Continuing Education Activity

Cholesterol embolization syndrome occurs when atheromatous plaques in large arteries release cholesterol emboli and atheromatous debris into the circulation, which become lodged downstream in smaller arterioles, and cause varying degrees of ischemia of the target organ. The partially occluded arterioles also 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 activity reviews the evaluation and management of cholesterol emboli and highlights the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Identify the etiology of cholesterol embolization syndrome.
• Review the appropriate evaluation of cholesterol embolization syndrome.
• Outline the management options available for cholesterol embolization syndrome.
• Describe some interprofessional team strategies for improving care coordination and communication in patients with cholesterol embolization syndrome to prevent further development of atheroembolism and improve outcomes.

Introduction

Cholesterol embolism or atheroembolism is a phenomenon where cholesterol crystals and atheroma debris such as cholesterol, platelets, and fibrins embolizes from proximal large arteries such as the aorta and its major branches to distal small arteries. Cholesterol embolism frequently occurs after the intraarterial procedures, but it can also occur spontaneously.[1] Cholesterol embolism is an uncommon multisystemic disease where multiple organs are involved, including the brain, muscles, skin, eyes, kidneys, and gastrointestinal (GI) tract.[2] 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.[3] It is important to note that cholesterol embolism is separate from thromboembolism in which thrombus forms on top of atherosclerotic plaque and large emboli break off, causing sudden infarction. Cholesterol embolism is a more gradual process and causes end-organ damage overtime. Note that here the emboli are usually made of debris from atherosclerotic plaques; mainly, cholesterol crystals.[4] 

Another name for cholesterol embolism syndrome or atheroembolism is "blue or purple toe syndrome."  Atheroembolism that causes digital vascular occlusion causes the syndrome. In this disease, embolisms usually occlude smaller diameter vessels, and hence peripheral pulses are often intact. Therefore, whenever distal gangrene, ulcers, and cyanosis are present, but the pulse is intact, then it is highly suggestive of blue or purple toe syndrome.[5]

Etiology

Predisposing risk factors for cholesterol embolism include male gender, hypertension, hyperlipidemia, diabetes mellitus, peripheral vascular disease, atherosclerosis of ascending aorta, renal failure, and advanced age.[6] Other likely scenarios include the patients who undergo interventional vascular procedures, cardiovascular surgery, those with an aortic aneurysm, have increased inflammation, have received thrombolytic therapy, or are on anticoagulation. The most important predisposing factor to CES (cholesterol embolism syndrome) is atherosclerosis. The severity of atherosclerosis is directly associated with the chance of getting CES.[4]

Epidemiology

Cholesterol embolization syndrome occurs either spontaneously or after intraarterial procedures such as aortic or cardiac surgery or thrombolytic therapy. About 80% of cholesterol embolism results from the intraarterial procedure, while less than 5% atheroembolism is due to spontaneous cholesterol embolism.[7] 

The exact incidence of CES is not known, 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 60 years or older who have atherosclerotic heart disease. For instance, studies that have looked at the incidence of CES by doing an autopsy in elderly who died after some form of intraarterial procedure found evidence of atheroembolism 10% to 77% of the time. In contrast, few autopsy studies of the generalized patient population reported CES incidence of only 0.31 to 2.4 percent.[4][6]

Pathophysiology

The presence of plaque in large-caliber arteries like aorta and its branches leads to spontaneous, traumatic, or iatrogenic plaque rupture. Plaque debris, including cholesterol crystals, fibrins, platelets, calcified debris embolize, and lodge 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.[8]

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.[6]

History and Physical

Typical history in the patients with cholesterol embolization will most commonly include recent endovascular procedures such as heart catheterization, valve replacement, stent placement in the vasculature, or carotid endarterectomy. Usually, the patients will have risk factors similar to risk factors for atherosclerosis. The patients are likely to 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.[6] 

Patients with cholesterol embolization syndrome frequently present with constitutional symptoms such as fever, fatigue, weight loss, myalgia, and anorexia. Besides, there are organ-specific clinical manifestations.[4][8][9] In CES, the three most commonly affected organ systems are kidney (31.5%), skin (15.5%), and gastrointestinal (GI) tract (13.4%).

In the kidneys, atheroembolism causes two types of manifestations: acute to subacute or chronic.[10][11][12] Acute or subacute form of kidney injury from embolization manifests clinically as microscopic hematuria, eosinophiluria, and minimal proteinuria on urine analysis. Whereas, chronic form most often manifests as heavy, nephrotic range proteinuria. CES should be a differential diagnosis when the intrinsic renal disease is suspected and especially in the case where secondary focal segmental glomerulosclerosis is high on the differential.[3]

The involvement of the GI tract leads to the development of symptoms that include abdominal pain, flank pain, back pain, GI bleed, bowel ischemia, infarction, or obstruction, splenic infarction, pancreatitis, cholecystitis, abnormal liver enzymes, and diarrhea.[9][13][14]

The most characteristic finding in skin includes retiform purpura, blue or purple toes, ulcers, gangrene, livedo reticularis, small nail bed infarcts, and foot or toe pain.[15][16][17][18][19][20] Clinically these signs are seen when cholesterol emboli cause non-vasculitic occlusion of cutaneous blood vessels, especially after endovascular procedures.   

Other organ manifestations include eye symptoms such as sudden blindness, amaurosis fugax, or retinal plaque (Hollenhorst crystals).[21][22]

When CNS is affected, clinical manifestations include headache, altered mental status (AMS), stroke, transient ischemic attack (TIA), paresthesia, spinal cord infarction.[23][24]  

On lab work, usually, signs of systemic inflammation are seen. Complete blood count (CBC) can show evidence of anemia, leukocytosis, thrombocytopenia. Hypereosinophilia, hypocomplementemia, elevated amylase, lipase, lactate, elevated LDH, elevated ESR, and high CRP levels are also possible. Urine analysis (UA) can show hematuria, eosinophiluria, and proteinuria of varying degrees. The renal function panel shows evidence of chronic kidney disease or acute kidney injury.[25]

Evaluation

There is no specific laboratory test for cholesterol embolization syndrome. However, as mentioned above, a basic lab workup with CBC with cell count differential, complete metabolic panel (CMP), and UA can help. The retinal exam should be done in case the presentation of amaurosis fugax or sudden blindness to look for "Hollenhorst plaques." The only way to confirm the diagnosis of CES is the biopsy of various organs such as skin, skeletal muscles, gut mucosa, bone marrow, or kidneys.[25] For instance, one study in the literature showed that non-renal biopsies identify cholesterol crystals in about 80% of the cases.[26]  

Depending on which organ is affected by cholesterol embolization, the evaluation and management of CES can be different. For instance, if stroke-like symptoms are seen in a patient, then CT scan of brain and MRI of the brain without contrast as well as 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, then the laboratory workup should include serum lactate and white blood cell count. In addition, high-resolution CT angiography should be considered to evaluate for bowel ischemia. In the case of suspected renal emboli, UA with proteinuria, eosinophiluria, or elevated LDH on the bloodwork should be seen. The renal US or high-resolution CT angiography should be done to diagnose renal emboli. Sometimes if the source is suspected to be valvular, then transesophageal echocardiogram (TEE) is performed.[27]

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

Treatment / Management

There is no specific treatment for cholesterol embolization syndrome. Acute treatment depends on which organ embolization has occurred to, duration of symptoms, and type of emboli. Usually, treatment in acute settings is mostly supportive. When there are no other indications, anticoagulation should be stopped in patients suspected of having CES as it can worsen the condition.[25][28][29] 

Long term treatment includes identifying the source of the emboli and preventing its further spread and risk modifications. Patients who have clots formed in heart structures are anticoagulated. Patients with atherosclerosis of the larger arteries are usually treated with antiplatelet agents and statins (HMG-CoA reductase inhibitors) to stabilize the plaques.[27] Further cardiovascular procedures, if possible, should be avoided as they are a known precipitant. Since the end-stage renal disease is the most common life-threatening complication, an aggressive approach in treating hypertension and regularly monitoring renal function is beneficial in long term management.[1][29][30]

Differential Diagnosis

The differential diagnosis of CES includes various conditions that produce both microvascular ischemia of various organs and systemic inflammation. These include the small- to medium-vessel vasculitis (Takayasu disease, polyarteritis nodosa, Henoch-Schonlein purpura), antiphospholipid syndrome, infective endocarditis, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, cryoglobulinemia, and left atrial myxoma. Cancer such as lymphoma and diseases such as polycythemia vera, pheochromocytoma, Raynaud phenomenon, and tuberculosis are other possible differentials. In specific cases where some contrast agents are used, and the patients develop renal failure because of CES, the most common differential diagnosis is radiocontrast nephropathy. Other potential differentials are rapidly progressive glomerulonephritis, focal segmental glomerulonephritis, and hypertensive nephrosclerosis.[4][29]

Prognosis

Patients diagnosed with cholesterol embolization syndrome have a poor prognosis due to cardiovascular comorbidities. One and two-year study 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%.[4][8][23][26]

Complications

Complications of cholesterol embolization syndrome depend on where the source of emboli is and in which organ arterial embolism is occurring. As discussed earlier, possible complications of CES include hypertension, bowel ischemia, renal insufficiency, stroke, end-stage renal disease, pancreatitis, cholecystitis, splenic infarction, carotid stenosis, blindness, skin rashes, myocardial ischemia, multiorgan failure, and death.

Deterrence and Patient Education

The treatment of cholesterol embolization syndrome is primarily medical, consisting of risk factor reduction. Patients should be educated about ways to reduce their risk factors. Diet and exercise should be advised to help with blood pressure control. Smoking cessation should be strongly recommended. The importance of medication compliance and regular follow up at the appointments, especially primary care physician and nephrology follow-up, should be stressed. Surgical or endovascular treatment may be indicated if a clear embolic source is identified, and the patient is an appropriate candidate for surgery. In that case, time should be taken to clearly explain to the patient the risk versus benefits of the indicated treatment. The patient should be given an idea about the prognosis, and discussion should be initiated about the code status and advance directives.

Enhancing Healthcare Team Outcomes

An interprofessional team that provides a holistic and integrated approach to care can help achieve the best possible outcomes. The medical teams, including nephrology, cardiology, rheumatology, radiological team; and, general and vascular surgical team must join their experience to make a decision between the hazards of treatment and the risk of CES.[26] A dietician should be consulted to give patients with CES appropriate parenteral nutrition if needed. Pharmacists should be asked to ensure that all medications are appropriately dosed for the patient. Nurses should be notified to watch for any new cutaneous manifestations that appear on the patient's body. The earlier signs and symptoms of a complication are identified, the better the prognosis and outcome. Because patients with CES who have delayed reperfusion end up having greater ischemic damage to the organ.[27] One major complication of CES is an end-stage renal disease, so care should be taken to preserve a site for the possible AV fistula creation in case the patient needs dialysis. Primary care physicians should be contacted and updated about the goals of care, including aggressive risk factor modifications for high-quality continued care to the patient. Palliative care should be consulted, and the family should have a good discussion with the palliative care team to understand options of patient care going forward as many patients have a high mortality burden. [Level 3]