Atheroembolic disease, Atheromatous Embolic Disease; Cholesterol Crystal Embolism; Micro-Embolic Atherosclerotic Disease; Cholesterol Embolism; Blue Toe Syndrome; Purple Toe Syndrome; Multiple Cholesterol Emboli Syndrome; Pseudovasculitic Syndrome

1. Description of the problem

Atheroembolic disease is a grouping of different end organ effects leading from one common etiology – the dislodging of arterial cholesterol plaque with distal embolization causing ischemia or infarction of the end organ involved.

Atheromatous embolization is a complication of advanced atherosclerotic disease that can have effects ranging from no significant clinical effect to significant morbidity and mortality. It occurs when pieces of cholesterol plaques, sometimes here called cholesterol crystals, break off and travel distally, lodging in a smaller artery, and causing its damage.

Acute atheromatous embolization

Of the risk factors listed below, the most common form that would be of interest to someone in a critical care setting is an acute atheromatous embolization that follows an interventional radiology procedure, cardiac catheterization, vascular surgery or stent deployment, or cardiac surgical procedure. Following such a procedure, if a patient develops acutely worsening renal function, hypertension, distal ischemia or acute multisystem organ dysfunction, the clinician needs to have an acute atheromatous embolization in the differential diagnosis.

A patient who is over 60 years old and presents with unexplained multisystem organ failure (meaning failure of more than one organ, not a more involved multisystem organ dysfunction syndrome from sepsis, for example) and a history in the recent past (last few months) of an interventional radiological procedure, cardiac catheterization, vascular surgical procedure or stent, cardiac surgery or anticoagulation should have this considered in the differential diagnosis.

The triad of livedo reticularis (a mottled reticulated vascular pattern on the skin that appears as a lace-like purplish discoloration on the lower extremities) plus acute renal failure and eosinophilia should be evaluated for cholesterol embolism with an evaluation including funduscopic examination.

Key management points

• Preventive care

• Supportive care

• Unproven therapies

2. Emergency Management

There is no treatment or cure for the entity itself, as most are unproven. Management consists purely of:

• Early recognition of risk factors – for example, ultrasound evaluation of arteries prior to manipulation of a cross-clamp – may reduce the changes of atheromatous embolization.

• Rapid discontinuation of anticoagulation and avoidance of further arterial procedures once the diagnosis has been entertained

• Observation for signs of embolization to other areas such as intestine, brain, etc.

• Aggressive supportive care.

3. Diagnosis

Making the diagnosis is easy when there is a fulminant organ failure and the presence of livedo reticularis within days of an interventional procedure involving the arteries (Figure 1 and Figure 2). It is more difficult when the sub-acute form of the disease manifests.

Figure 1.

Figure 2.

Differential diagnosis

Because the acute phase occurs in patients most often undergoing interventional radiological procedures and most have received iodinated contrast dye and the involvement is often renal, radiocontrast nephropathy is the most common entity that appears in the differential diagnosis of these patients.

Also, since major arterial surgical and cardiac surgical operations may be involved, acute tubular necrosis from hypoperfusion of the kidneys is also often in the differential diagnosis. Lower down on the list for renal complications would be hyptertensive renal disease and arteriosclerotic renal disease.

The skin findings and eosinophilia could be interpreted to represent some sort of an inflammatory vasculitis – in one study, atheromatous embolization was misdiagnosed as vasculitis 16% of the time and periarteritis nodosa 12% of the time.

Other entities in the differential diagnosis may be such things as bacterial endocarditis, non-bacterial thrombotic cardiac emboli, antiphospholipid syndrome, heparin-induced thrombocytopenia and thrombosis (HITT), atrial myxomata, or various malignancies and benign tumors. For many of these possibilities, an echocardiogram, starting with a trans-thoracic echocardiogram (TTE) and then progressing to a trans-esophageal echo (TEE) if the TTE is negative, will be part of the evaluation.

Diagnostic testing

Examination of the lower extremities for livedo reticularis and funduscopic examination looking for retinal crystals is non-invasive and easy to do.

Biopsies of the skin of the lower extremities (looking for cholesterol crystals) can make the diagnosis the majority of the time – according to one study, it can be used for definitive diagnosis 92% of the time, with false negatives occurring when the biopsy does not include the dermal vessels.

Muscle biopsies of the thigh or calf would be the next choice to make a definitive diagnosis. If those are negative and the diagnosis still must be confirmed, biopsies of the gastric or colonic mucosa would be the next locations to look.

If all those fail – which can happen rarely – a renal biopsy is the last option.

4. Specific Treatment

The mainstay of therapy is supportive care and avoidance of further interventional procedures. Avoidance of anticoagulant therapy must be weighed in a risk-benefit analysis, as the reasons for the anticoagulation may be more than the benefit gained from stopping the therapy.

There is no proven drug therapy, but the prostacyclin analog iloprost has been tried in a small study with some minor success, and statins, which stabilize plaque, have been tried in another small study. Corticosteroids have also been given to patients with signs of active inflammatory disease with some evidence of benefit.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

Overall prognosis is difficult to ascertain because it can be difficult to separate the morbidity and mortality of the atheromatous embolization from the underlying disease process that either caused the embolization or required the therapeutic intervention that caused the embolization. Quoted survival rates have generally improved, thought secondary to improved supportive care.

Incorrect diagnosis

The supportive care would not change in the setting of an incorrect diagnosis; the only difference would be that there would not have been the need to avoid anticoagulation or interventional procedures.

Follow-up

The patient should receive the usual follow-up care for the organ system that is involved, and will need constant re-assessing of risk-benefit if anticoagulation was involved and has either been stopped or temporarily withheld.

Pathophysiology

The emboli seem to originate most often in the abdominal aorta, although those that occur after cardiac surgical procedures most often come from the aortic arch and proximal thoracic aorta.

It is clear that the damage is not caused solely by a pure physical obstruction; there is a secondary inflammation that occurs when the crystals lodge in the new area, worsening the obstruction and ischemic effect. The inflammatory reaction causes secondary white cell accumulation, which then leads to thrombus formation, endothelial cell proliferation, and intimal fibrosis. Thus, the effect can be one of immediate ischemia or infarct, or a more gradual one over the course of days, weeks or even months as repeated events cause larger areas of ischemia and infarct to manifest themselves clinically.

The size of the original embolism, the size of the artery it lodges in, the presence or absence of collateral circulation to the affected area, and the intensity of the post-lodging inflammatory response and subsequent thrombosis all contribute to the severity and clinical presentation of the embolic event.

The dislodgement and subsequent dislodgement of the crystals can occur spontaneously, or as a result of therapeutic interventions such as aortic cannulation, interventional radiological or cardiac procedures, and surgical procedures involving the large vessels. The cholesterol emboli that occur spontaneously are generally smaller and cause less of an acute, catastrophic damage and more of a chronic one, whereas the ones that occur after interventional arterial procedures are more acute, sudden and serious.

In autopsy studies, the emboli are found most often in the kidneys, spleen, pancreas, gastrointestinal tract, adrenal glands and urogenital tract. In series where biopsies are looked at, however, they appear more often in muscle, skin and kidney specimens, which may reflect the frequency with which these tissues are biopsied more than any incidence of embolism.

Of all the etiologies the link between anticoagulation and atherosclerotic embolism is the least proven. The proposed mechanism is that anticoagulation prevents formation of a protective thrombin coating to the plaque, making it more likely to embolize. This is found in both older literature regarding warfarin therapy and more recent literature dealing with both unfractionated heparin and low-molecular-weight heparins. Still others feel that anticoagulation, rather than being detrimental, has a beneficial action.

Epidemiology

While atheromatous embolization was first described over 150 years ago and was described in detail in the middle of the 20th century, it remains underdiagnosed, unrecognized and poorly understood.

Its incidence is difficult to estimate since clinical manifestations may be almost non-existent or easy to miss, or misdiagnosed as something else entirely.

Depending on the autopsy series, the incidence can be <4% in all autopsies to as high as >70% in patients who have had abdominal aortic aneurysm resection.

The incidence after cardiac catheterization has ranged in reports from 0.5% to just under 2%.

The incidence after cardiac surgery is not as well documented, but it seems from the autopsy reports that there is at least more mention of more serious, sudden, catastrophic emboli than with other procedures, such as to the brain and GI tract.

Risk factors

Of course, the main risk factor for atheromatous embolization is the presence of atherosclerotic disease in the first place. The more severe the atherosclerosis, the higher the chance of an embolic event. Among these patients there are sub-conditions that increase the risk further:

1. Age >60

2. Patients with:

• coronary artery disease

• peripheral arterial occlusive disease

• abdominal aortic aneurysms

• mobile or non-mobile protruding atheromas of the aorta or increased aortic plaque thickness

• elevated C-reactive protein

3. Patients with the following precipitating conditions:

• angiographic or interventional procedures

• vascular surgical procedures (esp. abdominal aortic aneurysm repair)

• cardiac surgical procedures

• anticoagulation

• thrombolytic therapy

• trauma

Prognosis

Prognosis from the atheromatous embolization is difficult to separate from the underlying conditions that the patient also has. Older reports showed mortality rates of 64-87%, but they most likely represent selection bias of more severely ill patients.

More recent studies show a 1-year survival that ranges from 69% to 87%; this is most likely due to improvements in supportive care but there may also be some effect from the use of corticosteroids in patients who showed signs of inflammatory disease.

As would be expected, patients with purely cutaneous manifestations of atheromatous embolization have a better prognosis than those with visceral involvement in the GI tract or kidneys.

Special considerations for nursing and allied health professionals.

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What's the evidence?

Panum, PL. “Experimentelle Beitrage Zur Lehre Von der Embolie”. Arch Pathol Anat Physiol Klin Med. vol. 25. 1862. pp. 308-10. (Initial description of atherosclerotic embolism.)

Flory, C. “Arterial occlusions produced by emboli from eroded aortic atheromatous plaques”. Am J Pathol. vol. 21. 1945. pp. 549-65. (Modern description of the condition.)

Fine, MJ, Kapoor, W, Falanga, V. “Cholesterol crystal embolization: a review of 221 cases in the English literature”. Angiology. vol. 38. 1987. pp. 769-84. (Large case review with more recent data.)

Thadhani, RI, Camargo, CA, Xavier, RJ, Fang, LS, Bazari, H. “Atheroembolic renal failure after invasive procedures. Natural history based on 52 histologically proven cases”. Medicine (Baltimore). vol. 74. 1995. pp. 350-8. (Focusing purely on renal failure.)

Liew, YP, Bartholomew, JR. “Atheromatous embolization”. Vasc Med. vol. 10. 2005. pp. 309-26. (One of two excellent general review articles on the subject.)

Meyrier, A. “Cholesterol crystal embolism: Diagnosis and treatment”. Kidney International. vol. 69. 2006. pp. 1308-12. (Second, shorter review focusing on diagnosis and therapies.)

Belenfant, X, Meyrier, A, Jacquot, C. “Supportive treatment improves survival in multivisceral cholesterol crystal embolism”. Am J Kidney Dis. vol. 33. 1999. pp. 840-50. (Relatively large series of 67 patients with acute renal failure and atherosclerotic embolism treated with aggressive supportive care with impressive results.)

Elinav, E, Chajek-Shaul, T, Stern, M. “Improvement in cholesterol emboli syndrome after iloprost therapy”. BMJ. vol. 324. 2002. pp. 268-9. (Four patients treated with iloprost with some clinical effect – a jumping-off point for future studies in the area and an indication of the inflammatory component.)

Falanga, V, Fine, MJ, Kapoor, WN. “The cutaneous manifestations of cholesterol crystal embolization”. Arch Dermatol. vol. 122. 1986. pp. 1194-8. (Summary of the dermatological manifestations and the skin tissue biopsy results.)

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