Spontaneous cholesterol crystal embolization to bone marrow.

Abstract: Cholesterol crystal embolization is a well-established complication of arterial trauma and anticoagulation which may involve multiple organs including the skin and muscle, producing clinical features such as livedo reticularis, cyanosis and gangrene of the toes and intense myalgias. Cholesterol crystal embolization to bone marrow has been described in postmortem studies, but has been previously reported premortem in only two patients, both of whom had characteristic risk factors and clinical features. We report herein a case of spontaneous cholesterol crystal embolization to bone marrow in a patient with atypical clinical manifestations.

Key Words: cholesterol crystal embolization, bone marrow, fever, spontaneous

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Cholesterol crystal embolization typically emanates from the aorta or iliac arteries. (1) This phenomenon is frequently preceded by angiographic procedures, vascular surgery or anticoagulation. (1,2) Cholesterol crystal embolization may affect multiple organ systems. (1-5) Clinical manifestations characteristically reflect end-organ involvement. Cholesterol crystal embolization has been described in postmortem studies, both in the presence and absence of vascular trauma or anticoagulation. (2,5) However, only two cases of spontaneous cholesterol crystal embolization to bone marrow have been reported premortem, both of which were associated with characteristic clinical manifestations. (3,6) The case described herein involves a patient with cholesterol crystal embolization to bone marrow (diagnosed premortem) who presented with atypical clinical manifestations (unexplained fever) and no history of vascular intervention or anticoagulation.

Case Report

A 77-year-old woman with long-standing diabetes mellitus, hypertension and hypercholesterolemia was hospitalized for evaluation of dyspnea, lethargy and loss of appetite which developed over a 5-day period. She had a history of a nonproductive cough for many years which had not changed before admission. Her temperature was 99.0[degrees]F, her respiratory rate was 18 breaths per minute, her pulse rate was 78 beats per minute and her blood pressure was 124/58 mm Hg. Auscultation of the lungs showed bibasilar crackles in the posterior lung bases which cleared with cough. The remainder of her physical examination was normal. She was taking the following medications before admission: lamotrigine, tramadol, levothyroxine, furosemide, atorvastatin, insulin, losartan/hydrochlorothiazide, metoprolol, dorzolamide/timolol eye drops, and bromfenac eye drops.

Her chest x-ray showed bilateral basilar patchy pulmonary infiltrates. Her leukocyte count was 22,500 cells/[mm.sup.3]. The differential showed 82% neutrophils, 9% lymphocytes, 7% monocytes and 2% eosinophils. Her blood hemoglobin and hematocrit were 10.2 g/L and 39.1% respectively. Red blood cell morphology was normal. The platelet count was normal. Her serum creatinine level was 1.5 mg/dL and her blood urea nitrogen was 59 mg/dL. The erythrocyte sedimentation rate was 140 mm/h. The serum albumin level was 2.5 g/L and a serum protein electrophoresis showed small amounts of kappa chains. The [beta]-2 microglobulin level was elevated at 6.07 mg/L. Antinuclear antibodies were absent. The urinalysis showed one red blood cell per high powered field, 32 hyaline casts and few amorphous crystals. The remainder of her serum chemistry values were normal. One year earlier, her complete blood count and renal functions were normal.

Because of the presence of fever, cough, leukocytosis and pulmonary infiltrates, the presence of community-acquired pneumonia was suspected and she was treated with ceftriaxone and azithromycin. Over the ensuing 10 days, her symptoms remained unchanged. Her fever persisted, the leukocyte count remained elevated (19,000-22,500 cells/[mm.sup.3]) and her C-reactive protein remained high (13 mg/dL). A computed tomogram of the chest performed on day 10 showed resolution of pulmonary infiltrates. For this reason, antibiotics were discontinued. A variety of additional tests were obtained to evaluate her unexplained fever. Blood and urine cultures were negative. Duplex ultrasonography of the lower extremity veins was normal as was a transesophageal echocardiogram. A Doppler ultrasonogram of the temporal arteries was normal. A computed tomogram of the abdomen was normal except for mild enlargement of the iliac lymph nodes. A bone marrow biopsy from the iliac crest was performed to evaluate anemia. It was normal except for the presence of cholesterol crystals (Fig.) in two arteries. Magnetic resonance angiography showed no evidence of atheromata in the abdominal aorta or iliac arteries. The patient had no history of vascular interventions or anticoagulation.

Based on the bone marrow findings, the patient was diagnosed with cholesterol embolism syndrome. Prednisone was administered orally at a dose of 40 mg per day. The dosage was tapered by 10 mg per week over the ensuing month. She was also treated with atorvastatin 40 mg orally one per day and aspirin 325 mg daily. She continued to receive lamotrigine, tramadol, levothyroxine, furosemide, insulin, losartan/hydrochlorothiazide, metoprolol, dorzolamide/timolol eye drops, and bromfenac eye drops. One month after admission, she was afebrile and all of her symptoms had resolved. Her leukocyte count decreased to 4,900 cells/[mm.sup.3], her erythrocyte sedimentation rate was 10 mm/h and her hemoglobin rose to 12.4 g/L. Her serum creatinine level decreased to 1.5 mg/dL.

Discussion

The clinical manifestations of cholesterol crystal embolization were initially described by Panum (7) in 1862. The pathologic features of this syndrome were first reported by Flory (8) in 1945 based on postmortem examination of 245 patients. A variety of terms have been used over the years to characterize cholesterol crystal embolization, including cholesterol emboli, cholesterol embolism (emboli) syndrome and atheromatous emboli. (2)

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Cholesterol crystal embolization is now known to be distinct from atheromatous emboli based on target vessel characteristics and histology. (2,6,9,10) Cholesterol crystal embolization affects distal capillaries and small arterioles measuring 150 to 200 [micro]m in diameter. (2,6) Atheromatous emboli tend to affect larger arteries, (2,6) and cholesterol crystals intermixed with platelet/fibrin clots within the vascular lumen. (9,10) Cholesterol crystal embolization is associated with aortoiliac atheromas in 80% of cases. (1) The source of embolization remains unidentified in only 3% of patients with this syndrome. (1) Cholesterol crystal embolization most commonly results from iatrogenic or spontaneous dislodgement of atheromatous material. (2,11) Embolization of cholesterol crystals induces an intense inflammatory response in the affected capillaries and arterioles within one to two days. (2,11) Mononuclear and giant cells engulf the cholesterol crystals. (2,11) Interleukin 5 is released from T-lymphocytes and serves to induce eosinophil production, chemotaxis and maturation. (11,12) The site of embolization becomes infiltrated by neutrophils and eosinophils. (2,11) Endothelial proliferation, intravascular fibrosis and thrombosis develop from day two to day seven. (2) Cholesterol crystals may remain in the lumina of vessels for up to nine months. (2,11) Tissue hypoxia and microinfarction are presumed to predispose to the clinical manifestations of this syndrome. (6)

Risk factors for cholesterol crystal embolization include older age, male gender, a history of hypertension and the presence of diabetes mellitus. (1,2) Atherosclerotic vascular disease is present in most cases. (1,2) As previously noted, cholesterol crystal embolization emanates from aortoiliac atheromas. (1,2) Invasive procedures such as angiography may cause mechanical dislodgement of atheromas. (1,2) Anticoagulation has also been identified as a risk factor, even in the absence of vascular trauma. Anticoagulation may predispose to cholesterol crystal embolization in two ways. An ulcerated plaque may fail to form a thrombus in the presence of anticoagulation, thus leaving its cholesterol crystal contents exposed for potential embolization. (1,13) Alternatively, hemorrhage into a plaque may loosen cholesterol crystals which may subsequently embolize. (1)

Postmortem studies of patients with cholesterol crystal embolization indicate that the organs most commonly involved are the kidneys, spleen, pancreas, gastrointestinal tract and adrenal glands. (2,5,6) In those diagnosed with cholesterol crystal embolization, premortem skin involvement occurred in 51%. (2) In contrast, skin involvement occurred in only 4% of cases diagnosed postmortem. (2) In postmortem studies, at least three separate histologic sites were identified in most patients. (2) Thus, the clinical presentation of cholesterol crystal embolization can be quite variable depending on the organs involved. (2,6) Leukocytosis, eosinophilia and elevation of inflammatory markers such as the erythrocyte sedimentation rate consistently occur in patients with cholesterol crystal embolization. (2)

Among patients with cholesterol crystal embolization identified postmortem, bone marrow involvement has been noted in 20% of cases. (14) A prospective postmortem study of 34 consecutive patients over 60 years of age found evidence of cholesterol crystal embolization in 17.6%. (5) Skin involvement occurred in 35% of these patients including livedo reticularis, gangrene and cyanotic toes. (3,14) Evidence of embolization to kidneys or muscle was noted in 90% of cases. (3,13) In Fine's study, (2) 30% of cholesterol crystal embolization cases were diagnosed premortem. Kazmier et al (15) have classified cholesterol crystal embolization syndromes into three nonmutually exclusive subgroups: a peripheral syndrome, a renal syndrome, and a visceral syndrome. (1) The patient reported herein had no skin involvement or myalgias. Mild renal insufficiency improved promptly with hydration. Fever, leukocytosis, eosinophilia, anemia and elevation of inflammatory markers comprised the extent of abnormalities.

Pierce et al (3) reported the first case of cholesterol crystal embolization to bone marrow detected premortem by bone marrow biopsy in 1978. Clinical and laboratory manifestations in this case included altered mental status, cyanosis of three toes, splinter hemorrhages of the fingernails, anemia, eosinophilia, elevated erythrocyte sedimentation rate and an elevated serum creatinine level. (3) Bone marrow biopsy from the iliac crest showed multiple intravascular cholesterol crystals. (3) Treatment with "drug simplification" was associated with slow improvement of mental status and ischemic toes. (3) Muretto et al (6) reported a second case of cholesterol crystal embolization to bone marrow detected by iliac crest biopsy in an 82-year-old man with rheumatoid arthritis. This patient was afebrile, but developed violaceous nodules on both legs and several toes. (6) He also complained of intense myalgias and vertebral pain (associated with increased uptake on bone scintigraphy). He had mild leukocytosis, but no anemia or eosinophilia. Iliac crest biopsy of bone marrow showed multiple intra-arterial cholesterol crystals, thus confirming the diagnosis of cholesterol crystal embolization. Treatment with calciparin and nonsteroidal anti-inflammatory drugs results in resolution of skin lesions within four weeks and myalgias within eight weeks.

Our patient differs from the patients described by Pierce and Muretto in that the characteristic clinical findings (skin abnormalities, myalgias) were absent. Moreover, our patient had no history of vascular trauma or anticoagulation preceding this event. Thus, to our knowledge, this is the first reported case of atypical presentation of spontaneous cholesterol crystal embolization to bone marrow diagnosed premortem via bone marrow biopsy. We cannot completely exclude the presence of aortic or iliac atherosclerosis given our patient's cardiovascular risk factors, although plaque was not detected by magnetic resonance angiography.

We chose glucocorticoid therapy because of reports of rapid resolution of clinical manifestations of cholesterol crystal embolization to the viscera. (11,16) Treatment with atorvastatin was initiated due to hypercholesterolemia. Whether atorvastatin played a role in the resolution of clinical manifestations in our patient is uncertain.

Conclusion

In conclusion, a 77-year-old woman presented with atypical clinical features of cholesterol crystal embolization. She had no major risk factors and was diagnosed via bone marrow biopsy. Bone marrow biopsy should be considered a less invasive alternative to muscle or visceral biopsy to confirm the diagnosis of this serious condition.

References

1. Baumann DS, McGraw D, Rubin BG, et al. An institutional experience with arterial atheroembolism. Ann Vasc Surg 1994;8:258-265.

2. Fine MJ, Kapoor W, Falanga V. Cholesterol crystal embolization: a review of 221 cases in the English literature. Angiology 1987;38:769-784.

3. Pierce JR Jr, Wren MV, Cousar JB Jr. Cholesterol embolism: diagnosis antemortem by bone marrow biopsy. Ann Intern Med 1978;89:937-938.

4. Handler FP. Clinical and pathologic significance of atheromatous embolization, with emphasis on an etiology of renal hypertension. Am J Med 1956;20:366-373.

5. Gore I, Collins DP. Spontaneous atheromatous embolization. Am J Clin Pathol 1960;33 5:416-426.

6. Muretto P, Carevali A, Ansini AL. Cholesterol embolism of bone marrow clinically masquerading as systemic or metastatic tumor. Haemotologica 1991;76:248-250.

7. Panum PL. Experimentelle beitrage zur lehre von der embolie. Virchow's Arch Pathol Anat Physiol 1862;25:308-310.

8. Flory CM. Arterial occlusions produced by emboli from eroded aortic atheromatous plaques. Am J Pathology 1945;21:549-565.

9. Richards AM, Eliot RS, Kanjuh VI, et al. Cholesterol embolism: a multiple-system disease masquerading as polyarteritis nodosa. Am J Cardiol 1965;15:696-707.

10. Retan JW, Miller RE. Microembolic complications of atherosclerosis. Arch Intern Med 1966;118:534-545.

11. Koga J, Ohno M, Okamoto K, et al. Cholesterol embolization treated with corticosteroids. Angiology 2005;56:497-501.

12. Adkinson NF, Younginger JW, Busse WW, et al. In: Middleton's Allergy: Principles and Practice, Mosby. Philadelphia, 6th edition, 2003:143.

13. Moldveen-Geronimus M, Merriam JC Jr. Cholesterol embolization: from pathological curiosity to clinical entity. Circulation 1967;35:946-953.

14. Maurizi CP, Barker AE, Trueheart RE. Atheromatous emboli: a postmortem study with special reference to the lower extremities. Arch Pathol 1968;86:528-34.

15. Kazmier FJ, Bergan JJ, Yao JST. Aortic Surgery. Philadelphia: WB Saunders, 1989:189-194.

16. Belenfant X, Meyrier A, Jacquot C. Supportive treatment improves survival in multivisceral cholesterol crystal embolism. Am J Kidney Dis 1999;33:840-850.

To get back my youth I would do anything in the world, except take
exercise, get up early, or be respectable.
--Oscar Wilde

Matthew D. Reuter, MD, Paula J. Chor, MD, Amanda Dehlendorf, MD, and Martin A. Alpert, MD

From the Departments of Medicine and Pathology, St. John's Mercy Medical Center, St. Louis, MO.

Presented at the 100th Annual Scientific Assembly of the Southern Medical Association.

Reprint requests to Dr. Matthew D. Reuter, Suite 3019-B, St. John's Mercy Medical Center, Department of Medicine, 621 S. New Ballas Road, St. Louis, MO 63141. Email: [e-mail]

Accepted August 29, 2006.

RELATED ARTICLE: Key Points

* Cholesterol crystal embolization may occur following arterial trauma or anticoagulation.

* Spontaneous cholesterol crystal embolization has been reported.

* The clinical features of cholesterol crystal embolization reflect sites of embolization such as skin and muscle.

* Cholesterol crystal embolization to bone marrow has been reported premortem twice before in patients with characteristic clinical features.

* To our knowledge, this is the first reported case of cholesterol crystal embolization to bone marrow diagnosed premortem in a patient with an atypical clinical presentation.