Dr. Laura M. Dember: May we review the radiographs?

Figure 1. Figure 1. Chest Radiograph. Two weeks before admission, a posterior–anterior chest radiograph revealed a large right-sided pleural effusion extending to the level of the right hilum, a small left-sided pleural effusion, pulmonary venous hypertension, and persistent diffuse irregular parenchymal opacities.

Dr. Jo-Anne O. Shepard: A chest radiograph that was obtained nine months before admission showed moderately large bilateral pleural effusions, bilateral perihilar pulmonary edema, and cardiomegaly — signs that are most consistent with congestive heart failure. Five months before admission, there was a decrease in the pleural effusions and interstitial edema, but persistent cardiomegaly. The chest radiograph obtained two weeks before admission showed persistent mild interstitial edema; however, there had been a marked increase in the size of the right-sided pleural effusion, filling the lower half of the right hemithorax (Figure 1).

Figure 2. Figure 2. Transthoracic Echocardiogram. A four-chamber view shows mild symmetric left ventricular hypertrophy, left atrial enlargement, thickening of the mitral and tricuspid valves, and a small pericardial effusion (Panel A) (RV right ventricle, LV left ventricle, LA left atrium, RA right atrium). A four-chamber view shows moderate mitral regurgitation (MR) (Panel B). Pulsed-wave Doppler evaluation of the mitral inflow gives information about the diastolic filling properties of the left ventricle and is expressed by two waves (Panel C).The E wave corresponds to rapid early diastolic filling of the left ventricle, whereas the A wave corresponds to atrial contraction. (The A wave is not present in this patient because of the presence of atrial fibrillation.) When left ventricular diastolic pressure is elevated, the equalization of pressures between the ventricular and atrial chambers is rapid, and the deceleration time (dec time) of early transmitral filling is shortened. A deceleration time of less than 150 msec indicates a restrictive filling pattern. In this patient, the deceleration time was 120 msec.

Dr. Francesca Nesta: The transthoracic echocardiogram obtained two months before admission reveals diffuse hypokinesis of the left ventricle with predominant involvement of the base and the middle segments of the posterior wall. The dimensions of the left ventricular chamber are normal. There is increased thickness of both the interventricular septum and the posterior wall of the left ventricle, indicating symmetric hypertrophy (Figure 2A and , available with the full text of this article at www.nejm.org). The left atrium is enlarged, consistent with an increase in left atrial pressure.

The mitral valve is thickened and restricted in opening, but there is no stenosis. There is moderate mitral regurgitation, possibly resulting from both thickening of the mitral valve and hypokinesis of the inferior–posterior wall, which causes papillary muscle displacement, tethering of the mitral valve, and incomplete closure (Figure 2B). A mild increase in right ventricular systolic pressure but no restrictive filling pattern is observed. Pulsed-wave Doppler evaluation of the mitral inflow (Figure 2C) shows a restrictive filling pattern, with elevated left ventricular diastolic pressure.

Dr. Dember: A progressive systemic illness affecting the kidney, colon, heart, and liver developed during the year before admission in this elderly man with a history of atrial fibrillation and coronary artery disease. Congestive heart failure and recurrent large pleural effusions dominated the clinical picture. In addition, nephrotic-range proteinuria and a monoclonal gammopathy were present. There are several approaches to a differential diagnosis for this case. As a nephrologist, I will focus initially on the kidneys and then consider other affected organs. The renal disease is characterized by nephrotic-range proteinuria (urinary protein excretion, greater than 3000 mg per 24 hours) and what appears, from the serum creatinine concentration, to be a reasonably well preserved glomerular filtration rate. A substantial portion of the urinary protein is albumin, which is important, given the finding of a monoclonal λ light chain in the urine. The triad of hypoalbuminemia, peripheral edema, and nephrotic-range proteinuria fulfill the criteria for the nephrotic syndrome. The proteinuria had probably been in the nephrotic or near-nephrotic range for the year before the current hospitalization, and may have been present in subnephrotic quantities for at least one year before that. The absence of a substantial number of red cells or any red-cell casts in the urine sediment suggests a pure nephrotic syndrome rather than a combined nephritic–nephrotic process.

Causes of the Nephrotic Syndrome

Table 2. Table 2. Causes of Nephrotic Syndrome in Adults.

There are several causes of the nephrotic syndrome in adults (Table 2). Many possible causes are limited to diseases of the kidney and are thus unlikely in this case. Also unlikely are systemic illnesses that are associated with glomerulonephritis or interstitial renal disease but not the nephrotic syndrome, such as vasculitis or sarcoidosis, respectively. Systemic lupus erythematosus (SLE) can produce ischemic colitis, as was present in this patient, as a result of either mesenteric thrombosis, secondary to the antiphospholipid-antibody syndrome, or mesenteric vasculitis. Constrictive pericarditis can occur in SLE, but there was no history of pericarditis in this case, and this condition would not explain the ventricular wall thickening. Other cardiac processes associated with SLE, such as Libman–Sachs endocarditis or myocarditis could produce congestive heart failure but not a restrictive cardiomyopathy, as was seen here. Finally, there were no hematologic or joint manifestations, and this patient's age at onset would be unusual for SLE. Similarly, it is difficult to attribute the multisystem manifestations in this case to either cancers or infections that are associated with the development of the nephrotic syndrome.

Table 3. Table 3. Clinical or Laboratory Findings in This Patient That Might Be Due to Amyloidosis.

The constellation of findings is consistent with systemic amyloidosis (Table 3). Systemic amyloidosis is a group of diseases that have in common the extracellular deposition of insoluble fibrillar proteins with a characteristic β-pleated sheet configuration that allows them to bind to Congo red dye. The accumulation of amyloid fibrils in tissues results in progressive organ dysfunction.

Organ Dysfunction in Systemic Amyloidosis

The kidney is the most frequent site of amyloid fibril deposition in both immunoglobulin light chain (AL) amyloidosis and serum amyloid A (AA) amyloidosis, and this condition is typically manifested as the nephrotic syndrome, as we see in this patient. The proteinuria can be massive, and the accompanying edema can be resistant to diuretics, as in this case. The glomerular filtration rate may be normal, but progressive renal impairment typically follows unless new amyloid production can be reduced or eliminated.1,2 Renal insufficiency without marked proteinuria occurs less often, when amyloid deposition is restricted to the renal vasculature or tubulointerstitium but spares the glomeruli.

Amyloid deposition in the myocardium restricts the ventricles from dilating fully, so they cannot fill normally. The left ventricular wall is concentrically thickened, with normal or reduced cavity size. The ventricular ejection fraction may be normal or only somewhat decreased, despite substantial amyloid infiltration, but impaired ventricular filling limits cardiac output.3 Atrial and ventricular arrhythmias and abnormalities in the conduction system are relatively frequent manifestations of cardiac amyloidosis, although I suspect that the atrial fibrillation in this patient was unrelated, since survival for seven years with untreated cardiac amyloidosis is unusual. Although this patient had a history of coronary artery disease, the development of progressive heart failure after coronary artery revascularization is difficult to attribute to previous ischemic injury, and there was no evidence of ischemia on stress testing. Moreover, the echocardiographic findings of left ventricular wall thickening in the absence of a history of hypertension, normal left ventricular cavity size, and elevated left atrial pressure suggest a restrictive rather than an ischemic process. The left ventricular ejection fraction of 44 percent probably indicates severe amyloid disease, but atrial fibrillation or single-chamber ventricular pacing may have contributed as well. Although it was not described in this patient, low voltage on the electrocardiogram is often present in amyloidosis and reflects the infiltrative basis for thickening of the ventricular wall.

Pleural effusions may result from amyloid heart disease, but they can also result from pleural amyloid deposition.4 In this patient, the refractory nature of the effusions — with a poor response to diuretics and rapid reaccumulation after thoracentesis — is suggestive of pleural involvement. The transudative nature of the effusions is also consistent with pleural amyloid disease, although exudative effusions are present in approximately one third of cases.5 The interstitial opacities revealed on chest radiography may reflect parenchymal lung involvement, but it is difficult to draw this conclusion when congestive heart failure is part of the picture.

At the time of this patient's current hospitalization, he had hypotension with a systolic blood pressure of 80 mm Hg. The hypotension was probably due, at least in part, to the cardiac dysfunction, but autonomic dysfunction resulting from amyloidosis may have contributed as well. Other manifestations of autonomic neuropathy, such as orthostatic hypotension, early satiety, and either chronic diarrhea or constipation, were not present.

The patient underwent a partial colectomy for bleeding that was attributed to ischemic colitis. Gastrointestinal bleeding can result from amyloid deposits in the bowel mucosa, and ischemic colitis can occur as a result of vascular amyloid deposition. It is possible that ischemic colitis developed in this patient as a result of the combination of underlying atherosclerotic disease and reduced perfusion because of the cardiac dysfunction, vascular amyloidosis, or both.

The marked elevation in the serum level of alkaline phosphatase with only a mild aminotransferase elevation is characteristic of hepatic amyloidosis, in which infiltration of the sinusoids, rather than direct hepatocyte injury, occurs.6 Hepatic congestion due to right-sided heart failure is another frequent cause of abnormal levels of liver enzymes in patients with cardiac amyloidosis, but it would be unlikely to produce the cholestatic pattern of liver-enzyme abnormalities seen in this patient. The abnormalities of the liver enzymes are probably not related to the cholelithiasis, since neither stones in the common bile duct nor dilatation of the common bile duct was apparent, and the bilirubin level was normal.

Types of Systemic Amyloidosis

The amyloidoses are classified according to the amyloidogenic protein that forms the fibrillary deposits. In AL amyloidosis, the protein is an immunoglobulin light chain or light-chain fragment that is produced by a clone of plasma cells. The plasma-cell burden is usually low, with a specimen from the bone marrow biopsy typically containing 5 to 10 percent plasma cells.7 However, approximately 10 percent of patients with AL amyloidosis have frank multiple myeloma. AA amyloidosis occurs in association with long-standing inflammation. Serum amyloid A protein, an acute-phase reactant synthesized in the liver, is the amyloidogenic protein. In the familial amyloidoses, an amino acid substitution in a plasma protein renders it amyloidogenic. Transthyretin is the most common amyloidogenic protein in familial disease, but six other proteins (apolipoprotein A-I, apolipoprotein A-II, fibrinogen A α–chain, lysozyme, gelsolin, and cystatin C) have been identified as underlying rare forms.8 In senile systemic amyloidosis, wild-type transthyretin forms amyloid deposits predominantly in the heart.

In this case, there was no chronic inflammatory condition to suggest AA amyloidosis. In addition, symptomatic cardiac involvement is unusual in AA amyloidosis. Although the patient had a family history of cardiac disease, the combination of organs involved makes most of the familial amyloidoses unlikely. The age at which the patient presented is typical for senile systemic amyloidosis, but the multiorgan nature of his disease is not consistent with that diagnosis. AL is the most likely type of amyloidosis in this case. The distribution of organ involvement is typical, and the monoclonal immunoglobulin protein in the serum and urine indicates the presence of a plasma-cell dyscrasia. An informative finding is the tongue enlargement noted at admission. Macroglossia occurs in approximately 20 percent of patients with AL amyloidosis9 but is not present in other types of amyloidosis. In fact, macroglossia has a very limited differential diagnosis, and its presence should trigger an evaluation for AL amyloidosis.

Does the negative result of the Congo red staining for amyloid in the subcutaneous abdominal fat rule out the diagnosis of systemic amyloidosis? Needle aspiration of abdominal fat is a simple and relatively noninvasive method of obtaining tissue for staining with Congo red, and the result is positive in approximately 80 percent of patients with AL amyloidosis and approximately 65 percent of patients with AA amyloidosis.9-11 Thus, the negative result on staining of the abdominal-fat aspirate in this case does not necessarily eliminate amyloidosis as the diagnosis.

Nonamyloid Immunoglobulin Deposition Diseases

Diseases other than AL amyloidosis that are characterized by immunoglobulin deposition may cause nephrotic-range proteinuria, but they are unlikely to be the cause of this patient's illness. In light-chain– and heavy-chain–deposition diseases, monoclonal immunoglobulin light chains or heavy chains form nonfibrillary deposits in the glomerular or tubular basement membranes, or both. Deposition of monoclonal immunoglobulin in the lung, heart, and liver can result in organ dysfunction.12,13 However, the pace of disease progression is usually slower than in AL amyloidosis, and macroglossia does not occur. In the fibrillary and immunotactoid glomerulopathies, nonamyloid fibrils derived from immunoglobulin molecules are deposited in the mesangium and glomerular capillary walls. Nephrotic-range proteinuria is common and is often accompanied by microscopic hematuria, hypertension, and a reduction in the glomerular filtration rate. However, extrarenal manifestations appear to be rare.14,15

AL amyloidosis is the most likely diagnosis in this case. The diagnosis of amyloidosis requires demonstration of binding of Congo red dye to tissue deposits and birefringence when viewed with polarized-light microscopy. In this patient, there were multiple potential sources of tissue for making a diagnosis. The tissue obtained during the colectomy could be reexamined and stained for amyloid. A bone marrow biopsy could be performed to assess plasma-cell numbers and clonality and could yield the diagnosis of amyloidosis if Congo red–staining material were present in the vessels or in the interstitium. Alternatively, either a kidney biopsy or an endomyocardial biopsy could be performed.

Dr. Nancy Lee Harris (Pathology): Dr. Judge, as this patient's primary care physician, can you comment on your thinking?

Dr. David C. Judge (General Internal Medicine): My colleagues and I suspected that the patient had amyloidosis, for the reasons outlined by Dr. Dember, but had been unable to confirm the diagnosis. The acute clinical problem was the effusions that were reaccumulating rapidly and that we were trying to drain to keep him comfortable.

Dr. Harris: Dr. Januzzi performed the diagnostic procedure.

Dr. James L. Januzzi (Cardiology): The salient cardiovascular feature in this case was thickening of the myocardium. When an echocardiogram shows thickening of the ventricular myocardium in a patient without hypertension, an infiltrative process, such as amyloidosis, should be considered. We pursued this diagnosis, but the results of the fat-pad biopsy were negative, and the patient was reluctant to undergo a more invasive diagnostic procedure. When his condition began to decline rapidly, we needed to know whether there was any condition other than amyloidosis present that might be amenable to treatment; thus, the decision was made to perform an endomyocardial biopsy. We performed a right heart catheterization, which confirmed the presence of low filling pressures, and performed an endomyocardial biopsy of the right ventricle.