Cutaneous Manifestations of Cholesterol Embolism

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Background

Cholesterol embolism, or atheroembolism, is a condition that has historically been a diagnostic challenge owing to its nonspecific symptoms and because it often mimics other more common conditions and diseases. Autopsy studies have revealed that up to 15-20% of individuals older than 60 years with a history of atherosclerosis had cholesterol emboli present, which suggests that cholesterol embolism may be more frequently undiagnosed than originally believed.[1] Cholesterol embolism is categorized as a disorder of occlusion due to emboli, wherein there is luminal obstruction of small- and medium-caliber arteries (100-200 μm in diameter) by cholesterol crystals (see the image below) that form from fragmentation of ulcerated atheromatous plaques inside vasculature. Although it was initially reported by Panum over a century ago, the diagnosis of cholesterol embolism is often missed or overlooked, resulting in potentially devastating and even fatal consequences. In 1987, Fine et al. described certain hallmark skin findings in patients with cholesterol embolism, thereby linking cholesterol embolism to recognizable signs and symptoms that could be identified clinically.[2] In 1999, Belenfant et al reported new treatment regimens for the management of cholesterol embolism, allowing for breakthrough advances in patients with this disease.[3] Despite these medical developments, cholesterol embolism remains a challenging entity to accurately diagnose and effectively treat. Numerous comorbid conditions can be associated with the development of cholesterol embolism, including hypertension, hyperlipidemia, diabetes mellitus, peripheral vascular disease, and tobacco use.[4]



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

A high index of suspicion is imperative because the signs and symptoms of cholesterol embolism are often atypical, unrecognized, not temporally correlated with the onset of physical findings, and/or simply overlooked. Unfortunately, there is no laboratory testing that is specific for cholesterol embolism, although serologic markers checking for eosinophilia and inflammation may be helpful.[5] Additionally, diagnosis is suggested by progressive increases in blood urea nitrogen and creatinine levels following an invasive arterial procedure. On physical examination, the presence of netlike or lacelike, bluish to deep-purple patches with a mottled appearance involving the distal extremities and blue fingers or toes can be invaluable clinical features in diagnosing cholesterol embolism (see the image below). On pathology, cholesterol embolism can be identified by characteristic needle-shaped cholesterol clefts and intravascular microthrombi; however, one or both of these findings may be absent and do not necessarily correlate directly with a patient's clinical disease.



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Symmetric involvement of the feet with livedo reticularis on the plantar surface of the forefoot and cyanosis of the left fifth toe. The painful cyano....

Pathophysiology

Rupture and subsequent fragmentation of ulcerated atherosclerotic plaques inside of vessels leads to the formation of cholesterol emboli, which can then result in intraluminal obstruction of vessels. Thus, patients with cholesterol embolism usually have some degree of atherosclerosis. Fracturing of unstable atheromatous plaques can occur spontaneously, albeit rarely. Reports describe spontaneous cholesterol embolism in patients with likely unstable atheromatous plaques.[6, 7, 8] More commonly, cholesterol emboli typically occur in several clinical settings that serve as triggering events for the embolization process. These settings include vascular intervention procedures (eg, arterial catheterization), long-term use of anticoagulants (including warfarin),[9] and administration of acute thrombolytic therapy (as in the treatment of myocardial infarctions or cerebrovascular attacks).[10]

Regardless of the particular etiology, the rupture of atheromatous plaques inside of arteries releases a shower of fragmented cholesterol crystals into the bloodstream. These crystals then migrate distally until they lodge in smaller arterioles, where they provoke an acute inflammatory response. This response triggers a cascade of multiple events culminating in intravascular thrombus formation, endothelial proliferation, and vessel fibrosis. Microvascular ischemia leads to tissue loss, organ dysfunction, and, in some cases, catastrophic organ collapse such as renal failure.[5, 11]

The presenting clinical syndrome that a patient manifests depends on the location of the source of embolism as well as the pattern and distribution of vascular flow downstream. The most common sites of involvement for severe atheromatous disease are the abdominal aorta and the iliac and femoral arteries. Accordingly, the signs and symptoms of cholesterol embolism more commonly result from embolism to the lower half of the body, such as the lower legs, feet, and toes. In fact, 80% of cases are associated with disruption and fragmentation of aortoiliac atheromatous plaques. When the primary source of cholesterol crystals is inside of the aortic arch, the signs and symptoms of embolization may present in the eyes and the CNS.[12] Clinical manifestations may be detected immediately after the inciting event or may only present after a period of time has passed (anywhere from hours to weeks). A 1999 study by Belenfant et al of a group of patients diagnosed with cholesterol embolism found that the precipitating event occurred an average of 2 months prior to recognition of fulminant clinical disease.[3]

Etiology

Cholesterol embolism may occur spontaneously in patients with a history of atherosclerosis; however, a triggering event much more commonly results in full clinical manifestation of cholesterol embolism syndrome. There are various precipitating factors that can contribute to the development of cholesterol embolism and these are described below.[10]

Long-term use of anticoagulation and acute thrombolytic therapy

A history of antecedent therapy with anticoagulant agents, including warfarin, is present in approximately 30-35% of patients with cholesterol embolism.[13, 14, 15] These therapies are thought to predispose an individual to the development of cholesterol embolism by two distinct mechanisms. First, use of anticoagulants and thrombolytics progressively lyses a blood clot, thereby stripping away the protective layer of fibrin isolating subintimal deposits of cholesterol. Removal of this shieldlike coating exposes the friable cholesterol plaque to shearing forces of arterial blood flow, resulting in fragmentation. Second, hemorrhage of blood into a cholesterol plaque after therapy is administered can undermine the overall stability and integrity of the plaque and can lead to lysis of the fibrin cap. This causes cholesterol crystals to become dislodged and enter the circulation, where they can cause downstream intraluminal obstruction.[16]

Interventional vascular techniques

Various surgical or radiologic vascular procedures are reported to precede cholesterol embolism in nearly 65% of patients.[17] The introduction of a foreign object such as an arterial catheter or stent into a blood 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 that the most common precipitating factor among that group of individuals was coronary angiography via the femoral artery. Cholesterol embolism has also been reported after peripheral stenting procedures for arterial claudication.[18] Additional predisposing risk factors for the development of cholesterol embolism after cardiac catheterization include older age, male sex, hypertension, a history of smoking, and elevated preprocedural C-reactive protein levels.[19] 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.

Trauma

External trauma or injury may also predispose an individual with a history of atherosclerosis to the development of cholesterol embolism. This can include cardiopulmonary resuscitation or sudden deceleration injury as may occur in motor vehicle accidents. The forces generated by the traumatic event may cause an unstable ulcerated atheromatous plaque to become dislodged and fragment into numerous pieces, releasing cholesterol clefts into the vasculature.

Epidemiology

Frequency

The true incidence of cholesterol embolism is unknown because it is likely underdiagnosed and/or underrecognized. Reported estimates vary widely among populations. Reasonable estimation of cholesterol embolism incidence is complicated by the discrepancy between histologic and clinical disease. Published estimates in the medical literature approximate an average incidence of 2-4%, with reports ranging widely. One of the largest epidemiological studies performed was by Moolenaar and Lamers, using the Dutch National Pathology Information System.[20] They estimated an incidence of 6.2 cases per million per year in the general population living in the Netherlands, and a prevalence of 0.31% in all performed autopsies. However, these results are not necessarily generalizable to other populations given the supposed low prevalence of both atherosclerosis and invasive vascular procedures in the Dutch population.

Race

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 individuals with darkly pigmented skin. Additionally, evidence suggests that access to health care, including invasive vascular procedures (which can serve as inciting events), may be more limited in certain populations as in lower socioeconomic areas for example, and this may contribute to the sizeable epidemiological difference.

Sex

Cholesterol embolism occurs more often in males than in females, with an approximate male-to-female ratio of about 3.4:1. This could reflect the excess risk of cardiovascular disease due to atherosclerosis conferred by the male sex.

Age

The reported age range for cholesterol embolism is 26-90 years, and the mean age of patients who develop cholesterol embolism is 66-72 years.

Prognosis

Despite medical advances in both the diagnosis and treatment of cholesterol embolism, the overall prognosis remains poor. Cholesterol embolism is considered a marker for severe atherosclerosis and the associated morbidity and mortality reflect the gravity of the diagnosis of cholesterol embolism. Mortality rates are reported to be as high as 60-87% within 1 year of cholesterol embolism diagnosis in some studies, which are worse than the reported mortality rates associated with acute myocardial infarction.[19] Death from cholesterol embolism may occur via ruptured aortic aneurysm, CNS infarction, myocardial or gastrointestinal infarction, sepsis, cerebrovascular disease, critical limb ischemia, cachexia, and renal failure.[21]

Preexisting renal disease is a known marker for higher mortality in the setting of cholesterol embolism.[22] Furthermore, longstanding and poorly controlled hypertension is a recognized risk factor for the development of end-stage renal disease in these patients (P< .001).[23] 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 in patients with minor-to-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,[22] stroke resulting in paraplegia, unstable angina, amputation of the affected extremity (5-15% of patients), and malnutrition or significant weight loss (70% of patients).[21]

Patient Education

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

History

Once termed the great masquerader for its clinical similarity to other important systemic diseases (eg, polyarteritis nodosa), cholesterol embolism syndrome is often misdiagnosed. Thus, a high index of suspicion is essential for correct identification, especially in patients with atherosclerotic disease and a known history of 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 suspect for 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.[22] Cutaneous manifestations are the most common physical findings in patients with cholesterol embolism and can be one of the most helpful hints in establishing a diagnosis. However, the cutaneous features may be extremely varied.[24] Jucgla et al reported the presence of skin findings in 88% of patients with known cholesterol embolism disease,[22] and a 2004 report by Manganoni et al indicated that 50 (~96%) of 52 patients had recognizable skin findings, which included marked erythema of the toes.[25]

Cutaneous manifestations

Skin lesions reported in the setting of cholesterol embolism are described below.

Livedo reticularis

Livedo reticularis is the most common dermatologic manifestation of cholesterol embolism, comprising 50-74% of cholesterol embolism–related skin lesions.[22] It may even be the presenting clinical sign of cholesterol embolism.[26] This blue-red to even violaceous mottling of the skin appears in a netlike, or reticulated, pattern (see the image below) and usually affects the buttocks, thighs, lower legs, feet, and toes, although it can also involve the trunk and the upper extremities. There can be areas of skin on the verge of necrosis, as indicated by the presence of dusky-to-black color changes. 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 physically possible.



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

Skin necrosis and gangrene

Skin necrosis can develop in the setting of cholesterol embolism, leading to significant pain and death of vital tissues and organs. In a patient who also presents with acute renal failure and pain out of proportion to the physical examination findings, the presence of livedo reticularis with skin necrosis can be a significant hint toward a diagnosis of cholesterol embolism.[27] Occurring in up to 35% of patients with cholesterol embolism, gangrene is the loss (death) of tissue due to ischemia (lack of blood flow). In cholesterol embolism, it may develop within patches of acrocyanosis or livedo reticularis. Gangrene is often confined to the distal extremities, especially the toes (bilateral involvement in 50% of patients), but can rarely involve the penis and scrotum. It has even been reported to affect extensive areas of the abdomen, lower back, and bilateral hips. See the image below of toe involvement in a patient with cholesterol embolism.



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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....

Acrocyanosis or blue toe syndrome

Occurring in 28% of patients with cholesterol embolism, acrocyanosis is a characteristic blue-black to violaceous discoloration of the distal extremities. The lesions are usually painful and may progress to necrosis secondary to ischemia. Blue toe syndrome, a term coined by Karmody et al,[28] refers to acute digital ischemia caused by microembolism from the distal aorta, iliac artery, or femoral artery. See the image below.



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Symmetric involvement of the feet with livedo reticularis on the plantar surface of the forefoot and cyanosis of the left fifth toe. The painful cyano....



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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. Th....

Ulceration

Ulceration of the skin occurs in 17-39% of patients with cholesterol embolism and is typically unilateral.[22] The lower legs, feet, and toes are the most commonly involved sites. Unusual clinical presentations or refractory and recurrent ulcers of the digits and lower extremities have also been reported.[29, 30]

Nodules or indurated papules and plaques

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

Purpura

Purpura has been described in some 40% patients with cholesterol embolism, most commonly located on the lower legs and feet, although it can involve other areas of skin like the trunk.[31] The cutaneous lesions can resemble those seen in vasculitis, but quite unlike other features seen in cholesterol embolism, the purpura typically spares the toes.

Petechiae

Petechiae appear as small, pinpoint, and purpuric macules and do not blanch on diascopy. Petechiae may appear in individuals with cholesterol embolism, but are not a specific cutaneous finding because they can be seen in the setting of other pathologic conditions.

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

These have been reported in patients with cholesterol embolism and can reflect a distal aortic or iliofemoral source of the cholesterol clefts.

Punctiform subungual hemorrhages

Subungual hemorrhage has been described in association with cholesterol embolism and can present as purplish-black lesions underneath the nails.

Full-thickness cutaneous infarcts

Mimicking heparin necrosis, full-thickness cutaneous infarct and ulceration may occur in patients with cholesterol embolism.

Extracutaneous manifestations

Extracutaneous manifestations of cholesterol embolism are variable and can present in different stages of severity. These include constitutional symptoms (eg, fever, 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 one of the most common extracutaneous manifestations of cholesterol embolism and potentially one of the most devastating.[5, 11, 21, 32] While the skin has an extensive network of collateral circulation, the blood supply to the renal cortex consists predominantly of 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 two 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 blood pressure may result from obstruction of the 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.[33] 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 triggering event. Other features of renal cholesterol embolism may include flank or lower 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 gastrointestinal tract involvement, and age older than 60-70 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.

Pulses

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

Gastrointestinal manifestations (30%)

Cholesterol embolism can cause ischemia of the bowel and, if allowed to progress unabated, can lead to infarction and tissue death of the bowel. Unfortunately, gastrointestinal symptoms may be nonspecific and, thus, are often misattributed to other conditions. Symptoms include abdominal pain, diarrhea, and intestinal bleeding. Jucgla et al noted that all patients with gastrointestinal manifestations in their study had concomitant renal involvement.[22] 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.[34] Of patients with gastrointestinal 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 gastrointestinal involvement.[33] This high degree of tragic complications is thought to be due to nonspecific presentation and resulting diagnostic delay.

Ophthalmic manifestations (6%)

Retinal cholesterol crystals (known as 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.[35] Patients with carotid or vertebrobasilar atherosclerosis who undergo endarterectomy are at high risk. Thus, in patients who are suspected to have cholesterol embolism, a thorough ophthalmologic examination should be considered.

Musculoskeletal manifestations

Cholesterol embolization to muscular arterioles can cause intense myalgia at rest and/or weakness with exertion during physical activity. 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 the report from Sarwar et al describing a patient with extensive myonecrosis and compartment syndrome,[18] which led to bilateral below-the-knee amputations.

CNS manifestations

Cholesterol embolism involving the CNS may occur after vascular procedures such as carotid angiography or endarterectomy. The most frequent sources of emboli are the carotid arteries, the thoracic aorta, and the aortic trunk. Case reports have described delirium and dementia attributable to cholesterol embolism.[36] 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.[37] Although pulmonary symptoms have been considered rare in the past, Jucgla et al reported 57% of patients developed pulmonary edema secondary to cardiac failure.[22]

Endocrine manifestations

Postmortem examination of the adrenal glands has demonstrated the presence of cholesterol embolism.[22] One study reported the presumed death of a patient with visceral cholesterol embolism resulting from necrosis of the adrenal tissues.

Reproductive manifestations

Cholesterol embolism has also been demonstrated in postmortem examinations of the prostate, but was apparently asymptomatic in the patient.[22]

Hematopoietic manifestations

Reuter et al reported a case of spontaneous cholesterol crystal embolization to the bone marrow in a 77-year-old woman who presented with a fever, mild anemia, and leukocytosis.[16] Bone marrow biopsy revealed an absence of an identifiable abnormality, with the exception of the presence of cholesterol crystals. Pierce et al reported the presence of cholesterol embolism to bone marrow in a premortem patient with anemia and other clinical findings.[38] Muretto et al also described a case of cholesterol embolism to the bone marrow, and, although the patient was quite ill, anemia was not reported.[39] It remains unknown whether anemia is a nonspecific finding in cholesterol embolism.

Complications

Cholesterol embolism is extremely variable in its clinical presentation and can range from asymptomatic disease to permanent organ damage. Even in patients who survive the initial insult caused by cholesterol embolism, the destructive pathologic process may have devastating consequences that preclude return to baseline functioning levels. Stroke, limb amputation, and the need for long-term dialysis due to renal failure are frequent sequelae.

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 be helpful in diagnosing cholesterol embolism. Other laboratory studies should be ordered based on the patient's underlying disease and the overall clinical picture.

Peripheral eosinophilia (>300 cells/µL or 3-18% total WBCs) develops within about 3 days of embolization in 70-80% of patients, and levels 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 on urine testing may indicate cholesterol embolism when identified in patients with other findings of cholesterol embolism. One study found that 8 (~89%) 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 up to 50% of patients with cholesterol embolism.

The presence of elevated blood urea nitrogen levels and creatinine levels as well as proteinuria, pyuria, hematuria, and various urinary casts (in order of descending frequency: granular, hyaline, WBC, red blood cell, and oval fat bodies) are further indications that glomerular damage is occurring. However, these findings are nonspecific in the workup for cholesterol embolism because they are only general indicators that renal dysfunction is occurring.

The erythrocyte sedimentation rate is often elevated (>30 mm/h) in individuals with cholesterol embolism.

Elevated preprocedural plasma levels of C-reactive protein are associated with subsequent cholesterol embolism in patients who undergo invasive vascular procedures, according to Fukumoto et al.[43]

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 diagnostic 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 can be performed to exclude small valvular thrombi, which may be below the resolution capacity of transthoracic ultrasonography.

Doppler ultrasonography of the aorta may exclude the presence of aortic aneurysm.

Magnetic resonance imaging (MRI) and computed tomography (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. Efforts to avoid intravascular contrast and invasive vascular procedures should be undertaken.



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

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.

Procedures

Definitive diagnosis of the presence of cholesterol embolism is made by performing a biopsy of 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.[32, 44] 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.[45] 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:

Histologic Findings

An understanding of cholesterol embolism is dependent upon recognizing the relationship with atherosclerosis. Atherosclerotic lesions develop in the walls of vasculature that have undergone diffuse intimal thickening, a process carried out by smooth muscle cells and involving elastin and proteoglycans. The earliest atheromatous lesions are thought to be apolipoprotein B–containing lipids in macrophages, known as foam cells, in the outer layers of the thickened vessel walls.[46] Grossly, these can be identified as fatty streaks.[47] As the lesion progresses, lipids continuously accumulate and deposit, forming a lipid core. Fibrous and collagenous caps (as shown in the image below) cover these lesions and usually conceal denuded, friable endothelium. When the fibrin caps rupture, cholesterol plaques fragment, release showers of clefts into the bloodstream, and embolization may occur.



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Photomicrographs of histologic sections of an aorta with van Gieson stain. (Left) An atherosclerotic plaque with the fibrous cap (black arrowhead) ove....

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.[48, 49] 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.[50] 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.



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Low-power view of a skin biopsy specimen demonstrating an arteriole within the subcutaneous fat occluded with thrombus material that contains (black a....



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High-power view of occluded vessel (hematoxylin and eosin stain, original magnification X100).

Medical Care

Cholesterol embolization has an overall poor and potentially devastating prognosis.[51] Unfortunately, treatment options remain largely 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.[3] 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.[52]

In general, the optimal approach is to address and remove precipitating risk 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 and ideally eliminated to minimize the adverse effects of cholesterol embolism. Management of blood pressure using vasodilators (eg, ACE inhibitors, calcium channel blockers, nitrates) should be optimized, and use of statins and/or other lipid-lowering medications may be helpful in decreasing circulating levels of lipids and therefore decreasing the cholesterol plaque burden. Aspirin and clopidogrel may also be beneficial.[53]

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.[54] Institution of supportive care should occur as soon as cholesterol embolism is suspected. Administration of high-dose loop diuretics and/or ultrafiltration in patients with pulmonary edema can be helpful, although this should be balanced with the possibility of worsening renal dysfunction because the kidneys are often damaged by cholesterol embolism. Provide enteral or parenteral nutritional support where appropriately indicated.

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. Furthermore, there are reports of improvement with anticoagulation.[55, 56] 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.

Individual case reports show benefit from high-dose corticosteroids. Dahlberg et al,[57] Vacher-Coponat et al,[37] Belenfant et al,[3] 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.[58] 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/day and methylprednisolone at 80 mg/day, 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.[59, 60] 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. Additionally, combination therapy with corticosteroids and alprostadil has been reported to be beneficial in the treatment of cholesterol embolism.[61]

The 2003 and 2007 studies by Scolari et al underscored the theory that statin therapy may be beneficial in patients with known atheroembolic renal disease.[23, 33] 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 four cases.[62] Success has also been reported with oral pentoxifylline.[63]

Isolated case reports exist of successful management of cholesterol embolism with combination corticosteroid and cyclophosphamide therapy.[64] Yucel et al noted the treatment of a patient with corticosteroid and cyclophosphamide combination therapy, leading to improvement.[65] 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.[66] 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 two 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.

Other published anecdotal reports and case studies describe novel therapeutic approaches to cholesterol embolism, including topical fibroblast growth factor,[67] the serotonin receptor antagonist sarpogrelate,[68] , colchicine, and interleukin 1 inhibitors like canakinumab.[69] 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, although this is rare.

Surgical Care

The principal goal of surgical treatment of cholesterol embolism is to promptly identify and eradicate the embolic source and to restore adequate arterial flow. The risks versus benefits must be carefully and cautiously considered when choosing to perform surgical intervention and/or preoperative arteriography in a patient with cholesterol embolism. This is because invasive vascular procedures may worsen cholesterol embolism; however, in some select cases, procedural intervention may actually be a favorable treatment option.

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

Limb amputation or resection of infarcted and/or symptomatic tissues is often required in severe cases of cholesterol embolism. 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 highly controversial.

Prevention

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 7,621 patients by Eggebrecht et al indicates that use of catheters smaller than 8 French in angiographic procedures may prevent some cases of cholesterol embolism.[71] Use of distal filters in endovascular procedures is being studied to explore the 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,[72] 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.[73] Siablis et al described 16 patients who underwent lower limb recanalization for both acute and subacute occlusions with distal filter devices.[74] The recanalization rate was 16 (100%) of 16, without any clinical or angiographic evidence of periprocedural distal embolization. Cardaioli et al reported successful use of filter-assisted stenting in a 70-year-old man.[75]

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).[76] 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 primary goals of pharmacotherapy are to reduce morbidity and to prevent future complications resulting from cholesterol embolism.

Pentoxifylline (Trental)

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

Class Summary

These agents increase the fluid characteristics of blood.

Simvastatin (Zocor)

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

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.

Iloprost (Ilomedin)

Clinical Context:  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.

Class Summary

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

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?

Author

Laura F McGevna, MD, Assistant Professor of Medicine, Dermatology Division, University of Vermont College of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Carli P Whittington, MD, Chief Resident, Department of Dermatology, University of Vermont Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Disclosure: Nothing to disclose.

Warren R Heymann, MD, Head, Division of Dermatology, Professor, Department of Internal Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Emeritus Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

Additional Contributors

Catharine Lisa Kauffman, MD, FACP, Georgetown Dermatology and Georgetown Dermpath

Disclosure: Nothing to disclose.

Gregory J Raugi, MD, PhD, Professor, Department of Internal Medicine, Division of Dermatology, University of Washington at Seattle School of Medicine; Chief, Dermatology Section, Primary and Specialty Care Service, Veterans Administration Medical Center of Seattle

Disclosure: Nothing to disclose.

Samreen R Raza, MD, Resident Physician, Department of Internal Medicine, University of Vermont College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Edwin Rhim, MD, and Heather D. Rogers, MD, to the development and writing of this article.

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

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.

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

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.

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 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.

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

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.

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 and eosin stain, original magnification X100).

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.

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

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 and eosin stain, original magnification X100).

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 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.

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.

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

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.

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