patients who have Hollenhorst plaques are asymptomatic. Thus, additional evaluation may be needed to confirm the diagnosis of acute cholesterol embolization syndrome. (See 'Diagnosis' below.) Other Other vascular beds including coronary, pulmonary, prostate, thyroid, and adrenal glands may rarely be affected with diagnosis often established at autopsy [87]. https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 11/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate DIAGNOSIS A diagnosis of cholesterol crystal embolization should be highly suspected in a patient with known atherosclerotic disease and a classic history: the development of renal failure, abdominal pain or diarrhea, typical skin findings or a finding of Hollenhorst plaques of the retina following arteriography, cardiac catheterization, vascular surgery, or trauma to the abdomen. (See 'Clinical manifestations' above.) Laboratory testing is generally nonspecific and may show elevations in the white blood cell count, decreased red blood cell count, or thrombocytopenia. Inflammation markers including elevated erythrocyte sedimentation rate, C-reactive protein and fibrinogen have been associated with atheroembolism [16]. Other abnormalities may include transient hypocomplementemia and eosinophilia. Because there is an association between occlusive diseases in large peripheral arteries and cholesterol crystal embolization to smaller arteries, patients with extremity embolism should undergo noninvasive vascular testing to identify the presence of hemodynamically significant proximal peripheral artery disease. Even when a stenotic peripheral artery may not be the source of cholesterol crystal embolism, arterial revascularization may improve clinical outcomes. (See 'Revascularization' below.) Specific abnormalities may indicate end-organ dysfunction such as increased creatinine or eosinophiluria if the kidneys are involved [88-91], increased amylase with pancreatic (and possibly bowel) involvement, elevated transaminases with hepatic involvement, or elevated creatine kinase and myoglobinuria with sufficient muscle involvement. Imaging Plaques in the aorta can be visualized, characterized, and quantified by a variety of imaging techniques; however, the index plaque that is the cause of the cholesterol crystal embolization is rarely determined. The diagnosis is more difficult in patients without typical clinical features, particularly if cholesterol crystal embolism has occurred spontaneously. However, the identification of complex aortic plaque or multiple ischemic strokes on imaging studies may permit a presumptive diagnosis to be made [5,29,30]. Plaques can be simple or complex ( image 4). Simple plaques are characterized by wall thickness <4 mm and the absence of mobile components. Complex plaques are 4 mm in thickness and may exhibit irregular borders, ulceration, and mobile components that represent superimposed thrombus. Complex plaques are associated with an increased propensity for embolization. (See 'Plaque characteristics and location' above.) https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 12/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Transesophageal echocardiography, primarily two-dimensional (2D) transesophageal echocardiography (TEE), is the first-line diagnostic modality to identify a thoracic aortic source of atheroembolism. Real-time three-dimensional transesophageal echocardiography (3D-TEE) provides very detailed information on aortic plaque location and morphology ( picture 8 and movie 2). Transthoracic echocardiography, abdominal ultrasound, and endoscopic ultrasound ( image 5) of the upper gastrointestinal tract have occasionally incidentally identified atherosclerotic plaques in the thoracic or abdominal aorta. Compared with TEE, computed tomography (CT) ( image 6 and movie 3) and magnetic resonance imaging (MRI) ( image 7) are less invasive and more complete evaluations of the extent of atherosclerosis in the aorta. CT and MRI have several advantages over TEE [92,93]. These radiologic techniques are better than TEE for imaging aortic branches. In addition, they can image the entire abdominal aorta. In comparison, only the very proximal abdominal aorta between the diaphragm and the ostium of the superior mesenteric artery can be seen with TEE. Conventional arteriography has low sensitivity for detection of plaques and often fails to identify plaques detected by other imaging techniques and should be avoided given the potential disruption of atherosclerotic debris with instrumentation [94]. (See 'Instrumentation' above.) Radiologic studies of the brain may help suggest the diagnosis in demonstrating multiple small ischemic lesions. (See "Neuroimaging of acute stroke".) Biopsy and pathologic findings Biopsy is the only definitive means of confirming the diagnosis of cholesterol embolization syndrome. Thus, biopsy should be performed whenever the diagnosis is in doubt and when the specimen can safely be obtained from the patient. Histopathologic examination of amputated body parts or embolectomy specimens for cholesterol emboli pose no additional risk to the patient and should be performed if the diagnosis is suspected. Skin and skeletal biopsies are less invasive than renal and gastrointestinal biopsies. The histologic hallmark of cholesterol crystal embolism is the presence of "ghosts" of cholesterol crystals or cholesterol clefts within arterioles, since the cholesterol crystals are dissolved during tissue fixation ( picture 6A-B). The cholesterol clefts are crescentic (with pointed ends) or elongated ovoid spaces present in small or medium-sized arteries or arterioles. Inflammatory or fibrous intimal proliferation develops rapidly and may be the cause for vascular occlusion and resultant ischemic tissue damage [95]. Cholesterol clefts have also been demonstrated in the pulmonary arteries of patients with cholesterol crystal embolism. Since pulmonary arterial atherosclerosis is rare (eg, in end-stage Eisenmenger syndrome), the crystals presumably pass through the systemic capillary bed into https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 13/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate the venous system and lungs. In a case report, cholesterol crystal emboli were seen in 25 percent of the small pulmonary arteries in a patient with atheroembolic disease [96]. Differential diagnosis The diagnosis is often difficult to establish when the presenting symptoms and signs of cholesterol crystal embolism are subtle and nonspecific. Cholesterol crystal embolism needs to be distinguished from thromboembolism given differences in treatment. (See "Thromboembolism from aortic plaque", section on 'Clinical manifestations'.) Because of its many differing effects, cholesterol crystal embolism may be included as one of the "great imitators," (such as tuberculosis, brucellosis) given its often nonspecific symptoms, leading it to be confused with a number of other diseases, including vascular diseases such aortic dissection, and tumors such as left atrial myxoma, lymphoma, and renal cell carcinoma [55]. The differential diagnosis includes many systemic illnesses, including cyanotic congenital heart disease, secondary syphilis, and pheochromocytoma [72]. There is also an extensive differential diagnosis of livedo reticularis that includes Raynaud's phenomenon, vasculitis (polyarteritis nodosa, systemic lupus, dermatomyositis, leukocytoclastic angiitis, rheumatoid vasculitis, thromboangiitis obliterans), infection (syphilis or tuberculosis), cryoglobulinemia, antiphospholipid syndrome, and polycythemia vera. A familial form called Sneddon's syndrome is seen in association with cerebrovascular disease. There is also an extensive differential diagnosis for retiform purpura. (See "Approach to the patient with retiform (angulated) purpura".) Among patients who develop acute kidney injury, particularly if the sediment is relatively bland, the differential renal diagnosis includes contrast nephropathy and acute kidney injury, both of which are typically reversible. (See "Clinical presentation, evaluation, and treatment of renal atheroemboli".) TREATMENT Treatment for cholesterol embolization comprises managing cardiovascular risk factors, management of end-organ ischemia, and prevention of recurrent embolization. Cardiovascular risk factor management Patients with cholesterol crystal embolism should be aggressively treated for secondary prevention of cardiovascular disease [97]. These modalities include aspirin, statins, blood pressure control, cessation of smoking, and, in patients with diabetes, glycemic control. (See 'Lipid-lowering therapy' below and "Prevention of https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 14/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".) Managing ischemic manifestations The management of the microvascular obstruction leading to end-organ ischemia varies depending upon the vascular bed affected but is primarily supportive with measures to control pain and lessen inflammation. The inflammatory reaction that results from cholesterol crystal embolization is essentially a foreign body reaction to the cholesterol crystals that are resistant to breakdown by macrophages. Arterioles that are not immediately occluded may occlude as a chronic inflammatory infiltrate fills the lumen. Given this pathologic mechanism, various anti- inflammatory and antithrombotic agents have been used to lessen the inflammatory reaction and to prevent thrombosis. There are no large trials evaluating anti-inflammatory therapies for treating cholesterol crystal embolism. Isolated reports in small numbers of patients using steroids [98-103], iloprost [104,105], and LDL apheresis [106-108] have shown modest success. The inflammatory nature of cholesterol crystal embolism results in pain that is often out of proportion to the apparent degree of tissue ischemia, and pain management is of critical importance. (See "Pain control in the critically ill adult patient" and "Approach to the management of chronic non-cancer pain in adults".) For patients with significant muscle inflammation, aggressive saline hydration is important to reduce the risk of acute kidney injury associated with myoglobinuria. Other treatments may include bicarbonate or mannitol. The prevention and treatment of heme-pigment-induced acute kidney injury is discussed in detail elsewhere. (See "Prevention and treatment of heme pigment- induced acute kidney injury (including rhabdomyolysis)".) Preventing recurrent embolization The optimal treatment to prevent recurrent cholesterol crystal embolization is not clear. Secondary prevention seems warranted, particularly since aortic plaques 4 mm in size appear to be associated with an increased risk of recurrent stroke [6,109,110]. In patients whose cholesterol embolization syndrome was precipitated by instrumentation (such as arteriography, cardiac catheterization, or vascular surgery), any further invasive imaging or treatment should be avoided unless absolutely necessary. Noninvasive ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) should replace the invasive techniques whenever possible. When arterial cannulation is absolutely necessary, alternative access routes should be considered (eg, cardiac catheterization via radial artery approach in a patient with extensive plaques in the descending thoracic aorta). https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 15/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Lipid-lowering therapy Statin therapy may decrease the risk of future embolization. Statins lower LDL cholesterol and have a variety of other effects, one of which appears to be plaque stabilization. In a retrospective study of 519 patients with severe thoracic aortic plaque cited, statin therapy was associated with a significantly lower rate of recurrent stroke and thromboembolization [13]. However, the number of patients with atheroembolization was too small (five) for subset analysis. On multivariate analysis, the protective effect seen with statin therapy was not present for patients taking warfarin or antiplatelet agents. Specific lipid- lowering therapy regimens may affect atherosclerotic plaque in the thoracic versus the abdominal aorta differently [111]. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Dyslipidemia' and "Thromboembolism from aortic plaque", section on 'Statin therapy'.) Antithrombotic therapy Anticoagulant therapy for the treatment of cholesterol crystal embolism remains controversial [112]. Although it seems intuitive that anticoagulation would improve arterial patency, the obstruction is mostly due to the atheroembolic debris and the inflammatory reaction it incites, and not thrombus. Another important consideration is the association between anticoagulant and antithrombotic therapy and the development of cholesterol crystal embolism; however, due to paucity of data, a causal relationship between cholesterol crystal embolism and anticoagulation and/or thrombolytic therapy can be neither proven nor refuted with certainty. (See 'Anticoagulation/thrombolytic therapy' above.) There are no randomized trials that have evaluated the role of antithrombotic therapy in patients with aortic atheroma [109,113]. Nonrandomized retrospective studies have shown a benefit of oral anticoagulation over aspirin in patients with mobile thrombi in the aortic arch. Based on this low-quality evidence, the 2012 American College of Chest Physicians (ACCP) guidelines panel suggested oral anticoagulation or antiplatelet agents for patients with cryptogenic stroke and mobile aortic arch thrombi [113]. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Treatment'.) However, the 2012 ACCP guidelines stated that the hemorrhagic complications may outweigh the benefits of anticoagulation [113]. Other studies have not shown a benefit to anticoagulation. In a retrospective review of 519 patients with complex plaque, cholesterol crystal embolism occurred in only 5 (1 percent) during a follow-up of more than three years [13]. The risk was similar in the patients treated (2 of 206) and not treated with warfarin (3 of 313). This rate is similar to that noted in the Stroke Prevention in Atrial Fibrillation (SPAF-III) trial (1 of 134 warfarin-treated patients), most of whom had severe atherosclerotic plaques on transesophageal echocardiography [52,53]. https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 16/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate In our practice, we do not routinely use anticoagulants in patients who are diagnosed with cholesterol crystal embolism unless they have other indications for anticoagulation (such as atrial fibrillation or mechanical prosthetic valve). Definitive recommendations regarding the use of anticoagulant in this context should await the results of an ongoing randomized trial comparing oral anticoagulant with antiplatelet therapy in patients with thoracic aortic plaque. It is important to emphasize that the package insert for warfarin explicitly states that warfarin therapy may increase the risk of cholesterol crystal embolism and that discontinuation of warfarin is recommended when cholesterol crystal embolism is observed [114]. Plaque removal or exclusion Given the poor outcomes associated with cholesterol crystal embolism, surgical plaque removal (endarterectomy) or exclusion of the plaque (ligation and bypass, endovascular exclusion) may be indicated if a clear embolic source is identified, the source is surgically accessible, and the patient is an appropriate candidate for surgery. Patients with lower extremity symptoms and an infrarenal source for embolism may have more favorable outcomes [115]. In a prospective study of 100 patients who underwent surgery over a 12 year period following identification of the embolic source, occlusive aortoiliac disease (47 patients) and small aortic aneurysms (20 patients) were the most commonly identified embolic sources [116]. The most common surgical treatment was aortic bypass. Other procedures included aortoiliac endarterectomy with patching, femoral or popliteal endarterectomy, and infrainguinal or upper extremity bypass. (See "Management of chronic limb-threatening ischemia" and "Overview of upper extremity peripheral artery disease" and "Lower extremity surgical bypass techniques".) In this study, the reported outcomes were: Postoperative mortality 11 percent (all had a suprarenal aortic thrombus preoperatively) Survival rates at one, three, and five years 89, 83, and 73 percent, respectively Toe and leg amputations 9 and 10 percent, respectively Hemodialysis 10 percent Recurrent emboli 5 percent within eight months of surgery with no further emboli over the next three years In another surgical series of 62 patients who underwent surgery at one institution, bypass grafts were inserted in 42 patients after exclusion of the native diseased artery, 20 had endarterectomies (6 of them with bypass grafts), and 5 were treated medically [24]. The 30 day https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 17/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate mortality rate was 5 percent. "Minor" amputation was required in 19 patients (31 percent), and leg amputation in 2 patients. Limb salvage was possible in 86 of 88 limbs. There were no postoperative embolic incidents in the involved limbs during a mean follow-up of 20 months. Covered stents More recently, covered stents and endografts have been used to exclude the involved arterial segment in a small number of patients with aortic or iliac artery sources of cholesterol crystal embolism [27,117]. The disadvantage of this technique compared with open surgery is a greater risk for recurrent embolization related to the intraluminal manipulation of guidewires [17]. Definitive recommendations for the use of covered stents are not possible at this time. Revascularization For patients with lower extremity cholesterol embolism and a hemodynamically significant proximal stenosis (that may or may not be the source of embolism), arterial revascularization can restore normal pressures, improve distal perfusion, and may improve pain. (See 'Managing ischemic manifestations' above.) Surgical (eg, bypass) or endovascular (eg, stent) management may be appropriate depending on the location of the obstruction. Percutaneous angioplasty and stenting, mostly of the iliac and femoral arteries, have been performed in a small number of patients without causing recurrent embolization [116,118]. The decision on whether to perform revascularization in patients with cholesterol embolization syndrome should also take into account the severity and duration of ischemic symptoms. (See "Approach to revascularization for claudication due to peripheral artery disease".) PROGNOSIS The prognosis in medically treated patients with cholesterol crystal emboli is poor, in part because of severe underlying atherosclerosis [119]. Acute, in-hospital mortality was 16 percent (4 of 25) in one series [16], but mortality rates may be as high as 80 percent when cases that are diagnosed post-mortem are included [12]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute extremity ischemia".) https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 18/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate SUMMARY AND RECOMMENDATIONS Atheroembolism, also known as cholesterol crystal embolism or cholesterol embolism, refers to arterio-arterial embolism of cholesterol crystals or small pieces of atheromatous material originating from an atherosclerotic plaque usually from the aorta but occasionally from other arteries. Cholesterol crystal embolism results in partial or total occlusion of small arteries, leading to tissue or organ ischemia. (See 'Introduction' above.) Risk factors for atheroembolism include patient factors such as hypertension, advancing age, smoking, hypercholesterolemia, obesity, and diabetes. Anatomic factors associated with the aortic atherosclerotic plaque, such as plaque thickness 4 mm, plaque ulceration, or the presence of mobile debris, increase the risk for embolization. (See 'Epidemiology and risk factors' above.) The clinical diagnosis of cholesterol crystal embolism should be suspected in patients with known atherosclerotic disease and the development of renal failure; transient ischemic attack; cerebral infarction; signs of intestinal ischemia; digital ischemia; typical skin findings or Hollenhorst plaques in the retina, particularly following arteriography; cardiac catheterization; vascular surgery; or trauma to the abdomen. The diagnosis is more difficult in patients who do not have these features, particularly if cholesterol crystal embolism has occurred spontaneously. (See 'Clinical manifestations' above.) The presence of complex aortic plaque on imaging studies supports the diagnosis. Atherosclerotic plaques can also be seen using transthoracic echocardiography, abdominal ultrasound, and endoscopic ultrasound of the upper gastrointestinal tract. (See 'Imaging' above.) Laboratory testing is generally nonspecific but may indicate the effects of end-organ ischemia. A definitive diagnosis depends upon pathologic specimens. Biopsy should be performed whenever the diagnosis is in doubt and when the specimen can safely be obtained from the patient; debrided or amputated tissue and thrombectomy specimens should be sent for pathologic examination since these represent no risk to the patient. The histologic hallmark of cholesterol crystal embolism is the presence of "ghosts" of cholesterol crystals or cholesterol clefts within arterioles. (See 'Biopsy and pathologic findings' above.) The treatment of cholesterol crystal embolism is primarily medical, consisting of risk factor reduction. Statin therapy is indicated as part of risk factor reduction and appears to reduce the rate of recurrent embolism. (See 'Lipid-lowering therapy' above.) https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 19/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Surgical or endovascular treatment may be indicated if a clear embolic source is identified, the source is anatomically suitable, and the patient is an appropriate candidate for surgery. For patients who meet these criteria, we suggest surgical or endovascular treatment to remove or exclude the embolic source (Grade 2C). (See 'Treatment' above.) We suggest not routinely anticoagulating patients who are diagnosed with cholesterol crystal embolism (Grade 2C). 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