Continuing Education Activity

Cholesterol emboli occur as a result of the rupture of an atherosclerotic plaque, leading to the formation of an embolism. Cholesterol embolization syndrome occurs when atheromatous plaques in large arteries release cholesterol emboli and atheromatous debris into the circulation. These can then become lodged downstream in smaller arterioles and cause varying degrees of ischemia in target organs. This can result in worsening renal function, distal ischemia, hypertension, or acute multiorgan dysfunction. The partially occluded arterioles display an intense giant cell foreign body inflammatory response with fibrosis and eventually complete occlusion. Subsequent waves of arterial embolization are associated with increasing symptoms and signs of the syndrome and may explain why about 20% of cases go unrecognized. This is generally seen after an invasive arterial procedure but can occur spontaneously.

This activity reviews the evaluation and management of cholesterol emboli; participants can expect a detailed exploration of cholesterol emboli, its etiology, and the cascade of events following plaque fractures. The course reviews the evaluation process, covering diagnostic criteria and management strategies for patients with cholesterol emboli. Practical insights into recognizing symptoms and signs associated with this condition contribute to a holistic understanding. The interprofessional team's contributions to effective evaluation, management, and follow-up care are also thoroughly explored.

Objectives:

• Identify clinical signs and symptoms of cholesterol emboli, such as acute multisystem dysfunction, worsening renal function, and distal ischemia, particularly after invasive arterial procedures.

• Differentiate cholesterol emboli from thromboembolism by understanding their distinct mechanisms and gradual, organ-damaging process over time.

• Apply evidence-based interventions to manage cholesterol emboli, including optimizing risk factor modification and addressing specific organ complications.

• Coordinate care plans, treatment strategies, and follow-up for patients with cholesterol emboli, ensuring seamless transitions and optimal outcomes through a collaborative approach.

Introduction

Cholesterol embolism or atheroembolism is a phenomenon where cholesterol crystals and atheroma debris, such as cholesterol, platelets, and fibrin, embolize from proximal large arteries, such as the aorta and its major branches, to distal small arteries. Cholesterol emboli result from a fracture of an atherosclerotic plaque.[1] Cholesterol emboli should be suspected in patients with worsening renal function, hypertension, acute multisystem dysfunction, or distal ischemia after an invasive arterial procedure.[2] Cholesterol embolism frequently occurs after intraarterial procedures but can also happen spontaneously.[3] Cholesterol embolism is an uncommon multisystemic disease involving multiple organs, including the brain, muscles, skin, eyes, kidneys, and gastrointestinal (GI) tract.[4]

Organ damage usually manifests when cholesterol crystals break off from atherosclerotic plaques and shower to downstream vascular beds, causing mechanical obstruction and inflammatory response to the target organ.[2] It is important to note that cholesterol embolism is separate from thromboembolism, in which a thrombus forms on top of atherosclerotic plaque and large emboli break off, causing sudden infarction. In contrast, cholesterol embolism is a more gradual process and causes end-organ damage over time. The emboli are usually made of debris from atherosclerotic plaques, mainly cholesterol crystals.[1]

Another name for cholesterol embolism syndrome or atheroembolism is "blue toe syndrome." This syndrome is caused by atheroembolism that occludes the digital vasculature. In this disease, embolisms usually occlude smaller diameter vessels, and peripheral pulses are often intact. Therefore, whenever distal gangrene, ulcers, and cyanosis are present with intact pulses, it is highly suggestive of blue toe syndrome.[5]

Etiology

Predisposing risk factors for cholesterol emboli include the following:

• Male gender
• Hypertension
• Hyperlipidemia
• Diabetes mellitus
• Peripheral vascular disease
• Aortoiliac disease [6]
• Renal failure
• Age greater than 60 years
• Mitral annular calcification
• Cerebrovascular disease [7]

Other likely scenarios include patients who undergo interventional vascular procedures and cardiovascular surgery. Those with an aortic aneurysm have increased inflammation, predisposing them to cholesterol emboli. Thrombolytic therapy and anticoagulation are also etiological factors for developing cholesterol emboli. However, the most important predisposing factor is atherosclerosis. The severity of atherosclerosis is directly associated with the chance of forming cholesterol emboli.[1]

Epidemiology

Cholesterol emboli can occur spontaneously or after invasive arterial procedures such as aortic or cardiac surgery or thrombolytic therapy. About 80% of cholesterol emboli result from an intraarterial procedure, while less than 5% are due to spontaneous cholesterol embolism.[8] 

The exact incidence is unknown, but the reported incidence of clinically evident cholesterol embolism in the literature is generally less than 3.5%. Cholesterol emboli are much more common in patients with atherosclerotic heart disease who are 60 or older. For instance, studies examining the incidence of cholesterol embolism through autopsies of elderly patients who died following some form of intraarterial procedure found evidence of atheroembolism in 10% to 77% of the cases. In contrast, autopsy studies of the generalized patient population reported an incidence of only 0.31% to 2.4%.[1][7] 

The following is a list of diseases and procedures with their associated incidence of atheroembolic events:

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

Pathophysiology

The presence of atheromatous plaques in large caliber arteries like the aorta and its branches can lead to spontaneous, traumatic, or iatrogenic plaque rupture. Plaque debris, including cholesterol crystals, fibrin, platelets, and calcified debris, embolizes and lodges into small to medium arteries, causing mechanical occlusion. The combined effect of mechanical occlusion and resultant inflammation from the foreign body, leukocyte infiltration, and complement activation leads to end-organ damage.[9]

Histopathology

Cholesterol crystal embolization is seen on microscopic examination as an arterial lumen filled with large cholesterol crystal spaces or clefts surrounded by hyperplastic intimal tissue and giant cells. Cholesterol crystal spaces are seen as crystals dissolve during the preparation.[7]

History and Physical

The history in patients with cholesterol emboli most commonly includes recent endovascular procedures such as heart catheterization, valve replacement, vascular stent placement, or carotid endarterectomy. They will usually have increased risk factors for atherosclerosis and likely have a medical history of coronary artery disease, hypertension, hypercholesterolemia, cerebrovascular accident, transient ischemic attack, diabetes, abdominal aortic aneurysm, peripheral vascular disease, or renal failure.[7]

Patients with cholesterol embolization syndrome frequently present with vague constitutional symptoms such as fever, fatigue, weight loss, myalgia, and anorexia. Organ-specific clinical manifestations can also be seen.[1][9][10] The 3 most commonly affected organ systems are the kidney (31.5%), skin (15.5%), and GI tract (13.4%).

In the kidneys, atheroembolism causes 2 types of injuries: acute to subacute and chronic.[11][12][13] Acute or subacute kidney injury from embolization manifests clinically as microscopic hematuria, eosinophiluria, and minimal proteinuria on urine analysis (UA). The chronic form most often manifests as heavy proteinuria, like in nephrotic syndromes. Cholesterol emboli syndrome should be considered in the differential diagnosis when intrinsic renal disease is suspected, especially when secondary focal segmental glomerulosclerosis is high on the differential.[2]

Embolic involvement of the GI tract leads to symptoms that include abdominal pain, flank pain, back pain, GI bleeding, bowel ischemia or obstruction, splenic infarction, pancreatitis, cholecystitis, abnormal liver enzymes, and diarrhea.[10][14][15]

The most characteristic findings in skin include retiform purpura, blue or purple toes, ulcers, gangrene, livedo reticularis, small nail bed infarcts, and foot and toe pain.[16][17][18][19][20][21] Clinically, these signs are seen when cholesterol emboli cause non-vasculitic occlusion of cutaneous blood vessels, especially after invasive arterial procedures.

Other organ manifestations include eye symptoms such as sudden blindness, amaurosis fugax, or retinal plaques (Hollenhorst plaques).[22][23] 

When the CNS is affected, clinical manifestations include headache, altered mental status (AMS), stroke, transient ischemic attack (TIA), paresthesia, and spinal cord infarction.[24][25]

Signs of systemic inflammation are usually seen in lab work. A complete blood count (CBC) can show evidence of anemia, leukocytosis, and thrombocytopenia. Hypereosinophilia, hypocomplementemia, elevated amylase, lipase, lactate, LDH, ESR, and CRP levels are also possible. UA can show varying degrees of hematuria, eosinophiluria, and proteinuria. A renal function panel can show evidence of chronic kidney disease or acute kidney injury.[26]

Evaluation

No specific laboratory test is used to diagnose cholesterol emboli conclusively. However, as mentioned above, a basic lab workup, including CBC with cell count differential, complete metabolic panel (CMP), and UA, can help. A retinal exam looking for Hollenhorst plaques should be done in those presenting with amaurosis fugax or sudden blindness. The only way to confirm the diagnosis of cholesterol emboli syndrome is to biopsy various organs such as skin, skeletal muscles, gut mucosa, bone marrow, or kidneys.[26] For instance, 1 study in the literature showed that non-renal biopsies identified cholesterol crystals in about 80% of the cases.[27]  

The evaluation and management of this disease differ depending on which organ is affected by cholesterol embolization. For instance, if a patient presents with stroke-like symptoms, a computed tomography (CT) scan and magnetic resonance imaging (MRI) of the brain without contrast, as well as magnetic resonance angiography (MRA) of the head and neck, are indicated.

For acute limb ischemia, a CT angiogram should be considered based on the urgency of the presentation.

If bowel ischemia is suspected, the lab workup should include serum lactate and a white blood cell count, both of which will likely be elevated. In addition, an abdominal CT should be ordered, and high-resolution CT angiography of the abdomen should be considered.

If renal emboli are suspected, a UA should be obtained to evaluate for proteinuria and eosinophiluria. Labs should be ordered to look for an elevated LDH. Renal ultrasound or high-resolution abdominal CT angiography should be performed to assist in the diagnosis.

If there is concern the emboli have affected the heart valves, a transesophageal echocardiogram (TEE) should be performed.[28]

The diagnosis can also be made clinically when fulminant disease occurs within days after the endovascular procedure, usually accompanied by blue toes or livedo reticularis.

Treatment / Management

No one specific treatment for cholesterol emboli can be established because the details of the presenting condition influence treatment choices. Acute treatment depends on the organ involved, the duration of symptoms, and the type of emboli. Usually, treatment in acute settings is mostly supportive. If there are no other indications for anticoagulation, it should be stopped in patients suspected of having cholesterol emboli, as it can worsen the condition.[26][29][30]

Long-term treatment includes identifying the source of the emboli, preventing further spread, and risk modifications. Patients who have formed clots in their hearts should be anticoagulated. Patients with atherosclerosis of larger arteries are usually treated with antiplatelet agents and statins (HMG-CoA reductase inhibitors) to stabilize the plaques.[28] Further cardiovascular procedures should be avoided if possible as they are a known precipitant. Since end-stage renal disease is the most common life-threatening complication, an aggressive approach to treating hypertension and regularly monitoring renal function is beneficial in long-term management.[3][30][31]

Ishiyama et al observed that low-density lipoprotein (LDL) apheresis reduced the incidence of maintenance dialysis and mortality in 49 patients with cholesterol emboli.[32] A subsequent study found that LDL apheresis plus corticosteroids restored lost renal function better than corticosteroids alone in patients with cholesterol emboli.[33]

Patients suspected of having vasculitis can be treated with high-dose steroids and anti-inflammatory therapy. In a report of 4 patients with cholesterol emboli who had deteriorating renal function, low-dose corticosteroid therapy improved renal function in 3 of 4 patients.[34] However, steroids may result in infectious, metabolic, and nutritional complications and impaired wound healing. Therefore, weighing the risks versus the benefits of this treatment is imperative when caring for patients. 

Differential Diagnosis

The differential diagnosis of cholesterol emboli includes various conditions that produce microvascular ischemia of multiple organs and systemic inflammation. These include the following:

• Small- to medium-vessel vasculitis, eg, Takayasu disease, polyarteritis nodosa, Henoch-Schonlein purpura
• Antiphospholipid syndrome
• Infective endocarditis
• Thrombotic thrombocytopenic purpura
• Disseminated intravascular coagulation
• Cryoglobulinemia
• Left atrial myxoma

Cancer, such as lymphoma, and diseases like polycythemia vera, pheochromocytoma, Raynaud phenomenon, and tuberculosis are other possible differentials. Radiocontrast nephropathy must be considered and ruled out in cases of renal failure in which contrast agents were used during the workup. Other potential differentials are rapidly progressive glomerulonephritis, focal segmental glomerulonephritis, and hypertensive nephrosclerosis.[1][30]

Prognosis

Patients diagnosed with cholesterol embolization syndrome have a poor prognosis due to cardiovascular comorbidities. One- and 2-year survival rates are 87% and 75%, respectively, and a 4-year survival rate drops as low as 52%. Mortality has been cited in the literature to be as high as 63% to 81%.[1][9][24][27]

Complications

Complications of cholesterol embolization syndrome depend on where the source of embolus is and in which organ is affected. As discussed earlier, possible complications include the following:

• Hypertension
• Bowel ischemia
• Renal insufficiency
• Stroke [35]
• End-stage renal disease
• Pancreatitis
• Cholecystitis
• Splenic infarction
• Carotid stenosis
• Blindness [36]
• Skin rashes
• Myocardial ischemia
• Multiorgan failure
• Death

Deterrence and Patient Education

The prevention of cholesterol emboli is mainly achieved through risk factor reduction; therefore, patients should be educated about how to reduce their risk factors. Patients should be educated on how a sensible diet and adequate exercise can help with weight management and blood pressure control. Smoking cessation should be strongly advised. The importance of medication compliance and attendance at regular follow-up appointments with their physicians should be stressed. 

Surgical or endovascular treatment may be indicated if a clear embolic source is identified and the patient is deemed an appropriate candidate for surgery. In that case, time should be taken to clearly explain the risks versus benefits of the indicated treatment to the patient. The prognosis should be discussed, and code status and advance directives should be addressed. 

Enhancing Healthcare Team Outcomes

An interprofessional team that provides a holistic and integrated approach to care can help achieve the best possible outcomes. Physicians and surgeons, including specialists in nephrology, cardiology, rheumatology, radiology, general surgery, and vascular surgery, need to collaborate and leverage their expertise to weigh the potential risks associated with treatment against the risk of cholesterol emboli.[27] Pharmacists ensure all medications are appropriately dosed for the patient. Nurses assess the patients and monitor for new cutaneous manifestations. Nurses assess patients and vigilantly monitor for new cutaneous manifestations. Early identification of signs and symptoms of complications is key to improving prognosis and outcomes. This is particularly important for patients with cholesterol emboli, as delayed reperfusion can result in more substantial ischemic damage to the affected organ.[28] 

A dietician may be consulted if patients need parenteral nutrition or to help educate the patient and family on proper diet after treatment to reduce further risk. Primary care physicians should be contacted and updated about care goals, including aggressive risk factor modifications for high-quality continued patient care. In patients with a high mortality burden, a palliative care consult should be considered to discuss care options moving forward with the patient and the family.