Cholesterol crystal embolization to the digestive system: characterization of a common, yet overlooked presentation of atheroembolism

THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2003 by Am. Coll. of Gastroenterology Published by Elsevier Inc.

Vol. 98, No. 7, 2003 ISSN 0002-9270/03/$30.00 doi:10.1016/S0002-9270(03)00361-7

Cholesterol Crystal Embolization to the Digestive System: Characterization of a Common, Yet Overlooked Presentation of Atheroembolism Shomron Ben-Horin, M.D., Eytan Bardan, M.D., Iris Barshack, M.D., Nurit Zaks, M.D., and Avi Livneh, M.D. Department of Medicine F, Gastroenterology Unit, and Pathology Department, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

ABSTRACT In the 1359 published patients with multiorgan cholesterol crystal embolism (CCE), the digestive system seems to be the third most frequently affected system. Yet, this system received hitherto only little attention in the medical literature. Therefore, the aim of the present study was to clinically characterize the subset of patients with CCE involving the digestive system, based on our institutional experience and a review of the literature. Cases with CCE in a 7-yr period (1995–2001) were sought in the computerized records of our medical center. Of the CCE patients, those with digestive system involvement that could be related to CCE were included in this study. The clinical features of CCE were determined and compared with those found in published series. Fourteen cases with CCE were identified, giving an annual incidence of 0.8 per 105. Digestive system involvement was found in five (36%) of the 14 patients. All five patients had established atherosclerosis. Precipitating factors were vascular manipulations or anticoagulation treatment in four of these five patients. Two patterns of disease appeared: acute catastrophic multiorgan disorder with poor prognosis and chronic and more indolent GI disease. Abdominal pain, GI bleeding, fever, and diarrhea were the most common manifestations, resulting from bowel infarction, mucosal ulcerations, hepatocellular liver disorder, and/or pancreatitis. CCE is a systemic disorder with a frequent involvement of the digestive system and protean clinical manifestations. It should, therefore, be considered in any gastroenterological patient with atherosclerosis and recent vascular manipulations or systemic anticoagulation. (Am J Gastroenterol 2003;98:1471–1479. © 2003 by Am. Coll. of Gastroenterology)

INTRODUCTION Cholesterol crystal embolism (CCE), frequently referred to as atheroembolism or atheromatous embolism, is a disorder caused by embolization to the tissues of cholesterol-containing material from atherosclerotic plaques in the aorta and great arteries. It was first described by Panum in 1862

(1) but received little, if any attention from the medical community for nearly a century, until rekindled in 1945 by Flory’s description of CCE in a series of nine of 267 autopsies (2). Flory was also the first to suggest that cholesterol emboli originated from ulcerated aortic plaques (2). It was since appreciated that CCE is a many-facet disorder, commonly affecting multiple organs, and presenting as a systemic illness, usually associated with progressive renal failure (3). GI and hepatobiliary involvements are common as well, sometimes dominating the clinical presentation and mimicking primary disorders of the digestive system (4, 5). Nevertheless, systematic studies focusing on the clinical aspects of digestive organs involvement with CCE are scant. The present survey was, therefore, undertaken to better characterize the digestive system involvement in patients with CCE.

ILLUSTRATIVE CASES Cases of CCE occurring in a 7-yr period (1995–2001) were sought in the records of our medical center. Because CCE does not have a specific international code of disease, patients’ charts having codes denoting vascular injury or inflammation, renal failure, or digestive organ ischemia were sought and reviewed for a diagnosis of CCE. The same method was implemented for searching the computerized pathological data bank, which similarly does not have a specific code for CCE. When the clinical context was suggestive of a diagnosis of CCE, but CCE was not mentioned in the pathological report, the histopathological specimen was retrieved and reviewed for evidence of cholesterol emboli. Patients with a definite or probable diagnosis of CCE were looked for in the first screening. A diagnosis of CCE was considered definite if it was established by histopathological findings of cholesterol emboli. A diagnosis of probable CCE was made in patients who lacked histopathological proof of CCE (either because a biopsy was not done, or the biopsy specimen was inadequate) but met three predefined criteria: 1) presence of a typical precipitating factor;

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Table 1. Clinical Characteristics of Patients With Digestive System CCE

Patient 1

Sex and Age

Risk Factors for ASVD

2

M64 HTN, NIDDM, smoking M73 HTN, smoking

3

F65

Type of ASVD PVD CVA TIA

4

NIDDM, HTN, CVA hyperlipidemia M73 HTN, smoking PVD

5

M82 HTN

IHD

Triggering Factor

Time From Trigger to Disease

Eosi

Duration of CCE Disease*

Aortobifemoral BPG and angiography Spontaneous ⫹ angiography Spontaneous

5 days and 35 days Not relevant ⫹ 1 day Not relevant

None

No

6 days

Death

No

5 wk

Recovery

10%

1 yr

Recovery

3 days ⫹ 18 days

Kidney, feet (skin), penis Brain, feet (skin), kidney Kidney, feet (skin)

Aortic aneurysm repair ⫹ angiography Anticoagulation ⫹ coronary angiography

No

6 wk

Recovery

3 wk ⫹ 2 days

Kidney, feet (skin)

13%

5 wk

Death

Extradigestive Involvement

Outcome

ASVD ⫽ arteriosclerotic vascular disease; BPG ⫽ bypass graft; CVA ⫽ cerebrovascular accident; Eosi ⫽ eosinophilia; ESR ⫽ erythrocyte sedimentation rate; HTN ⫽ hypertension; IHD ⫽ ischemic heart disease; NIDDM ⫽ non insulin dependent diabetes mellitus; PVD ⫽ peripheral vascular disease; TIA ⫽ transient ischemic attack. *From initiation to the termination (spontaneously or by operation or patient’s death) of CCE-related manifestations.

2) development of progressive renal failure; and 3) presence of typical cutaneous manifestations (purple toe syndrome) or Hollenhorst’s plaques on ophthalmic funduscopy (6). Cases not meeting the requirements for definite or probable CCE were excluded, even if diagnosed with CCE by the attending physician. Digestive system involvement with CCE was diagnosed if there was histopathological proof of cholesterol crystals in digestive tissue or if a patient with CCE disease had an endoscopically visible lesion or a clinical disorder known to be associated with CCE and for which no alternative etiology could be identified. The patients recruited by this approach were characterized clinically, and the involvement of the digestive system and each of the digestive organs was analyzed and compared with findings in published case series of CCE. The overall incidence of systemic CCE was also calculated, based on the size of the population served by our center, estimated at 250,000 people. Of 416 patients identified, 14 fulfilled the inclusion criteria for CCE, three of whom were not diagnosed as CCE before the present study. In eight patients, the diagnosis was definite, and in six, it was probable. Six of the 14 had concurrent digestive system disorder. One of the six, with cholesterol emboli to the skin, retina, and kidney, had recurrent GI bleeding, but was excluded from our series because other GI pathologies could account for the bleeding. Thus, we identified altogether three definite (patients 1–3, as follows) and two probable (patients 4 and 5) subjects with CCE and digestive system involvement. One of these (patient 3) was previously described elsewhere (7). As our medical center serves a population of roughly 250,000 people, with an average annual hospitalization rate of 40,000 admissions, the computed annual incidence of CCE in our population, based on the present study, is eight per one million, or one of 20,000 admissions. The digestive system was affected in five patients in our study, giving a prevalence of five of 14 (36%) of digestive system involvement in CCE.

Tables 1 and 2 summarize the clinical data of our patients. Analysis of the findings, with reference to published cases of CCE, is detailed in the discussion section. Following is a detailed description of the five patients with alimentary system involvement in CCE. Patient 1 A 64-yr-old man was admitted for an elective aortobifemoral bypass graft surgery caused by symptomatic bilateral femoral stenosis diagnosed by an angiography performed 1 month before admission. The history included hypertension, type 2 diabetes mellitus, a cerebrovascular event, and heavy smoking. On postoperative day 5, the patient complained of diarrhea and bloating and had mild distension of the abdomen. Plain abdominal film demonstrated distention of the colon, with gas seen down to the rectum. On colonoscopy, the sigmoid and distal descending colon appeared bluish, suggesting ischemia. Biopsies were not taken because of concurrent use of aspirin. Enteral feeding was withheld, but the diarrhea continued. A temperature of 38.8°C and white blood cell (WBC) count of 19,000/mm3 appeared, and left lower quadrant abdominal tenderness was noted. Blood and stool cultures as well as Clostridium toxin were negative. Abdominal CT showed distention of small bowel loops and left colon. On explorative laparotomy, feculent-free fluid was found in the abdomen, and a gangrenous bowel was resected by left proctocolectomy with an end colostomy. Nevertheless, the patient’s condition continued to deteriorate, with ensuing multiorgan failure leading to his death 3 days after laparotomy and 11 days after the vascular surgery. The histopathological examination of the colon revealed ischemic necrosis with peritonitis and cholesterol clefts with occlusion of the lumen in the mesenteric blood vessels. Patient 2 A 73-yr-old man was admitted with hematochezia and melena. His history was notable for amaurosis fugas 2 yr

Dilated bowel with Supportive thickened wall Pancreatic pseudocyst Supportive Focal bowel necrosis NA No ⫹ 5

Abd ⫽ abdominal; GIB ⫽ gastrointestinal bleeding; NA ⫽ not available.

⫹ ⫹ ⫹

No

Aminotransferases NA ⫹ ⫹ ⫹ 4

Stomach, sigmoid colon, liver Small bowel—suspected Ascending colon to rectum, liver Pancreas, stomach, bowel—suspected 2

No

⫹ No

Left colon to rectum 1

3

Organ Involved

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Figure 1. Multiple cholesterol clefts (arrows) in an arteriole of the colonic serosa (patient 2).

Fresh blood

Normal No NA No

⫹ ⫹

No

NA

Dilated large bowel

Discrete mucosal ulcers Normal Aminotransferases NA ⫹

⫹ ⫹

⫹

NA ⫹

Diarrhea Abd Pain

No

Mucosal erosions Normal

Dilated large bowel NA

Ischemic mucosa

Emergency proctocolectomy Emergency sigmocolectomy Supportive

Cholesterol Embolization to the Digestive System

Patient

Table 2. Digestive System Manifestations of CCE

GIB

Fever

Elevated Amylase

No

Elevated Liver Enzymes

Gastroscopy Findings

Colonoscopy Findings

Imaging Studies Findings

Therapeutic Intervention

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earlier, hypertension, and heavy smoking. Rectal examination revealed fresh blood, mixed with melena. Hb level was 9.2 mg/dl. Two colonoscopies, on two consecutive days, showed fresh blood in the colon precluding the identification of a bleeding source. Gastroscopy was normal. Labeled erythrocytes scan showed mild extravasation at the midleft colon, but selective angiography failed to disclose a source of bleeding. One day after angiography, painful cyanotic lesions with livedo reticularis appeared in his right foot, and the creatinine level rose to 1.8 mg/dl (normal ⬍ 1.1 mg/dl). Bloody stools continued, and more blood had to be transfused. A repeated colonoscopy showed several sigmoidal ulcers, with a diameter ranging between 4 and 40 mm, and necrotic tissue in their floor. The histopathological specimen from one of those ulcers showed necrotic tissue with regenerative changes but no evidence of cholesterol emboli. After colonoscopy, hematemesis occurred, and at gastroscopy, coffee ground was seen, as well as several new erosions at the greater gastric curvature. Painful ulceration of the penis and the scrotum subsequently appeared, and liver aminotransferases rose to five times the normal levels, with normal bilirubin and ALP levels. During the next several days, episodic hematochezia continued, requiring an overall 14 units of transfused packed cells. Fever and left abdominal tenderness with localized peritoneal signs eventually evolved. An urgent laparotomy revealed several necrotic lesions in the sigmoid and distal left colon wall, with perforations sealed by omentum and small bowel adhesions. Intraoperative colonoscopy to the cecum was normal. Left sigmocolectomy was performed. The postoperative course was uneventful, and liver transaminases and serum creatinine gradually returned to normal within 2 wk. A right below knee amputation caused by a gangrenous foot was carried out 1 month later. No further GI bleeding occurred at 1-yr follow-up. The resected colon specimen showed perforated bowel with necrosis, inflammation, organizing peritonitis, and multiple cholesterol emboli in the mesenteric arteries (Fig. 1).

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Patient 3 A 65-yr-old woman was admitted for transient confusional states and watery diarrhea, starting 1 month before admission. History included type 2 diabetes, hypertension, hypercholestrolemia, and right hemiparesis caused by a cerebrovascular accident 20 yr earlier. On physical examination, bilateral carotid and abdominal bruits were heard. Blood tests revealed creatinine of 1.9 mg/dl, Hb of 10.1 mg/dl, and WBC of 6500/mm3, of which 10% were eosinophils. Electroencephalogram was normal, and ultrasound Doppler of the carotid arteries revealed a nonsignificant atherosclerotic disease. The patient was discharged for ambulatory evaluation, during which she had normal gastroscopy and colonoscopy, and abdominal CT showing only severely atherosclerotic aorta. The patient was readmitted 3 months after discharge because she continued to suffer from the same symptoms. On evaluation, a blood pressure of 200/100 mm Hg was recorded, carotid and abdominal bruits were heard, and tender purple lesions on the toes were present with preserved peripheral pulses. Laboratory results were notable for Hb of 8.6 g/dl, WBC of 13,000/mm3, of which 10% were eosinophils, and the erythrocyte sedimentation rate was 132 mm in the first hour. Urea and creatinine levels were 144 mg/dl and 9.3 mg/dl, respectively. Funduscopy revealed grade II diabetic retinopathy. Extensive workup, including stool for culture and parasites, antinuclear antibodies, antiphospholipid antibodies, antineutrophilic cytoplasmic antibodies, rheumatoid factor, cryoglobulins, and complement, was normal. The leg lesions progressed to overt purple toes. On punch biopsy of the toes, multiple cholesterol clefts within the blood vessels were evident. The patient was treated with hemodialysis. The diarrhea and transient confusion episodes gradually diminished over the next several months and resolved completely on a follow-up examination 1 yr after hospitalization. Patient 4 A 73-yr-old man was hospitalized for elective subrenal aortic aneurysmectomy. Angiography was performed 2 wk before admission. On day 3 postoperatively, oliguria and a rise in creatinine level occurred, and dopamine in a diuretic dose was started. On day 5, tender blue toes appeared on the left leg, with good peripheral pulse on palpation and flow on Doppler examination. Three days later, diarrhea, with somewhat distended abdomen, developed. Stool culture and Clostridium difficile toxin were negative. Intermittent fever peaking to 38°C was recorded, leukocytosis with WBC of 16,000/mm3, and elevation of liver aminotransferases to three times the normal level were noted. On colonoscopy, focal bowel wall necrosis was seen at 40 cm, but abdominal CT showed dilated bowel from the rectum to the ascending colon, with thickened edematous bowel wall. The patient was treated with i.v. fluids and broad-spectrum antibiotics. His fever and diarrhea slowly resolved over the next several weeks, and the serum creatinine and liver aminotransferases

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normalized. However, amputation of three necrotic toes had to be performed. During 8 yr of follow-up, no further episodes of cholesterol embolism were evident. Patient 5 An 82-yr-old patient was hospitalized for unstable angina pectoris. His history was notable for myocardial infarction, hypertension, and chronic renal failure. After admission, he was treated for angina pectoris with several medications including heparin. However, he remained severely symptomatic and was referred to coronary angiography, which revealed diffuse triple vessel disease, precluding angioplasty, or surgical revascularization. Two days after the procedure, creatinine level elevation from 3.5 to 7.5 mg/dl was noted, and hemodialysis was started. A day later, watery diarrhea and abdominal pain appeared. Workup for infectious causes was negative, and symptoms resolved within several days. The patient continued hemodialysis and was transferred to a rehabilitation center. He was readmitted 1 month later with hematemesis and pulmonary edema requiring mechanical ventilation. Gastroscopy showed a large volume of coffee ground and fresh blood in the fundus, with no identifiable source. The antrum and duodenum were normal. The patient was successfully extubated the next day, at which point he complained of epigastric pain. Abdominal ultrasound revealed cholelithiasis with normal common bile duct. Blood tests were notable for amylase levels of five times the upper normal level. Leukocytosis with WBC of 14,000/mm3 and 13% eosinophils were also noted. On abdominal CT, a pancreatic pseudocyst formation was seen. The next day, several tender cyanotic lesions appeared in the left toes, suggesting cholesterol embolism. Massive upper GI bleeding and pulmonary edema recurred the following day, leading to the patient’s death. Autopsy was declined. The clinical spectrum of CCE in the digestive system in our patients was wide, ranging from a catastrophic presentation, with acute bowel infarction or pancreatitis (patients 1, 2, and 5), to a more indolent vasculitic-like form, such as chronic diarrhea and eosinophilia (patient 3). This diverse presentation arises from a composite underlying pathogenesis. First, parts of an atherosclerotic plaque in the aorta or other large arteries, consisting mostly of cholesterol, dislodge and embolize downstream in the arterial system (3). Large particles may cause mechanical occlusion of arteries and rapid tissue ischemia and infarction. Smaller particles (⬍200 ␮m) get lodged in arterioles (5). These insoluble cholesterol particles are not cleared by phagocytosis, and have been shown in animal models to persist in the body for up to 9 months (8, 9). Thus, a foreign body-type inflammatory response to the cholesterol material develops, with eosinophilic and neutrophilic infiltrates, giant cell granulomas, intimal proliferation, and subsequent fibrosis of the blood vessel with additional occlusion of the lumen (10). The variability in the size and number of emboli, the degree of occlusion of blood vessels, and the extent of the inflam-

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Table 3. Rate of Various Digestive Organ Involvement in Published Series of CCE Author and Reference Number

No. of Patients in Series

GI Tract (%)

Pancreas (%)

Liver (%)

Gall Bladder (%)

Moolenaar (16)* Moolenaar (16)† Fine et al. (19)* Fine et al. (19)† Dahlberg et al. (21) Probestein et al. (22) Overall

614 452 75 173 22 23 1359

17.4 9.1 6.6 31.2 18.1 0 15.2

0.5 6.2 0 52 13.6 52.1 10

0.2 5.1 0 16.7 4.5 8.7 4.1

0.2 0 0 2.9 0 13 0.7

In two series, the available data were subdivided to premortem* and postmortem† cases.

matory response and subsequent obliteration of the arterial bed form the basis for the divergent clinical presentation.

RISK AND PRECIPITATING FACTORS The highest risk factor for CCE is established atherosclerosis, manifested as cerebrovascular, coronary, or peripheral vascular disease (3). This was present in all our patients (Table 1). Atherosclerosis tends to be more common and more severe with advanced age. Thus, CCE primarily affects the elderly, and in our series, the average age was 71 yr (range 64 – 82), comparable to other series (3). Several precipitating factors have been implicated in the occurrence of CCE. One is manipulation of large vessels, as in vascular surgeries (e.g., aortic aneurysm repair), angiographic studies, or intra-aortic balloon (11, 12). In all, the mechanism is probably mechanical disruption of an atherosclerotic plaque. A second precipitating factor is systemic anticoagulation or thrombolysis, either caused by bleeding into the plaque or by disruption of a protecting thrombus lying over ulcerated plaques (13, 14). Notably, in up to 20% of patients, no precipitating factor can be identified. In these cases, CCE is designated spontaneous (3). In our series, CCE occurred after angiographies and vascular surgeries in four patients, whereas in one patient (patient 3), it was spontaneous.

INCIDENCE AND RATES OF SYSTEMIC AND DIGESTIVE SYSTEM CCE The prevalence of CCE is estimated as 0.18 – 0.31% in unselected populations at autopsy (15, 16) but has been as high as 15% in autopsy series of patients with atherosclerosis and aortic manipulation (17). Our data were not adequate for prevalence computation, but our observed incidence seems to be lower than would be expected from the above-mentioned prevalence rates. Notably, our estimates are hindered by the lack of a specific international code of disease for cholesterol embolism (18), underdiagnosis, and the retrospective nature of the study. Nevertheless, the fact that the annual incidence of 8 CCE patients per one million population we found is closely comparable to the incidence among patients diagnosed premortem in a large national Dutch survey (six per million) may support the validity of our estimations (16).

The kidneys and skin are the organs most commonly affected by CCE, and each is involved in a little over half of the cases (3). This involvement presents with progressive renal failure and cutaneous lesions, notably livedo reticularis, distal ischemic lesions (purple toe), petechiae, and raised nodules of subepidermal foci of inflammation (19). Typical kidney and skin involvement occurred in four of our patients (Table 1). The digestive system was affected in five of 14 (36%) patients in our series. To better estimate the prevalence of digestive organ involvement, we reviewed all the reported case series of systemic CCE in the English literature. Nine case series were found (3, 11, 16, 18 –23). Five were excluded because of insufficient pertinent information on digestive system involvement or lack of clarity regarding the method of diagnosis (3, 11, 18, 20, 23). Thus, there remained four case series, encompassing 1359 patients with CCE, with adequate data for analysis. The rate of various digestive system organ involvement with CCE in these series is presented in Table 3. The overall prevalence of digestive system involvement was not reported in any of these series, and accurate calculation is precluded by the fact that the same patient may have several digestive organs affected. However, it is probably safe to indirectly infer from the figures that roughly 20% (range 5.6 –52%) of patients with CCE will have one or more digestive organs affected by CCE. Thus, the rate of digestive system CCE in our series is comparable to that of other series. The digestive system is, therefore, the third most common system involved with CCE, both in our experience and the reported series, with the GI tract being the most frequently affected part (Table 3) and the colon being the most frequently affected segment (Table 3) (24). The preferential involvement of the GI tract is probably a result of its rich vascular supply. The central nervous system and the retina are the next most common sites involved with CCE (16). Central nervous system involvement may present as a transient ischemic event, a cerebrovascular event, or a confusional state (patient 3) (3), whereas retinal CCE is evident as yellow bright plaques (Hollenhorst’s plaques) at arterial bifurcations on ophthalmic funduscopy (6, 25), which, regrettably, was not done in most of our patients.

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CLINICAL MANIFESTATIONS OF CCE IN THE DIGESTIVE SYSTEM GI Tract Manifestations GI tract involvement can take many forms. The most common manifestations are abdominal pain, diarrhea, and GI blood loss (Table 2) (24). Abdominal pain was present in 80% of our patients and is caused by ischemia of the bowel wall. Blood loss occurred in 40% of our patients and is caused by superficial mucosal ulcerations, erosions, and microinfarcts (5, 26). Erosions and bowel wall necrosis or ischemia were seen on endoscopy in three of our patients, and in another patient, luminal blood precluded adequate visualization (Table 2). Rarely, blood loss can also arise from a pseudopolyp, caused by inflammatory tissue reaction to cholesterol crystals (27, 28). In a single report, CCE was implicated in the finding of gastric angiodysplasia (29), but this observation was not reproduced. Blood loss can be recurrent and necessitates multiple massive transfusions (patient 2) (30, 31). The origin of CCE-induced blood loss can be obscure, when embolization is restricted to the distal duodenum or jejunum, which are less accessible to endoscopy (30, 32). In addition, as cholesterol crystals are mostly stuck in deep mucosal and submucosal arterioles, the diagnosis may be missed if biopsies are not deep enough (26, 33), as possibly happened in patient 2, or overlooked, if CCE is not specifically considered (13). Diarrhea is another common manifestation, and in our series, was present in all patients. The pathogenesis is unclear but may be related to various mechanisms such as mucosal inflammation, the accumulation of luminal blood, and malabsorption (3). Diarrhea is usually clinically accompanied by other GI manifestations, such as blood loss or abdominal pain. Only rarely is it the sole manifestation, and chronic, painless, nonbloody diarrhea caused by CCE was reported in only two patients (34, 35), in addition to our patient 3. Frank bowel infarction and perforation may be seen in the presentation of CCE, as occurred in two of our patients. This complication has been reported anywhere along the GI tract, from the stomach to the rectum (12, 36 –38). It may result from massive or large cholesterol particle embolization, combined with reactive mesenteric vasoconstriction, associated volume depletion, and an antecedent inadequate collateral circulation. CCE that causes small and large bowel obstruction secondary to stricture formation has seldom been reported (39, 40). The pathogenesis is probably prolonged inflammation with ensuing fibrosis of the bowel wall, ischemic injury leading to ischemic stricture, or an interplay of these two mechanisms. None of the patients in our series experienced this complication. Finally, although GI tract involvement is often a part of a severe systemic illness caused by multiple CCE, it can also

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be the sole manifestation (patient 1) (12, 13, 32), thereby mimicking other primary GI tract disorders such as inflammatory bowel disease or GI tumor (4, 37). Pancreatic Manifestations One patient in our series had overt pancreatitis. In three patients, although clinically relevant, pancreatic enzymes were not recorded. Thus, pancreatic involvement cannot be safely ruled out. Pancreatic involvement in CCE is probably more common than clinically appreciated. High serum amylase levels were found in 44% of patients with CCE in one series (18). Although hyperamylasemia could have reflected bowel infarction in some of these cases, the figure quoted was comparable to the rate of histologically proved CCE in the pancreas in two autopsy series (19, 22). The overall prevalence of histologically proved pancreatic CCE in all published series is, however, significantly lower (Table 3), but perhaps is underestimated because of the low accessibility of the pancreas to biopsy sampling and a low index of suspicion (41). Pancreatic CCE may be clinically silent, with limited foci of inflammation (42), or, as in our patient, symptomatic, usually presenting with abdominal pain. In the latter, it may be caused by a spectrum of pancreatic injuries, ranging from extensive necrotizing pancreatitis to chronic fibrosing pancreatitis (41, 43). Hepatobilitary Manifestations Elevated liver aminotransferase levels were noted in two of our patients. No reference in the charts was made to these results as a possible reflection of CCE-related hepatitis. This is in accordance with previous reports, suggesting that liver CCE is remarkably clinically underdiagnosed, as opposed to findings at autopsies (Table 3). This attests to the benign nature of liver involvement, which usually manifests only as a rise of transaminases (43). When hepatic tissue is obtained, the histological picture is generally that of focal liver cell necrosis (43). Cholesterol embolization to the gall bladder is even rarer, affecting 0.7% of patients with CCE in the pooled published case series (Table 3) and none of our patients. However, in contrast with the generally silent liver CCE, gall bladder involvement tends to be clinically significant, with a spectrum ranging from chronic acalculous cholecystitis to acute necrotizing ischemic cholecystitis (34, 43– 46). This vulnerability of the gall bladder was speculated to stem from the tenuous blood supply of the gall bladder (43). Cholecystitis may be the sole manifestation of CCE, and, therefore, CCE may not be suspected until confirmed by examination of the resected specimen (45). Thus, cholesterol embolism should be suspected in elderly atherosclerotic patients with acalculus cholecystitis, particularly if presenting shortly after a known possible CCE-inciting insult.

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LABORATORY, IMAGING, AND HISTOPATHOLOGY FINDINGS Blood tests usually reflect nonspecific end-organ damage. Elevated sedimentation rate was documented in one of our patients (Table 1) and is reported in roughly 25% of patients (18). Transient eosinophilia was noted in two of our patients (Table 1). Its incidence varies greatly between different series of CCE and ranges between 22% and 73% of patients (3, 19, 23). Eosinophiluria also occurs but usually concurrent with blood eosinophilia (3). Imaging studies findings are also not specific and mostly reflect inflammation or ischemia of affected organs. Thus, dilated bowel loops, reactive or ischemic, may be seen on plain abdominal films and abdominal CT (patients 1, 2, and 4). The latter modality may also show an edematous thickened bowel wall, perforation, or evidence for pancreatic inflammation (patients 4 and 5). In endoscopic studies, the most common finding is a congested mucosa. Normal looking mucosa on the one hand (patient 3) and ulcerations, erosions, focal areas of bluish, ischemic or necrotic mucosa, and pseudopolyps on the other hand (patients 1, 2, and 4) are other possible findings (5, 26 –28). The hallmark of histopathology findings is the demonstration of cholesterol crystals in arterioles of the affected organs. These crystals are dissolved during standard tissue fixation techniques and leave biconvex needle-shaped spaces within the blood vessel lumen (Fig. 1). Associated perivascular inflammatory reaction is commonly found, consisting of eosinophilic and neutrophilic infiltrates and giant-cell granuloma formation.

DIAGNOSIS The diagnosis of CCE is often challenging. Indeed, 75% of our patients originally bore a diagnosis of CCE, but this figure is undoubtedly methodologically skewed. When CCE are multiple and affect several organs, other systemic disorders such as vasculitis or infective endocarditis are usually suggested. In contrast, when a single-organ involvement occurs, primary diseases are often considered first. Several clues may, however, suggest CCE. The patient is almost always known to have atherosclerotic disease, as in all of our patients (Table 1). A precipitating factor, such as angiography, vascular surgery, or systemic anticoagulation, is present in 80% of cases, comparable to our series (Table 1). Cutaneous manifestations are commonly found, but may be subtle and, therefore, must be looked for specifically (Table 1). Concurrent renal function deterioration is common (Table 1), and wrong attribution to other insults should be avoided. Eosinophilia may be another supportive laboratory finding. Retinal CCE, designated as Hollenhorst’s plaques, can be sometimes seen on funduscopy (25). Although relatively uncommon and occurring in 10% of cases, these lesions are considered pathognomonic and should, therefore, be sought in every patient with suspected CCE

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(3). Notably, only one of our patients was referred to this noninvasive examination. These clues may be assembled to a highly sensitive set of clinical diagnostic criteria. However, the specificity of such a set in the elderly population, which is affected by other forms of inflammatory and cardiovascular disorders, must be determined. Definite diagnosis, made in three of our five patients, relies on the histological examination of an adequate tissue, which includes arterioles from the involved site. Thus, deep biopsy of the bowel wall containing submucosal arterioles during endoscopies is essential. The timing of the biopsy is also pivotal because mucosal lesions tend to reepithelialize quickly and, therefore, may be missed during endoscopic or postmortem examination (47).

TREATMENT There are no controlled trials of specific treatments for patients with CCE, and no agent has been strongly correlated with favorable outcomes in case series. Thus, therapy is mostly supportive. Proscribing further inciting events, such as aortic catheterizations or anticoagulation, is the mainstay of treatment (3, 11). Although the inflammatory process and the arteriolitis caused by CCE (see beginning of discussion) may suggest a role for anti-inflammatory therapy, the use of corticosteroids had conflicting results. In a series of 67 patients, of whom 18 were treated with corticosteroids, no survival benefit could be attributed directly to this therapy (11). Moreover, in the large retrospective series of Fine et al., corticosteroid use was associated with 100% mortality (19). In contrast, corticosteroid administration seemed beneficial, especially in relieving symptoms related to mesenteric ischemia, such as abdominal pain and food intolerance, and for ischemic leg pain (11). Two other series reported a benefit from steroids, but the number of patients treated was very small (21, 48). Statins were lately reported in two cases to be beneficial in CCE, presumably owing to the plaque-stabilizing activity of these drugs, which further diminishes CCE showers (49, 50). Iloprost, i.v., a prostacyclin analog, was also recently reported to benefit the leg ulcers of CCE in a small group of patients (51). However, more data are needed before either of these agents can become an established treatment for cholesterol embolism. No patient in our series was treated by any of these agents (Table 2). Two prospective series reported favorable outcome with vascular resection of atherosclerotic segments of large arteries identified as being the source of previous CCE (20, 52). However, patients with suprarenal source of embolization and visceral involvement suffered from unacceptable postoperative mortality rate (52). Thus, surgical elimination of the presumed source of CCE should be reserved for patients with lower limb ischemia and infrarenal source of embolization (3). CCE can infrequently present with isolated digestive system involvement (patient 1), or the digestive system in-

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volvement may dominate the clinical picture and determine the prognosis (patients 1, 2, and 5). In these cases, resection of the involved organ, whether a bowel segment, part of the pancreas, or the gall bladder, has been mostly curative (12, 37, 43, 53). Emergency sigmocolectomy has proved life saving in patient 2, but bowel resection did not prevent the fatal outcome of patient 1.

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9. 10. 11. 12.

COURSE AND PROGNOSIS The course of CCE is variable and may range from a fulminant multiorgan disease with fatal outcome to a more indolent and prolonged disorder taking months to resolve (Table 1). Although the prognosis for systemic CCE has improved compared with that of several decades ago (3, 11), mainly because of better supportive care, including hemodialysis, it is still grave. The mortality in our series (40%, Table 1) was somewhat higher but comparable to a recent experience, which suggests a 1-year mortality rate of 30% (3). In conclusion, although the digestive system is the third most common part of systemic atheroembolism, it is often overlooked. It presents with abdominal pain, diarrhea, and GI bleeding, resulting from various levels of ischemic involvement of bowel, liver, gall bladder, and pancreas. High index of suspicion and attention to the presence of risk factors, precipitating factors, certain concurrent manifestations (Table 1), and findings of the pathognomonic histological picture are important diagnostic clues for early diagnosis, which on certain occasions may be life saving.

13.

14. 15. 16. 17. 18. 19. 20. 21. 22.

Reprint requests and correspondence: Avi Livneh, M.D., Department of Medicine F, Sheba Medical Center, Tel Hashomer, 52621 Israel. Received Dec. 3, 2002; accepted Mar. 10, 2003.

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