Cholesterol Embolism 

Updated: Oct 25, 2019
Author: Lisa Kirkland, MD, FACP, FCCM, MSHA; Chief Editor: Vincent Lopez Rowe, MD 

Overview

Practice Essentials

Cholesterol embolism is a type of embolism resulting from fracture of an atherosclerotic plaque. Cholesterol embolism syndrome (CES) should be suspected in a patient who develops worsening renal function,[1]  hypertension, distal ischemia, or acute multisystem dysfunction after an invasive arterial procedure. Atheroemboli may also occur spontaneously.

Key components of CES include proximal large-caliber arterial plaque, plaque rupture with embolization of debris, mechanical occlusion of small arteries, intense foreign-body inflammation, end-organ damage from mechanical obstruction, and inflammatory vascular changes. The protean manifestations of this syndrome make the diagnosis challenging. 

Any risk factor for atherosclerotic disease is a risk factor for cholesterol embolism.

Cholesterol embolism is a disease of persons ranging from middle-aged to elderly, with a minimum age of 50 years. Men are at higher risk than women are. As the population ages, the incidence of this syndrome will increase.

Medical management of CES is supportive. Pharmacologic therapy has not been particularly successful. Surgical therapy (eg, aortic aneurysm resection) may be necessary to remove the source of atheroembolic material. Stent-grafting may be a less invasive method to reduce embolization risk.

Pathophysiology

Key components of CES include the following:

  • Proximal large-caliber arterial plaque
  • Plaque rupture with embolization of debris
  • Mechanical occlusion of small arteries
  • Intense foreign-body inflammation
  • End-organ damage from mechanical obstruction
  • Inflammatory vascular changes

Any organ system, with the exception of the lungs, may be directly affected. CES has two mechanisms of action.

With the first mechanism, cholesterol crystals spontaneously break off from severely atherosclerotic plaques and shower into downstream organs, occluding arterioles 100-200 μm in diameter. The crystals induce an inflammatory foreign-body reaction and adventitial fibrosis, which eventually obliterate the vessel lumen. Local vasospastic mediators compound tissue ischemia and produce progressive, irreversible organ damage.

With the second mechanism, larger cholesterol plaques break off and occlude larger arteries, causing tissue infarction with acute organ dysfunction. This can occur after local trauma to the atherosclerotic plaque, such as that caused by angiography or aortic trauma, or it can occur after destabilization of the protective clot overlying the plaque, which can occur as a result of anticoagulation.

Cholesterol crystal embolization (see the image below) occurs from the arterial system, and crystals are trapped in the arterioles, where they either immediately occlude the vessels or induce an intense inflammatory response that leads to tissue ischemia. Crystals do not travel to the lungs; however, inflammatory mediators released by ischemic tissue may result in acute lung injury.

Cholesterol crystal embolization from upstream cor Cholesterol crystal embolization from upstream coronary artery plaque after percutaneous transluminal coronary angioplasty.

Etiology

Any risk factor for atherosclerotic disease is a risk factor for cholesterol embolism.

Preoperative risk factors for CES after coronary artery bypass grafting (CABG) include the following:

Although the other factors have been well known for some time, it was only comparatively recently that the association between mitral anular calcification and aortic atherosclerosis was identified.

Identifying patients at risk and making efforts to minimize aortic-wall trauma help reduce the chance of cholesterol embolism. The risk that cholesterol embolism will develop may be reduced by taking a brachial or axillary approach in patients known to have severely ulcerated aortic plaque, using soft flexible catheters, and avoiding high-pressure jets of contrast material.

Epidemiology

International statistics

Estimates of the incidence of cholesterol embolic disease are usually based on autopsy data. Tissue sections from patients with the following diseases or procedures indicate the incidence of atheroembolic events:

  • Aortic aneurysms (31%)
  • Abdominal aortic aneurysm repair (up to 77%)
  • Severe aortic disease (13-16%)
  • Mild aortic disease (1-2%)

Of patients undergoing angiography, 25-30% may have atheroembolic events, whereas 2.5-3% of patients undergoing percutaneous transluminal coronary angioplasty (PTCA) vein grafts and 1.4-3% of patients undergoing renal artery angioplasty or cardiac catheterization have been reported to have clinical signs of atheroemboli. CES has been reported as occurring months after thrombolytic therapy for stroke, but the true incidence is unknown.[2, 3]

Age- and sex-related demographics

Cholesterol embolism is a disease of persons ranging from middle-aged to elderly, with a minimum age of 50 years. The risk is greater for men than it is for women.

Prognosis

Patients with multisystem CES have a poor prognosis. The mortality of acute multisystem organ failure resulting from CES is 58-90%. Jucgla et al found an overall incidence of 58% at 15 months, increasing to 65% if visceral organs were involved.[4] Preexisting chronic renal insufficiency had a relative risk of death of 4.54.

The mortality of severe cholesterol embolism is 90% at 3 months. Mild cases with renal dysfunction, with or without skin findings, have a mortality of 16%.

Cholesterol crystal showers can become stabilized, leaving patients with varying degrees of organ dysfunction. Renal function can recover if no further insults occur, even to the point where dialysis can be discontinued. However, patients remain at risk for recurrence of emboli.

Patient Education

Patients should be educated to watch for ulcerations and infections in chronically ischemic areas, particularly feet and toes. Ischemic neuropathy may exacerbate injury and tissue loss, predisposing the patient to gangrene.

For patient education resources, see the Cholesterol Center, as well as High Cholesterol, Cholesterol Charts (What the Numbers Mean), Lifestyle Cholesterol Management, and Cholesterol Lowering Medications.

 

Presentation

History

The diagnosis of cholesterol embolism must be considered in patients older than 50 years who have atherosclerotic disease and who present with multisystem dysfunction after undergoing an invasive vascular procedure or receiving an anticoagulant or thrombolytic agent within the past several months. All patients with the classic triad of livedo reticularis, acute renal failure, and eosinophilia should undergo evaluation for cholesterol embolism, including a fundoscopic examination.

Clinicians should be aware that cholesterol embolism syndrome (CES) may not manifest until chronic crystal embolization and inflammatory changes have occluded vessels sufficiently to create detectable organ damage. Patients may have unexplained fever, weight loss, myalgias, or anorexia for weeks or months after a procedure before presenting with acute renal failure, hyperkalemia, gastrointestinal (GI) bleeding, or stroke.

Physical Examination

Constitutional manifestations of cholesterol embolism include the following:

  • Fever
  • Weight loss
  • Hypermetabolic state

Cardiovascular manifestations include the following:

  • Tachycardia
  • Uncontrolled or accelerating hypertension
  • Intact peripheral pulses with livedo reticularis and tissue ischemia - These findings suggest small-vessel occlusion, such as cholesterol embolization, in a patient at risk

Neurologic manifestations include the following:

  • Hollenhorst plaques in retinal arteries
  • Hemispheric ischemic stroke
  • Paraplegia
  • Confusion
  • Delirium

Renal manifestations include the following:

Dermatologic manifestations include the following:

  • Gangrene, nodules, purpura, cyanosis, ulcerations (in 35-90% of patients)
  • Livedo reticularis
  • Infarction of perineal area
  • Ischemic patches involving lower extremities more often than upper
  • Blue toe syndrome and splinter hemorrhages [5]

GI manifestations include the following:

Other manifestations are as follows:

Complications

Cholesterol embolism can directly affect all organs except the lungs, resulting in complications that range from mild dysfunction to complete organ failure. Supportive care of organ dysfunction may be necessary and may include hemodialysis, bowel resection, cholecystectomy, and pancreatitis management.

 

DDx

 

Workup

Laboratory Studies

Laboratory studies to be considered in the workup for cholesterol embolism include the following:

  • Complete blood count (CBC) - Leukocytosis with left shift is nonspecific; eosinophilia strongly suggests atheroembolization and is present in as many as 80% of patients with cholesterol embolism syndrome
  • Chemistry - Elevated blood urea nitrogen (BUN) and creatinine levels are present in virtually all cases of cholesterol embolism syndrome (CES)
  • Urinalysis - Microscopic hematuria, proteinuria, and hyaline casts are common; pyuria actually may be eosinophiluria, a major clue for the diagnosis of CES
  • Tissue-specific laboratory tests - Muscle injury causes an elevated creatine kinase (CK) level; myocardial, pancreatic, and hepatobiliary involvement produces increases in cardiac enzymes, amylase, and hepatobiliary enzymes
  • Inflammatory mediators - Nonspecific findings include hypocomplementemia, positive rheumatoid factor (RF), antinuclear antibodies (ANAs), and elevated C-reactive protein [6] (CRP) and erythrocyte sedimentation rate (ESR); one study found a CRP level higher than 1.0 mg/dL to be an independent predictor of cholesterol emboli in patients with coronary artery disease (CAD)

Imaging Studies

Angiography

Contrast angiography of involved organs may be performed to rule out more treatable causes of tissue ischemia, such as polyarteritis nodosa. Angiography may induce atheroembolism.

Echocardiography

Transesophageal echocardiography (TEE) is an increasingly well accepted imaging tool for detecting atheromatous lesions in the ascending and thoracic aorta.[7, 8, 9, 10] Protruding mobile atheromatous masses have been associated with a higher incidence of stroke or cholesterol embolism in patients who undergo cardiac bypass or patients who receive anticoagulants. TEE may eventually be performed in all patients undergoing bypass before aortic cannulation. It also may be performed in all patients with ischemic stroke with an unclear etiology.

Computed tomography

Thin sections viewed on nonenhanced dual helical (spiral) computed tomography (CT) may be useful for rapid and noninvasive detection of protruding aortic atheroma.[11] This test can help visualize areas that are poorly imaged on TEE, such as the distal ascending aorta and arch. One study suggests 87% sensitivity, 82% specificity, and 84% overall accuracy.

Magnetic resonance imaging

Data on magnetic resonance imaging (MRI) and atheromatous plaque are relatively sparse, but a reasonable expectation is that MRI should exhibit good sensitivity in this setting.

Procedures

Demonstration of cholesterol crystals in occluded arterioles is the only definitive test for cholesterol embolism. Skin,[12] renal, muscle, or gastrointestinal (GI) tract biopsy may reveal crystal ghosts inside vessels. Often, multiple samples may be necessary to demonstrate the crystals.

Histologic Findings

The actual cholesterol crystals are dissolved during fixation, leaving intra-arterial biconvex ghosts. Often, the crystals are missed because the depth of the tissue sample is inadequate. If these ghosts are absent, the diagnosis still may be inferred from the presence of fibrinoid necrosis (see the image below) and a foreign-body reaction in tissues commonly involved by atheromatous emboli in a patient with consistent clinical findings. Exuberant adventitial fibrosis contributes to vessel lumen occlusion.

Necrosis of the abdominal wall in a patient with c Necrosis of the abdominal wall in a patient with cholesterol embolism syndrome who received anticoagulation.
 

Treatment

Medical Care

Medical management is supportive.[13] Hemodynamic monitoring, including pulmonary artery catheterization, may be helpful for fluid and vasopressor adjustments. If acute respiratory distress syndrome (ARDS) occurs, mechanical ventilation may be required for a prolonged period. Dialysis should be started when indicated because patients can recover limited renal function. Aggressive nutritional and metabolic support is essential because these patients often lose considerable lean body mass to ongoing catabolism.

Pharmacologic therapy has not been particularly successful in patients with cholesterol embolism syndrome (CES). Vasodilator therapy with calcium-channel blockers may help relieve the local ischemia resulting from vasospasm, but angiotensin-converting enzyme (ACE) inhibitors should not be used, because of their negative effects on renal afferent arterioles and the glomerular filtration rate (GFR).

Patients presumed to have vasculitis have been treated with high-dose steroids and anti-inflammatory agents, with anecdotal reports of recovery. However, steroids may predispose patients to infectious, metabolic, and nutritional complications and difficulties with wound healing. In a report of four cases of cholesterol embolism after cardiac catheterization that were associated with deteriorating renal function, low-dose (0.3 mg/kg/day) corticosteroid therapy yielded improved renal function in three of the four patients.[14]

The use of anticoagulants is controversial because anticoagulants and thrombolytics have been shown to induce atheroemboli. Anecdotal reports of treatment with apheresis, as well as with iloprost, statins, colchicine, or combinations of these drugs with steroids, reported improvement in some cases.[15, 16, 17, 18, 19]

A study by Ishiyama et al found that low-density-lipoprotein (LDL) apheresis (LDL-A) reduced the incidence of maintenance dialysis and mortality at 24 weeks in 49 patients with cholesterol crystal embolism.[20]  In a subsequent study, the same group found that LDL-A plus corticosteroids restored deteriorated renal function better than corticosteroids alone did in patients with cholesterol crystal embolism.[21]

Further invasive vascular procedures and anticoagulant or thrombolytic therapies should be avoided. If such treatments are unavoidable, downstream protection devices to trap atheromatous debris after stenting or angioplasty are suggested.[22]

Surgical Care

Surgical therapy (eg, aortic aneurysm resection) may be necessary to remove the source of atheroembolic material. Stent-grafting may be a less invasive method to reduce risk of embolization.[23]

Damaged tissue should be protected and allowed to demarcate for several months. Surprisingly, a majority of the damaged area may recover. Necrotic tissue should be debrided, and establishing vascular access for dialysis also may be necessary.

In severe cases, lumbar sympathetic block (rarely, surgical sympathectomy) has been used to avoid impending lower-extremity tissue loss resulting from intense vasoconstriction.

Prevention

If an invasive radiologic procedure is necessary, the risk of inducing cholesterol embolism must be considered. If the patient is at high risk, with known or suspected severe aortic atherosclerosis or aortic aneurysm, the Judkins (ie, brachial) approach or a radial artery approach may be used for introducing the catheter into the aorta. However, some investigators found that the approach made no difference, which led them to suspect the ascending aorta as a major source of atheroemboli.

Gentle handling of the severely diseased aorta during cardiac or aortic surgery can reduce the risk of cholesterol embolism. Careful clamping techniques and careful selection of aortotomy sites may minimize disruption of the atherosclerotic plaque.

Consultations

The following consultations should be considered as indicated:

  • Nephrologist
  • Critical care specialist
  • Metabolic and nutritional support specialists
  • General surgeon, vascular surgeon, or both
 

Questions & Answers

Overview

What is cholesterol embolism syndrome?

What are the key components in the pathogenesis of cholesterol embolism syndrome?

What is the pathophysiology of cholesterol embolism syndrome?

What causes cholesterol embolism syndrome?

What is the prevalence of cholesterol embolism syndrome?

Which patient groups have the highest prevalence of cholesterol embolism syndrome?

What is the prognosis of cholesterol embolism syndrome?

What is included in patient education about cholesterol embolism syndrome?

Presentation

Which clinical history findings are characteristic of cholesterol embolism syndrome?

What are the signs and symptoms of cholesterol embolism syndrome?

What are the possible complications of cholesterol embolism syndrome?

DDX

What are the differential diagnoses for Cholesterol Embolism?

Workup

What is the role of lab testing in the workup of cholesterol embolism syndrome?

What is the role of angiography in the workup of chronic mesenteric ischemia (CMI)?

What is the role of echocardiography in the workup of cholesterol embolism syndrome?

What is the role of CT scans in the workup of cholesterol embolism syndrome?

What is the role of MRI in the workup of cholesterol embolism syndrome?

What is the role of biopsy in the workup of cholesterol embolism syndrome?

Which histologic findings are characteristic of cholesterol embolism syndrome?

Treatment

How is cholesterol embolism syndrome treated?

What is the role of surgery in the treatment of cholesterol embolism syndrome?

How is the risk of cholesterol embolism syndrome reduced?

Which specialist consultations are beneficial to patients with cholesterol embolism syndrome?