Hospital Medicine

Cholesterol embolization syndrome (atheroembolism, "blue toe syndrome")

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Cholesterol embolization syndrome (atheroembolism, "blue toe syndrome").

I. What every physician needs to know.

Cholesterol embolization syndrome (CES), also known as atheroembolism, or "blue toe syndrome" from its most peripheral manifestation, refers to the release of cholesterol crystals from ruptured atherosclerotic plaque in a large artery resulting in embolization to more distal small and medium sized arteries.

The hallmark pattern is microvascular ischemia in the presence of normal blood pressure and adequate flow in the larger arteries. The ischemia in the territory of the downstream vessels is due to arterial occlusion and to the inflammatory response incited by the cholesterol crystals.

Rarely, CES may occur spontaneously in patients with severe atherosclerotic disease, but more often develops as a complication of angiographic or vascular surgical procedures. Some cases are also perceived to be precipitated by initiation of antithrombotic therapy, a controversy discussed further below.

CES is distinct from the more common arterioarterial thromboembolism, in which the embolic material consists of thrombus associated with ulcerated plaque rather than cholesterol crystals themselves, involving larger vessels and more often producing frank infarction of the target organ.

II. Diagnostic Confirmation: Are you sure your patient has cholesterol embolization syndrome?

CES should be considered when manifestations of microvascular ischemia develop in a patient with atherosclerosis, particularly in the aftermath of a recent cardiovascular surgical or angiographic procedure. In cases following a procedure, the development of manifestations downstream from the anatomic site of the intervention is an important clue to the diagnosis.

A. History Part I: Pattern Recognition.

CES may affect any organ or the lower extremities, depending upon the location of plaque rupture. Due to their predisposition to more severe atherosclerosis, the abdominal aorta and iliofemoral arteries are the most frequent sources of emboli. Organs most commonly affected include the skin, kidneys, gastrointestinal tract, and brain.

The clinical spectrum ranges from asymptomatic or incidental findings to a fulminant presentation with multiorgan ischemia and failure. Protean constitutional symptoms including fever (15-20% of patients) and anorexia may mimic infectious or primary inflammatory conditions.

The common full-blown presentation is that of an older male with a recent vascular procedure presenting with the constellation of acute kidney injury, livedo reticularis, abdominal pain, one or more ischemic toes, and perhaps low-grade systemic inflammatory symptoms.

The classic triad of antecedent vascular procedure, acute kidney injury and livedo reticularis is considered sufficient for clinical diagnosis. Organ specific manifestations are discussed further below.

Cutaneous manifestations

These are present in a large proportion of patients with CES, ranging from 35-96% in various series. There is a strong concordance between skin and renal involvement. Small vessel ischemia produces livedo reticularis, a reticular or lacy purplish discoloration that is the hallmark physical finding in CES. It is most often found in the lower extremities but may appear on the lower abdomen or flanks. This finding is not specific to CES, as it is also seen with vasculitis or cutaneous hypoperfusion of any cause, but is highly suggestive of CES in the appropriate context.

Less often, cutaneous ischemia may progress to produce local ulceration and necrosis. In the toes, a terminal location without collateral perfusion, more intense microvascular ischemia may appear as the "blue toe syndrome" which can progress to frank gangrene. Painful muscle ischemia may also affect the lower extremities.

Renal involvement

This is estimated to occur in 50% of cases of CES. Manifestations may include acute, subacute or chronic kidney injury and accelerated hypertension. Onset of iatrogenic CES occurs within 1 week following the inciting event and typically progresses stepwise over several weeks due to recurrent cycles of embolization and inflammatory response.

A chronic form of renal involvement in spontaneous CES may lead to gradually progressive renal failure that is difficult to distinguish from hypertensive or renovascular disease often present in the same population. Prognosis in renal CES depends upon baseline renal function and the severity of the insult. Renal function may normalize or stabilize, however dialysis requirements range from roughly 30-60% in various series and a sizable minority progress to end stage renal disease.

Gastrointestinal manifestations

These occur in roughly 20% of cases of CES, due to microvascular ischemia of the mucosa. Lesions have been reported from the esophagus to the anus, but the colon and small intestine account for most cases. Typical symptoms include abdominal pain, diarrhea and bleeding. A fulminant presentation may include frank intestinal infarction or perforation.

In those with more chronic disease, occult bleeding may persist indefinitely, requiring transfusion support. Mucosal injury may have long-term sequelae including malabsorption and chronic diarrhea. Rarely, acalculous cholecystitis and ischemic pancreatitis have been attributed to CES

Central nervous system involvement

This may follow plaque rupture in the ascending aorta or carotid arteries, usually during cardiac or carotid surgical procedures, which may send showers of cholesterol crystals and other microemboli to the brain. Despite large volumes of such emboli detected by transcranial Doppler studies of patients undergoing these procedures, only a small minority develop neurologic symptoms.

The use of filtering devices reduces the occurrence with carotid stenting. Due to the numbers of emboli and the small size of the target vessels, neurologic symptoms when present are typically diffuse, e.g. confusion, rather than focal. A notable exception is amaurosis fugax, the prototype of spontaneous CES, in which retinal artery occlusion produces sudden monocular vision loss. Spinal cord infarction has been rarely reported as well.

B. History Part 2: Risk Factors and Prevalence.

Atherosclerosis is the sine qua non of CES, thus older males are most affected. Autopsy series have estimated the prevalence of spontaneous atheroembolism as approximately 1-3% in the presence of aortic atherosclerotic disease. In a prospective study of patients with aortic plaque identified on transesophageal echocardiography, the incidence of clinically apparent spontaneous CES was 1% over 3 years of follow-up.

Beyond the presence of atherosclerosis, the main risk factor for CES is surgical or radiologic vascular intervention. Estimates of the incidence of clinically evident CES complicating various procedures range up to 1.9% for cardiac catheterization and roughly 3% for abdominal aortography and lower extremity vascular surgery. The risk appears to be higher with angiographic procedures, which account for 80% of cases, than with open vascular surgery.

As expected, risk appears to increase with severity of atherosclerosis and its risk factors, including diabetes, hypertension, hyperlipidemia, and smoking. Elevated C-reactive protein (CRP) is associated with increased risk, perhaps as a marker of plaque instability. Autopsy series have found rates as high as 20-30% after aortic and coronary artery bypass surgery, suggesting that some degree of atheroembolism occurs frequently but is usually clinically silent.

Based upon numerous case reports, anticoagulant and thrombolytic therapy have traditionally been associated with CES, hypothetically through destabilization of intra-plaque hemorrhage, or dissolution of capping thrombus. Although still cited as an important risk factor in some current reviews, available prospective data do not confirm an increased incidence of CES in anticoagulated patients, much less a causal relationship between antithrombotic therapy and CES.

C. History Part 3: Competing diagnoses that can mimic cholesterol embolization syndrome.

The differential diagnosis of CES includes other conditions producing the combination of multiorgan microvascular ischemia and systemic inflammatory symptoms.

These include the small- to medium-vessel vasculitides (polyarteritis nodosa), antiphospholipid syndrome, endocarditis, drug rash with eosinophilia and systemic symptoms (DRESS), thrombotic thrombocytopenic purpura (TTP) or disseminated intravascular coagulation (DIC) (easily distinguished by their characteristic hematologic findings), and rarely, left atrial myxoma. The major differential diagnosis of individual organ manifestations follows.

The most frequent differential diagnosis in this condition is that between kidney injury due to CES and radiocontrast nephropathy (RCN). They are most easily distinguished by their natural histories. The onset of RCN is detected within 24 hours after the inciting procedure, peaks within several days and subsequently resolves, usually without sequelae. Systemic inflammatory symptoms and involvement of other organs are absent. In contrast, renal and other manifestations of CES typically begin only after several days following the procedure. Renal injury, the only feature that is easily quantified, typically progresses subacutely and commonly comes to clinical attention only several weeks later.

Systemic inflammatory symptoms and involvement of other organs are absent. In contrast, perhaps reflecting the important role of the inflammatory response in pathogenesis, renal and other manifestations of CES typically begin only after several days following the procedure. Renal injury, the only feature that is easily quantified, typically progresses subacutely and commonly comes to clinical attention only several weeks later.

Allergic interstitial nephritis (AIN) may share several features with CES, including acute kidney injury, fever and eosinophilia. Distinction may be difficult if the patient has been exposed to both a new medication and a vascular intervention.

Livedo reticularis, although a classic finding in CES, is a non-specific sign of cutaneous ischemia that may be seen in other disorders of the small arteries (vasculitides) and in shock of any etiology. The vasculitides favor a quite different demographic group, and in CES, systemic perfusion is maintained. Superimposed shock, e.g. from sepsis due to intestinal ischemia, would of course obscure the diagnosis of CES, but at the same time render it essentially irrelevant.

Gastrointestinal symptoms overlap broadly with those of infectious and inflammatory bowel disease, so the diagnosis of less acute or spontaneous CES may be easily overlooked. A history of vascular procedures or presence of other manifestations of CES may help with identification. The same clues help distinguish an acute presentation of CES from intestinal ischemia due to arterial thrombosis or embolism.

Careful assessment of lower extremity perfusion is critical to distinguish microvascular ischemia ("blue toe syndrome") from limb-threatening arterial thrombosis. The diagnosis of CES is relatively clear when frank ischemic changes are bilateral and limited to the toes with intact pedal pulses, and livedo reticularis is present, however the underlying vascular disease common to patients at risk for CES may result in pre-existing diminished or absent pulses.

Acute unilateral lower extremity ischemia, manifesting with the classic triad of pain, pallor and pulselessness, indicates arterial thrombosis, a limb-threatening surgical emergency that must not be overlooked.

D. Physical Examination Findings.

Physical findings indicative of CES are limited to the skin, toes and ocular fundi.

Characteristic microvascular, ischemic skin findings are present in most cases of CES. The most frequent is livedo reticularis, a diffuse lacy bluish or purplish discoloration found nearly always in the lower extremities, but occasionally on the abdomen or flanks. Digital ischemia produces the eponymous blue toes, which may become ulcerated or gangrenous.

The presence of normal or elevated blood pressure and intact peripheral pulses help distinguish the cutaneous ischemiaof CES from that of systemic hypoperfusion due to shock, or regional ischemia due to arterial thromboembolism. Although all of these skin findings may occur with microvascular ischemia of any etiology, in the context of a recent vascular procedure and in combination with acute kidney injury they are considered diagnostic of CES.

With central nervous system involvement, particularly amaurosis fugax,funduscopic examination may reveal cholesterol crystals lodged at bifurcations of the retinal arterioles, a lesion named after its first describer as a Hollenhorst plaque, which is pathognomonic of CES.

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The only confirmatory test for CES is biopsy of affected tissue. Skin biopsy of involved areas is easily performed and highly sensitive, but rarely necessary if CES is recognized clinically.

Hypereosinophilia is characteristic in CES, present early in the clinical course in up to 80% of cases with renal involvement, but not specific as it may also occur in RCN, AIN and DRESS. Elevated inflammatory markers (erythrocyte sedimentation rate (ESR) and CRP) and depressed complement levels have been reported in CES, but none sufficiently consistent or specific to aid in diagnosis or guide therapy.

Kidney injury, marked by increased blood urea nitrogen (BUN) and creatinine, is a salient feature of CES, but as noted above is not by itself diagnostic. Urinalysis is unremarkable. Proteinuria may occur but is usually mild if present and urine sediment is usually bland, in contrast with the findings in vasculitis.

Intestinal involvement may produce a spectrum of non-specific laboratory findings, from anemia due to occult bleeding, to lactic acidosis in the presence of frank bowel ischemia. Involvement of other viscera, such as the liver or pancreas, may produce non-specific elevations of their respective enzymes.

Blood cultures are important in the presence of fever or other constitutional symptoms to exclude infectious endocarditis, which can mimic CES.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

No imaging studies are diagnostic of CES. If regional rather than microvascular ischemia suggests arterial thrombosis, prompt angiography and intervention may be limb-saving. When intestinal ischemia or perforation is suspected, abdominal radiography may aid in confirmation, and the associated finding of patent larger arteries may heighten the suspicion of CES as the etiology.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

NA

III. Default Management.

A. Immediate management.

There is no specific therapy definitely known to alter the course of CES. Treatment is mainly supportive for each identified complication: meticulous wound care for ulcerating skin lesions, avoidance of other renal insults, with renal replacement therapy if needed and timely surgical consultation if intestinal ischemia or perforation is suspected.

Observational data strongly suggest that statin therapy, perhaps by virtue of atherosclerotic plaque stabilization, is protective against progressive renal failure from CES, and should be instituted in patients not already receiving it. Benefit of corticosteroid therapy is supported by several case reports in patients with a progressive course and prominent inflammatory symptoms but clinical trials have shown no consistent improvement in outcomes.

Because the pathophysiology does not involve thrombosis, antiplatelet and antithrombotic therapies have no direct role in therapy. Controversy surrounds the decision whether to continue established antithrombotic therapy in patients who develop CES. Some experts recommend cessation, however in the absence of evidence for a causal relationship between anticoagulation and CES, the individual's thromboembolic risk must be weighed against the hypothetical benefit of stopping therapy for patients with valid indications for anticoagulation.

B. Physical Examination Tips to Guide Management.

After onset of CES, repeated embolic showers of cholesterol crystals may lead to new and progressive manifestations. Attention on physical exam should be paid to the function of involved organs: volume status and signs of uremia pertinent to kidney function, integrity of ischemic skin areas and signs of sepsis or peritonitis that could indicate intestinal ischemia or perforation.

Regular assessment of pedal pulses is important to ensure that arterial thrombosis has not been overlooked. If new neurologic symptoms develop, the patient should be assessed for the possibility of ischemic stroke. Repeat funduscopic examination may reveal new Hollenhorst plaques, helping to confirm the diagnosis of CES.

C. Laboratory Tests to Monitor Response to, and Adjustments in, Management.

Renal function and electrolytes should be assessed daily during an episode of acute kidney injury with rising creatinine. It may plateau, at which point if the patient is otherwise stable for discharge, it should be monitored frequently at outpatient follow-up as intermittent progression over several weeks is typical.

Development of metabolic acidosis could reflect renal failure but if associated with abdominal pain could signal lactic acidosis from intestinal ischemia. Hemoglobin and/or hematocrit levels should be monitored in patients with intestinal bleeding.

Hypereosinophilia, present in a majority with acute presentation of CES, appears to wane naturally and therefore is not useful for monitoring; unfortunately, this decline does not imply a favorable prognosis.

D. Long-term management.

Statin therapy should be maintained as noted above. Other long-term measures should emphasize treatments otherwise indicated in patients with atherosclerosis, including control of hypertension and hyperlipidemia, smoking cessation and antiplatelet therapy for reduction of myocardial infarction and stroke.

For patients with established indications for anticoagulation, the benefit of continuation probably exceeds the hypothetical risk of exacerbating CES. For patients with residually impaired renal function, avoidance of further renal insults is paramount. For patients with recurrent episodes of spontaneous atheroembolism in a consistent vascular territory distal to the renal arteries, surgical bypass of the culprit artery may be considered.

E. Common Pitfalls and Side-Effects of Management.

IV. Management with Co-Morbidities.

A. Renal Insufficiency.

Patients with pre-existing kidney disease are at increased risk of progression to end-stage renal disease and should be monitored closely.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure.

Congestive heart failure is also a risk factor for progressive renal disease and may warrant closer monitoring.

D. Coronary Artery Disease or Peripheral Vascular Disease.

Atherosclerosis is a prerequisite for development of CES.

E. Diabetes or other Endocrine issues.

No change in standard management.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc.).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

Iron deficiency may develop in patients with chronic intestinal bleeding from CES, and those with pre-existing deficiencies of iron, B12 or folate may have additional difficulty compensating. Malabsorption may also ensue.

J. Hematologic or Coagulation Issues.

As previously noted, anticoagulation has been anecdotally associated with CES, leading some authorities to recommend cessation if CES develops. However, in the absence of evidence of a causal relationship, for patients with a valid indication for anticoagulation, the known risk of thromboembolism without therapy must be weighed against any hypothetical benefit of termination.

K. Dementia or Psychiatric Illness/Treatment.

No change in standard management.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

The most immediately life-threatening manifestation of CES is intestinal ischemia, thus new development of abdominal pain in patients with suspected CES should prompt careful evaluation for this possibility. For patients with severe kidney injury, as with that from any other cause, one should be alert to the potential complications of volume overload, hyperkalemia or uremic symptoms. The population affected by CES is obviously at increased risk of other cardiovascular events including myocardial infarction and stroke, thus symptoms suggestive of these events require careful evaluation.

B. Anticipated Length of Stay.

The variability of manifestations and severity of CES precludes general prediction of the length of stay.

C. When is the Patient Ready for Discharge.

CES typically evolves subacutely over a period of weeks to months. Hospitalization is generally driven by acute kidney injury or intestinal manifestations ranging from pain to ischemia, thus discharge depends upon stabilization of these entities. When renal function reaches a plateau, discharge is reasonable with close outpatient follow-up, as stepwise deterioration may occur.

D. Arranging for Clinic Follow-up.

1. When should clinic follow up be arranged and with whom.

Close follow-up is essential due to the frequency of progression over the weeks following onset. At least weekly monitoring is prudent until it is clear that all manifestations have stabilized. Cognizant patients with well-established physician communication may self-monitor for symptoms and skin changes, combined with laboratory monitoring and clinic visits as indicated by deterioration in any parameter.

If renal function is severely impaired such that further deterioration would necessitate dialysis, follow-up with a nephrologist is prudent; otherwise it may be with a primary care physician with access to consultation if needed. Patients with evolving ischemic changes in the toes may require surgical follow-up as well.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

No tests are required prior to discharge beyond the laboratory monitoring discussed above, however clear communication between hospital and outpatient physicians must include renal function, skin findings and any neurologic deficits at the time of discharge.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Renal function and relevant electrolytes, and hemoglobin or hematocrit levels for patients with occult intestinal bleeding can expedite the clinic visit if obtained prior.

E. Placement Considerations.

NA

F. Prognosis and Patient Counseling.

CES is associated with high mortality, mostly attributable to the severe underlying cardiovascular disease present in these patients. In the largest case series reported, mortality was roughly 17 and 25% after 1 and 2 years, respectively. Gastrointestinal involvement portends a poorer overall prognosis, with 1-year mortality as high as 30-40%.

Renal prognosis is highly variable. In the aforementioned series, roughly 33% required dialysis in the acute phase and 25% progressed to end-stage renal disease requiring long-term renal replacement therapy. Poorer renal outcome was associated with pre-existing kidney disease, diabetes, congestive heart failure, older age, and lack of statin therapy.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

None.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

NA

VII. What's the evidence?

Kronzon, I, Saric, M. "Cholesterol embolization syndrome". Circulation. vol. 122. 2010. pp. 631-641.

Tunick, PA, Nayar, AC, Goodkin, GM. "Effect of treatment on the incidence of stroke and other emboli in 519 patients with severe thoracic aortic plaques". Am J Cardiol. vol. 90. 2002. pp. 1320-1325.

Scolari, F, Ravani, P. "Atheroembolic renal disease". Lancet. vol. 375. 2010. pp. 1650-1660.

Scolari, F, Ravani, P, Gaggi, R. "The challenge of diagnosing atheroembolic renal disease: clinical features and prognostic factors". Circulation. vol. 116. 2007. pp. 298-304.

Hirschman, JV, Raugi, GJ. "Blue (or purple) toe syndrome". J Am Acad Dermatol. vol. 60. 2009. pp. 1-20.

Moolenaar, W, Lamers, CBHW. "Cholesterol crystal embolization to the alimentary tract". Gut. vol. 38. 1996. pp. 196-200.

Ben-Horin, S, Bardan, E, Barshack, I, Zaks, N, Livneh, A. "Cholesterol crystal embolization to the digestive system: characterization of a common, yet overlooked presentation of atheroembolism". Am J Gastroenterol. vol. 98. 2003. pp. 1471-1479.

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