eMedicine Specialties > Dermatology > Internal Medicine

Cutaneous Manifestations of Cholesterol Embolism

Author: Laura F McGevna, University of Vermont College of Medicine
Coauthor(s): Molly T Hogan, MD, Resident Physician, Department of Dermatology, University of Minnesota Medical School; Gregory J Raugi, MD, PhD, Professor, Department of Internal Medicine, Division of Dermatology, University of Washington at Seattle; Chief, Dermatology Section, Primary and Specialty Care Service, Veterans Administration Medical Center of Seattle
Contributor Information and Disclosures

Updated: Feb 23, 2009

Introduction

Background

Cholesterol embolism (CE), also known as atheroembolism, is a condition that is often unrecognized in medicine. It is defined by the occlusion of small- and medium-caliber arteries (100-200 m m in diameter) by cholesterol crystals. Although it was first reported by Panum nearly 150 years ago, clinicians have only recently become aware of its potentially devastating and rather frequent 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 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 a disease that has troubled clinicians for more than a century.2  

Despite these advances, cholesterol embolism is still a troublesome entity to clinically diagnose and effectively treat. Fine’s description of livedo reticularis or blue toes 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 not reported by the patient. Additionally, laboratory test results are not specific for cholesterol embolism. More importantly, although biopsy results demonstrating the needle-shaped cholesterol clefts and intravascular microthrombi are the most specific findings, histologic diagnosis does not always correlate with clinical disease. 

Pathophysiology

Despite its often inconspicuous presence on magnetic resonance angiography, atherosclerosis is a necessary prerequisite for cholesterol embolism. However, its mere existence is not always sufficient to cause clinically significant disease. Instead, cholesterol embolism is often triggered by events or procedures that disrupt unstable atherosclerotic plaques, most frequently during invasive vascular radiographic or surgical procedures and the administration of anticoagulants or thrombolytics. Although rare, reports describe spontaneous cholesterol embolism in patients with predisposing risk factors and unstable plaques.3,4,5

Regardless of proximate cause, the rupture of atheromatous plaques in major arteries 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, eventually causing intravascular thrombus formation, endothelial proliferation, and, finally, fibrosis of the vessel. Microvascular ischemia leads to tissue loss by segmental infarction, organ dysfunction, and, rarely, catastrophic organ failure. The end result may be devastating ischemia, infarction, and necrosis of the organs supplied by the affected vessels.

In any given patient, the precise clinical syndrome depends on the location of the source of embolism and the pattern and distribution of flow downstream. The most common sites for severe atheromatous disease are in the abdominal aorta and the iliac and femoral arteries; accordingly, signs and symptoms more commonly result from embolism to the lower half of the body. In fact, 80% of cases are associated with aortoiliac atheromatous plaques. Patients with cholesterol embolism frequently present with lower limb ischemia (blue or purple toe syndrome), abdominal pain, melena, and a stepwise decline in creatinine clearance levels resulting from focal underperfusion of the intestine and the kidneys. When the source of crystals is in the aortic arch, 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 likely precipitating event occurred an average of 2 months before their admittance to the ICU with fulminant disease.2

Frequency

International

The true incidence of cholesterol embolism is unknown, and estimates vary widely among populations. Estimating the incidence is also complicated by the previously noted discrepancies between histologic and clinical disease. Published estimates approximate an average incidence of 2-4%, with reports ranging from 1.9-77%. The largest epidemiological study performed was by Moolenaar and Lamers, using the Dutch National Pathology Information System.7 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, it has been suggested that the discrepancy between the Dutch and other studies may be a function of the potentially lower prevalence of both atherosclerosis and invasive vascular procedures in the Dutch population.

Mortality/Morbidity

Cholesterol embolism is regarded as 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. The leading causes of death are cardiovascular in nature, but include myocardial infarction, ruptured aortic aneurysm, GI infarction, congestive heart failure, sepsis, and cachexia.

  • Preexisting renal disease is a known marker for higher mortality.8 Additionally, longstanding, poorly controlled hypertension is a recognized marker for the development of end-stage renal disease (P <.001).9
  • 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 are common in both minor and severe disease. However, patients with peripheral manifestations alone have only a 38% mortality rate within 15 months.
  • Morbidity includes chronic renal insufficiency requiring hemodialysis (with most patients in this category having fatal outcomes),8 stroke resulting in paraplegia, unstable angina, amputation of the affected extremity (5-15% of patients), and malnutrition or significant weight loss (70% of patients).
  • Male sex, in one study,9 was associated with a decreased risk of mortality (P = .007). Nevertheless, these findings were eventually questioned due to the small number of women enrolled in the study and the association of male sex and severe atherosclerosis.

Race

Cholesterol embolism is more commonly found in whites than in persons of other racial groups, with a ratio of 32:1 in whites compared with blacks. 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, is limited in black populations, which may indicate that blacks are less likely to have an inciting event. Nevertheless, recognizing that hypertension is both a risk factor in the development of atherosclerosis and more common among blacks, the racial discrepancy in cholesterol embolism suggests that the epidemiological data may be flawed.

Sex

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. 

Age

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

Clinical

History

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 the setting of a history of preexisting atherosclerotic disease and specific precipitating events. The classic triad of excruciating lower extremity pain, livedo reticularis, and good peripheral pulses in a person older than 50 years should be considered to be due to cholesterol embolization until proven otherwise.

Physical

The onset of physical findings may be delayed by days to months. Cutaneous manifestations are the most common physical findings in patients with cholesterol embolism (on average, 35% of patients) and the most helpful in establishing a diagnosis. Jucgla et al revealed skin findings in 88% of patients with known disease,8 and a 2004 report by Manganoni indicated that 50 of 52 patients had recognizable skin findings, often marked erythema of the toes.10 On average, when using postmortem findings as the criterion standard for diagnosis, dermatologic findings were associated with a 3-fold increased likelihood of establishing a premortem diagnosis of cholesterol embolism. The following percentages represent all skin lesions found in cholesterol embolism in multiple studies; the total exceeds 100% because more than one manifestation is usually present in an individual.

  • Livedo reticularis: This is the most common dermatologic manifestation of cholesterol embolism, comprising 50-74% of cholesterol embolism – related skin lesions.8 This blue-red mottling of the skin in a netlike pattern usually affects the feet, the legs, the buttocks, and the thighs and can extend to the trunk and the upper extremities. Occasionally, livedo reticularis may be noted only while the patient is standing; therefore, examining patients in both the supine position and the standing position is important. Livedo occurs with any process that increases the visibility of the venous plexus. 
  • Gangrene: Occurring in 35% of patients, gangrene is the loss of tissue due to ischemia. In cholesterol embolism, it may develop in preexisting acrocyanosis or livedo reticularis. Gangrene is almost always dry and confined to the toes (bilaterally in 50% of patients), but rarely it involves the scrotal area. It usually demarcates within weeks and eventually requires surgical debridement.
  • 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,11 refers to acute digital ischemia caused by microembolism from the distal aorta, iliac artery, or femoral artery.
  • Ulceration: This occurs in 17-39% of patients8 and is typically unilateral and located on the toes and the feet. Unusual presentations, refractory and recurrent ulcers of the digits and the lower extremities, have also been reported.
  • 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.
  • Purpura: Occurring in 9% of patients, this is most commonly seen on the legs and the feet. The lesions resemble those of vasculitis, but, unlike other features in cholesterol embolism, they typically spare the toes.
  • Petechiae: Small, pinpoint, purpuric spots, petechiae do not blanch on diascopy and may rarely appear in persons with cholesterol embolism (4%).
  • 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.
  • Cholesterol clefts: Isolated case reports describe cholesterol clefts in solitary lesions in unusual locations (eg, a nodule on an ear, red and painful swelling on the chest) with microscopic findings of hemorrhagic panniculitis.
  • Punctiform subungual hemorrhages: These may occur.
  • Full-thickness cutaneous infarcts mimicking heparin necrosis: These have been reported in patients with cholesterol embolism.

Extracutaneous manifestations of cholesterol embolism are multifarious. These include constitutional symptoms, such as fever and weight loss, as well as the following: 

  • Renal manifestations (34%): The frequency of localization to viscera is suggested to roughly correspond to the amount of blood flow delivered. Receiving 20-25% of the cardiac output, all distal to atherosclerotic lesions in the abdominal aorta, renal cholesterol embolism is the best marker for visceral involvement. 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. The clinical diagnosis of cholesterol embolism can be made when stepwise loss of glomerular function is accompanied by other nonrenal manifestations of cholesterol embolism. The 2 most common renal manifestations of cholesterol embolism are hypertension and loss of glomerular function. 
    • Hypertension resulting from cholesterol embolism can be accelerated and intractable. In cholesterol embolism, hypertension is thought to be associated with high circulating plasma renin and angiotensin levels. Renin is released by the juxtaglomerular cells of the afferent arterioles in response to decreased blood flow, in this case caused by the obstruction resulting from cholesterol emboli.
    • 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 rule out other causes, including contrast-induced nephropathy.
    • Also regarding renal failure, 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.12 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. They also found that the time course to renal insufficiency was a fairly accurate prognostic factor in predicting outcomes for renal and patient death.
    • 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. The exact nature of the reversible component to the acute renal failure is unknown.
    • 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 forming a wedge-shaped scar in the kidney.
  • Pulses: Pedal pulses are palpable in 60% of patients, bilaterally decreased in approximately 40%, and absent on the side of the cutaneous lesions in less than 5% 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 vessels, sparing the dorsal pedalis and posterior tibial arcades.
  • GI manifestations (30%)
    • Cholesterol embolism causes ischemia or infarction of the bowel. Unfortunately, most GI symptoms are nonspecific and, thus, are often misattributed to other conditions.
    • Symptoms include abdominal pain, diarrhea, and GI bleeding. Jucgla et al8 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.13
    • 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 both renal and patient death was considerably elevated at 2.57 in patients with any degree of GI involvement.12 This high degree of tragic complication is thought to be due to nonspecific presentation and diagnostic delay, coupled with the catastrophic effects of ischemic GI injury.
  • 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 intermittent monocular blindness or 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 embolism to arterioles in muscles can cause intense myalgia at rest or muscle tenderness and/or weakness with exertion. Involvement of lower extremity muscles with upper limb sparing is characteristic in cholesterol embolism. Muscle infarcts have also been described.8
    • Development of rhabdomyolysis after cholesterol embolism is uncommon; however, reports describe this disastrous complication, underscored by Sarwar et al.14 In this report, researchers identified a patient with extensive myonecrosis, rapidly leading to rhabdomyolysis and compartment syndrome. Ultimately, the tissue ischemia progressed despite therapy, and the outcome was gangrene and 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. Manifestations may include transient ischemic attack and stroke from involvement of the cerebral arteries. Case reports have described delirium and dementia attributable to cholesterol embolism.15 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.16 Renal and skin biopsies revealed cholesterol embolism. Although pulmonary symptoms have been considered rare in the past, Jucgla et al8 reported 57% of patients had pulmonary edema secondary to cardiac failure.
  • Endocrine manifestations: Postmortem examination of adrenal glands has demonstrated cholesterol embolism.8 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.8
  • Hematopoietic manifestations: Reuter et al reported a case of spontaneous cholesterol crystal embolization to the bone marrow diagnosed in a 77-year-old woman with fever, anemia (hemoglobin value, 10.2 g/dL), and leukocytosis.17 Bone marrow biopsy was performed to evaluate the etiology of her anemia. No abnormalities were discovered, 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.18 Muretto also reported a case of cholesterol embolism to bone marrow.19 Although his patient was quite ill, anemia was not reported. However, it is now known that anemia is frequently a nonspecific finding in cholesterol embolism.

Causes

Cholesterol embolism occurs spontaneously in patients with atherosclerosis, but a trigger is usually required for full expression of cholesterol embolism syndrome. Precipitating factors include the following:

  • Anticoagulation and thrombolytic therapy: A history of antecedent therapy with anticoagulants is present in approximately 30-35% of patients.20,21,22 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 fibrin cap thrombi, causing cholesterol crystals to dislodge and enter the circulation.17
  • Interventional vascular techniques: Various surgical or radiologic vascular procedures precede cholesterol embolism in nearly 65% of patients.23 The introduction of a foreign object into the vessel can cause intimal trauma, exposing the underlying cholesterol-rich extracellular matrix to the arterial circulation. This risk is proportionally increased with increased sheath size of the catheter.
    • 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.14
    • Mere passage of the catheter into the luminal space is now thought to place the patient at risk for cholesterol embolism, disrupting and exposing the soft cholesterol core to the arterial circulation.
  • Trauma: This includes cardiopulmonary resuscitation or sudden deceleration injury, and it may also result in cholesterol embolism.

More on Cutaneous Manifestations of Cholesterol Embolism

Overview: Cutaneous Manifestations of Cholesterol Embolism
Differential Diagnoses & Workup: Cutaneous Manifestations of Cholesterol Embolism
Treatment & Medication: Cutaneous Manifestations of Cholesterol Embolism
Follow-up: Cutaneous Manifestations of Cholesterol Embolism
Multimedia: Cutaneous Manifestations of Cholesterol Embolism
References
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References

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Further Reading

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Keywords

cholesterol embolism CE, cholesterol embolism syndrome, CE syndrome, atheroembolization, cholesterol crystal embolization, multiple cholesterol emboli syndrome, cholesterol microembolization, cholesterol emboli, atheromatous embolization, atherosclerosis, atherosclerotic cardiovascular disease, microthrombi, limb ischemia

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Contributor Information and Disclosures

Author

Laura F McGevna, University of Vermont College of Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Molly T Hogan, MD, Resident Physician, Department of Dermatology, University of Minnesota Medical School
Molly T Hogan, MD is a member of the following medical societies: Alpha Omega Alpha
Disclosure: Nothing to disclose.

Gregory J Raugi, MD, PhD, Professor, Department of Internal Medicine, Division of Dermatology, University of Washington at Seattle; Chief, Dermatology Section, Primary and Specialty Care Service, Veterans Administration Medical Center of Seattle
Gregory J Raugi, MD, PhD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

Medical Editor

Catharine Lisa Kauffman, MD, FACP, Georgetown Dermatology and Georgetown Dermpath
Catharine Lisa Kauffman, MD, FACP is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Royal Society of Medicine, Society for Investigative Dermatology, and Women's Dermatologic Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Warren R Heymann, MD, Head, Division of Dermatology, Professor, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey
Warren R Heymann, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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