CASE REPORT

            CASE REPORT- A                                                       CASE REPORT- B

CASE REPORT - B
CHOLESTEROL CRYSTAL EMBOLIZATION SYNDROME

Muhammad Asim, MBBS, MRCP

 Introduction

 Case Presentation

 DISCUSSION

 References
 MEDICAL HUMOR

Introduction

Low density lipoprotein (LDL) particles had been filtering through the luminal endothelium of the aortic wall penetrating into the intimal layer.
Here, they were oxidized and then engulfed by macrophage forming foam cells – the hallmark of atherosclerotic lesion.
Together with intercellular lipid, the foam cells constituted the fatty streaks.
Fibrous cap, composed of ground substance, collagen fiber and reticulum fibrils had covered some of the lipid cores to form the fibrous plaques.
The engorgement of foam cells with lipids led to cellular necrosis and release of cholesterol esters.
Destruction of vasa-vasorum and local hypoxia had set the stage for the final complication, plaque rupture.
Platelet-fibrin thrombi actively sealed the cracks that had started to appear on the surface of plaques.
These tiny clots formed the last barrier between the cholesterol crystals in the plaque, and the circulating blood.

Case Presentation

A 58-year-old Indian gentleman with no history of ethanol abuse was brought to the hospital in acute confusional state.
His medical record revealed that he had hypertension and ischemic heart disease.
A coronary arteriography performed two months before admission showed severe stenosis of the circumflex artery.
A percutaneous coronary angioplasty was planned but was postponed as he developed left hemiparesis soon after the angiogram.
CT scan of head showed right frontoparietal and occipital infarction. The neurological deficit, however, resolved almost completely within a week and was discharged.
He was re-admitted 6 weeks later with uncontrolled hypertension (220/ 150 mmHg), left ventricular failure.
and renal impairment (creatinine 250 umol/l). His clinical condition improved with a combination of a loop diuretic, intravenous (IV) nitrate and ACE inhibitor.
However, his creatinine rose to 367 umol/ l.The ACE inhibitor was withdrawn and diuretic dose was reduced and his serum creatinine came down and stabilized at around 260 umol/ l. No vascular bruits were heard and the renal ultrasound did not show any renal asymmetry.
Doppler study could not be done due to technical difficulties.
An autoantibody screen was negative and complement studies were normal.
Quantification of proteinuria showed a daily loss of about 0.5g/ day.
The patient had an episode of “acute delirium” that responded to haloperidol.
He was discharged with the following medications: atenolol, isosorbide dinitrate, aspirin and haloperidol.
Arrangements were made for him to be seen in the nephrology clinic after MRA of renal arteries. Physical examination at the time of current admission showed that he was disoriented in time, space and person.
Temperature was normal and BP 160/ 100mmHg. There were no focal neurological signs or meningism.
There was no skin rash. Examination of the heart, chest and abdomen was unremarkable.
Fundoscopic examination revealed bright yellow plaques at the bifurcation of retinal arterioles in the right fundus.
CT scan of the head showed old infarction in the right frontoparietal and occipital region. Laboratory findings showed creatinine 496 umol/ l, BUN 16 mmol/ l, Na 128 mmol/ l, K 5.5 mmol/l, HCO3 21 mmol/ l, Glucose 6.2 mmol/ I, Hb 11g/ dl, ESR 44, WBC 12,000 and Platelets 145,000. He passed very little amount of urine in the next 12 hours and there was progressive deterioration in serum biochemistry. The mental status however improved spontaneously.
A detailed review of old notes revealed that a couple of months ago, i.e. before the coronary angiogram, his renal function was normal.
A renal ultrasound ruled out hydronephrosis. MRA of renal vessels did not show any stenosis.
A repeat serum complement study showed reduced C3. Percutaneous renal biopsy was performed and light microscopy showed needle shaped cholesterol clefts in several blood vessels (figure 1).
No significant changes were noted in the glomeruli or the interstitium.
The patient required hemo-dialysis. Further clinical course is not known as he went back to his home country.

DISCUSSION

Cholesterol Crystal Embolization Syndrome (CCES) is a multisystem disorder resulting from occlusion of small caliber arteries in multiple vascular beds by cholesterol emboli.
These emboli originate from eroded atheromatous plaques in the aorta or major blood vessels.
Panum in 1862 noted occlusion of coronary arteries by atheromatous material at autopsy and described it as a pathological curiosity.
In1945 Flory1 found evidence of cholesterol emboli in multiple organs and CCES became a recognized pathological entity.
This syndrome is more frequently diagnosed in men than in women2,3 probably due to higher prevalence of atherosclerosis in men.4 The proximity of the kidneys to the abdominal aorta and the large renal blood supply make the kidney a frequent target organ for atheroemboli.5 CCES is frequently overlooked as a cause of renal dysfunction during life.
Cholesterol embolization in kidney causing renal failure was first reported by Thurlbeck & Castleman.
They found out that the majority of patients who died after aortic surgery had cholesterol emboli in their kidneys.
Interestingly, these emboli were never seen in the kidneys of patients whose aorta was free from atherosclerosis.
6 In addition to kidneys, cholesterol emboli have been described in skin, muscles, G.I.tract, heart, brain, bone and various other anatomic sites.2,4 Vascular radiology investigations and vascular surgery are the usual precipitating factors.4,7,8 Coronary arteriography is a notorious precipitating procedure.2,3,4,9,10 Aortic manipulations during surgery and mechanical trauma induced by angiographic catheter can dislodge atheromatous material from the plaques.
Anticoagulation and thrombolysis have been associated with CCES. Anticoagulants11,12,13 and thrombolytic agents14,15 dissolve or impair the build-up of clots isolating the contents of ulcerated plaques from the circulation.
It is possible that many cases of “purple toe syndrome” associated with oral anticoagulation maybe a manifestation of CCES.
Arteriolar obstruction with subsequent peripheral desaturation of blood can explain cyanotic toes.
11 Spontaneous renal cholesterol embolization can also happen in the absence of a recognizable precipitating factor. The cholesterol emboli occlude the lumina of small caliber arteries stimulating endothelial

Fig.1 - Cholesterol clefts. Courtesy – Dr. A. C. Lopez, Department of Pathology, HMC

proliferation and perivascular fibrosis.16,17 The cholesterol crystals behave like a foreign body.
The first response consists of mononuclear cells, foreign body giant cell reaction and transient appearance of neutrophils and eosinophils.
A process of thrombosis then takes place followed by fibrous organisation.
This can lead to luminal obstruction18 and ischemia to the tissues distal to the site of cholesterol embolism.
Cholesterol crystals can be detectable up to nine months after the acute event.
These crystals are dissolved during tissue fixation for histological examination, leaving behind biconvex needle shaped clefts in the blood vessels (fig.1).
Ischemic glomerular changes are often seen in the form of “collapsed glomeruli” and wrinkled basement membrane. Acute renal failure with necrotizing glomerulonephritis related to CCES has also been reported.16,17,19 CCES presents clinically as: a) Acute CCES after an invasive Vascular/ radiological procedure and b) Indolent CCES characterised by progressive renal failure20 and diagnosis is made at renal biopsy.
The acute form produces a variety of clinical syndromes ranging from livedo-reticularis, cyanotic toe to multiorgan involvement mimicking vasculitis.
21 The renal features are quite different from those seen with clot emboli related to cardiac arrhythmias and myocardial infarction.
Thus, flank pain, hematuria and rise in LDH22 is unusual in CCES.
This is because cholesterol emboli produce incomplete occlusion with secondary ischemic atrophy rather than infarction.23 The interval from the inciting event to the onset of renal symptoms varies greatly.
Some patients show immediate renal dysfunction but in others appearance of symptoms could be delayed by weeks or months.2,3,4,24,25 Renal impairment can also rogress in a step-wise fashion due to cyclical shedding of cholesterol crystals.
The degree of renal dysfunction can likewise be mild, moderate or severe requiring dialysis support at least temporarily.
A number of patients recover some renal function due to resolution of concurrent acute tubular necrosis in borderline ischemic areas, recanalization of organised thrombus,26 development of collateral blood flow or hypertrophy in surviving nephrons.8,10,23 Major extra-renal features are seen in the skin (livedo-reticularis, digital cyanosis with well preserved peripheral pulses2,4,9,24 and gangrene), heart (congestive heart failure),nervous system (Amaurosis fugax, TIA, cerebral infarction, confusional state) and gastrointestinal tract ( abdominal pain, diarrhea, malabsorption, infarction and perforation).
A decrease in creatinine clearance and hematoproteinuria are common. Hematuria is usually microscopic and proteinuria is low grade though nephrotic range proteinuria has been reported.
Eosinophilia is the most common hematological feature and is seen in 14%-71% of cases.10,27,28 An increase in ESR is frequent with very low false negative rate suggesting that a normal ESR is a strong evidence against the diagnosis of CCES. Hypocomplementemia (low C3), due to complement activation resulting from exposure of plasma to cholesterol crystals in the plaque, is a frequent accompaniment of CCES. This in turn can amplify the inflammatory response causing vascular damage associated with CCES. Receptors for activated complement fragments have been identified within the atherosclerotic lesions.29 CCES is a great mimicker because of its protean clinical manifestations.
After a contrast study, the usual diagnostic challenge is to differentiate CCE from contrast nephropathy.

Typically, contrast-associated nephropathy causes an abrupt onset of renal insufficiency within 12-24 hours following contrast administration.
Creatinine rises over the ensuing 2-3 days, generally stabilizes by days 3-5 and usually improves over the next 7-10 days.30 On the other hand, renal dysfunction in CCE develops insidiously over days to weeks following the procedure.2,6,8,21,31 Similarities between multiple cholesterol crystal emboli and small vessel vasculitis are striking but the latter is usually associated with a positive ANCA.
The diagnosis of CCES can be made confidently in the presence the triad of an inciting event, renal impairment, and specific set of clinical features of peripheral cholesterol embolism.
Our patient was admitted because of acute confusion without focal neurological deficits.
Laboratory tests showed renal impairment, elevated ESR, and reduced serum C3.
CT scan of the head showed old infarctions in the right frontoparietal and occipital area.
A detailed review of his medical record revealed that his renal function was normal before he underwent coronary arteriography.
This made us wonder about CCES as a cause of his renal failure, embolic stroke, and episodic confusion. This was confirmed on fundoscopic examination, which showed typical cholesterol emboli in the right fundus.
Percutaneous renal biopsy provided definite diagnosis of CCES.
Until recently, CCES was considered to have a dismal overall prognosis.
The first year mortality rates of acute disseminated CCES in various studies ranged from 65%-85%. The three main causes of death are recurrent bouts of cholesterol embolization, cardiac failure and cachexia.
However, with an intensive supportive treatment regimen,27 a mortality rate of as low as 23% has been described.
Since anticoagulation may interfere with healing of ulcerated plaques,11,23,32,33 the most important treatment strategy is to avoid anticoagulation and aortic instrumentation in patients with this diagnosis.
Belenfant et al have instituted a strict regimen of withdrawal of anticoagulation, despite strong clinical indications for further cardiological/ renal arterial interventions in a number of patients.27 However, if continued anticoagulation is essential, other investigators have suggested intermittent parenteral heparin therapy to minimize further atheroembolism.34 Intermittent release of heparin from subcutaneous administration provides a short anti-coagulant free period that might permit some healing of eroded plaques.
There is disagreement regarding the use of steroids.

Some reports indicate that steroids may be beneficial.27,35 The logic behind the use of steroids is the presence of inflammatory reaction associated with cholesterol emboli, evidenced by high ESR, CRP and serum complement changes.
There are reports of favorable effect on mesenteric ischemia and severe lower limb ischemic pain.
On the other hand, some studies have shown 100% mortality with steroids.4 Cardiac failure is the leading cause of death in patients with CCES and should be treated with a combination of loop diuretics and high dose vasodilators.36 ACE nhibitors can be particularly helpful in view of the activation of renin-angiotensin system and renin induced hypertension in these patients. Despite the presence of renal impairment (and underlying renal artery stenosis in some of these patients), many patients tolerate the ACE inhibitors quite well.
High catabolic rate due to occluded vascular beds and mesenteric ischemia can cause malnutrition, which is another cause of high mortality in patients with CCES. Particular attention has to be given to the nutritional requirements in these patients; some of these patients would be candidates for enteral/ parenteral nutrition.
Both peritoneal dialysis and hemodialysis have been used in patients with CCES and renal failure.
Better outcome was reported with peritoneal dialysis in one study37 but in fact, heparin free (or low dose heparin) hemodialysis is probably the preferred mode of dialysis since peritoneal dialysis is associated with considerable protein loss and high risk of peritonitis in these frail patients.27 Mesenteric ischemia is considered a definite contraindication to peritoneal dialysis.
Statins might play a role in plaque stabilization and regression38,39 but their role has not been evaluated in a proper prospective study. Surgical excision of the source of cholesterol crystal emboli is usually not a feasible option as most patients are too fragile to undergo major surgery and also because the source of cholesterol emboli is frequently not certain.
The population at risk of developing CCES (elderly subjects with aortic atherosclerosis) is increasing; angiographic and vascular surgical procedures are becoming a routine practice and there is widespread use of thrombolytic therapy for Myocardial infarction and systemic anticoagulation in cardiac arrhythmias.
It can therefore be predicted that CCES will be diagnosed more frequently in the coming years. It is important that clinicians should have a high index of suspicion to diagnose CCES and institute early and appropriate therapy.
© 2001 Hamad Medical Corporation

References

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MEDICAL HUMOR