Cholesterol embolism

Case Reports Cholesterol A Multiple-System

Embolism

Disease Masquerading

Polyarteritis

A. MACDONELL

as

Nodosa*

RICHARDS, M.D., ROBERT s. ELIOT, M.D., VLADIMIR I. KANJUH, M.D., ROBERT D. BLOEMENDA.~L,M.D. and JESSE E. EDWARDS, M.D.

St. Paul,

Minnesota

C

of cholesterol embolism was made during life by It is hoped that this communication biopsy. will contribute to a better clinical recognition of this disease.

HOLESTEROL embolism, a complication of ulcerous atherosclerosis, is the process of obstruction of small arteries in many organs of the body by cholesterol crystals, causing a multiple-system disease. The crystals are derived from ruptured atheromas of the aorta. Cholesterol embolism is to be distinguished from the other type of atheroathero-embolism,’ matous embolism, in which a portion of an atheromatous plaque of the aorta or great arteries is dislodged and obstructs a large artery in of localone organ, resulting in manifestations ized disease of the particular organ involved. Both types of atheromatous embolism have been reported to involve almost every organ of the In only a few cases, however, has the body.? + diagnosis of cholesterol embolism been made during life. In these, the diagnosis was usually made by histologic examination of amputated legs or feet.7-g There is also an obvious discrepancy in the literature between the accumulated data concerning the pathologic anatomy of cholesterol embolism and the lack of recognition of the protean clinical manifestations of this condition. The purpose of this communication is to present the clinical picture and supporting anatomic data of cholesterol embolism observed in 2 cases which clinically simulated polyarteritis nodosa. In 1 case, the correct diagnosis

c.4~~ REPORTS 1. A 64 year old woman was hospitalized 13 weeks before death, complaining of acute dyspnea and left anterior thoracic pain radiating down the left arm. She had been treated for atypical angina and left ventricular failure since the occurrence of a posterior myocardial infarction seven years previously. In the past, she had been hospitalized on two occasions with severe anterior thoracic pain and paroxysmal systemic hypertension (230/120), a slight polymorphonuclear leukocytosis and elevated sedimentation rate (93 mm./hr.). On each occasion, after a few days the thoracic pain became less severe, and the blood pressure, leukocyte count and sedimentation rate returned to normal. .4t/inal admission, the blood pressure was 180/100; there were moist bubbling rales over both lung fields; and the heart was enlarged to the left. Laboratory studies showed a hemoglobin concentration of 12.8 gm.% and a leukocyte count of 16,5OO/cu. mm., with 84yc neutrophils, 10% lymphocytes, and 2% monocytes. The sedimentation rate was 42 mm./hr. Urinalysis was normal except for a trace of albumin. Serum glutamic oxalacetic transaminase was 220 units. The electrocardiogram, taken four years prior to the last admission (June 19, 1957, Fig. l), revealed a normal QRS axis (+45 degrees) in the frontal (t.4~~:

* From the Departments of Medicine and Pathology, The Charles T. Miller Hospital, St. Paul, Minn., and the University of Minnesota, Minneapolis, Minn. This study was supported by Research Grant HE-5694 and Research Training Grant 5 Tl HE 5570 of the National Heart Institute, U. S. Public Health Service. 696

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Cholesterol Embolism plane, Q waves in leads II, III, aVF, V5 and V6 with T wave inversion in leads I, aVR, aVL and Vd through Vg. This electrocardiogram suggested, but was not diagnostic of, old diaphragmatic-lateral myocardial infarction. The admission electrocardiogram (Sept. 6, 1961) revealed a normal frontal QRS axis and a relatively deep Q wave in leads III, aVF and VI with T wave inversion in leads I, III, aVR, VS and Vg. There was, in addition, poor R wave progression in the precordial leads, absence of R waves in V1 and VZ and increased QRS voltages of these leads. This tracing suggested left ventricular hypertrophy, old diaphragmatic-lateral myocardial infarction and more recent anterior myocardial infarction. A thoracic roentgenogram showed the heart was enlarged, but the lungs appeared normal (Fig. 2). On the day following admission, although the dyspnea had improved remarkably, the patient suffered a transient episode of mental confusion with left hemiplegia, and also complained of pain in the left calf. Lumbar puncture obtained normal cerebrospinal fluid. In the next two weeks the dyspnea disappeared, and the strength in the left arm and leg returned. The values for blood pressure, leukocyte count and transaminase returned to normal within two weeks. In the third week of hospitalization, the patient began to complain of severe, scattered pains in the legs, shortly followed by epigastric pain, with nausea and vomiting. In the fourth week of hospitalization a rash appeared in the skin over the legs and lower

Thoracic roentgenograms in FIG. 2. Case 1. frontal (left) and lateral (right) views. Initial roentgenograms (Aug. 21 and 29, 1961) show cardiomegaly. Those of September 13, made shortly before death, show signs of bilateral pleural effusion.

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A FIG. 1. Case 1. A, electrocardiogram (June 19, 1957) shows left ventricular hypertrophy and old diaphragmatic lateral myocardial infarction. B, signs of recurrent acute myocardial infarction are seen in tracing of Sept. 6, 1961. (N/2 = half normal standardization.)

Richards

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FmcM

FIG. 3. showing

t

P

4

x,

Alb.

Case 1. Electrophoretic study of sewn frotrins elevated levels of globulin, particularly the beta

fraction.

Physical examination at this time showed abdomen. A flame-shaped hemora blood pressure of 190/120. rhage distal to a small, flat, yellow arterial embolus was seen in the left optic fundus. The fundi otherwise showed only grade I arteriosclerotic changes. Dullness and distant breath sounds were apparent at the right pulmonary base. An evanescent pericardial friction rub was heard over the apex of the heart. There were vioiaceous, tender, indurated nodules ranging from 2 to 4 cm. in diameter scattered over the A purplish, mottled, back of the left thigh and calf. fivedo reticularis, accentuated by dependency, was present over both legs, to mid-thigh level. Pedal

et al. pulses were absent on the right side and diminished on the left. Subsequent studies of the blood showed an eosinophilia of 7 per cent, marked rouleaux formation and a sedimentation rate of 106 mm./hr. Urinalysis revealed 1+ albuminuria and 0 to 7 erythrocytes per high-power field. Concentrations of blood constituents per 100 ml. of material tested were as follows: urea nitrogen 33 mg., fasting sugar 120 mg., serum cholesterol 351 mg., and total serum protein 8 gm. (3.4 gm. albumin, 4.6 gm. globulin). Electrophoresis of serum protein showed moderate elevation of globulin fractions, especially beta globulin (Fig. 3). The results of lupus erythematosus tests and blood cultures were negative. A thoracic roentgenogram showed slight cardiomegaly with a “left ventricular” configuration. An area of consolidation in the lower lobe of the right lung suggested pulmonary infarction. A small left pleural effusion was present (Fig. 2, C and D). The presumptiue clinical diagnosis was polyarteritis nodosa. Two weeks after the onset of the cutaneous rash, a biopsy of a subcutaneous nodule in a calf was taken. The lumen of a muscular artery immediately below the dermis was filled with cholesterol crystals (see Fig. 5A). On the basis of this finding, the clinical diagnosis was changed to cholesterol embolism. The patient was treated with digitalis, diuretics, restriction of salt, oxygen. antibiotics, anticoagulants and sedatives, but her condition progressively deteriorated. Four days before death, she suffered a generalized seizure which was immediately followed

FIG. 4. Case 1. A, arch and thoracicportion of the aorta show some ulcerated atheromas. There is an ulcerated atheroma at the common orifice of the innominate and left common carotid arteries. B, abdominal aorta shows severe ulcerated atheromas and overlying thrombi. C, cleft-like spaces of cholesterol crystals photomicrograph of aortic atheroma. Note characteristic X 100, reduced by and amorphous atheromatous material. (Hematoxylin-eosin stain; 307.1 THE

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FIG. 5. Case 1. Photomicrographs. A, biopsy of the leg shows necrosis of the epidermis and cholesterol clefts in the lumen of a subcutaneous artery (Stage I). (H.-E. stain; X 100.) B, splenic artery shows clefts of cholesterol crystals (Stage II). (H.-E.; X 100.) C, small renal artery with cholesterol clefts in lumen (Stage III). (H.-E.; X 160.) D, bonemarrow. Cholesterol clefts in lumen of a small artery (Stage IV). (H.-E.; X 100.) Magnifications reduced by 35%. by the development of right hemiparesis. died without regaining consciousness.

The patient

PATHOLOGIC FINDINGS The abdominal aorta displayed extensive ulcerative atherosclerosis (Fig. 4B). Histologically, there were atheromas which appeared to be partially emptied of cholesterol crystals and of amorphous eosinophilic atheromatous material (Fig. 4C). Superimposed thrombi covered some ruptured atheromas (Fig. 4A). Fresh hemorrhage was present beneath the base of one atheroma. Some ulcerated atheromas were also present in the thoracic aorta and at the origin of the branches of the aortic arch (Fig. 4A). The heart weighed 490 gm. and showed left venVOLUME 15,

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tricular hypertrophy. In addition to scattered myocardial fibrosis, there were healed posterior and apical transmural and lateral subendocardial myocardial infarcts of the left ventricle. A mural thrombus in the apex of the left ventricle partially overlay the posterqlateral wall of the left ventricle at the site of the healed infarct, and it showed the beginning of an organizing process. The coronary arteries showed severe obstructive atheromatous lesions causing marked luminal narrowing. Each pleural cavity contained 200 to 300 cc. of clear, yellow fluid. The pulmonary parenchyma was emphysematous and, in addition, the middle and lower lobes of the right lung exhibited recent small A branch of the right lower pulmonary infarcts.

700

Richards et al. tested were as follows: sugar

77 mg.

and

urea nitrogen

cholesterol

171

20 mg., fasting mg.

The

electrocardio~gram showed rapid atria1 fibrillation waves in leads III and aVF, and diphasic

“2

“6

FIG. 6. Case 2. Electrocardiogram suggests posterior myocardial infarction and focal intraventricular conduction defect. artery was obstructed by fresh thrombotic material. The liver showed evidence of passive congestion with atrophy of parenchymal cells in the central portion of the lobule and fatty infiltration at the periphery of the lobule. Grossly, the kidneys were of normal size, but the outer surfaces were pitted. The remaining abdominal organs were not remarkable on gross examination. Histologically. many cholesterol emboli were seen in the arteries of the kidneys, spleen, subcutaneous adipose tissue and bone marrow, in this order of decreasing frequency (Fig. 5j. The pancreas, intestines, skeletal muscles, sciatic nerve: adrenals. thyroid and uterus were also examined histologically and did not show cholesterol emboli. Permission for examination of the brain was denied. CASE 2. .4 50 year old male construction worker was hospitalized nine weeks before death, with severe epigastric and anterior thoracic pain associated with dyspnea and an irregular pulse. of two hours’ duration. For eight years he had experirnced exertional angina and moderate hypertension. On admission, the blood pressure was 150; 82, and the pulse was irregular and the rate 112 beats ‘min. ~l‘here was grade 2 arteriolar narrowing of the retinal arteries. Fine crepitant rales were noted over the pulmonary bases. The heart was enlarged, and a grade 2: blowing, systolic murmur present at the apex was transmitted to the base of the heart. Other physical findings were within normal limits. Laboratory studies showed a hemoglobin concentration of 15.5 gm.oj, and a leukocyte count of 6,800/ mm. with 86 per cent neutrophils and 14 per cent lymphocytes. Urinalysis showed a trace of albumin. The sedimentation rate was 11 mm./hr. Concentrations of blood constituents per 100 ml. of material

initial with Q

as well as S-T depression

‘1‘waves in leads I, II, III, aVF,

V5 and Vs.

A thoracic roentgenogram showed enlargement of the heart with tortuosity of the aorta and pulmonary congestion, bilaterally. The patient was given anticoagulants and digitalized. Within eight hours the cardiac rhythm reverted to normal, and the thoracic pain and dyspnea rapidly abated. In an effort to avoid a recurrence of the arrhythmia, maintenance therapy with quinidine sulfate was initiated. Serial electrocardiograms then showed sinus rhythm and Q waves in leads II, III and aVF, with variable S-T and T changes in leads I, II, III. aVF, V5 and V, (Fig. 6). The tracing suggested left ventricular hypertrophy with strain or ischemia. On the eighteenth day of hospitafization, the patient experienced sudden pain in the left flank, associated with microhematuria and elevation of the blood sedimentation rate. This episode was followed by a slight elevation of blood pressure. Despite therapy with rauwolfia serpentina, the blood pressure continued to rise. The sedimentation rate rose to 60 mm./hr., and smears of the peripheral blood showed 6 per cent eosinophils. During the sixth week of hospitciiization, sudden, intense aching pain appeared in the lower extremities, and this was associated with multiple foci of tenderness in the same regions. The patient continued to complain of intense pain in the legs, coldness of the feet and soreness of the right great toe. ‘l’hree days after the onset of pain, livedo reticularis of the legs was noted. Some areas of necrosis appeared in the tips of the toes. In certain areas of the skin of the calves addition, seemed barely viable, and a tender nodule was noted deep in the left calf. The femoral, popliteal and dorsalis pedis pulses were normal in both legs. The pain, coldness and livedo reticularis of the legs progressed and extended upward to involve the hips, buttocks and lower back. Quinidine and anticoagulants were discontinued. Laboratory examination showed a gradual fall in hemoglobin concentration to 7.8 gm. %. The leukocyte count showed 77 per cent neutrophils, 19 per cent lymphocytes, 3 per cent monocytes and 1 eosinophil. ‘I‘he result of a cuff test was positive, although the platelets numbered 18O,OOO/‘cu. mm., and tests for clotting time and clot retraction gave normal results. Bleeding and prothrombin times were prolonged. The sedimentation rate rose to 93 mm./hr. Urinalysis showed a trace to 2f of albuminuria and 100 to 125 erythrocytes per highpower field. The concentration of urea nitrogen rose to 150 mg. %. ‘The guaiac test for blood in the stool gave a 4f reaction. Results of studies for liver function were within normal limits, except for a 2-t cephalin cholesterol flocculation. Serum albumin was 4.6 gm.g;b and globulin 2.1 pm.%, resulting in a ratio of 2.2. The results of a serologic test for THE

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Embolism

FIG. 7. Case 2. Photomicrographs. A, biopsy of the left gastrocnemius muscle shows small artery containing cholesterol clefts (Stage II). (H.-E. ; X 200.) B, ruptured atheroma of the abdominal (H.-E. ;. aorta with some cholesterol clefts and amorphous atheromatous material remaining. X 40.) C, small intramural coronnry artery contains cholesterol clefts (Stage III). (H.-E.; X 110.) D, kidnev. A small artery contains cholesterol clefts (beginning of Stage IV). (H.-E.; X 110.) Magnifications reduced by 20%. syphilis, a blood culture and search for cryoglobulins were negative. A thoracic roentgenogram showed increased cardiac size and evidence of pulmonary congestion and edema. An intravenous pyelogram showed no excretion of dye by the right kidney and Eleven only very slight excretion by the left kidney. days after the onset of the livedo reticularis, a tender nodule in the left gastrocnemius muscle and adjacent skin were biopsied. The biopsy was reported to show “patchy degeneration, necrosis and mild arteriolar sclerosis” in the muscle, with “early ischemic necrosis and a thrombosed vessel in direct association with the area of necrosis in the skin.” Despite all therapy, including hexamethonium, VOLUME 15, MAY

1965

intraarterial papaverine and steroids, the patient’s condition progressively deteriorated. He : became febrile and died five days later, nine week s after admission. Several years after observation of the patient, new sections were made from the original paraffin blocks of the preserved biopsy tissue. The’se revealed a cholesterol crystal embolus in a small artery of tl ae gastrocnemius muscle (Fig. 7A). PATHOLOGIC

FINDINGS

The entire aorta, particularly the abdomina ~1portion, atheromas containing varying showed ruptured amounts of residual cholesterol crystals a nd amor-

702

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et al.

FIG. 8. Case 2. Photomicrogrufdu. A, f~ancreas. Large artery has cholesterol clefts in lumen Arrow indicates small artery with (Stage II). (H.-E.; X 75.) B, interstitial pancreat~cjibrosis. cholesterol clefts in lumen. (H.-E.; X 75.) C, spleen. Large trabecular artery has cholesterol clefts (late Stage I). (H.-E. : X 75.) I), infarcted area in spleen and obstructed arteries showing

cholesterol

clrfts.

(H.-E.

; X

75.)

phous eosinophilic atheromatous material (Fig. 7B). Severe atheromatous changes were present, also, in arteries at the base of the brain. The lumen of the basilar artery was diminished to 50 per cent of normal size. The coronary arteries showed marked obstruction of lumen by fibrous thickening and calcification of the intima resulting from atheromatosis and organized thrombi. No cholesterol crystals were fo ‘nd in these atheromatous lesions, although eosinophilic Several small intraamorphous material was seen. mural coronary arteries contained cholesterol emboli (Fig. 7C).

Magnifications

reduced

by 207;).

The heart weighed 650 gm. The left ventricle was hypertrophied, its left wall being 22 mm. thick. A healed subendocardial infarct and widespread, isolated, small areas of sclerosis were present. The right cusp of the aortic valve showed marantic vegetations. Histologically the kidneys resembled those of Case 1, including the presence of many cholesterol emboli (Fig. 7D). The pancreatic arteries, both large and small, showed innumerable cholesterol emboli (Fig. 8, A and B), and the large arteries contained severe nonulcerative atheromas, as well. Interstitial fibrosis replaced large areas of pancreatic parenchyma (Fig. THE

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Weeks

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1

Adm July 2,196l

FIG. 9.

Case 1.

Summary

8B). The spleen was found to be the organ next most involved with cholesterol emboli. The emboli were present in many large and small arteries located in the trabeculae (Fig. 8C). Where hemorrhagic infarcts occurred in the spleen (Fig. 8D), the supplying arteries were obstructed by cholesterol crystals. The histologic examination of lymph nodes, adrenals, pons and cerebral cortex did not reveal cholesterol emboli. COMMENT Cholesterol embolism is a disease which involves many organ systems of the body. Although some facets of the clinical picture of cholesterol embolism have been reviewed in the literature,+-12 unawareness of the complete spectrum of this disease and its apparent simiVOLUME

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Embolism

3

5

7

9

II

13

E H. 64 yr. 0 Case I

of clinical

data.

larity to polyarteritis nodosa have resulted in failure of clinical recognition. HandlerlO in 1956 emphasized the relationship of renal hypertension to cholesterol embolization to the kidneys. Sayre and Campbell” in 1959 described the pertinent clinical data of a case with cholesterol embolism found at necropsy. In 1960 Fisher and associates12 reported a case of cholesterol embolism found at necropsy which clinically simulated necrotizing Snyder angiitis, notably polyarteritis nodosa. and Shapiro9 in 1961 described the clinical features of a case in which cholesterol emboli were found in biopsy of the leg. Our 2 cases permit one to define the clinical

704

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Probable

cholesterol

embolizotion

minor

major

Muscle biopsy

aa Left flank pain renal Infarct

Symptoms

Blood Pressure Clinic01 Signs

Systolic

Diastolic 50

Temp. -

‘e 96 15000

Laboratory

0 3-5

00 8-20 z-3

00 0

Adm Aug. 6,1956 FIG.

picture of cholesterol embolism tiate it from that of polyarteritis CLINICAL

ENTITY

10.

Case

5Byr d Cose It

LF 2.

Summary

and to differennodosa.

DEFINED

If the clinical features of the 2 cases reported are charted with respect to time (Fig. 9 and lo), This a strikingly clear-cut picture emerges. pattern is almost identical in both cases: 1. Abrupt onset of intense pain scattered in the muscles of the legs and feet, with eventual appearance of tender subcutaneous and muscular nodules or gangrene. Presence of normal peripheral arterial pulses is noteworthy. 2. Ill-defined abdominal pain with nausea, vomiting and anorexia, suggesting pancreatitis and/or gastrointestinal or splenic infarction. 3. Acute paroxysmal or progressive systolic and diastolic arterial hypertension. This is

of clinical

data

considered to be secondary to renal involvement. 4. Livedo reticularis of the legs and lower portion of the trunk becoming apparent within a few days after the onset of pain and hypertension. 5. Less commonly, neurologic symptoms of embolism to the brain or eye. Funduscopic demonstration of retinal emboli is possible. 6. Laboratory evidence of moderate neutrophilic leukocytosis, transient eosinophilia, marked elevation of sedimentation rate, melena, hematuria, albuminuria and azotemia. 7. Biopsy of subcutaneous or muscular nodule showing cholesterol crystal embolus. In each of our cases, the terminal episode of major cholesterol embolism was attended by alterations, many of which are mentioned in the above rCsumt. It is very likely, however, that THE

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Cholesterol each patient survived several earlier, minor In Case 1 the episodes of cholesterol embolism. coincidence of pain in the legs, sudden onset of hypertension and transient hemiparesis suggests cholesterol embolism. Similarly, two earlier episodes of perplexing paroxysmal hypertension may, perhaps, have been on the basis of cholesterol embolism with renal involvement. The clinically assumed retinal cholesterol embolus very likely originated in the ruptured atheroma discovered at necropsy which lay at the common origin of the innominate and left common Retinal and cerebral carotid arteries (Fig. 4A). cholesterol embolism secondary to ulcerated atheromas of the aortic arch has been reported.13J4 In Case 2 the sudden episode of pain in the flanks, slight hypertension and hematuria sugThis is also borne out by gest renal embolism. the failure of the kidneys to excrete dye normally after intravenous pyelography. DIFFERENTIAL

DIAGNOSIS

In each of our cases, initially, the patients were thought to be suffering from polyarteritis In Case 1 the correct diagnosis was nodosa. established by biopsy a month prior to death. The second case, however, remained enigmatic until a second review of biopsy and necropsy slides, years after death. Only then was the diagnosis of cholesterol embolism established. Cholesterol embolism and polyarteritis nodosa are each multiple-system arterial diseases. They have many features in common, and final differentiation is possible only by histologic examination. Cholesterol embolism is suggested by the sudden onset of myalgia, followed by appearance of subcutaneous muscular nodules and livedo reticularis over the legs and Abdominal symptoms suggesting lower trunk. pancreatiti@ or splenic infarction, paroxysmal and progressive hypertension, hematuria and azotemia16 support this diagnosis. Previous myocardial infarction, atherosclerotic aneurysms, or other evidence of atherosclerosis are frequently the companion of cholesterol embolism. Funduscopic demonstration of yellowish arterial embolus, as in Case 1, may be diagnostic. Livedo reticularis, present in both of our cases, represents the consequence of arterial obstruction, with local disturbance of the circulationlrS1* of the skin. This conspicuous sign, reported also by other authors,s~gJ1J2 is of great diagnostic value. Since the lesions of cholesterol embolism result VOLUME

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Embolism from downstream showers of material from clinically silent, ruptured aortic atheromas, and because the abdominal aorta is most severely involved with ulcerous atheromatosis, the lower half of the body is the site of predilection for receiving cholesterol emboli. Polyarteritis nodosa, unlike cholesterol embolism, shows a generalized distribution of the lesions which may even include the pulmonary The presence of other features in polyvessels. arteritis nodosa, such as the history of hypersensitivity, involvement of fairly large arteries and, occasionally, of veins and/or response to steroids may help in differentiation. Certain phenomena in our cases are not explained. These include the transient eosinophilia, elevated sedimentation rate and reversal of the albumin-globulin ratio. It may be that the degraded protein component of the amorphous atheromatous material acts antigenically to cause an immune reaction. Cholesterol embolism may also be confused with other rare forms of disseminated angiitis and subacute bacterial endocarditis.‘g It is of interest that cholesterol embolism may complicate surgical manipulation of the aorta.*O TREATMENT

All therapy attempted in the 2 reported cases was ineffectual. The onset of symptoms in both cases occurred while the patients were adequately treated with anticoagulants, and if anticoagulation diminished the tendency to superimposed thrombosis, this was not evident clinically. Likewise, steroids, intraarterial papaverine and antihypertensive therapy were of no avail. It is of interest that after the appearance of symptoms of cholesterol embolism in the second case, medications were temporarily discontinued because of the possibility that the clinical picture may have represented a drug reaction. HISTOLOGIC

PICTURE

The histologic diagnosis of the cholesterol embolus (on biopsy or necropsy material) is the only definitive means for diagnosis of this condition. Grossly, it is possible only to suspect cholesterol embolism in the presence of the widespread infarction of organs or tissues supplied by the aortic branches arising distally to the ruptured aortic atheromas. The histologic lesions, identical in both of This our cases, were classified into four stages. was possible on the basis of the evolution

Richards of the intimal reaction in response to the presence of cholesterol crystals and characteristic manner of obliteration of the arterial lumen. The first stage (Fig. 5A and 8C) represents lodging of the cholesterol crystals with amorphous atheromatous material in the lumen of small arteries. There is no reaction of the intima. Between the free crystals are erythrocytes outlining the slit-like passages of the lumen. The second stage (Fig. 5B, 7A and 8A) is characterized by pronounced fibroblastic reaction of the intima with rare giant cells. Some of the macrophages have vacuolated cytoplasm suggesting phagocytosis of amorphous atheromatous material. The surfaces of cholesterol crystals are covered by large, plump Erythrocytes can be seen cells (fibroblasts). only in the slit-like passages of the lumen, between fibroblasts, and no longer between cholesterol crystals. Occasionally lymphocytes or polymorphonuclear leukocytes or both are present in the intima. In tile third stage (Fig. 5C and 7C) the rare giant cells and amorphous atheromatous material disappear. Fibroblasts are few and collagen increases. The surfaces of the cholesterol crystals are now covered with flattened and elongated cells, presumably fibroblasts. Erythrocytes are still present in the slit-like passages of the lumen, between fibroblasts. Finally, in the fourth stage (Fig. 5D and 7D) the intima of the vessels shows great acellular the cholesterol crystals fibrous thickening, being completely encased in dense collagenous The slit-like passages of the lumen tissue. Thus, in most with erythrocytes are absent. affected vessels, the lumen becomes completely obliterated. In those arteries with retained lumens, superimposed thrombi may be present. In our material the majority of involved arteries fell into Stage II or III. The changes in all stages were confined to the intima. No eosinophilic 1eukocyteP were encountered in the arterial walls. No signs of a hypersensitive reaction of the vessel walls were detected. Likewise, penetration of the wall by cholesterol Therefore, in both of crystals16 was not seen. our cases the histologic picture of the arteries obstructed with cholesterol emboli showed only The an intimal fibrous foreign-body reaction. most frequently described histologic picture in this condition was also reported in the fibrous foreign body literature as “intimal

et al. In some reported cases,1Q1J3,24 however, the reaction of the arterial wall is said to take the form of arteritis. In rare reported cases, fibrinoid necrosis of the involved arteries was described and attributed to arterial spasm.12 The most frequently involved class of artery is that of small muscular artery. Less often, arterioles and mediumsized muscular arteries, and, least often, elastic arteries, if their lumens were already narrowed by sclerotic process, contain emboli. The lumens of the involved arteries in our 2 cases ranged from 55 to 640 micra, being, therefore, in the case of some arteries, much larger than the individual cholesterol crystal. In these areas, many cholesterol crystals, together with larger amounts of amorphous atheromatous material, usually obstructed the arterial lumens. The impaction of such emboli occurred at bifurcations. reaction

~‘X.11,13,15,16,21~-23

SUMMARY The clinical picture and necropsy data of 2 cases of cholesterol embolism, clinically masquerading as polyarteritis nodosa, are described. In 1 case, the correct diagnosis was made during life by biopsy of the skin. The clinical entity of cholesterol embolism is defined as the rupture of intimal atheromas of the aorta causing impaction of cholesterol crystals in small arteries of many organs and a characteristic picture of sudden obliterative arteritis primarily throughout the lower half of the body. Some of the specific clinical features are (1) the abrupt onset of scattered intense pains in the legs and feet with subcutaneous and muscular nodules or gangrene despite, in some cases, paradoxically normal peripheral arterial pulses; (2) abdominal pain with nausea and vomiting suggesting pancreatitis and/or gastrointestinal or splenic infarction; (3) arterial hypertension thought to be secondary to impairment of renal function; (4) livedo reticularis or cyanosis of the legs and lower trunk within a few days after the onset of pain and hypertension; (5) less commonly, neurologic symptoms and possible funduscopic demonstration of retinal emboli; (6) laboratory evidence of neutrophilic leukocytosis, transient eosinophilia, markedly increased sedimentation rate, hematuria, albuminuria, azotemia and melena; and (7) a biopsy showing cholesterol crystal Although some of the features suggest emboli. a state of hypersensitivity, recognition of the distinctive pattern found in our 2 cases may THE

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Cholesterol Embolism allow the clinician to differentiate cholesterol embolism from polyarteritis nodosa. Final diagnosis rests upon the biopsy showing the A new gracharacteristic histologic changes. dation of the histologic changes into four stages of evolution is suggested. ACKNOWLEDGMENT The authors are grateful to Dr. John I. Coe, Department of Pathology, Hennepin County General Hospital, for his kindness in furnishing the pathologic material of Case 2.

11.

12.

13.

14.

REFERENCES 1. ELIOT, R. S., KANJUH, V. I. and EDWARDS, J. E. Atheromatous embolism. Circulation, 30:611,1964. 2. PANUM, _P. L. ,Experimentelle Beitrlge zur Lehre Virchows Arch. path. Anat., 25: von der Embolie. 308, 1862. 3. FLORY, C. M. Arterial occlusions produced by emboli from eroded aortic atheromatous plaques. Am. J. Path., 21: 549, 1945. 4. GORE, I. and COLLINS, D. P. Spontaneous atheromatous embolization. Review of the literature and a report of 16 additional cases. Am. J. Clin. Path., 33: 416, 1960. 5. WENCER, N. K. and BAUER, S. Coronary embolism. Review of the literature and presentation of fifteen cases. Am. J. Med., 25: 549, 1958. 6. WINTER, W. J., JR. Atheromatous emboli; a cause of cerebral infarction. Report of two cases. Arch. Path., 64: 137, 1957. 7. CANDIANI,G. L’ostruzione da cristalli di colesterina delle grosse arterie delle estremita inferiori. Riu. anat. pat. e enc., 9: 319,, 1954-55. 8. HOYE, S. J., TEITELBAUM,S., GORE, I. and WARREN, R. Atheromatous embolization. A factor in peripheral gangrene. New England J. Med., 261: 128, 1959. 9. SNYDER, H. E. and SHAPIRO, J. L. A correlative study of atheromatous embolism in human beings and experimental animals. Surgery, 49 : 195, 1961. 10. HANDLER, F. P. Clinical and pathologic significance

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