the fixation process. The birefringent nature of cholesterol crystals can be demonstrated by using polarized light on frozen preparations. On frozen sections, the Schultz test stains the acicular (ie, needle shaped) cholesterol crystals green within a few minutes and brown within 30 minutes; however, in the clinical setting, demonstration of the characteristic biconvex cholesterol clefts suffices to establish a diagnosis of CE.

In the skin, the artery is usually located at the dermal-subcutaneous junction. In the muscle, the findings occur in small arteries adjacent to areas of patchy myocyte atrophy and necrosis with surrounding infiltrate.

Lesions in different stages of evolution may be found in the same patient as evidence of recurrent showers of emboli. The earliest lesions typically reveal the cholesterol clefts surrounded by nonagglutinated red blood cells, reflecting partial occlusion of the arterial lumen. The cutaneous livedo reticularis pattern is believed to be secondary to this local incomplete disturbance of circulation. Macrophages and foreign body giant cells may surround the cholesterol clefts. Later, a more complete occlusion may occur as encasement of clefts by intimal proliferation and fibrosis ensues. This final stage most likely underlies tissue necrosis and gangrene.

At times, only fibrinous thrombosis of blood vessels is found, especially if the biopsy was not performed deeply enough or an insufficient number of sections were examined. Therefore, the lack of characteristic cholesterol clefts does not exclude the diagnosis.

Rarely, necrotizing vasculitis of small arteries with fibrinoid necrosis and disruption of the arterial wall caused by CE has been reported.

TREATMENT

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Medical Care

Cholesterol embolization has a serious prognosis; unfortunately, treatment options remain limited. Currently, 2 approaches to care are available, conservative medical care or surgical therapy. However, management principles for CE are often conflicting because therapeutic vascular procedures and/or dialysis can also aggravate the disorder and because many of the patients with CE are considered high risk for surgery.

In 1999, Belenfant et al published a prospective study of 67 patients with CE using therapies targeted at the most common causes of death in CE. This approach reduced the 1-year mortality rate by 40-50% compared with historical controls. The treatment includes the following:

• Remove precipitating factors, as follows:
• • Discontinue all forms of anticoagulants.
  • Avoid invasive vascular procedures normally indicated by underlying disease.
• Modify risk factors, as follows:
• • Manage blood pressure (goal blood pressure <140/80 mm Hg) using vasodilators (eg, ACE inhibitors, calcium channel blockers, nitrates).
  • Use statin lipid-lowering medications.
  • Use prednisolone in patients with laboratory evidence of inflammation (ie, elevation of C-reactive protein and fibrinogen levels, increased erythrocyte sedimentation rate, a change in serum complement levels).
• Institute supportive care, as follows:
• • Use high-dose loop diuretics and/or ultrafiltration in some patients with pulmonary edema.
  • Avoid or minimize anticoagulation in patients who require hemodialysis.
  • Provide enteral or parenteral nutritional support.
• Many published anecdotal reports describe other therapeutic approaches to CE. None have been studied critically; however, these methods may be of some value if surgical intervention cannot be performed or must be delayed.
• • Case reports exist of spontaneously healing cutaneous lesions.
  • Individual case reports show benefit from high-dose corticosteroids. Some authors recommend a trial of steroids in patients in whom the clinical course resembles vasculitis, in those with ARF, or in those with pronounced cutaneous manifestations. Steroids may have a theoretical benefit by limiting the secondary inflammatory effects of ischemia and resultant vascular occlusion. Further study is needed to clearly define the role of corticosteroids in the management of CE. Doses have included prednisone at 60 mg/d and methylprednisolone at 80 mg/d, with therapy lasting from 5 days to months, depending on the patient's response.
  • Multiple case reports have found that low-density lipoprotein (LDL) apheresis with the concomitant administration of other medications has led to favorable clinic outcomes. Simvastatin or alprostadil with LDL apheresis improved livedo reticularis and the pain of the toes in one study. LDL apheresis with corticosteroids and/or an angiotensin receptor blocker has been found to decrease skin and brain manifestations, decrease eosinophilia, and improve kidney function.
  • Woolfson and Lachmann report a case of CE syndrome reversal with simvastatin treatment; Cabili et al report similar success with lovastatin. Statins reduce the risk of myocardial infarction and stroke and have a theoretical benefit on plaque stabilization and regression.
  • Successful pain relief and the improvement of purpura, livedo reticularis, and severe cyanosis on the lower extremities have been reported after treatment with intravenous iloprost in 4 cases.
  • One case has been reported to have been successfully treated with oral pentoxifylline.
  • One case report described improvement in ischemic symptoms in a patient with antineutrophil cytoplasmic antibody%#150;positive CE treated with steroids and cyclophosphamide.
  • The use of vasodilators, sympathetic blockers, and low molecular weight Dextran has not been convincingly effective.

Surgical Care

The principal goal of surgical treatment of CE is to promptly identify and eradicate the embolic source and to restore arterial continuity. Carefully weigh the risk versus benefit of the surgical therapies described below, and apply the results individually to patients with CE syndrome; often, both the required preoperative arteriography and the surgery itself are factors that appear to precipitate or perpetuate this syndrome.

• Amputation or resection of infarcted or symptomatic tissues is often required in severe cases.
• Identification of the embolic source and removal of the atheromatous lesions by endarterectomy, a bypass graft, stent grafting, or excision and replacement of the involved segment of aorta are important in preventing recurrent showers of emboli. In one study of endovascular stent-graft repair of abdominal aortic aneurysm, resolution of CE was noted in only 2 of 19 patients at 30-day postoperative follow-up. At 1 year, 8 of 9 patients had complete resolution of their ischemic symptoms.
• For small uncomplicated aneurysms, intraluminal grafts inserted on a balloon catheter via the transfemoral route may offer an alternative to open surgery.
• Blue toe syndrome is usually an indication for limb salvage surgery.
• The role of lumbar sympathectomy to relieve symptoms from ischemic lower extremities in selected patients with blue toe syndrome remains controversial.

MEDICATION

Section 7 of 11  

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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Blood viscosity reducing agents

These agents increase the fluid characteristics of blood.

Drug Category: HMG-CoA reductase inhibitors

These agents usually lower low-density lipoprotein cholesterol (LDL-C) levels and sometimes lower triglyceride levels, and they may modestly elevate high-density lipoprotein cholesterol (HDL-C) levels. These agents may be of value to patients with hypercholesterolemia.

Drug Category: Prostaglandin analogs

These agents inhibit the cyclooxygenase system, decreasing the level of thromboxane A₂, which is a potent platelet activator.

FOLLOW-UP

Section 8 of 11  

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Deterrence/Prevention

• Carefully weigh the risks versus benefits of surgical therapies, and apply the results individually to patients with CE syndrome.
• Prevention of recurrent CE can be achieved by discontinuing all forms of anticoagulants.
• Identification of the embolic source and removal of atheromatous lesions by endarterectomy, bypass graft surgery, or excision and replacement of the involved segment of aorta can be important in preventing recurrent showers of emboli.
• One study of 7621 patients by Eggebrecht et al indicates that use of catheters smaller than 8F in angiographic procedures may prevent some cases of CE.
• Use of distal filters in endovascular procedures is being studied to explore feasibility for procedural effectiveness and prevention of distal embolization.
• • In one study by Holden and Hill, 46 renal arteries in patients with ischemic nephropathy underwent renal artery angioplasty and stenting with distal main renal artery protection. In 95% of patients, renal function was stabilized or improved at follow-up. In the control group without distal protection, 25% of patients experienced either unchanged decline or acute deterioration in renal function after the procedure.
  • Whitlow et al describe 75 patients with severe internal carotid artery stenosis who were treated with stents deployed with a distal system protection system. All 75 patients (100%) had grossly visible particulate material aspirated from the filter, and all were without major or minor stroke or death at 30 days.
  • Siablis et al describe 16 patients who underwent lower limb recanalization for both acute and subacute occlusions with distal filter devices. The recanalization rate was 100% (16 of 16), without any clinical or angiographic evidence of periprocedural distal embolization.
• New strategies for minimizing cholesterol emboli as a result of cardiopulmonary bypass are emerging.
• • One possible preventive measure is off-pump bypass surgery. Lund et al studied cerebral microembolization in 52 patients during cardiopulmonary bypass (29 off-pump). While a significant reduction was noted in the number of cerebral microemboli during off-pump compared with on-pump surgery, clinical outcomes were not significant.
  • Another possible preventive measure is the separation of lipids from red cells when on bypass. In one ex vivo evaluation study, ultrasonic waves were used to separate lipid particles from red blood cells. The procedure was atraumatic and did not cause hemolysis.

Complications

• Survivors often have long-term clinical sequelae that prevent function from returning to prehospitalization levels. These include stroke, amputation, long-term hemodialysis, malnutrition, and weight loss.

Prognosis

• The prognosis is poor for CE, and no specific treatment is available.

Patient Education

• For excellent patient education resources, visit eMedicine's Cholesterol Center and Statins Center. Also, see eMedicine's patient education articles High Cholesterol, Cholesterol FAQs, and Simvastatin (Zocor).

MISCELLANEOUS

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Medical/Legal Pitfalls

• A high index of suspicion is needed to diagnose CE because symptoms are vague and a significant clinical overlap exists between CE and other systemic diseases. Thus, a long delay may occur between the onset of symptoms and the development of physical findings. Because of the seriousness of the disease, CE needs to be on the differential diagnosis for anyone older than 50 years with livedo reticularis or a blue toe and lower extremity pain in the presence of good pulses.
• Be clear with patients and family members that the prognosis is poor for CE, no specific treatment is available, and that the current standard of care is supportive in nature. Other options are available, but their risks and benefits remain unproven.
• To help avoid serious complications in patients with already compromised extremities, only perform a biopsy on a patient with suspected CE when the patient lacks 1 or more of the following clinical criteria:
• • A history of exposure to a known CE-precipitating factor or factors in a patient with documented diffuse atherosclerosis
  • ARF with an increase in creatinine levels more than 150% of the baseline
  • Characteristic cutaneous lesions or retinal embolism

MULTIMEDIA

Section 10 of 11  

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Media file 1:  A 76-year-old man with a history of aortobifemoral bypass graft developed this eruption after an angiographic procedure. This image shows the plantar surface of the right foot with some of the discoloration resulting from petechiae arranged in a reticulated pattern. This is not livedo reticularis. Petechiae do not blanch on diascopy, but the lesions of livedo reticularis do blanch.
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Media type:  Photo

Media file 2:  Aorta with an ulcerated plaque (black arrowhead) on the luminal side photographed under water to enhance reflection of cholesterol crystals (white arrowhead).
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Media file 3:  Low-power view of a skin biopsy specimen demonstrating an arteriole within the subcutaneous fat occluded with thrombus material that contains (black arrowhead) needle-shaped cholesterol clefts (hematoxylin and eosin stain, original magnification X40).
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Media file 4:  High-power view of occluded vessel (hematoxylin and eosin stain, original magnification X100). Same patient as in Image 3.
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Media file 5:  Symmetric involvement of the feet with livedo reticularis on the plantar surface of the forefoot and cyanosis of the left fifth toe. The painful cyanotic toe is typical of blue toe syndrome.
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Media file 6:  Dorsal surface of the toes of the right foot (same patient as in Image 1). This image shows cyanosis of the fourth toe. The dominant eruption is petechial. Note the pallor of the tip of the great toe and the second toe. This finding indicates acute loss of perfusion.
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Media file 7:  Plantar surface of the right foot. The distal half of the great toe is gangrenous, with a sharp demarcation between the necrotic tissue and the normal proximal skin. Livedo reticularis is present on the distal plantar forefoot, and petechiae are present on the distal pad of the second and fourth toes.
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Media file 8:  The lower extremities show well-developed livedo reticularis and focal areas of erosion and ulceration.
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Media file 9:  Photomicrographs of histologic sections of an aorta with van Gieson stain. (Left) An atherosclerotic plaque with the fibrous cap (black arrowhead) overlying a necrotic core of cellular debris, extracellular lipids, and cholesterol clefts (white arrowhead). Underneath the plaque is the elastic media (arrow). (Right) A ruptured atherosclerotic plaque exposing the atheromatous debris containing cholesterol crystals to the bloodstream on the luminal side of the aorta.
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Media file 10:  CT scan of an infrarenal abdominal aortic aneurysm showing the mural thrombosis (white arrowhead) and the bright atherosclerotic calcifications (black arrowhead).
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REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Abdelmalek MF, Spittell PC. 79-year-old woman with blue toes. Mayo Clin Proc. Mar 1995;70(3):292-5. [Medline].
• Anderson WR. Necrotizing angitis associated with embolization of cholesterol. Case report, with emphasis on the use of the muscle biopsy as a diagnostic aid. Am J Clin Pathol. Jan 1965;43:65-71. [Medline].
• Bauwens F, Duprez D, Clement DL. Relapsing digital ulcers. Acta Cardiol. 1989;44(4):323-7. [Medline].
• Becker KA, Schwartz RA, Rothenberg J. Leg ulceration and the cholesterol embolus. J Med. 1997;28(5-6):387-92. [Medline].
• Belenfant X, Meyrier A, Jacquot C. Supportive treatment improves survival in multivisceral cholesterol crystal embolism. Am J Kidney Dis. May 1999;33(5):840-50. [Medline].
• Blackshear JL, Oldenburg WA, Cohen MD. Making the diagnosis when the patient has ''blue toes''. Geriatrics. Dec 1994;49(12):37-9, 43-5. [Medline].
• Blankenship JC, Butler M, Garbes A. Prospective assessment of cholesterol embolization in patients with acute myocardial infarction treated with thrombolytic vs conservative therapy. Chest. Mar 1995;107(3):662-8. [Medline].
• Borrego L, Gil R, Mazuecos A, et al. Cholesterol embolism to the skin. Clin Exp Dermatol. Nov 1992;17(6):424-6. [Medline].
• Brenowitz JB, Edwards WS. The management of atheromatous emboli to the lower extremities. Surg Gynecol Obstet. Dec 1976;143(6):941-5. [Medline].
• Brown NJ, Morgan HJ. Spontaneous cholesterol emboli presenting as livedo reticularis. J Tenn Med Assoc. Feb 1992;85(2):64. [Medline].
• Cabili S, Hochman I, Goor Y. Reversal of gangrenous lesions in the blue toe syndrome with lovastatin- -a case report. Angiology. Oct 1993;44(10):821-5. [Medline].
• Carr ME Jr, Sanders K, Todd WM. Pain relief and clinical improvement temporally related to the use of pentoxifylline in a patient with documented cholesterol emboli--a case report. Angiology. Jan 1994;45(1):65-9. [Medline].
• Carroccio A, Olin JW, Ellozy SH, et al. The role of aortic stent grafting in the treatment of atheromatous embolization syndrome: results after a mean of 15 months follow-up. J Vasc Surg. Sep 2004;40(3):424-9. [Medline].
• Chandrashekariah R, Fresko O, Lynfield YL. Cholesterol embolism: a case report and review of the literature. Cutis. Oct 2001;68(4):263-7. [Medline].
• Chaudhary K, Wall BM, Rasberry RD. Livedo reticularis: an underutilized diagnostic clue in cholesterol embolization syndrome. Am J Med Sci. May 2001;321(5):348-51. [Medline].
• Chesney TM. Atheromatous embolization to the skin. Am J Dermatopathol. Jun 1982;4(3):271-3. [Medline].
• Colt HG, Begg RJ, Saporito JJ, et al. Cholesterol emboli after cardiac catheterization. Eight cases and a review of the literature. Medicine (Baltimore). Nov 1988;67(6):389-400. [Medline].
• Cross SS. How common is cholesterol embolism?. J Clin Pathol. Oct 1991;44(10):859-61. [Medline].
• Dahlberg PJ, Frecentese DF, Cogbill TH. Cholesterol embolism: experience with 22 histologically proven cases. Surgery. Jun 1989;105(6):737-46. [Medline].
• Darsee JR. Cholesterol embolism: the great masquerader. South Med J. Feb 1979;72(2):174-80. [Medline].
• Davies DJ, Thurasingham K. Intractable leg ulceration caused by cutaneous cholesterol embolism. Med J Aust. Aug 17 1992;157(4):267-8. [Medline].
• Day LL, Aterman K. Hemorrhagic panniculitis caused by atheromatous embolization. A case report and brief review. Am J Dermatopathol. Oct 1984;6(5):471-8. [Medline].
• Delen S, Boonen A, Landewé R, et al. An unusual case of ANCA positive disease. Ann Rheum Dis. Aug 2003;62(8):780-1. [Medline].
• Deschamps P, Leroy D, Mandard JC. Cutaneous crystal cholesterol emboli. Acta Derm Venereol. 1980;60(3):266-9. [Medline].
• Deschamps P, Leroy D, Mandard JC, et al. Livedo reticularis and nodules due to cholesterol embolism in the lower extremities. Br J Dermatol. Jul 1977;97(1):93-7. [Medline].
• Eggebrecht H, Oldenburg O, Dirsch O, et al. Potential embolization by atherosclerotic debris dislodged from aortic wall during cardiac catheterization:: histological and clinical findings in 7,621 patients. Catheter Cardiovasc Interv. Apr 2000;49(4):389-94. [Medline].
• Elinav E, Chajek-Shaul T, Stern M. Improvement in cholesterol emboli syndrome after iloprost therapy. BMJ. Feb 2 2002;324(7332):268-9. [Medline].
• Eliot RS, Kanjuh VI, Edwards JE. Atheromatous embolism. Circulation. Oct 1964;30:611-8. [Medline].
• Falanga V, Fine MJ, Kapoor WN. The cutaneous manifestations of cholesterol crystal embolization. Arch Dermatol. Oct 1986;122(10):1194-8. [Medline].
• Finch TM, Ryatt KS. Livedo reticularis caused by cholesterol embolization may improve with simvastatin. Br J Dermatol. Dec 2000;143(6):1319-20. [Medline].
• Fine MJ, Kapoor W, Falanga V. Cholesterol crystal embolization: a review of 221 cases in the English literature. Angiology. Oct 1987;38(10):769-84. [Medline].
• Flory CM. Arterial occlusions produced by emboli from eroded aortic atheromatous plaques. Am J Pathol. 1945;21:549-64.
• Fukumoto Y, Tsutsui H, Tsuchihashi M, et al. The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac catheterization: a prospective study. J Am Coll Cardiol. Jul 16 2003;42(2):211-6. [Medline].
• Glassock RJ, Ritz E, Bommer J, et al. Acute renal failure, hypertension and skin necrosis in a patient with streptokinase therapy. Am J Nephrol. 1984;4(3):193-200. [Medline].
• Gore I, Collins DP. Spontaneous atheromatous embolization. Review of the literature and a report of 16 additional cases. Am J Clin Pathol. May 1960;33:416-26. [Medline].
• Graziani G, Santostasi S, Angelini C, Badalamenti S. Corticosteroids in cholesterol emboli syndrome. Nephron. Apr 2001;87(4):371-3. [Medline].
• Hasegawa M, Sugiyama S. Apheresis in the treatment of cholesterol embolic disease. Therap Apher Dial. Aug 2003;7(4):435-8. [Medline].
• Hendrickx I, Monti M, Manasse E, Gallotti R. Severe cutaneous cholesterol emboli syndrome after coronary angiography. Eur J Cardiothorac Surg. Feb 1999;15(2):215-7. [Medline].
• Hiramoto J, Hansen KJ, Pan XM, et al. Atheroemboli during renal artery angioplasty: an ex vivo study. J Vasc Surg. Jun 2005;41(6):1026-30. [Medline].
• Hitti WA, Anderson J. Cholesterol emboli-induced renal failure and gastric ulcer after thrombolytic therapy. South Med J. Feb 2005;98(2):235-7. [Medline].
• Holden A, Hill A. Renal angioplasty and stenting with distal protection of the main renal artery in ischemic nephropathy: early experience. J Vasc Surg. Nov 2003;38(5):962-8. [Medline].
• Hyman BT, Landas SK, Ashman RF, et al. Warfarin-related purple toes syndrome and cholesterol microembolization. Am J Med. Jun 1987;82(6):1233-7. [Medline].
• Jönsson H, Holm C, Nilsson A, et al. Particle separation using ultrasound can radically reduce embolic load to brain after cardiac surgery. Ann Thorac Surg. Nov 2004;78(5):1572-7. [Medline].
• Joakimsen O, Bonaa KH, Stensland-Bugge E, Jacobsen BK. Age and sex differences in the distribution and ultrasound morphology of carotid atherosclerosis: the Tromso Study. Arterioscler Thromb Vasc Biol. Dec 1999;19(12):3007-13. [Medline].
• Kalter DC, Rudolph A, McGavran M. Livedo reticularis due to multiple cholesterol emboli. J Am Acad Dermatol. Aug 1985;13(2 Pt 1):235-42. [Medline].
• Kang K, Botella R, White CR Jr. Subtle clues to the diagnosis of cholesterol embolism. Am J Dermatopathol. Aug 1996;18(4):380-4. [Medline].
• Kaplan-Pavlovcic S, Vizjak A, Vene N, Ferluga D. Antineutrophil cytoplasmic autoantibodies in atheroembolic disease. Nephrol Dial Transplant. Apr 1998;13(4):985-7. [Medline].
• Karmody AM, Powers SR, Monaco VJ, Leather RP. "Blue toe" syndrome. An indication for limb salvage surgery. Arch Surg. Nov 1976;111(11):1263-8. [Medline].
• Kasinath BS, Lewis EJ. Eosinophilia as a clue to the diagnosis of atheroembolic renal disease. Arch Intern Med. Aug 1987;147(8):1384-5. [Medline].
• Kawakami Y, Hirose K, Watanabe Y, et al. Management of multiple cholesterol embolization syndrome--a case report. Angiology. Mar 1990;41(3):248-52. [Medline].
• Klein R, Klein BE, Moss SE, Meuer SM. Retinal emboli and cardiovascular disease: the Beaver Dam Eye Study. Arch Ophthalmol. Oct 2003;121(10):1446-51. [Medline].
• Kusaba A, Imayama S, Furue M. Delayed appearance of livedo reticularis in 3 cases with a cholesterol embolism. Arch Dermatol. Jun 1999;135(6):725-6. [Medline].
• Lim J, Ramachandran R, Madhok R, Capell H. An unusual case of "giant cell arteritis". Ann Rheum Dis. Oct 2004;63(10):1347-8. [Medline].
• Lund C, Hol PK, Lundblad R, et al. Comparison of cerebral embolization during off-pump and on-pump coronary artery bypass surgery. Ann Thorac Surg. Sep 2003;76(3):765-70; discussion 770. [Medline].
• Maeshima E, Yamada Y, Mune M, Yukawa S. A case of cholesterol embolism with ANCA treated with corticosteroid and cyclophosphamide. Ann Rheum Dis. Jul 2001;60(7):726. [Medline].
• Mann SJ, Sos TA. Treatment of atheroembolization with corticosteroids. Am J Hypertens. Aug 2001;14(8 Pt 1):831-4. [Medline].
• Maurizi CP, Barker AE, Trueheart RE. Atheromatous emboli. A postmortem study with special reference to the lower extremities. Arch Pathol. Nov 1968;86(5):528-34. [Medline].
• Mayo RR, Swartz RD. Redefining the incidence of clinically detectable atheroembolism. Am J Med. May 1996;100(5):524-9. [Medline].
• Meenakshi-Sundaram S, Palanirajan S, Mani R, et al. Cognitive dysfunction in cholesterol embolic disease. J Neurol Sci. Oct 15 2004;225(1-2):161-4. [Medline].
• Moldveen-Geronimus M, Merriam JC Jr. Cholesterol embolization. From pathological curiosity to clinical entity. Circulation. May 1967;35(5):946-53. [Medline].
• Moolenaar W, Lamers CB. Cholesterol crystal embolization in the Netherlands. Arch Intern Med. Mar 25 1996;156(6):653-7. [Medline].
• Om A, Ellahham S, DiSciascio G. Cholesterol embolism: an underdiagnosed clinical entity. Am Heart J. Nov 1992;124(5):1321-6. [Medline].
• Otsubo H, Kaito K, Takahashi H, et al. Cholesterol emboli following percutaneous transluminal coronary angioplasty as speculated by toe skin biopsy. Intern Med. Feb 1995;34(2):134-7. [Medline].
• Peat DS, Mathieson PW. Cholesterol emboli may mimic systemic vasculitis. BMJ. Aug 31 1996;313(7056):546-7. [Medline].
• Pennington M, Yeager J, Skelton H, Smith KJ. Cholesterol embolization syndrome: cutaneous histopathological features and the variable onset of symptoms in patients with different risk factors. Br J Dermatol. Mar 2002;146(3):511-7. [Medline].
• Quintart C, Treille S, Lefebvre P, Pontus T. Penile necrosis following cholesterol embolism. Br J Urol. Aug 1997;80(2):347-8. [Medline].
• Radauceanu A, Avignon A, Ribstein J, Monnier L. Use of a prostacyclin analogue in cholesterol crystal embolism. Diabet Med. Mar 1998;15(3):262-3. [Medline].
• Ramirez G, O''Neill WM Jr, Lambert R, Bloomer HA. Cholesterol embolization: a complication of angiography. Arch Intern Med. Sep 1978;138(9):1430-2. [Medline].
• Richards AM, Eliot RS, Kanjuh VI, et al. Cholesterol embolism: a multiple-system disease masquerading as polyarteritis nodosa. Am J Cardiol. May 1965;15:696-707.
• Ridker PM, Michel T. Streptokinase therapy and cholesterol embolization. Am J Med. Sep 1989;87(3):357-8. [Medline].
• Robinson RJ, Pemberton M, Goddard MJ. Myositis due to cholesterol emboli. Postgrad Med J. Dec 1993;69(818):947-9. [Medline].
• Rodot S, Lacour JP, Van Elslande L, et al. Cholesterol crystal embolization presenting as erythema induratum of bazin. Acta Derm Venereol. Mar 1995;75(2):160-1. [Medline].
• Rosansky SJ. Multiple cholesterol emboli syndrome. South Med J. Jun 1982;75(6):677-80. [Medline].
• Rosman HS, Davis TP, Reddy D, Goldstein S. Cholesterol embolization: clinical findings and implications. J Am Coll Cardiol. May 1990;15(6):1296-9. [Medline].
• Scholten E, Crolla RM, Blomjous FJ, Moll FL. Preputial necrosis as an unusual cutaneous manifestation of cholesterol crystal embolization. J Urol. Mar 1995;153(3 Pt 1):741-2. [Medline].
• Schwartz MW, McDonald GB. Cholesterol embolization syndrome. Occurrence after intravenous streptokinase thera