Cutaneous Cholesterol Emboli

Updated: Jun 22, 2016
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

The general term atheromatous emboli describes the embolization of any atheromatous material. Atheroemboli refers to the dislodgment of relatively large portions of atheromatous plaques containing RBCs and fibrin aggregates, which includes cholesterol crystals of sufficient size to occlude a major systemic artery and potentially result in major organ dysfunction. Cholesterol emboli (CE), on the other hand, result from ulceration of plaques and the subsequent release of cholesterol crystals. These emboli are smaller and usually more numerous, often producing multisystem disease.

Chronic leg ulcer due to cutaneous cholesterol emb Chronic leg ulcer due to cutaneous cholesterol emboli on the leg of a 79-year-old woman.

The term cutaneous CE (CCE) is used when CE result in disease of the skin, as shown in the image below. The terms peripheral emboli, lower extremity atheromatous emboli syndrome, blue toe syndrome, purple toe syndrome, and trash foot refer to special cases of CE to the lower extremities in which cutaneous manifestations are usually present, the latter 3 occurring in association with anticoagulation or vascular surgery.

In 1945, Flory was the first to suggest that CE may produce skin disease. [1] His hypothesis was later validated by Hoye and associates in 1959, who observed arteries occluded with cholesterol crystals in areas of gangrene on the feet and toes. [2]

It is more commonly associated with iatrogenic manipulation via invasive vascular procedures or therapies (anticoagulation or thrombolytics) and, most commonly, affects the kidneys, gastrointestinal system, and skin. [3] Skin findings can facilitate clinical diagnosis, since about 88% of patients with CCE have them, most commonly livedo reticularis and cyanotic changes of the toes.

CCE is a disease primarily of elderly white men with ulcerous atherosclerosis. Atherosclerotic foci release cholesterol crystals spontaneously or after anticoagulation or endovascular manipulation, inducing the obstruction of small arteries. Cholesterol embolization syndrome is a systemic disease due to distal showering of cholesterol crystals after angiography, major vessel surgery, or thrombolysis. Obstruction of cutaneous vasculature most often results in a clinical picture of livedo reticularis (LR). It is more common in patients with atherosclerotic disease, hypertension, a history of smoking, and elevated baseline plasma C-reactive protein levels.

Gangrene, cyanosis, ulcers, nodules, and purpura can also be observed. In cases of multisystem involvement, CCE may masquerade as many different diseases, but the clinical picture most often mimics a vasculitis. Skin or muscle specimens demonstrate the cholesterol crystals characteristic of this disease.

Treatment is based on the identification of the source of emboli through angiography and on the exclusion of that source from the circulation. Medical therapy has largely been unsuccessful. Gangrene necessitating amputation is the major complication of CCE, but complications may occur in practically any organ system. Without surgery, CCE is a recurrent process with a high mortality rate.

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Pathophysiology

The most likely explanation for the cutaneous manifestation of CCE is trapping of cholesterol crystals in blood vessels leading to occlusion and tissue ischemia. Other contributing factors include underlying lowered arterial pressure from proximal atherosclerosis and the ability of emboli to activate the complement system.

The pattern of LR may be the first clinical sign of CCE and is thought to result from incomplete disturbance of circulation and desaturation of blood that initially occurs with subtotal occlusion of vessels. [4, 5, 6, 7, 8] As spasm and complete occlusion occur, the other signs of CCE become evident. In addition to the blockage of small vascular channels, lower arterial pressure from narrowing of larger proximal arteries may be necessary for the cutaneous manifestations of CCE because intact collateral supply should normally avert it. In one study, injections of a cholesterol suspension in the femoral arteries of dogs produced gangrene, but only in cases with associated thrombosis of the femoral artery. This indicates that embolism is a contributing factor in necrosis with a vascular supply already compromised by atherosclerosis or other occlusive disease. Neither thrombosis alone nor CE alone would produce necrosis.

Other evidence suggests that in addition to a purely mechanical effect, crystalline cholesterol may amplify infarctive tissue damage through the activation of plasma complement, which is capable of potently aggregating polymorphonuclear (PMN) leukocytes and provoking them to damage endothelial cells via toxic oxygen radical release. In both experimental and clinical infarction, evidence of plasma complement activation, often with depletion of complement components, is observed. Animals depleted of complement prior to experimental infarction experience smaller infarcts than controls. In one report, a man suspected of having CE with cutaneous lesions, including LR and digital infarcts, reportedly had plasma with PMN leukocyte–aggregating activity that contained a component of molecular weight and antigenicity consistent with C5a.

Cholesterol crystals and lipids from atheromata incubated with plasma or serum activate complement, as evidenced by immunoelectrophoresis that showed conversion of C3 to C5. On the other hand, serum or plasma depleted of complement or from a patient with congenital C5 deficiency resists activation. PMN leukocytes incubated with endothelial cells to which C5a or cholesterol-incubated plasma was added show evidence of endothelial damage via increased superoxide production, while the addition of plasma alone or cholesterol-incubated plasma without PMN leukocytes does not cause any damage beyond that which spontaneously occurs. This damage is partially inhibited by the addition of superoxide dismutase and catalase.

A related Medscape Reference article is Cutaneous Manifestations of Cholesterol Embolism.

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Epidemiology

Frequency

United States

The incidence of CCE is rising in association with increased use of interventional vascular procedures, angioplasties, and anticoagulant/thrombolytic therapy. [3] The frequency of CCE is difficult to estimate because routine necropsy is often limited and does not include evaluation of the skin; however, because the abdominal aorta is usually the site of the most advanced intimal disease, one would anticipate that the lower extremities and associated skin and musculature would be one of the most frequently involved sites. In one study, skin and muscle biopsy specimens were obtained from the lower extremities of 100 consecutive autopsies and a 4% rate of CCE was observed. In a large review of 223 patients with all types of CE, 78 (35%) had skin involvement.

International

In the Netherlands, cutaneous involvement is observed in approximately 24% of cases of CE. [9]

Race

Of 31 cases of CCE in which race was mentioned, all patients were white.

Sex

In the same study, 64 (82%) of 78 cases of CCE were in men.

Age

Ages of those affected with CCE in the same study ranged from 26-90 years (mean, 63 y).

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Prognosis

CCE is a repetitive process. Untreated patients often have recurrent episodes with significant morbidity and mortality; however, patients with only peripheral involvement, as opposed to both peripheral and visceral involvement, have a much better prognosis. In the most extensive review of CCE cases, the mortality rate was very high. Forty-nine (78%) of 68 patients died.

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Patient Education

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