Cardiomyopathy, nephropathy, and death in a 44-year-old man

CLINICOPATHOLOGIC CONFERENCE

i-.---i

Cardiomyopathy, Nephropathy, 44-year-old Man

A

44-year-old white male was admitted to Barnes Hospital September 4, 1990 for evaluation of dyspnea and cough. Five months prior to admission the patient developed sinus drainage and hoarseness that was not relieved by decongestants. Three weeks prior to admission he noted increasing dyspnea. Four days prior to admission he was seen in the emergency room for dyspnea and cough; a chest radiograph revealed a right perihilar infiltrate, a right pleural effusion, and cardiomegaly. He was given oral antibiotics without relief and was admitted four days later. He denied fever, chills, or chest pain but did note rusty colored sputum. The patient was well until four years ago, when he presented with hypertension, hematuria, and proteinuria. A renal biopsy revealed advanced nodular glomerulopathy, a thickened basement membrane, hyahne deposition in the arterioles and glomeruli, and interstitial fibrosis with chronic inflammationah consistent with a diagnosis of kappa light chain disease. In July 1988, a bone marrow biopsy showed a normal pleomorphic pattern and normal maturation of the myeloid and erythroid series, with an increased M:E ratio of 1O:l. There was no increase in the number of lymphoid cells. The biopsy was thought not diagnostic for multiple myeloma. He was treated with melphalan, prednisone (7-8 months), and cytoxan. Three years prior to admission the patient developed chronic renal failure requiring dialysis; he was listed for a renal transplant. He had an 80 pack-year smoking history. On physical examination, the temperature was normal, the blood pressure 122/82 mm/Hg, the heart rate 82/min, and the respiratory rate 16/min. The head, eyes, ears, nose, and throat were normal. There were diminished breath sounds in the right base; no wheezes were noted. Cardiac examination revealed a nondisplaced point of maximal impulse, normal heart sounds, and no murmurs; an S4 was present. There was no jugular venous distention or hepatojugular reflwr. Normal bowel sounds were

Am J Med. 1997;102:496-502. Stenographic reports of weekly cllnicopathologic conferences held In Barnes and Wohl Hospitals are published bimonthly in the Journal. Members of the Departments of Internal Medicine, RadIology, and Pathology of the Washington University School of Medicine participate jointly in these conferences. Kenneth M. Ludmerer, MD, and John M. Kissane, MD, Washington University School of Medicine, are the editors of this feature.

496

01997 by Excerpta All rights resewed.

Medica,

Inc.

and Death in a present; there was mild right lower quadrant tenderness without rebound. No masses or organomegaly were detected. There was no pedal edema, and the neurological examination was unremarkable. The hemoglobin level was 8.2 g/dL, the hematocrit value 24%, the platelet count 257,000/mm3, and the white blood count 7,200/mm3. The serum sodium was 131 mmol/L, the chloride 93 mmol!L, the potassium 3.5 mmol/L, the bicarbonate 26 mmoYL, the creatinine 10.0 mg/dL, the blood urea nitrogen (BUN) 80 mg/dL, the lactic dehydrogenase (LDH) 127 IU/L, the creatine kinase (CK) 84 Ill/L, the albumin 2.9 mg/ dL, the total protein 5.5 gm/dL, and the uric acid 8.2 mg/dL. Total bilirubin, calcium, alkaline phosphatase, serum glutamic oxaloacetic transaminase (SGOT), and cholesterol were normal. The urinalysis revealed a pH of 5, a specific gravity of 1.012, 3+ albumin, negative occult blood, and1 3 to 4 white blood cells/high-power field. The chest radiograph revealed cardiomegaly, a possible right middle lobe infiltrate, and a right side pleural effusion; there was also evidence of old granulomatous disease. An electrocardiogram (ECG) showed normal sinus rhythm, a nonspecific intraventricular conduction delay, a prolonged QT interval, and premature ventricular contractions (PVCs) (Figure 1). Therapy with Timentin was started for a presumed diagnosis of pneumonia. The patien.t continued to have dyspnea. On September 11 he developed chest pain. Arterial blood gases on room air revealed a pH of 7.46, a pC0, of 30 mm Hg, and a pOZ of 103 mm Hg. Lower extremity dopplers were negative. An echocardiogram revealed marked biatrial enlargement and moderate left ventricular s:ystolic dysfunction consistent with ischemic or dilated cardiomyopathy. There was increased echogenicity of the myocardium consistent with an infiltrative process. A serum protein electrophoresis was performed. The total protein was 5.3 gm/dL, the albumin 2.9 gm/dL, the alpha-l component 0.5 gm/dL, the alpha-2 component 0.7 gm/dL, the beta globulin 0.7 gm/dL, and the gamma globulin 0.4 gm/dL. On September 13 a dipyridamole thallium test was performed, which revealed a partially reperfusing deffect in the inferior and lateral ventricular wall consistent with circumflex disease. !Left anterior descending (LAD) ischemia was also noted. On September 19 right and left heart catheterization was performed. No evidence of coronary artery disease was observed, though the left ventricular end diastolic pressure (LVEDP) was severely elevated (30 mm Hg). The mean pulmonary capillary wedge presooo2-9343/97/$17.00 PII soclo2-9343(97)00100-9

CPC/CARDIOMYOPATHY,

TABLE

NEPHROPATHY, AND DEATH

I

Key Findings Chronic renal failure (proternuria) - Congestive heart failure Pulmonary hypertension (out of proportion to CHF) - Hemoptysis (pulmonary infiltrate) Upper respiratory symptoms (sinus drainage, hoarseness) l

l

l

TABLE

II

Figure 1. EKG at time of hospital admission for the patient. -

Key Cardiac Findings Congestive heart failure High LVEDP Impaired systolic and diastolic performance Pulmonary hypertension Abnormal thallium (DIP/delay) Normal epicardial coronary arteries Regional wall motion abnormalities (concordant with ZolTI defect) Increased echogenicity of myocardium

sure was 14- 16 mm Hg. The pulmonary artery pressure (PAP) was 75/35 mm Hg. An endomyocardial * biopsy revealed occasional hypertrophic muscle fibers and sparsely scattered lymphocytes. There was no significant fibrosis and no evidence of amyloid by Congo red stain. . A thoracentesis revealed 900 cc of serous fluid with the following laboratory values: specific gravity 1.010; glucose 128 mg/dL; LDH 34 IU/L; total protein 0.7 gm/dL. Cytologic analysis was negative, as were have amyloidosis and do stain positive for a.myloid all cultures. On September 21 bronchoscopy was by Congo red.le4 What are the key issuesinvolved? In this case (Taperformed, which revealed visible bleeding in the ble I) the key findings are: 1) chronic renal failure left upper lobe. No endobronchial lesion was seen. with proteinuria, and 2) congestive heart failure The patient became apneic later that day. Resusci(CHF). We have to decide whether the CHF is due tation was unsuccessful. to a dilated or restrictive cardiomyopathy, because the patient has some features of each. He certainly CLINICAL DISCUSSION has systolic dysfunction and possibly diastolic dysDr. Edward M. Geltman: I would like to begin function. He had marked pulmonary hypertension by making a few comments about the protocol. The with a PA systolic of 65 and RV systolic of 75. The ECG is not terribly specific. With the S-waves across pulmonary hypertension seems to be out of proporthe precordium and the SI-QIII pattern, right ventriction to the degree of LV dysfunction. A PA wedge ular hypertrophy is suggested, as in chronic obstruc- pressure mean of about 16 is insufficient to cause tive pulmonary disease or pulmonary emboli. In- the elevated PA diastolic pressure. The data indicate creased echogenicity on an echocardiogram needs that there is increased resistance in the pulmonary to be interpreted cautiously because that finding is microvasculature. The patient has hemoptysis, very machine- and operator-dependent. When pres- which certainly can be due to heart failure, but some ent, it suggests an infiltrative process in the myocar- other primary pulmonary process could be etiologidium. It sometimes occurs in patients with chronic tally important. The patient did manifest upper rerenal failure because the calcium and phosphate ab- spiratory symptoms, sinus drainage, and hoarseness. normalities of renal failure can lead to calcification We would like to try to see if there is any way to put and subsequent fibrosis in the myocardia. The ob- these findings together with a single diagnosis. Alservation in this patient of an LVEDP more elevated ternatively, are all of these findings just a viral :illness than the average PA capillary wedge pressure sug- causing a cardiomyopathy? Is there one diagnosis gests that the elevated LVEDP resulted from an A that we can find that will cause renal failure, conwave, consistent with some degree of restrictive gestive heart failure, pulmonary hypertension, hephysiology. The material from the myocardial biopsy moptysis and upper respiratory symptoms, which is did not stain positive by Congo red stain. However, associated with kappa light chains in the urine? Key cardiac findings (Table II) are congestive light chains do not necessarily stain positive with Congo red. There have been descriptions of patients heart failure, a high LV end-diastolic pressure, imwith light chain deposition disease where the depos- paired systolic and diastolic performance, pulmoits are amorphous and fibrillar in nature, which may nary hypertension, and abnormal thallium, suggeststain negative with Congo red. Of course, many pa- ing regional abnormalities of perfusion at a time tients with light chain deposition disease do in fact when the epicardial coronary arteries are normal, l

l

May

1997

The American

Journal

of Medicine8

Volume

102

497

CPC/CARDIOMYOPATHY,

NEPHROPATHY, AND DEATH

and regional wall motion abnormalities that match the thallium defects. We have possible increased echogenicity of the myocardium. We have heart disease, lung disease, renal disease, and the heart diseasewith regionality. At this time, I would like to ask our radiologist to review the radiographic data. Dr. Paul Molina: The admission chest radiograph shows a mildly enlarged heart and small bilateral pleural effusions. Enlarged central pulmonary arteries are also seen, compatible with pulmonary arterial hypertension. No pulmonary infiltrates are present. Subsequent chest CT examination confirmed the plain lilm findings and also demonstrated several mildly enlarged pretracheal lymph nodes. No definite parenchymal or endobronchial lesions were noted. Dr. Geltman: Thank you very much. Could all of the findings in this patient be due to kappa light disease (Table III)? Light chain deposition disease can occur with or without frank amyloidosis, and light chain disease can occur with or without a malignancy, specifically a malignancy of plasma cells. Light chain deposition disease can occasionally occur with other malignancies, or be due merely to an over production of a kappa light chain in the absence of a malignancy. Alternatively, we could try to tie this all together with a vasculitis affecting the heart, lungs, and kidneys. The patient has sinusitis and hoarseness. Wegener’s is something that comes to mind as an entity that can cause upper respiratory and pulmonary abnormalities. Usually pulmonary hypertension is not part of the picture. Polyarthritis nodosa would be unlikely since it usually spares the lungs. There could be some vasculitic process. Sarcoid was mentioned; that can certainly affect the heart, lungs, and kidney. The patient had renal pathology that was most likely due to kappa light chain deposition. I’ll focus on light chain disease and amyloidosis because of the renal pathology and the echogenicity of the LV. Another possibility is that there could be several combined illnesses-for instance, chronic renal failure due to the kappa light chain disposition ehich led to hypertension, which in turn caused LV dysfunction that resulted in multiple pulmonary emboli or some other ultimate cause of pulmonary hypertension and death. The latter approach is much less intellectually satisfying. How did this patient develop proteinuria comprised of light chains? Immunologically, the appearance of light chains in urine is usually thought of as an overflow because of excess production and release into the circulation. The light chains are small molecules that can be filtered by the glomerulus and excreted in the urine. There appears to be an overflow, which could come from overproduction of a normal clone, a poly clonal over production, or an abnormal monoclonal overproduction. The patient 498

May

1997

The American

Journal

of Medicine@

Volume

102

TABLE III Potential Diagnoses . K Light Chain Disease (Amyloidosis) With or without malignancy (myeloma? lyi-nphoma?) . Vasculitis Polyarteritis nodosa Wegener’s granulomatosis . Sarcoidosis . Several combined illnesses CRF + HTN -+ LVH -, CHF + PE or CRF+ HTN and post-viral CM +/- PE

also had albuminuria and frank nephrotic syndrome, which could be due to excessive glom1erula.rpermeability allowing larger molecules to be filtered. It is quite reasonable to postulate that an excess of light chains filtered over a long enough interval could damage the glomerulus and its filtration mechanism and lead secondarily to albuminuria atnd nephrotic syndrome. It is possible that the biopsy was wrong, and there was a vasculitic process, but that is certainly not my primary diagnosis. There are a number of processes that can lead to a rapidl;y progressive glomerulonephritis and nephrotic syndrome. The differential diagnosis includes the vasculitides, polyarthritis, and Wegener’s as well as the nephropathy due to immunoglobulins. The most likely diagnoses are a vasculitic process or an immune deposit process, in this case, the kappa light chains, which could be from a malignant source or form benign overproduction. I would like to discuss the differential diagnosis of a monoclonal glomerulopathy, even though the patient did not have elevated gamma globulin. He did have an abnormal immunoprotein in his urine. The thought process in the differential diagnosis is quite similar because you have a clone or multiple clones of cells overproducing immunoglobulin, which can be either a plasma cell myeloma or a benign excess of plasma cells, a premyelomatous condition. There are occasional reported cases of a lymphoproliferative nonmyelomatous disease producing a light chain excess, but this is uncommon. T1hereare nonmalignant illnesses which can cause increases in the globulins (like rheumatoid arthritis), which in turn can cause secondary amyloid. However, these illnesses are not really operative in this patient. Patients with a gammopathy can shlow dramatic temporal variability in the amount ojf paraprotein present in the plasma. Therefore, with a. single serum protein electrophoresis, one might miss the diagnosis. I’m going to presume that this patient had an abnormality of deposition of paraprotein in his tissue. We know he had it in his kidneys.. I’m going to at least begin with the assumption that this process

CPC/CARDIOMYOPATHY,

cardiomyopathy

40

60 End-Diastolic

Volume

120 (ml)

160

Figure 2. Enddiastolic pressure increases exponentially as enddiastolic volume increases in normal hearts. In patients with disorders involving still ventricles (eg, amyloidosis, hypertrophic cardiomyopathy) a small change in enddiastolic volume causes a large change in end-diastolic pressure. In patients with chronic volume overload or dilated cardiomyopathy, the relationship is quite flat, until the limit of distensibility of the ventricle is reached, at which point the curve be comes very steep.

be going on in other organs. The deposition could be of an amyloid protein or a nonamyloid immunoglobulin. Light chain deposition disease can be associated with frank amyloidosis with typical staining amyloid or it can be associated with an amorphous, non-Congo red staining material.3*4The staining characteristic is related to the portion of the light chain that is secreted; the proportion of variable portion and tied regions secreted will determine whether the pleated sheets of pathologic protein are deposited in tissue, which we call amyloid.5*6 Whether it is pleated sheets or amorphous in nature, if a sufficient mass of protein is deposited, there can be interference with normal organ function. In general, amyloidoses have been classified as either AL, the type which is seen in primary amyloidosis, or AA, the kind secondary to chronic infection illness, chronic inflammatory bowel disease, or arthritides.7 I will focus on the AL type, which is seen in primary amyloidosis, and would be seen if this patient had myeloma and a premyelomatosis condition, such as light chain deposition disease. Nephrotic syndrome and congestive heart failure are fairly frequent initial presentations of amyloidosis. Among patients with amyloidosis but no myeloma, nephrotic syndrome and congestive heart failure are the two most frequent forms of presentation. Symptoms of amyloidosis are very nonspecific. They include fatigue, weight loss, pain, and bone pain if frank myeloma is present. Gross bleeding can occur because of factor 10 deficiency. Purpura can occur as well, and there are often other abnormalities on physical examination, such as palpable liver, spleen, lymphadenopathy other than mediastinal lymphadenopathy and macroglossia. 7

might

NEPHROPATHY, AND DEATH

This patient exhibited none of these. This, patient doesn’t have the appearance of frank amyloidosis. It appears that the probability of amyloidosis is somewhat less likely due to the atypical presentation in this patient. Proteinuria occurs frequently and in fairly substantial amounts in patients with amyloidosis. Bence-Jones protein is present in a significant but small proportion. Light chains are present in the urine in a significant proportion of patients with AL type amyloidosis, but the kappa light chain is not the most frequent. I am not going to let that dissuade me from this train of thought. The appearance of the initial bone marrow biopsy is not very predictive of prognosis.7 At initial presentation, a large proportion of patients with amyloidosis do not have a very high percentage of plasma cells in their bone marrow without having myeloma. The fact that the patient had a modest number of plasma cells and the bone marrow was not diagnostic of myeloma does not dissuade me from thinking the patient could subsequently develop a deposition disease of either just a kappa light chain of frank amyloid. How do we analyze the cardiac problems of this patient? Is the heart disease congestive or :restrictive? There certainly are different differential diagnoses.* The patient exhibited some features of each. On the echocardiogram there was some restriction to left ventricular filling, but there were definite abnormalities of systolic function as well. The patient has some features of both congestive and restrictive cardiomyopathy. Since we are mostly concerned about amyloidosis and deposition diseases,we will focus on restrictive pathology. The left ventricular pressure volume curves are quite different in patients with congestive and restrictive cardiomyopathy (Figure 2). With a dilated myopathy there is a gradual increase in pressure as volumes increase until the limits of distensibility are re.ached. With restrictive myopathy ventricular pressube rises more steeply as volume is increased. This patient’s left ventricular waveforms recorded at catheterization were not classic for restrictive physiology. The classic pressure waveform of restriction is comprised of a short and sharp rapid filling phase wave followed by a plateau and a prominent atrial filling wave. The right ventricular pressure waveform parallels the LV pressure curve with a small difference between them, with relative equalization of pressures (Figure 3). The differential diagnosis of restrictive cardiomyopathy includes: 1) endomyocardial fibrosis; 2) amyloidosis; 3) sarcoidosis; 4) hemachromatosis; 5) Fabry’s disease; and 6) idiopathic or primary restrictive cardiomyopathy. In a series of patients who succumbed to amyloid heart disease and had autopsies, pulmonary artery systolic pressure ranged from 36May

1997

The American

Journal

of Medicine”

Volume

102

499

CPC/CARDIOMYOPATHY,

NEPHROPATHY, AND DEATH

Figure 3. Pressure

wave forms from a patient with restrictive myopathy. The solid line represents left ventricular pressure dashed line represents right ventricular pressure. In early dip a prominent plateau (arrowheads) and a prominent atrial wave arrow) are seen.

cardioand the (arrow), (curved

70, averaging 57.” They can have significant elevations of PA pressures. Our patient had a PA pressure of 65. PA diastolics were generally in the 3Os, as in the patient discussed here. In this instance there was increased pulmonary resistance which is typical of published series of patients with cardiac amyloidosis. In addition, pulmonary artery wedge pressures are elevated, but the wedge pressure was normal in this case. The increased pulmonary resistance makes me think more about the potential for the vasculitides in this case. The age of presentation of our patient is fairly typical for patients with amyloidosis. Echo findings do not exclude amyloidosis since normal wall thickness can be seen in about 25% of patients with documented cardiac amyloidosis.‘“-‘” Patients with normal wall thickness and amyloidosis usually don’t have overt CHF and have longer median survival than patients with cardiac amyloidosis and more severe echocardiographic manifestations.” In this case we have a disparity between normal wall thickness and significant LV systolic and diastolic dysfunction. The other echocardiographic findings indicative of amyloidosis are increased myocardial echogenicity, increased intra-atria1 septal thickness, RV wall thickness and increased thickness of the valves, none of which were present in this case. Another diagnostic hint is the ratio of the R wave height in the electrocardiogram to LV mass derived by echocardiography. With cardiac amyloidosis the R waves are relatively small by EKG compared to the thickened walls. The EKG in this patient is not suggestive of an infiltrative myopathy. Among patients with cardiac amyloidosis, cardiac disorders are major causes of death, as is renal disease. Pul500

May

1997

The American

Journal

of Medicine*

Volume

102

monary abnormalities are relatively infrequent causes of death in patients with cardiac amyloidosis. We must consider the vasculitides alswell. There are a large number of them to consider. Polyarteritis nodosa and Wegener’s granulomatosis are two I will focus on. In autopsy studies of patients dying of polyarteritis, the lung, heart, and kidney are frequently involved in the diseaseprocess. l3 Involvement of the kidney is ubiquitous, the lung is less frequently involved, and the heart is involved in about 25-35% of patients. Renal failure is a common cause of death in polyarteritis, although CHF is a relatively infrequent cause of death.‘“,” Among patients with Wegener’s gnmulomatosis, pulmonary infiltrates are noted at initial presentation in 71% of patients, with sinus involvement in 67%, rhinitis in 22%, and cough in 34%. Renal failure can be evident at initial presentation in 11% and cardiac abnormalities can be seen as well.” In general involvement of the lung and kidney are prominent in Wegener’s. The heart is less frequently involved, but it is not a rare event. Coronary arteritis can be found in up to 50% of patients dying with Wegener’s. Wegener’s can affect the vasculature of the lung, heart, and kidney along with nearly any other organ. So we must consider Wegener’s because of the pulmonary hypertension, but Wegener’s is a rare cause of pulmonary hypertension.‘“,‘” In summary, we are in a quandary. We have conflicting data. We have a kidney biopsy showing kappa light chains and findings suggestive of amyloid type deposits. We have a myocardial lbiopsy which does not show them. So we have disparate data; which do we weigh more heavily? A wise man once told me that absence of evidence is not evidence of absence. So the fact that we don’t see something does not mean it is not there. We may merely have a sampling problem. I am going to conclude that the central problem in this patient is a deposition disease due to the kappa light chains. Whether the protein stains with Congo red or not will depend upon whether 1:he protein is amorphous or in pleated sheets as amyloid. I believe the process is involving the heart. The regional wall motion abnormalities of the heart are a little bothersome, but there is a manuscript by Dr. Saffitz describing two cases of myocardial infarction induced by deposits of amyloid in the coronary arteries.17The amyloid does affect coronary arteries and can affect any arteries, so that there may be amyloid in the pulmonary arteries and arterioles as well as in the coronary arteries and the arteries of the kidney. I think that vasculitis is less likely since there is no fever, arthralgia, or other systemic symptoms. In addition, the indolent course of a $-year illness makes arteritis somewhat less likely.

CPC/CARDIOMYOPATHY,

Figure 4. Massive

deposition of amyloid in the wall of a small intramural coronary artery reducing the lumen to a central slit. No significant interstitral amyloid deposrtion is seen. In other areas, amyloid completely replaced vessels and was seen as bulky nodular accumulations in perivascular spaces. (Original magnification 100X.)

Therefore, my final diagnosis is a protein deposition disease involving kappa light chains with or without frank amyloid, depending upon the staining characteristics. The process involves the heart. I think the pulmonary abnormalities are probably secondary to the heart failure, although there might be amyloid deposition in the pulmonary arterioles causing the elevated pulmonary resistance. I would not be surprised if the kidney disease is related to the amyloid.

PATHOLOGICAL DISCUSSION Dr. Jeffrey Saffitz: Autopsy revealed that the patient had primary amyloidosis that was presumably related to a kappa light chain gammopathy. The organs involved included the heart, lungs, kidneys, liver, spleen, and gastrointestinal tract. This organ distribution is typical of amyloidosis related to B cell dyscrasias. Chemical characterization of the amyloid was not reported, but it is likely that it was the AL type and composed mainly of denatured kappa light chains. Despite the typical organ system involvement, the pattern of distribution within each individual organ was unusual in that the accumulation of amyloid was confmed largely if not exclusively to blood vessels. The most extensive amyloid deposition was observed in the heart, which weighed 570 g (normal < 400 g) and exhibited a globular configuration due to four-chamber dilatation. The epicardial coronary arteries showed mild to moderate atherosclerotic narrowing. There were no grossly apparent areas of transmural scarring. Thus, the macroscopic appearance of the heart was consistent with a dilated cardiomyopathy perhaps related, in part, to the reported history of heavy ethanol consumption. However, closer gross examination revealed the presence of multiple nodules < 1 mm in diamet,er studding the

NEPHROPATHY, AND DEATH

Figure 5. Luminal narrowing with acute hemorrhage parenchyma. (Original

of a small pulmonary artery by amyloid involving the adjacent airway and ipulmonary magnification 200X.)

valve cusps and scattered beneath the endocardial surface of the atria. Microscopically, the heart showed regions of focal subendocardial scarring, hypertrophic changes of cardiac myocytes, and focal areas of left ventricular subendocardial myocytolysis suggestive of sublethal ischemic injury. Abundant nodular deposits of amyloid were observed in the cardiac valves, the atria1 endocardium and occasionally in the ventricular endocardium and interstitium. However, the most conspicuous sites of amyloid accumulat,ion were noted in the intramural coronary arteries (Figure 4L).Here, the amyloid often completely effaced the vascular architecture and formed large elongat,ed nodules filling the perivascular spaces. In some fields, remnants of vessel walls could be identified whereas in other areas, large nodular accumulations filled spaces formerly occupied by vessels. Occasionally, the amyloid that spilled out of the vessels elicited a perivascular foreign body response characterized ‘by giant cells engulfing calcified particles of amyloid. Usually, amyloid accumulates diffusely in interstitial spaces encircling and encasing individual car-

Figure 6. Nodular lesser extent, May

1997

The

deposition of amyloid in renal glomeruli and, to a in the renal interstitium. (Original magnification 150X.) American

Journal

of Medicine@

Volume

102

501

WC/CARDIOMYOPATHY,

NEPHROPATHY, AND DEATH

-

disc myocytes resulting in pressure atrophy and their eventual drop out.” This diffuse interstitial pattern as well as the predilection of amyloid to accumulate in the endocardium accounts for the high probability of diagnosing cardiac amyloidosis in an affected patient who undergoes endomyocardial biopsy. However, in the present case, the relative absence of amyloid in the myocardial interstitium and ventricular endocardium explains why the previous endomyocardial biopsy was not diagnostic of cardiac amyloidosis. Furthermore, the focal, nodular pattern of amyloid deposition in small mural coronary arteries is consistent with the “speckled” pattern seen by echocardiography and also accounts for the absence of typical pathophysiological features of restrictive cardiomyopathy. Indeed, the vascular insufficiency caused by the obstruction of intramural vessels by amyloid explains the clinical signs and symptoms of ischemic heart disease and the pathological correlates of subendocardial scarring and myocytolysis. The predominant vascular deposition pattern in the heart was also observed in the lungs. Small pulmonary arteries and arterioles contained amyloid that narrowed their lumens (Figure 5). The more severely affected areas of lung exhibited abundant perivascular and intra-alveolar hemorrhage and occasional periarterial foreign body granulomas elicited by amyloid. Thus, it seems likely that the pulmonary hypertension, the degree of which appeared to be out of proportion to the amount of left ventricular dysfunction that was present, was related mainly to narrowing of pulmonary arteries and arterioles by amyloid. In the kidney, nearly all glomeruli contained large amounts of amyloid that signiiicantly disrupted glomerular structure (Figure 6). An incidental finding in the kidney was a small papillary renal cell carcinoma that was not apparently associated with clinical signs or symptoms. Although amyloid of the AL type is known to have a predilection for the vessel wall, it is unusual for amyloid to be confined exclusively to vascular structures. There are a few case reports describing patients with myocardial ischemia, sudden cardiac death, or visceral ischemia in whom amyloidosis was found to be deposited exclusively in the vasculature.‘7~1g-21 Final pathological diagnosis: amyloidosis.

502

May

1997

The American

Journal

of Medicine@

Volume

102

REFERENCES 1. Mallick of paraprotetn

NP, Dosa S, Achseon EJ et al. Detection, in patients presenting with “idiopathic”

significance proteinuria

and treatment without mye

loma. Quart J Med., New Series XLVII, Apr 1978;186:145-175, 2. Randall RE, Williamson WC Jr, Mullinax F, et al. Manifestations light chain deposition. Am J Med. 1976;60:293-299. 3. Ganeval Its relation

D, Noel L-H, Preud’homme with AL-type amyloidosis.

of systemic

J-L, et al. Light-chain deposrtion Editorial review, lnternat Sot

disease: Nephrol.

1984;26:1. 4. Stone

MJ, Frenkel

EP. The clinical

spectrum

of light chain

myeloma.

A study

of 35 patients with special reference to the occurrence of amyloidosis. Med. 1975;58:601-619, 5. Glenner GG. Amyloid deposits and amyloidosis. The beta-fibrilloses NEJM. 1980;302:1283-1292. 6. Glenner GG. Amyloid deposits NEJM. 1980;302:1333-1343,

and amyloidosis.

7. Kyle RA, Greipp PR. Amyloidosis (AL). Clinical cases. May Clin Proc. 1983;58:665-683. 8. Benotti

JR, Grossman

W. Restrictive

The beta-fibrilloses and laboratory

Am J (part I). (part II).

features

cardiomyopathy.

Ann

in 229

Rev

Med.

1984;35:113-125. 9. Roberts WC, Waker Analysis of 54 necropsy

BF. Cardiac amylotdosis patients. Am J Cardiol.

causing

(cardiac

dysfunction:

1983;52:137-146.

10. Falk RH, Plehn JF, Deering T, et al. Sensitivity and specificity of the echocardiographic features of cardiac amyloidosis. Am J Cardiol. 1987;59:418422. 11. Cueto-Garcia

L, Reeder

GS, Kyle RA, et al. Echocardrographic

systemic amyloidosis: spectrum of cardiac J Am Coil Cardiol. 1985;6:737-743.

involvement

findings

and relation

in

to survival.

12. Eriksson P, Backman C, Bjerle P, et al. Noninvasive assessment of the presence and severity of cardiac amyloidosis. A study in familial amyloidosis with polyneuropathy by cross sectional pyrophosphate scintigraphy. Br Heart

echocardiography J. 1984;52:321-326.

(and technetium-99m

13. Schrader ML, Hochman JS, Bulkley BH. The heart in polyarteritis A clinicopathologic study. Am Heart J. 1985;109:1353-1359. 14.

Zeek PM. Periarteritis

nodosa

and otherforms

of necrotizingangitis.

nodosa: NEJM.

1953;248:764-772, 15. Fauci AS, Haynes clinical and therapeutic

BF, Katz P, et al. Wegener’s granulornatosis: prospective experience with 85 patients for 21 years. Ann Jntern

Med. 1983;98:76-85. 16. Forstot JZ, Overlie

PA, Neufeld

GK, et al. Cardiac

granulomatosis: a case report of complete ature. Sem Atth Rheumat. 1980;10:148-154. 17. Saffitz JE, Sazama causing angina pectoris

1235. 18. Buja LM, Khoi dosis.

Clinicopathologrc

394-405. 19. Case

23-1968.

complications block

Case

records

WC. Cknically in 15 patients. of the

of Wegener

and review

K, Roberts WC. Amyloidosis limited and sudden death. Am J Cardiol.

NG, Roberts findings

weekly clinicopathologrcal 20. Jennette JC, Sheps

heart

of the liter-

to small arteries

1983;51:1234-

significant cardiac amyloiAm J Cardiol. 1970;26:

Massachusetts

General

exercises. NEJM. 1968;278:1276-1286. DS, McNeil1 DD. Exclusively vascular

Hospital: systemic

amyloidosis with visceral ischemia. Arch Pathol Lab Med. 1982;106: 323-327. 21. Arai H, Yamezaki J, Nakano, et al. A case of cardiac amyloidosis showing the ischemic change by exercise Nucl Med. 1990;27:1157-1162.

Tl-201

myocardial

scinhgraphy.

Japanese

J