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Case 15-2005 — An 80-Year-Old Man with Shortness of Breath, Edema, and Proteinuria
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     Presentation of Case

    An 80-year-old man was admitted to the hospital because of shortness of breath, pleural effusions, and edema of the legs.

    Atrial fibrillation had developed seven years earlier, with bradycardia and syncope, and a pacemaker had been placed. Angina developed two and a half years before admission and was treated with three-vessel coronary-artery bypass grafting. The patient had several episodes of congestive heart failure thereafter. Eleven months before admission, urinalysis revealed 3+ proteinuria, an increase from 1+ one year earlier. Nine months before admission, a subtotal colectomy was performed because of ischemic colitis with bleeding. Bilateral pleural effusions, pulmonary edema, and cardiomegaly were noted on chest radiography. Five months before admission, an increase in exertional fatigue and shortness of breath developed. A chest radiograph showed small pleural effusions, diffuse irregular opacities, cardiomegaly, and pulmonary venous hypertension. The patient received treatment with furosemide, and there was improvement in his symptoms and radiographic findings.

    Four months before admission, an abdominal ultrasonographic examination showed cholelithiasis; the liver appeared normal. A stress test showed reduced exercise capacity with no evidence of ischemia. A cardiac ultrasonographic examination showed incomplete closure of the mitral valve that was consistent with papillary muscle displacement, and moderate mitral regurgitation. The left atrium was dilated, with evidence of elevated left atrial pressure. The aortic leaflets were tricuspid and thickened; there was mild aortic insufficiency without stenosis. The left ventricle cavity size was normal, with symmetric left ventricular hypertrophy, segmental left ventricular wall dysfunction, and an estimated ejection fraction of 44 percent. There was mild-to-moderate tricuspid insufficiency and trace pulmonary insufficiency. The right ventricular systolic pressure was estimated to be 43 mm Hg, and the wall showed mild hypokinesis. A right-sided pleural effusion was present.

    Three months before admission, a 24-hour collection of urine revealed a moderate amount of lambda Bence Jones protein in a 50-fold concentrated urine specimen, with a large amount of albumin, moderate amounts of -globulin, -globulin, and probably intact immunoglobulin present. Lambda Bence Jones protein was present in the serum, as was a very-low-concentration band identified as IgG lambda M component. Tests for the presence of hepatitis C antibody, hepatitis B surface antigen, and hepatitis B surface antibody were negative.

    Two months before admission, transesophageal echocardiography showed moderate biventricular failure and mitral regurgitation. One and a half months before admission, an endoscopic retrograde cholangiopancreatographic examination revealed multiple stones in the cystic duct and gallbladder. Abdominal and pelvic computed tomographic scanning showed no discrete hepatic lesions, but there was diffuse, heterogeneously decreased attenuation in the liver; bilateral pleural effusions were larger than in previous studies. A 24-hour urine collection contained 4311 mg of protein. A fine-needle aspiration biopsy of an abdominal fat pad was performed; a Congo red stain for amyloid was negative. One month before admission, the patient was hospitalized elsewhere with shortness of breath and was found to have a pleural effusion, congestive heart failure, and possible pneumonia. His respiratory symptoms improved.

    Two weeks before admission, the patient again had shortness of breath; a chest radiograph showed enlargement of the right-sided pleural effusion to the level of the right hilum, with a small left-sided pleural effusion, pulmonary venous hypertension, and diffuse irregular interstitial opacities. Urinalysis showed 3+ protein, 0 to 2 red cells, and 0 to 2 white cells per high-power field and was otherwise normal. Eight days later, an ultrasonographically guided right chest thoracentesis removed 1200 ml of transudative effusion. There was no sign of malignant tumor cells on cytologic examination. Another radiographic scan of the chest showed a persistent, moderately large right-sided pleural effusion, small left-sided pleural effusion, pulmonary venous hypertension, and diffuse irregular interstitial opacities. Shortness of breath increased, edema of the legs developed, and he was admitted to this hospital.

    The patient had had single episodes of cholelithiasis and nephrolithiasis many years previously and had hyperlipidemia. He did not drink alcohol, smoke cigarettes, or use illicit drugs. He had not traveled recently, was retired, and lived with his wife. Both parents and several uncles had had coronary artery disease. His medications were warfarin sodium and furosemide.

    He appeared fatigued, with increased respiratory effort. The temperature was 36.1°C, the pulse was irregular at 77 beats per minute, and the respiratory rate was 22 breaths per minute. The blood pressure was 80/40 mm Hg. The oxygen saturation was 93 percent while the patient was breathing two liters of oxygen with the use of a nasal cannula. The tongue was enlarged and had a whitish shallow ulceration on the right side. The neck was supple with a jugular venous pressure of 7 cm of water. There were decreased breath sounds two thirds of the way up the posterior chest on the right side and halfway up on the left side, with dullness to percussion. There were irregular first and second heart sounds. The abdomen was normal, and there was pitting edema (+++) of the legs from the feet to the knees. The complete blood count was within normal range; urinalysis showed 3+ protein, 3 to 5 red cells and 0 to 2 white cells per high-power field, and 3 to 5 hyaline casts per low-power field; tests for the presence of antinuclear antibody and antineutrophil cytoplasmic antibodies and an enzyme-linked immunosorbent assay for antibodies to proteinase 3 and myeloperoxidase were all negative; results of other laboratory tests are shown in Table 1. An electrocardiogram showed atrial fibrillation without acute ischemic changes.

    Table 1. Laboratory Data.

    A chest tube was placed and thoracentesis performed. Analysis revealed a transudative fluid with no malignant tumor cells. A diagnostic procedure was performed.

    Differential Diagnosis

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

    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 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. 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 Video Clip 1 of the Supplementary Appendix, 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.

    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.

    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 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

    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 2. Causes of Nephrotic Syndrome in Adults.

    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 -pleated sheet configuration that allows them to bind to Congo red dye. The accumulation of amyloid fibrils in tissues results in progressive organ dysfunction.

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

    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 –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.9,10,11 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.

    Clinical Diagnosis

    Amyloidosis, AL type.

    Dr. Laura M. Dember's Diagnosis

    AL amyloidosis involving the kidney, heart, liver, pleura, and possibly lungs, colon, and the autonomic nervous system.

    Pathological Discussion

    Dr. James R. Stone: Histologic examination of the endomyocardial-biopsy specimen revealed deposits of amorphous extracellular material in a vascular and endocardial distribution. After staining with Congo red, the deposits were pink–orange when viewed with standard light microscopy; when viewed under plane-polarized light, they had classic apple-green birefringence, which is diagnostic of amyloid (Figure 3A, Figure 3B, and Figure 3C).

    Figure 3. Right Ventricular Endomyocardial-Biopsy Specimen.

    There is amorphous extracellular material present in a vascular distribution (Panel A, hematoxylin and eosin). With Congo red staining (Panel B), the deposits have a pink–orange color; under plane-polarized light (Panel C), the deposits display apple-green birefringence, which is indicative of the presence of amyloid.

    The presence of amyloid in tissue is not always readily apparent, and pathologists frequently do not recognize it on examination of sections routinely stained with hematoxylin and eosin. Examination of slides from the resected colon revealed the presence of amyloid in the walls of blood vessels in the submucosa and serosa (Figure 1 of the Supplementary Appendix).

    Although potentially any protein could adopt the extended -sheet structure and contribute to amyloid formation, specific proteins are prone to this phenomenon.16 In particular, light chains are two to three times more likely to form amyloid than are light chains. On histologic examination, amyloid deposits in AL amyloidosis may be present in either a vascular or an interstitial distribution.17

    Since new treatment strategies are based on the elimination of the specific amyloidogenic protein, it is becoming increasingly important to establish the type of amyloid present in the deposits.18,19 For AL amyloidosis, this has traditionally been accomplished indirectly, by demonstration of a monoclonal gammopathy. However, monoclonal gammopathies are not uncommon in the elderly, and most do not result in amyloid deposition; there have been reports of the misdiagnosis of AL amyloidosis in elderly patients with monoclonal gammopathy who in fact have a hereditary amyloidosis.19,20,21 There are ongoing efforts to use immunologic methods to determine the specific protein present in a given amyloid deposit,17,22,23 but these methods have both high false positive and high false negative rates.20,21,22,23 In this case, immunohistochemical staining for immunoglobulin light chains yielded only nonspecific staining.

    Genetic analysis can be used to assess for the hereditary amyloidoses. However, there are more than 20 proteins that can form amyloid, and for many of them, multiple amyloid-inducing mutations have been discovered.24 Biochemical techniques, primarily liquid chromatography and mass spectrometry, have been applied to identify amyloidogenic proteins.21 Although still experimental, these new techniques may become the gold standard for the subclassification of amyloid deposits.

    This patient had systemic amyloidosis, with a predominantly vascular distribution, which in the setting of a monoclonal gammopathy, is best classified as AL amyloidosis.

    Dr. Judge: The patient was discharged on the 10th hospital day. Treatment with melphalan and prednisone was initiated on an outpatient basis, but his symptoms did not improve; he died at home of cardiac arrest approximately two months later.

    Anatomical Diagnosis

    Systemic amyloidosis involving the heart and colon, in the setting of a monoclonal gammopathy; probably AL amyloidosis.

    Dr. Dember reports having received consulting fees and grant support from Neurochem.

    Source Information

    From the Renal Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine (L.M.D.); the Departments of Radiology (J.O.S.), Cardiology (F.N.), and Pathology (J.R.S.), Massachusetts General Hospital; and the Departments of Radiology (J.O.S.), Cardiology (F.N.), and Pathology (J.R.S.), Harvard Medical School — all in Boston.

    References

    Dember LM, Sanchorawala V, Seldin DC, et al. Effect of dose-intensive intravenous melphalan and autologous blood stem-cell transplantation on AL amyloidosis-associated renal disease. Ann Intern Med 2001;134:746-753.

    Skinner M, Sanchorawala V, Seldin DC, et al. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med 2004;140:85-93.

    Dubrey SW, Cha K, Anderson J, et al. The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement. QJM 1998;91:141-157.

    Celli BR, Rubinow A, Cohen AS, Brody JS. Patterns of pulmonary involvement in systemic amyloidosis. Chest 1978;74:543-547.

    Berk JL, Keane J, Seldin DC, et al. Persistent pleural effusions in primary systemic amyloidosis: etiology and prognosis. Chest 2003;124:969-977.

    Park MA, Mueller PS, Kyle RA, Larson DR, Plevak MF, Gertz MA. Primary (AL) hepatic amyloidosis: clinical features and natural history in 98 patients. Medicine (Baltimore) 2003;82:291-298.

    Swan N, Skinner M, O'Hara CJ. Bone marrow core biopsy specimens in AL (primary) amyloidosis: a morphologic and immunohistochemical study of 100 cases. Am J Clin Pathol 2003;120:610-616.

    Benson MD, Liepnieks JJ, Yazaki M, et al. A new human hereditary amyloidosis: the result of a stop-codon mutation in the apolipoprotein AII gene. Genomics 2001;72:272-277.

    Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med 1997;337:898-909.

    Libbey CA, Skinner M, Cohen AS. Use of abdominal fat tissue aspirate in the diagnosis of systemic amyloidosis. Arch Intern Med 1983;143:1549-1552.

    Gertz MA, Li CY, Shirahama T, Kyle RA. Utility of subcutaneous fat aspiration for the diagnosis of systemic amyloidosis (immunoglobulin light chain). Arch Intern Med 1988;148:929-933.

    Buxbaum J, Gallo G. Nonamyloidotic monoclonal immunoglobulin deposition disease: light-chain, heavy-chain, and light- and heavy-chain deposition diseases. Hematol Oncol Clin North Am 1999;13:1235-1248.

    Pozzi C, Locatelli F. Kidney and liver involvement in monoclonal light chain disorders. Semin Nephrol 2002;22:319-330.

    Masson RG, Rennke HG, Gottlieb MN. Pulmonary hemorrhage in a patient with fibrillary glomerulonephritis. N Engl J Med 1992;326:36-39.

    Wallner M, Prischl FC, Hobling W, et al. Immunotactoid glomerulopathy with extrarenal deposits in the bone, and chronic cholestatic liver disease. Nephrol Dial Transplant 1996;11:1619-1624.

    Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med 2003;349:583-596.

    Crotty TB, Li C-Y, Edwards WD, Suman VJ. Amyloidosis and endomyocardial biopsy: correlation of extent and pattern of deposition with amyloid immunophenotype in 100 cases. Cardiovasc Pathol 1995;4:39-42.

    Gertz MA, Lacy MQ, Dispenzieri A, et al. Stem cell transplantation for the management of primary systemic amyloidosis. Am J Med 2002;113:549-555.

    Anesi E, Palladini G, Perfetti V, Arbustini E, Obici L, Merlini G. Therapeutic advances demand accurate typing of amyloid deposits. Am J Med 2001;111:243-244.

    Lachmann HJ, Booth DR, Booth SE, et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med 2002;346:1786-1791.

    Murphy CL, Eulitz M, Hrncic R, et al. Chemical typing of amyloid protein contained in formalin-fixed paraffin-embedded biopsy specimens. Am J Clin Pathol 2001;116:135-142.

    Rocken C, Schwotzer EB, Linke RP, Saeger W. The classification of amyloid in clinicopathological practice. Histopathology 1996;29:325-335.

    Rocken C, Sletten K. Amyloid in surgical pathology. Virchows Arch 2003;443:3-16.

    Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med 1997;336:466-473.(Laura M. Dember, M.D., Jo)