Blue Toe Syndrome ( Cholesterol Embolization Syndrome)

Blue toe syndrome is characterised by tissue ischaemia secondary to cholesterol crystal or atherothrombotic embolisation. It leads to the occlusion of small vessels. Cyanosis of the digits may have several etiologies ranging from trauma to connective tissue disease, however the most common cause of blue toe syndrome is atheroembolic disease or aneurysm. Embolisation occurs typically following an ulcerated atherosclerotic plaque or aneurysms located in the aorto-iliac-femoral arterial system. Embolisation can occur spontaneously or due to a variety of causes. Most often, microembolisation appears in elderly men who have undergone an angiographic procedure or vascular surgery or even anticoagulant or thrombolytic treatment .

The differential diagnosis of blue toe syndrome includes Raynaud’s (especially secondary) phenomenon. In Raynaud’s syndrome ishaemic lesions are usually more diffuse, larger areas of distal parts of different fingers (rarely toes) are involved and are affected by vasospastic disorders. The patients are usually younger and without any known atherosclerotic disease. In blue toe syndrome skin lesions are usually restricted and related to the occluded artery, fingers are rarely affected as opposed to toes and vasospasm is usually absent. Painful red, purple, blue or black toes can also be seen in patients with thrombocythemia associated with polycythemia vera or in essential thrombocythemia (3). In these patients, ischemic lesions of fingers or toes are caused by arteriolar inflammation and the thrombosis of microvessels that appear as a consequence.

 The following 6 key elements are required for the development of cholesterol embolization syndrome:

1. Presence of a plaque in a proximal, large-caliber artery (such as the internal carotid artery, the iliac arteries, or the aorta)
2. Plaque rupture (spontaneous, traumatic, or iatrogenic)
3. Embolization of plaque debris (containing cholesterol crystals, platelets, fibrin, and calcified detritus)
4. Lodging of the emboli in small to medium arteries with a diameter of 100 to 200 μm, leading to mechanical occlusion
5. Foreign-body inflammatory response to cholesterol emboli
6. End-organ damage due to a combined effect of mechanical plugging and inflammation.

 Clinically apparent atheroembolism is an uncommon complication of cardiac catheterization. In a prospective study of 1786 consecutive patients aged ≥40 years, who underwent left-heart catheterization in Japan, cholesterol embolization syndrome (defined as livedo reticularis, blue toe syndrome, digital gangrene, or renal failure) was found in 25 patients (incidence of 1.4%). There was no significant difference in the risk of atheroembolism between femoral and brachial approach, suggesting that the ascending aorta is the predominant source of cholesterol emboli. In another prospective study that examined renal failure as the only manifestation of cholesterol embolization syndrome after cardiac catheterization, the incidence was also relatively low. Among 263 study patients, renal failure was attributed to cholesterol emboli in 5 patients (incidence of 1.9%).

Cholesterol embolization during coronary angioplasty is uncommon. In a prospective study of 1579 patients undergoing coronary angioplasty in the United States, clinical evidence of cholesterol embolization was found in 1 patient (0.06% of cases). Interestingly, in a prospective study of 1000 patients undergoing percutaneous revascularization procedures via the femoral approach, plaque debris was retrieved from >50% of all guiding catheters.

Surgical manipulation of the aorta and its major branches carries the highest risk of cholesterol emboli. Atheromatous embolization as a complication of vascular surgery was first recognized in the 1950s. The high risk persists in the modern era of cardiovascular surgery.

The syndrome of cholesterol embolism is often a multiorgan disorder. Clinical presentation can range from a cyanotic toe or livedo reticularis to a diffuse multiorgan systemic disease that can mimic other systemic illnesses. Mild forms of the disease have a good prognosis and subside without sequelae. However, diffuse multisystemic forms have a very poor prognosis. The kidney is the organ that is most often affected (in approximataly 50 % of cases). In the systemic form prognosis is poor, with a mortality rate of about 70 % . 

Blue toe syndrome is frequently misdiagnosed on initial presentation. Pedal pulses are often palpable, which may misdirect the physician from a diagnosis of vascular pathology. The differential diagnosis can be divided into three categories: emboli from the cardiac and arterial system, acquired hypercoagulability disorders and syndromes that lead to peripheral vascular pathology. Non-invasive vascular testing, peripheral angiography, abdominal and popliteal ultrasonography and echocardiography may be useful in discovering the origin of emboli. Recently, transesoephageal echocardiography and MRI have been shown to be a helpful tool in imaging the thoracic aorta and greatly detailed delineating of the anatomy of the aortic atheroma. Diagnosis is usually (definitely) confirmed with skin or muscle biopsy and fundoscopic examination presenting cholesterol crystals.

At present, surgery (endartectomy or bypass with exclusion of the source of emboli) remains the most viable treatment option for patients with aneurysms. In all other patients, surgery is rarely indicated because the origin of cholesterol crystal embolisation is not certain and patients are usually too weak for a major surgical intervention. In some of these cases endovascular procedures (angioplasty with stenting or endoprosthesis) can substitute reconstructive surgery in eliminating the source of embolisation .
Medical treatment is mostly symptomatic: rest, warm condition, appropriate dressing, hydration, and organ support when necessary, principally to ensure renal function. Treatment of pain that is usually disproportionate to the extension of tissue lesion is of utmost importance. Because these patients usually have advanced atherosclerotic disease, secondary prevention with elimination of risk factors of atherosclerosis is mandatory. Antiplatelet drugs represent one of the basic treatment options of blue toe syndrome . The complete relief of pain and restoration of circulation is also obtained by aspirin administration in ischaemic complications of polycythemia vera complete. Vasodilator drugs, including alpha-1 blocking agents that are usually used for the treatment of vasospastic disorders have no proven efficacy in blue toe syndrome. In diffuse and multi-visceral embolisation either colchicine or corticosteroids adjuvant therapy may be useful. According to our experience prostanoid drugs are also effective in treating ischaemic lesions caused by microembolisation. In the future large randomised studies will be needed to help predict embolisation and thus decide on the proper medical therapy.

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• References:
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1-Circulation ; Cholesterol Embolization Syndrome 

Itzhak Kronzon, MD; 

Muhamed Saric, MD, PhD, 

Circulation.2010; 122: 631-641

2-Vol2 N°18 ,17 Jan 2004 European Society of Cardiology.