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Cutaneous Manifestations of Cholesterol Embolism Workup

  • Author: Laura F McGevna, MD; Chief Editor: William D James, MD  more...
 
Updated: Jun 27, 2016
 

Laboratory Studies

Laboratory abnormalities in cholesterol embolism are nonspecific. However, the basic metabolic panel, a complete blood cell count with differential, a urinalysis with microscopic evaluation of the sediment, an erythrocyte sedimentation rate, and a C-reactive protein level may all prove helpful in diagnosing cholesterol embolism. Other laboratory studies should be ordered based on the patient's underlying disease and the clinical picture.

Eosinophilia (>300 cells/µL or 3-18% total WBCs) develops within 3 days of embolization in 70-80% of patients and may remain elevated for up to 1 month after a new diagnosis of cholesterol embolism. Cholesterol crystals in tissue initiate a cascade of reactions, including the systemic release of interleukin 5. T lymphocytes are thought to release interleukin 5 in order to induce eosinophil production, chemotaxis, and maturation.

Eosinophiluria may indicate cholesterol embolism when identified in patients with other findings of cholesterol embolism. One study found that 8 of 9 patients with biopsy-proven cholesterol embolism had positive Hansel staining for eosinophiluria. However, like many other findings in cholesterol embolism, eosinophiluria is nonspecific. In addition to cholesterol embolism, the differential diagnosis of eosinophiluria includes acute interstitial nephritis.

Leukocytosis is found in 50% of patients.

The presence of elevated blood urea nitrogen levels, creatinine levels, proteinuria, pyuria, hematuria, and various urinary casts (in order of descending frequency: granular, hyaline, white blood cell, red blood cell, and oval fat bodies) are further indications that glomerular damage is occurring.

The erythrocyte sedimentation rate is often elevated (>30 mm/h) in persons with cholesterol embolism.

Elevated preprocedural plasma levels of C-reactive protein are associated with subsequent cholesterol embolism in patients who undergo vascular procedures, according to Fukumoto et al.[25]

Hypocomplementemia and antineutrophil cytoplasmic antibody positivity have been reported in persons with cholesterol embolism. It is suspected that this may result from neutrophil activation.

Because pancreatitis may be a complication of cholesterol embolism, serum amylase should be evaluated in any patient with abdominal pain. Similarly, transaminase levels should be monitored because of the potential for hepatic involvement.

Fecal occult blood and digital rectal examination should also be performed in a patient with symptoms of cholesterol embolism and severe abdominal pain.

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Imaging Studies

Establishing the source of cholesterol emboli remains a formidable challenge, especially in patients with diffuse atherosclerotic disease. Noninvasive procedures should be performed first, if possible.

A transthoracic echocardiography may aid in excluding an intracardiac source of embolism.

Transesophageal studies may exclude small valvular thrombi, which may be below the resolution capacity of transthoracic ultrasonography.

Doppler ultrasonography of the aorta may exclude aortic aneurysm.

Magnetic resonance imaging and CT scanning offer alternative means to effectively evaluate thoracic and abdominal aortic sources of embolism. The image below shows a CT scan of the abdomen, demonstrating the infrarenal aorta with an aneurysm and a mural thrombus. Obviously, efforts to avoid intravascular contrast should be undertaken.

CT scan of an infrarenal abdominal aortic aneurysm CT scan of an infrarenal abdominal aortic aneurysm showing the mural thrombosis (white arrowhead) and the bright atherosclerotic calcifications (black arrowhead).

Unfortunately, angiography may be necessary before surgical intervention can be performed, despite the risk of exacerbating cholesterol embolism by mechanical trauma. Peripheral angiography is the best test for establishing a diagnosis of atheroembolism involving the abdominal aorta and the lower extremity arteries.

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Procedures

Definitive diagnosis of the presence of cholesterol embolism is made by performing a biopsy on affected tissue. Skin and muscle are the most accessible sites for obtaining a biopsy specimen and seem to offer the most reliable specificity and favorable sensitivity.[26] Include symptomatic skin or muscle in the biopsy site whenever possible, but even asymptomatic extremities in patients with visceral disease may yield positive biopsy results. Biopsy incisions should probe to subcutaneous fat, if possible, to sample the small vessels, in which cholesterol embolism commonly occurs. Instruct the laboratory to cut sections at multiple levels through the tissue block because changes may be present in only short segments of affected arteries. In one instructive case report, premortem diagnosis of cholesterol embolism was missed when the first sections of a muscle biopsy were interpreted as being consistent with vasculitis. Cholesterol clefts were found in the tissue at postmortem examination, and further sectioning of the original muscle biopsy sample revealed cholesterol crystals amid the vasculitic lesions.

In evaluating a patient with suspected cholesterol embolism, the consulting dermatologist is often faced with the daunting prospect of performing a skin biopsy on an already compromised extremity. Biopsy should be selectively performed. In unfavorable circumstances, biopsy is recommended if one or more of the following criteria for diagnosis is lacking:

  • A patient with documented diffuse atherosclerosis and exposure to a known cholesterol embolism–precipitating factor or factors
  • Acute renal failure with an increase in creatinine levels of more than 150% of the baseline
  • Characteristic cutaneous lesions or retinal embolism
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Histologic Findings

An understanding of cholesterol embolism is predicated on recognizing the relationship with atherosclerosis. Atherosclerotic lesions develop in the walls of vasculature that has undergone diffuse intimal thickening, a process carried out by smooth muscle cells and involving elastin and proteoglycans. Earliest lesions are thought to be apolipoprotein B–containing lipids in macrophages, known as foam cells, in the outer layers of these thickened vessel walls.[27] Grossly, these can be identified as fatty streaks.[28] As the lesion progresses, lipids continuously accumulate and deposit, forming a lipid core. Fibrous, collagenous caps, as shown below, cover these lesions, which usually conceal denuded, friable endothelium. When the fibrin caps rupture, cholesterol embolization may occur.

Photomicrographs of histologic sections of an aort Photomicrographs of histologic sections of an aorta with van Gieson stain. (Left) An atherosclerotic plaque with the fibrous cap (black arrowhead) overlying a necrotic core of cellular debris, extracellular lipids, and cholesterol clefts (white arrowhead). Underneath the plaque is the elastic media (arrow). (Right) A ruptured atherosclerotic plaque exposing the atheromatous debris containing cholesterol crystals to the bloodstream on the luminal side of the aorta.

Cholesterol embolism is histologically defined by the presence of birefringent crystals with polarized light or biconvex needle-shaped ghostly clefts within the arterial lumen, corresponding to cholesterol crystals dissolved during the fixation process. On frozen sections, the Schultz test stains the acicular (ie, needle shaped) cholesterol crystals green within a few minutes and brown within 30 minutes; however, in the clinical setting, demonstration of the characteristic biconvex cholesterol clefts suffices to establish a diagnosis of cholesterol embolism. In the skin, the artery is usually located at the dermal-subcutaneous junction. In the muscle, the findings occur in small arteries adjacent to areas of patchy myocyte atrophy and necrosis with surrounding infiltrate.

Lesions in different stages of evolution may be found in the same patient, and this is considered evidence of recurrent showers of emboli. The earliest lesions typically reveal the cholesterol clefts surrounded by nonagglutinated red blood cells, reflecting partial occlusion of the arterial lumen. The cutaneous livedo reticularis pattern is believed to be secondary to this local incomplete disturbance of circulation. Macrophages and foreign body giant cells may surround the cholesterol clefts, usually within 24-48 hours. Later, a more complete occlusion may occur as encasement of clefts by intimal proliferation and fibrosis ensues. A vasculitic pattern may be seen in biopsies performed well after initial tissue injury.[29] This final stage most likely underlies tissue necrosis and gangrene. Even in late disease and with recanalization, cholesterol crystals may still be found in affected tissue. See the images below.

Low-power view of a skin biopsy specimen demonstra Low-power view of a skin biopsy specimen demonstrating an arteriole within the subcutaneous fat occluded with thrombus material that contains (black arrowhead) needle-shaped cholesterol clefts (hematoxylin and eosin stain, original magnification X40).
High-power view of occluded vessel (hematoxylin an High-power view of occluded vessel (hematoxylin and eosin stain, original magnification X100).
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Contributor Information and Disclosures
Author

Laura F McGevna, MD Assistant Professor of Medicine, Dermatology Division, University of Vermont College of Medicine

Laura F McGevna, MD is a member of the following medical societies: American Academy of Dermatology, Dermatology Foundation

Disclosure: Nothing to disclose.

Coauthor(s)

Gregory J Raugi, MD, PhD Professor, Department of Internal Medicine, Division of Dermatology, University of Washington at Seattle School of Medicine; Chief, Dermatology Section, Primary and Specialty Care Service, Veterans Administration Medical Center of Seattle

Gregory J Raugi, MD, PhD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Samreen R Raza, MD Resident Physician, Department of Internal Medicine, University of Vermont College of Medicine

Samreen R Raza, MD is a member of the following medical societies: American College of Physicians, Royal Society of Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Texas Medical Association, Association of Military Dermatologists, Texas Dermatological Society

Disclosure: Nothing to disclose.

Warren R Heymann, MD Head, Division of Dermatology, Professor, Department of Internal Medicine, Rutgers New Jersey Medical School

Warren R Heymann, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Catharine Lisa Kauffman, MD, FACP Georgetown Dermatology and Georgetown Dermpath

Catharine Lisa Kauffman, MD, FACP is a member of the following medical societies: American Academy of Dermatology, Royal Society of Medicine, Women's Dermatologic Society, American Medical Association, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Edwin Rhim, MD, and Heather D. Rogers, MD, to the development and writing of this article.

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A 76-year-old man with a history of aortobifemoral bypass graft developed this eruption after an angiographic procedure. This image shows the plantar surface of the right foot with some of the discoloration resulting from petechiae arranged in a reticulated pattern. This is not livedo reticularis. Petechiae do not blanch on diascopy, but the lesions of livedo reticularis do blanch.
Aorta with an ulcerated plaque (black arrowhead) on the luminal side photographed under water to enhance reflection of cholesterol crystals (white arrowhead).
Low-power view of a skin biopsy specimen demonstrating an arteriole within the subcutaneous fat occluded with thrombus material that contains (black arrowhead) needle-shaped cholesterol clefts (hematoxylin and eosin stain, original magnification X40).
High-power view of occluded vessel (hematoxylin and eosin stain, original magnification X100).
Symmetric involvement of the feet with livedo reticularis on the plantar surface of the forefoot and cyanosis of the left fifth toe. The painful cyanotic toe is typical of blue toe syndrome.
Dorsal surface of the toes of the right foot of a patient with discoloration resulting from petechiae. This image shows cyanosis of the fourth toe. The dominant eruption is petechial. Note the pallor of the tip of the great toe and the second toe. This finding indicates acute loss of perfusion.
Plantar surface of the right foot. The distal half of the great toe is gangrenous, with a sharp demarcation between the necrotic tissue and the normal proximal skin. Livedo reticularis is present on the distal plantar forefoot, and petechiae are present on the distal pad of the second and fourth toes.
The lower extremities show well-developed livedo reticularis and focal areas of erosion and ulceration.
Photomicrographs of histologic sections of an aorta with van Gieson stain. (Left) An atherosclerotic plaque with the fibrous cap (black arrowhead) overlying a necrotic core of cellular debris, extracellular lipids, and cholesterol clefts (white arrowhead). Underneath the plaque is the elastic media (arrow). (Right) A ruptured atherosclerotic plaque exposing the atheromatous debris containing cholesterol crystals to the bloodstream on the luminal side of the aorta.
CT scan of an infrarenal abdominal aortic aneurysm showing the mural thrombosis (white arrowhead) and the bright atherosclerotic calcifications (black arrowhead).
 
 
 
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