Cutaneous Manifestations of Cholesterol Embolism 

Updated: Jun 27, 2019
Author: Laura F McGevna, MD; Chief Editor: William D James, MD 



Cholesterol embolism (CE), also known as atheroembolism, is a condition that has historically been a diagnostic challenge and a true mimicker. It is defined by the occlusion of small- and medium-caliber arteries (100-200 μ m in diameter) by cholesterol crystals (see the image below). Although it was first reported by Panum nearly 150 years ago, clinicians have only recently become aware of its potentially devastating consequences. Too often, the diagnosis of cholesterol embolism is missed or overlooked, with its nonspecific symptoms misattributed to other, more common entities. In 1987, Fine et al described recognizable, hallmark skin findings in patients with cholesterol embolism, thereby linking cholesterol embolism to conclusive, conspicuous signs and symptoms.[1] In 1999, Belenfant et al described a successful treatment regimen, unleashing breakthrough advances for the disease.[2]

Aorta with an ulcerated plaque (black arrowhead) o Aorta with an ulcerated plaque (black arrowhead) on the luminal side photographed under water to enhance reflection of cholesterol crystals (white arrowhead).

Despite these advances, cholesterol embolism is still a challenge to diagnose and effectively treat. Fine’s description of livedo reticularis and blue toes (as shown below) in the presence of good peripheral pulses remains invaluable in recognizing cholesterol embolism. However, a high index of suspicion is imperative because symptoms of cholesterol embolism are often atypical, unrecognized, not temporally correlated with the onset of physical findings, or simply overlooked. Additionally, to date, there is no laboratory testing that is specific for cholesterol embolism, though serum markers for eosinophilia and inflammation may be helpful. The characteristic needle-shaped cholesterol clefts and intravascular microthrombi may be absent and do not always correlate with clinical disease.

Symmetric involvement of the feet with livedo reti 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.


Atherosclerosis is a necessary prerequisite for cholesterol embolism. The embolic process is often triggered by events or procedures that disrupt unstable atherosclerotic plaques, most frequently during invasive vascular procedures, be they surgical or radiographic, and the administration of anticoagulants or thrombolytics. Diagnosis is suggested by progressive increases in blood urea nitrogen and creatinine levels following the invasive arterial procedure. Although rare, reports describe spontaneous cholesterol embolism in patients with likely unstable atheromatous plaques.[3, 4, 5]

Regardless of proximate cause, the rupture of atheromatous arterial plaques releases a shower of cholesterol crystals into the bloodstream. These crystals migrate distally until they lodge in small arterioles, where they provoke an acute inflammatory response. This response triggers a cascade of events culminating in intravascular thrombus formation, endothelial proliferation, and, finally, vessel fibrosis. Microvascular ischemia eventuates in tissue loss, organ dysfunction, and, in some cases, catastrophic organ failure.

The precise clinical syndrome depends on the location of the source of embolism and the pattern and distribution of flow downstream. The most common sites for severe atheromatous disease are 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. In fact, 80% of cases are associated with aortoiliac atheromatous plaques. When the source of crystals is in the aortic arch, signs and symptoms of embolization may occur in the eyes and the CNS.[6]

Clinical manifestations may be immediate, or a delay of several months may occur after the inciting event. A 1999 study by Belenfant et al of patients with cholesterol emboli found that the precipitating event occurred an average of 2 months prior to recognition of fulminant disease.[2]


Cholesterol embolism may occur spontaneously in patients with atherosclerosis, but a trigger is usually required for full expression of cholesterol embolism syndrome. Precipitating factors are described below.

Anticoagulation and thrombolytic therapy

A history of antecedent therapy with anticoagulants is present in approximately 30-35% of patients.[7, 8, 9] These therapies are thought to predispose to cholesterol embolism by 2 distinct mechanisms. First, anticoagulation and thrombolytics strip away the protective layer of fibrin isolating the subintimal deposits of cholesterol from the bloodstream. Second, hemorrhage into a plaque after therapy undermines the stability of the plaque and may lead to lysis of the fibrin cap, causing cholesterol crystals to dislodge and enter the circulation.[10]

Interventional vascular techniques

Various surgical or radiologic vascular procedures precede cholesterol embolism in nearly 65% of patients.[11] The introduction of a foreign object into the vessel may cause intimal trauma, exposing the underlying cholesterol-rich matrix to the arterial circulation. This risk is proportionally increased with increased sheath size of the catheter. With novel intravascular techniques becoming more common in medical practice, the risk of disease may be increasing.

An Italian study of 354 patients demonstrated the most common precipitating factor to be coronary angiography via the femoral artery.

Additional risk factors for developing cholesterol embolism after cardiac catheterization include hypertension, a history of smoking, and elevated preprocedural C-reactive protein levels.

Although most reports of cholesterol embolism are noted to occur with endovascular procedures involving the large vessels, it is important for the clinician to be aware that this complication may occur after manipulation of any vascular bed.

Cholesterol embolism has been reported after peripheral stenting procedures for claudication.[12]


This includes cardiopulmonary resuscitation or sudden deceleration injury, and it may also result in cholesterol embolism.



The true incidence of cholesterol embolism is unknown, and estimates vary widely among populations. Reasonable estimation is complicated by discrepancy between histologic and clinical disease. Published estimates approximate an average incidence of 2-4%, with reports ranging widely. The largest epidemiological study performed was by Moolenaar and Lamers, using the Dutch National Pathology Information System.[13] They estimated an incidence of 6.2 cases per million per year in the general population in the Netherlands, and a prevalence of only 0.31% in all autopsies. However, this result is not generalizable given the supposed low prevalence of both atherosclerosis and invasive vascular procedures in the Dutch population.


Cholesterol embolism is much more commonly described in white populations than in other racial groups. This observation may be related to ascertainment bias and the failure to detect the subtle cutaneous findings in darkly pigmented skin. Additionally, evidence suggests that access to health care, including invasive vascular procedures (ie, inciting events), may be more limited in black populations, and this may contribute to the sizeable epidemiological difference.


Cholesterol embolism occurs more often in males than in females, with a male-to-female ratio of approximately 3.4:1, reflecting the excess risk of cardiovascular disease due to atherosclerosis conferred by male sex.


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


Despite advances in both diagnosis and treatment, the prognosis remains poor for cholesterol embolism.

Cholesterol embolism is a marker of severe atherosclerosis; the associated morbidity and mortality reflect the gravity of the diagnosis. Mortality rates are reported up to 65-87% within 1 year of diagnosis in some studies, worse than those associated with acute myocardial infarction, which often has a dramatic clinical presentation.

Death from cholesterol embolism may occur via ruptured aortic aneurysm, myocardial or gastrointestinal infarction, sepsis, cerebrovascular disease, critical limb ischemia, and cachexia.

Preexisting renal disease is a known marker for higher mortality.[14] Additionally, longstanding, poorly controlled hypertension is a recognized marker for the development of end-stage renal disease in these patients (P< .001).[15]

Patients with visceral involvement (many of whom also present with skin findings) are reported to have mortality rates of 50% and 65% within 6 and 12 months, respectively.

The presence of cutaneous manifestations does not appear to predict survival because the features may occur with minor or severe disease. However, patients with peripheral manifestations alone have a 38% mortality rate within 15 months.

Those who survive may be left with chronic renal insufficiency requiring hemodialysis,[14] stroke resulting in paraplegia, unstable angina, amputation of the affected extremity (5-15% of patients), and malnutrition or significant weight loss (70% of patients).

Patient Education

For patient education resources, visit the Cholesterol Center. Also, see the patient education articles High Cholesterol, and Cholesterol FAQs.




Once termed the great masquerader for its clinical similarity to several other important systemic diseases (eg, polyarteritis nodosa), cholesterol embolism syndrome is often misdiagnosed. Thus, a high suspicion is needed, especially in patients with suspected atherosclerotic disease and specific precipitating events. In a person older than 50 years, the classic triad of excruciating lower extremity pain, livedo reticularis, and palpable peripheral pulses should be considered cholesterol embolization until proven otherwise.

Physical Examination

The recognition of physical findings may be delayed by days to months. In a small series published by Jucgla et al, atheroembolism was the admitting diagnosis in only 35% of patients, with a delay in diagnosis of up to 81 days[14] . Cutaneous manifestations are the most common physical findings in patients with cholesterol embolism and the most helpful in establishing a diagnosis. Jucgla et al revealed skin findings in 88% of patients with known disease,[14] and a 2004 report by Manganoni indicated that 50 of 52 patients had recognizable skin findings, often marked erythema of the toes.[16]

Cutaneous manifestations

Skin lesions described in cholesterol embolism in multiple studies are described below.

Livedo reticularis

Livedo is the most common dermatologic manifestation of cholesterol embolism, comprising 50-74% of cholesterol embolism–related skin lesions.[14] This blue-red mottling of the skin in a netlike pattern usually affects the feet, the legs, the buttocks, and the thighs, but can extend to the trunk and the upper extremities. The presence of livedo reticularis may be noted only while the patient is standing; therefore, examining patients in both the supine position and the standing position is imperative when possible. See the image below.

The lower extremities show well-developed livedo r The lower extremities show well-developed livedo reticularis and focal areas of erosion and ulceration.

Gangrene/tissue necrosis

Occurring in 35% of patients, gangrene is the loss of tissue due to ischemia. In cholesterol embolism, it may develop within patches of acrocyanosis or livedo reticularis. Gangrene is often confined to the toes (bilaterally in 50% of patients), and rarely it involves the scrotal area. It has been reported with extensive involvement of the abdomen, lower back, and bilateral hips. See the image below of toe involvement.

Plantar surface of the right foot. The distal half 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.

Acrocyanosis or blue toe syndrome

Occurring in 28% of patients, this is a characteristic blue-black or violaceous discoloration of the distal extremities. The lesions are painful, discolored, or even necrotic from ischemia. Blue toe syndrome, a term coined by Karmody et al,[17] refers to acute digital ischemia caused by microembolism from the distal aorta, iliac artery, or femoral artery. See the image below.

Symmetric involvement of the feet with livedo reti 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.
Dorsal surface of the toes of the right foot of a Dorsal surface of the toes of the right foot of a patient with discoloration resulting from petechiae. 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.


This occurs in 17-39% of patients[14] and is typically unilateral and located on the toes and the feet. Unusual presentations or refractory and recurrent ulcers of the digits and the lower extremities have also been reported.[18]

Nodules or indurated papules

These are present in 10% of patients and are firm, violaceous, and painful. They can appear on the legs, thighs, toes, or feet as a result of an inflammatory reaction surrounding cholesterol crystals. Isolated case reports describe cholesterol clefts in solitary lesions in unusual locations (eg, a nodule on an ear, red nodules on the chest) with microscopic findings of hemorrhagic panniculitis.


Purpura has been described in some 40% patients, most commonly on the legs and the feet. The lesions resemble those of vasculitis, but, quite unlike other features in cholesterol embolism, purpura typically spares the toes.


Small, pinpoint, purpuric spots, petechiae do not blanch on diascopy and may appear in individuals with cholesterol embolism.

Balanitis and necrosis of the penile foreskin, perineal area, and scrotum

This has been reported with cholesterol embolism, reflecting a distal aortic or iliofemoral source.

Punctiform subungual hemorrhages

Subungual hemorrhage has been described in association with cholesterol embolism.

Full-thickness cutaneous infarcts

Mimicking heparin necrosis, full-thickness cutaneous infarct and ulceration may occur.

Extracutaneous manifestations

Extracutaneous manifestations of cholesterol embolism are multifarious. These include constitutional symptoms, such as fever and weight loss, as well as those described below.

Renal manifestations (34%)

Receiving 20-25% of the cardiac output, and distal to the abdominal aorta, renal involvement is common. While the skin has an extensive network of collateral circulation, the blood supply to the renal cortex consists of predominantly end-arterioles. Therefore, embolic events in the kidneys often result in an irreversible loss of glomerular function. This portends a poor prognosis for the patient. The clinical diagnosis of cholesterol embolism can be made when stepwise loss of glomerular function is accompanied by cutaneous involvement. The 2 most common renal manifestations of cholesterol embolism are hypertension and loss of glomerular function.

Hypertension resulting from cholesterol embolism may be intractable. Acute rise in pressure may result from obstruction of vasculature by crystals or high circulating plasma renin and angiotensin levels in the setting of renal damage. Renin is released by the juxtaglomerular cells of the afferent arterioles in response to decreased blood flow, often due to obstruction from cholesterol plaques.

Acute renal failure is common in cholesterol embolism, and one study estimated it to account for 5-10% of all cases of acute renal failure. Loss of glomerular function in cholesterol embolism 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. In fact, if renal impairment occurs immediately after an invasive procedure, the clinician must first rule out other causes, including contrast-induced nephropathy.

A 2007 study of 354 patients by Scolari et al demonstrated that patients with iatrogenically acquired cholesterol embolism were more likely to develop acute or subacute renal failure and have a worse outcome than patients with spontaneous forms.[19] In this study, 32.7% of patients required dialysis after the development of cholesterol embolism, with the largest risk occurring within the first 6 months of the event.

Other features of renal cholesterol embolism may include flank or back pain, gross or microscopic hematuria, pyuria, and/or urinary casts.

Risk factors for renal insufficiency are the presence of heart failure, lower limb or GI tract involvement, and age older than 70 years.

Visualization of cholesterol crystal clefts in a renal biopsy specimen is pathognomonic for cholesterol embolism. 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 the formation of a wedge-shaped scar in the kidney.


Pedal pulses are palpable in more than 60% of patients. Pulses are purported to be present in cholesterol embolism, even in patients at risk for peripheral vascular disease, because emboli and microthrombi travel to the most distal, small vessels, sparing the dorsal pedalis and posterior tibial arcades.

GI manifestations (30%)

Cholesterol embolism causes ischemia or infarction of the bowel. Unfortunately, GI symptoms may be nonspecific and, thus, are often misattributed to other conditions.

Symptoms include abdominal pain, diarrhea, and GI bleeding. Jucgla et al[14] noted that all patients with GI manifestations in their study had concomitant renal involvement. Indeed, patients with bowel disease frequently have concurrent evidence of embolism to other sites, including the spleen (57%), the liver (15%), and the gallbladder (8%).

Ischemic cholecystitis has been reported, along with perforation of the gallbladder after cholesterol embolism.[20]

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 cholesterol embolism.

Digestive involvement is known to be associated with a poor outcome. A 2007 study demonstrated that the hazard ratio indicating risk for patient death was considerably elevated at 2.57 in patients with any degree of GI involvement.[19] This high degree of tragic complication is thought to be due to nonspecific presentation and resulting diagnostic delay.

Ophthalmic manifestations (6%)

Retinal cholesterol crystals (Hollenhorst plaques) are bright-yellow, glittering intravascular plaques situated at the bifurcation of the narrow arterioles of the retina. These are often readily apparent on funduscopic examination and are refractile on fluorescein angiography. Patients may be asymptomatic, with microvascular disease occurring distal to the macula, or they may report monocular amaurosis fugax (transient blindness). Retinal infarction resulting from complete occlusion of the vasculature also may occur. Patients with carotid or vertebrobasilar atherosclerosis who undergo endarterectomy are at high risk.

Musculoskeletal manifestations

Cholesterol embolization to muscular arterioles can cause intense myalgia at rest and/or weakness with exertion. Involvement of lower extremity muscles with upper limb sparing is characteristic in cholesterol embolism.

Development of rhabdomyolysis after cholesterol embolism is uncommon; however, reports describe this disastrous complication, underscored by Sarwar's[12] report of a patient with extensive myonecrosis and compartment syndrome which led to bilateral below-the-knee amputations.

CNS manifestations

CNS cholesterol embolism may occur after vascular procedures such as carotid angiography or endarterectomy. The most frequent sources of emboli are the carotid arteries, the thoracic aorta, or the aortic trunk. Case reports have described delirium and dementia attributable to cholesterol embolism.[21] Case reports also describe spinal cord infarction following cholesterol embolism, as well as other symptoms resulting from anterior spinal artery involvement.

Pulmonary manifestations

Alveolar hemorrhage, presumably resulting from cholesterol embolism, has been rarely reported. One patient with severe atherosclerosis was noted to develop 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.[22] Although pulmonary symptoms have been considered rare in the past, Jucgla et al[14] reported 57% of patients developed pulmonary edema secondary to cardiac failure.

Endocrine manifestations

Postmortem examination of adrenal glands has demonstrated cholesterol embolism.[14] One study reported the presumed death of a patient with visceral cholesterol embolism resulting from necrosis of the adrenals.

Reproductive manifestations

Cholesterol embolism has also been demonstrated in postmortem examinations of the prostate, apparently asymptomatic in the patient.[14]

Hematopoietic manifestations

Reuter et al reported a case of spontaneous cholesterol crystal embolization to the bone marrow in a 77-year-old woman with fever, mild anemia, and leukocytosis.[10] Bone marrow biopsy revealed an absence of abnormality, with the exception of the presence of cholesterol crystals. Pierce reported the presence of cholesterol embolism to bone marrow in a premortem patient with anemia and other clinical findings.[23] Muretto also reported a case of cholesterol embolism to bone marrow.[24] Although his patient was quite ill, anemia was not reported. It remains unknown whether anemia is a nonspecific finding in cholesterol embolism.


Cholesterol embolism is a destructive disease, and even patients who survive the initial insult may have damaging consequences that preclude return to baseline functioning levels. Stroke, amputation, and the need for long-term dialysis are frequent sequelae.



Diagnostic Considerations

Also consider the following:

A high index of suspicion is needed to diagnose cholesterol embolism because symptoms are vague and a significant clinical overlap exists between cholesterol embolism 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, cholesterol embolism must be on the differential diagnosis for anyone older than 50 years with livedo reticularis or a blue toe and severe lower extremity pain in the presence of good pulses. Be clear with patients and family members that the prognosis is poor for cholesterol embolism, treatment options are limited and controversial, and that the current standard of care is supportive therapy.



Laboratory Studies

Laboratory abnormalities in cholesterol embolism 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 may all prove helpful in diagnosing cholesterol embolism. Other laboratory studies should be ordered based on the patient's underlying disease and the clinical picture.

Eosinophilia (>300 cells/µL or 3-18% total WBCs) develops within 3 days of embolization in 70-80% of patients and may remain elevated for up to 1 month after a new diagnosis of cholesterol embolism. Cholesterol crystals in tissue initiate a cascade of reactions, including the systemic release of interleukin 5. T lymphocytes are thought to release interleukin 5 in order to induce eosinophil production, chemotaxis, and maturation.

Eosinophiluria may indicate cholesterol embolism when identified in patients with other findings of cholesterol embolism. One study found that 8 of 9 patients with biopsy-proven cholesterol embolism had positive Hansel staining for eosinophiluria. However, like many other findings in cholesterol embolism, eosinophiluria is nonspecific. In addition to cholesterol embolism, the differential diagnosis of eosinophiluria includes acute interstitial nephritis.

Leukocytosis is found in 50% of patients.

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 blood cell, red blood 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 cholesterol embolism.

Elevated preprocedural plasma levels of C-reactive protein are associated with subsequent cholesterol embolism in patients who undergo vascular procedures, according to Fukumoto et al.[25]

Hypocomplementemia and antineutrophil cytoplasmic antibody positivity have been reported in persons with cholesterol embolism. It is suspected that this may result from neutrophil activation.

Because pancreatitis may be a complication of cholesterol embolism, serum amylase should be evaluated in any patient with abdominal pain. Similarly, transaminase levels should be monitored because of the potential for hepatic involvement.

Fecal occult blood and digital rectal examination should also be performed in a patient with symptoms of cholesterol embolism and severe abdominal pain.

Imaging Studies

Establishing the source of cholesterol emboli remains a formidable challenge, especially in patients with diffuse atherosclerotic disease. Noninvasive procedures should be performed first, if possible.

A transthoracic echocardiography may aid in excluding an intracardiac source of embolism.

Transesophageal studies may exclude small valvular thrombi, which may be below the resolution capacity of transthoracic ultrasonography.

Doppler ultrasonography of the aorta may exclude aortic aneurysm.

Magnetic resonance imaging and CT scanning offer alternative means to effectively evaluate thoracic and abdominal aortic sources of embolism. The image below shows a CT scan of the abdomen, demonstrating the infrarenal aorta with an aneurysm and a mural thrombus. Obviously, efforts to avoid intravascular contrast should be undertaken.

CT scan of an infrarenal abdominal aortic aneurysm CT scan of an infrarenal abdominal aortic aneurysm showing the mural thrombosis (white arrowhead) and the bright atherosclerotic calcifications (black arrowhead).

Unfortunately, angiography may be necessary before surgical intervention can be performed, despite the risk of exacerbating cholesterol embolism by mechanical trauma. Peripheral angiography is the best test for establishing a diagnosis of atheroembolism involving the abdominal aorta and the lower extremity arteries.


Definitive diagnosis of the presence of cholesterol embolism is made by performing a biopsy on affected tissue. Skin and muscle are the most accessible sites for obtaining a biopsy specimen and seem to offer the most reliable specificity and favorable sensitivity.[26] 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. The pale skin encircled by livedo should be considered for biopsy if possible, but this is optimized by the inclusion of subcutaneous fat to sample the small vessels in which cholesterol embolism commonly occurs. Instruct the laboratory to cut sections at multiple levels through the tissue block because changes may be present in only short segments of affected arteries. In one instructive case report, premortem diagnosis of cholesterol embolism was missed when the first sections of a muscle biopsy were interpreted as being consistent with vasculitis. Cholesterol clefts were found in the tissue at postmortem examination, and further sectioning of the original muscle biopsy sample revealed cholesterol crystals amid the vasculitic lesions.

In evaluating a patient with suspected cholesterol embolism, the consulting dermatologist is often faced with the daunting prospect of performing a skin biopsy on an already compromised extremity. Biopsy should be selectively performed. In unfavorable circumstances, biopsy is recommended if one or more of the following criteria for diagnosis is lacking:

  • A patient with documented diffuse atherosclerosis and exposure to a known cholesterol embolism–precipitating factor or factors
  • Acute renal failure with an increase in creatinine levels of more than 150% of the baseline
  • Characteristic cutaneous lesions or retinal embolism

Histologic Findings

An understanding of cholesterol embolism is predicated on recognizing the relationship with atherosclerosis. Atherosclerotic lesions develop in the walls of vasculature that has undergone diffuse intimal thickening, a process carried out by smooth muscle cells and involving elastin and proteoglycans. Earliest lesions are thought to be apolipoprotein B–containing lipids in macrophages, known as foam cells, in the outer layers of these thickened vessel walls.[27] Grossly, these can be identified as fatty streaks.[28] As the lesion progresses, lipids continuously accumulate and deposit, forming a lipid core. Fibrous, collagenous caps, as shown below, cover these lesions, which usually conceal denuded, friable endothelium. When the fibrin caps rupture, cholesterol embolization may occur.

Photomicrographs of histologic sections of an aort 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.

Cholesterol embolism is histologically defined by the presence of birefringent crystals with polarized light or biconvex needle-shaped ghostly clefts within the arterial lumen, corresponding to cholesterol crystals dissolved during the fixation process. 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 cholesterol embolism. 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, and this is considered 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, usually within 24-48 hours. Later, a more complete occlusion may occur as encasement of clefts by intimal proliferation and fibrosis ensues. A vasculitic pattern may be seen in biopsies performed well after initial tissue injury.[29] This final stage most likely underlies tissue necrosis and gangrene. Even in late disease and with recanalization, cholesterol crystals may still be found in affected tissue. See the images below.

Low-power view of a skin biopsy specimen demonstra 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).
High-power view of occluded vessel (hematoxylin an High-power view of occluded vessel (hematoxylin and eosin stain, original magnification X100).


Medical Care

Cholesterol embolization has a serious prognosis. Unfortunately, treatment options remain limited to conservative medical care and cautious surgical intervention. In 1999, Belenfant et al published a prospective study of 67 patients with cholesterol embolism using therapies targeted at the most common causes of death in cholesterol embolism.[2] This approach reduced the 1-year mortality rate to as low as 23%. Since then, in-hospital mortality rates have been reported to be lower when supportive therapy can be optimized.[30]

In general, the optimal approach is to address and remove precipitating factors. If possible, discontinue planned invasive endovascular procedures. The decision to remove anticoagulation remains controversial, and treatment with warfarin may be harmful.

Risk factors must be modified where possible. Manage blood pressure (goal blood pressure < 140/80 mm Hg) using vasodilators (eg, ACE inhibitors, calcium channel blockers, nitrates). Use statin lipid-lowering medications. Aspirin and clopidogrel may be helpful.[31] 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) corticosteroids may be used.

Institute supportive care. Use high-dose loop diuretics and/or ultrafiltration in patients with pulmonary edema. Provide enteral or parenteral nutritional support.

It must be emphasized that management principles for cholesterol embolism are often conflicting because therapeutic vascular procedures and/or dialysis may aggravate the condition, and these patients tend to be high risk for surgery. Further, there are reports of improvement with anticoagulation.[32, 33] This is likely because damage is not solely from cholesterol crystals, but the clinical picture of thrombosis and vessel obstruction that occur concomitantly and the cascade of inflammation resulting from endothelial damage.

Many published anecdotal reports describe other therapeutic approaches to cholesterol embolism. None has 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. Dahlberg et al,[34] Vacher-Coponat et al,[22] Belenfant et al,[2] and others detailed the potential use of steroid therapy for advanced disease, including those with acute renal failure or in those with pronounced cutaneous manifestations.[35] Steroids may limit the inflammatory effects of ischemia and resultant vascular occlusion. Further study is needed to clearly define the role of corticosteroids in the management of cholesterol embolism. 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 produced favorable clinical outcomes. Simvastatin or alprostadil with LDL apheresis reportedly improves livedo reticularis.[36, 37] 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.

The 2003 and 2007 studies by Scolari et al[15, 19] underscored the theory that statin therapy may be beneficial in patients with known atheroembolic renal disease. In these patients, statin therapy was associated with a better prognosis (P< .001), even when initiated well after diagnosis. The favorable outcomes associated with statin therapy may be secondary to both the anti-inflammatory and lipid-lowering properties of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, contributing to plaque stabilization and regression, perhaps initiating recanalization.

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.[38]

Success has been reported with oral pentoxifylline.[39]

Isolated case reports exist of successful management of cholesterol embolism with combination corticosteroid and cyclophosphamide therapy.[40] Yucel et al noted the treatment of a patient with corticosteroid and cyclophosphamide combination therapy, leading to improvement.[41] The outcome was appreciable improvement in skin lesions, but ultimately the patient was lost to follow up and succumbed to complications associated with infection.

Filip and Dillon reported successful therapy for cholesterol embolism using circulator boot therapy.[42] A circulator boot is a compression boot designed to restore blood flow to areas of ischemia. In the study, 41 legs were treated. Of these, 81% healed completely, 15% improved, and only 2 required amputation. Levels of evidence were not reported. The circulator boot is thought to function by expelling venous and lymphatic columns from the leg, thereby increasing the arterial-to-venous pressure ratio and providing force substantial enough to reperfuse areas of ischemia.

Surgical Care

The principal goal of surgical treatment of cholesterol embolism is to promptly identify and eradicate the embolic source and to restore arterial flow. Carefully weigh the risks versus benefits of the surgical intervention and/or preoperative arteriography. In select cases, procedural intervention may be a favorable option.

Amputation or resection of infarcted or symptomatic tissues is often required in severe cases. Blue toe syndrome is usually an indication for limb salvage surgery.

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 may be important in preventing recurrent showers of emboli. In one study of endovascular stent-graft repair of an abdominal aortic aneurysm, resolution of cholesterol embolism 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.[43]

For small uncomplicated aneurysms, intraluminal grafts inserted on a balloon catheter via the transfemoral route may offer an alternative to open surgery.

The role of lumbar sympathectomy to relieve symptoms from ischemic lower extremities in selected patients with blue toe syndrome remains controversial.


Carefully weigh the risks versus benefits of surgical therapies, and apply the results individually to patients with cholesterol embolism syndrome.

Prevention of recurrent cholesterol embolism may 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 may be important in preventing recurrent showers of emboli.

One study of 7621 patients by Eggebrecht et al indicates that use of catheters smaller than 8 French in angiographic procedures may prevent some cases of cholesterol embolism.[44]

Use of distal filters in endovascular procedures is being studied to explore feasibility for procedural effectiveness and prevention of distal embolization. Although these procedures have shown favorable results with the immediate release of cholesterol emboli, it is unlikely that they will prove useful in delayed events. In one study by Holden and Hill,[45] 46 ischemic nephropathic renal arteries 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 described 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.[46]

Siablis et al described 16 patients who underwent lower limb recanalization for both acute and subacute occlusions with distal filter devices. The recanalization rate was 16 (100%) of 16, without any clinical or angiographic evidence of periprocedural distal embolization.[47]

Cardaioli et al reported successful use of filter-assisted stenting in a 70-year-old man.

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 greater reduction of cerebral microemboli was noted during off-pump compared with on-pump surgery, clinical outcomes were not significant.



Medication Summary

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

Blood viscosity reducing agents

Class Summary

These agents increase the fluid characteristics of blood.

Pentoxifylline (Trental)

Pentoxifylline is a methylxanthine derivative that reduces blood viscosity and improves erythrocyte flexibility.

HMG-CoA reductase inhibitors

Class Summary

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

Simvastatin (Zocor)

Simvastatin inhibits HMG-CoA reductase, which, in turn, inhibits cholesterol synthesis and increases cholesterol metabolism.

Prostaglandin analogs

Class Summary

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

Iloprost (Ilomedin)

Iloprost is a chemically stable analog of prostacyclin (epoprostenol) and effective inhibitor of platelet aggregation by increasing intracellular levels of cyclic adenosine monophosphate. Clinical benefit has been observed in occlusive peripheral vascular disease and Raynaud phenomenon, although further clinical trials are needed to assess its place in therapy in these conditions.


Questions & Answers


What are cholesterol emboli (CE)?

What is the pathophysiology of cholesterol emboli (CE)?

What causes cholesterol emboli (CE)?

What is the role of thrombolytic therapy in the etiology of cholesterol emboli (CE)?

What is the role of interventional vascular procedures in the etiology of cholesterol emboli (CE)?

What is the role of trauma in the etiology of cholesterol emboli (CE)?

What is the prevalence cholesterol emboli (CE)?

What are the racial predilections of cholesterol emboli (CE)?

What are the sexual predilections of cholesterol emboli (CE)?

Which age groups have the highest prevalence of cholesterol emboli (CE)?

What is the prognosis of cholesterol emboli (CE)?


Which clinical history findings are characteristic of cholesterol emboli (CE)?

Which physical findings are characteristic of cholesterol emboli (CE)?

Which cutaneous findings are characteristic of cholesterol emboli (CE)?

Which extracutaneous findings are characteristic of cholesterol emboli (CE)?

Which renal findings are characteristic of cholesterol emboli (CE)?

Which pulse findings are characteristic of cholesterol emboli (CE)?

Which GI findings are characteristic of cholesterol emboli (CE)?

Which ophthalmic findings are characteristic of cholesterol emboli (CE)?

Which musculoskeletal findings are characteristic of cholesterol emboli (CE)?

Which CNS findings are characteristic of cholesterol emboli (CE)?

Which pulmonary findings are characteristic of cholesterol emboli (CE)?

Which endocrine findings are characteristic of cholesterol emboli (CE)?

Which genitourinary findings are characteristic of cholesterol emboli (CE)?

Which bone marrow findings are characteristic of cholesterol emboli (CE)?

What are the possible complications of cholesterol emboli (CE)?


Which conditions are included in the differential diagnoses of cholesterol emboli (CE)?


What is the role of lab tests in the workup of cholesterol emboli (CE)?

What is the role of imaging studies in the workup of cholesterol emboli (CE)?

What is the role of biopsy in the workup of cholesterol emboli (CE)?

Which histologic findings are characteristic of cholesterol emboli (CE)?


How are cholesterol emboli (CE) treated?

What is the role of surgery in the treatment of cholesterol emboli (CE)?

How are cholesterol emboli (CE) prevented?


What is the role of medications in the treatment of cholesterol emboli (CE)?

Which medications in the drug class Prostaglandin analogs are used in the treatment of Cutaneous Manifestations of Cholesterol Embolism?

Which medications in the drug class HMG-CoA reductase inhibitors are used in the treatment of Cutaneous Manifestations of Cholesterol Embolism?

Which medications in the drug class Blood viscosity reducing agents are used in the treatment of Cutaneous Manifestations of Cholesterol Embolism?