Immunoglobulin light-chain amyloidosis needs to be considered in any patient presenting with cardiomyopathy with preserved systolic function, heavy albuminuria, an unexplained sensorimotor peripheral neuropathy, hepatomegaly, or atypical MGUS (monoclonal gammopathy of undetermined significance) or myeloma. The prognosis of the disease is determined by the levels of cardiac biomarkers and the pretreatment levels of immunoglobulin free light chains. All patients with systemic light-chain amyloid require therapy. There is no presymptomatic phase that warrants observation. Stem-cell transplantation produces a high response rate but is a viable option in only 20% of patients. Corticosteroids, alkylating agents, immunomodulatory drugs, and proteasome inhibitors all have shown activity in this disorder, and combinations are currently being explored in clinical trials. Despite advances in the past decade, 30% of patients still die within a year of diagnosis, suggesting that failure to recognize this disorder prior to advanced organ dysfunction remains a major impediment to improving outcomes.
Light-chain (AL) amyloidosis occurs when a clonal population of bone marrow plasma cells secretes an immunoglobulin light chain that undergoes misfolding. The resulting insoluble light-chain or heavy-chain fragments deposit in tissues in a β-pleated sheet configuration and lead to organ dysfunction. There is no diagnostic blood test or imaging study for AL amyloidosis. Recognition requires a high index of suspicion and a tissue biopsy that demonstrates green birefringence when a Congo red–stained specimen is viewed under polarized light.
A 79-year-old male had symptomatic dyspnea on exertion and lower extremity edema for 1 year. The patient had CT imaging of the abdomen that showed small retroperitoneal nodes. This finding led to a laparoscopic biopsy. Sinus histiocytosis was found; no malignancy was present. He underwent echocardiography that showed concentric left ventricular hypertrophy. His ECG demonstrated an anterior infarction pattern. The ECG finding led to a cardiac catheterization that showed both a normal ejection fraction and normal coronary arteries. Following the catheterization, the patient was informed that his dyspnea did not have a cardiac cause, and he was referred to the Mayo Clinic Division of Thoracic Diseases for evaluation.
When the patient came to the Mayo Clinic, a serum protein electrophoresis was performed (Figure 1). The protein electrophoretic finding led to a 24-hour urine protein electrophoresis (Figure 2). The echocardiogram was repeated and was reinterpreted as showing thickening of the heart walls and valves consistent with an infiltrative cardiomyopathy with restrictive hemodynamics. A subcutaneous fat aspiration was performed, which demonstrated amyloid. The original retroperitoneal node biopsy was obtained from the local hospital. It was stained with Congo red and was positive.
Comments on Patient 1
This patient had an ECG that showed a pseudo-infarction pattern; considered in conjunction with his dyspnea, it was felt to represent silent ischemic heart disease. The presence of a pseudo-infarction pattern on ECG is a post-hoc diagnosis that requires knowledge of the correct process in order to be interpreted. The thickening of the ventricular walls was assumed to be hypertrophy rather than infiltration, presumably because hypertrophy secondary to hypertension is so much more common in the US population. The performance of cardiac catheterization without a right ventricular biopsy indicated a failure to recognize an important cause of heart failure with preserved systolic function. The key diagnostic test was the serum protein electrophoresis, which showed an extremely small (size, 0.5 g/dL) monoclonal protein migrating in the gamma fraction. The 24-hour urine protein measurement demonstrated only 220 mg for the 24-hour period, which is quantitatively insignificant; however, the electrophoresis demonstrated that all of the protein was monoclonal immunoglobulin light chain and not albumin. Most physicians assume that proteinuria equates to albuminuria, but this was not the case here. This patient had a 1-year delay in diagnosis, reducing the likelihood of chemotherapy being effective.
Light-chain amyloidosis should be considered in any patient who has symptoms consistent with cardiomyopathy. These may be as subtle as mild dyspnea on exertion or modest edema in the lower extremities. Exertional fatigue is a common presentation of cardiac amy-loidosis; to arrive at the correct diagnosis requires a careful physical examination that could reveal distention of the jugular veins. This finding reflects restriction to flow and high filling pressures on the right side of the heart. An assessment of cardiac biomarkers, particularly brain natriuretic peptide (BNP) or N-terminal prohormone-BNP (NT-proBNP), and an echocardiogram with Doppler studies that can recognize changes in diastolic flow patterns, will reveal infiltrative cardiomyopathy.
A 47-year-old male was found to have 9.7 grams of protein in a 24-hour urine collection. The patient received a trial of high-dose corticosteroids, which produced no reduction in urinary protein. Because of increasing edema and fatigue, an echocardiogram was performed; this showed a ventricular septal thickness of 18 mm. The cause of the thickening was not commented on. A renal biopsy was performed, and amyloid deposits were detected. Subsequent testing with serum and urine electrophoresis with immunofixation and serum immunoglobulin free light chains revealed monoclonal free λ light chains in the serum and urine (Bence-Jones proteinemia and proteinuria). The κ free light chain was 9.7 mg/L (normal, 3.3-19.4 mg/L), and the λ free light chain was 137 mg/L (normal, 5.7-26.3 mg/L), with a ratio of 0.07 (normal, 0.26-1.65), reflecting excess production of λ immunoglobulins.
Comments on Patient 2
All patients with heavy albuminuria that is not attributable to an obvious cause such as long-standing diabetes mellitus should be screened for amy-loidosis. Frequently, these patients are assumed to have minimal-change glomerulonephropathy or membranoproliferative glomerulonephropathy and undergo an empiric trial of corticosteroids, which delays more effective interventions. Screening with the combination of a serum protein electrophoresis with immunofixation and a serum immunoglobulin free light chain has a sensitivity of 96% for detection of a monoclonal protein in patients with AL amyloidosis. The addition of a urine immunofixation increases sensitivity to 98%. The detection of a monoclonal protein reduces the differential diagnosis to myeloma cast nephropathy, ? light chain deposition disease, cryoglobulin-emia, and light-chain amyloidosis. In this instance, the patient had an 8-month delay between the first recognition of proteinuria and the initiation of effective therapy. This patient underwent stem-cell transplantation and is alive with normal renal function at 180 months. His lowest recorded urinary protein post-transplant was 0.27 g/day.
1. Baden EM, Sikkink LA, Ramirez-Alvarado M. Light chain amyloidosis—current findings and future prospects. Curr Protein Pept Sci. 2009;10:500-8.
2. Bhat A, Selmi C, Naguwa SM, et al. Currents concepts on the immunopathology of amyloidosis. Clin Rev Allergy Immunol. 2010;38:97-106.
3. Halloush RA, Lavrovskaya E, Mody DR, et al. Diagnosis and typing of systemic amyloidosis: the role of abdominal fat pad fine needle aspiration biopsy. Cytojournal. 2010;6:24.
4. Merlini G, Seldin DC, Gertz MA. Amyloidosis: pathogenesis and new therapeutic options. J Clin Oncol. 2011;29:1924-33.
5. Bellavia D, Abraham RS, Pellikka PA, et al. Utility of Doppler myocardial imaging, cardiac biomarkers, and clonal immunoglobulin genes to assess left ventricular performance and stratify risk following peripheral blood stem cell transplantation in patients with systemic light chain amyloidosis (AL). J Am Soc Echocardiogr. 2011;24:444-54.
6. Mesquita M, Fosso C, Bakoto Sol E, et al. Renal biopsy findings in Belgium: a retrospective single center analysis. Acta Clin Belg. 2011;66:104-9.
7. Katzmann JA, Kyle RA, Benson J, et al. Screening panels for detection of monoclonal gammopathies. Clin Chem. 2009;55:1517-22.
8. Gertz MA, Lacy MQ, Dispenzieri A, Hayman SR. Amyloidosis: diagnosis and management. Clin Lymphoma Myeloma. 2005;6:208-19.
9. Merlini G, Stone MJ. Dangerous small B-cell clones. Blood. 2006;108:2520-30.
10. Turesson I, Velez R, Kristinsson SY, Landgren O. Patterns of multiple myeloma during the past 5 decades: stable incidence rates for all age groups in the population but rapidly changing age distribution in the clinic. Mayo Clin Proc. 2010;85:225-30.
11. Angiero F, Seramondi R, Magistro S, et al. Amyloid deposition in the tongue: clinical and histopathological profile. Anticancer Res. 2010;30:3009-14.
12. Lee HJ, Chang SE, Lee MW, et al. Systemic amyloidosis associated with multiple myeloma presenting as periorbital purpura. J Dermatol. 2008;35:371-2.
13. Dispenzieri A, Kyle R, Merlini G, et al. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia. 2009;23:215-24.
14. Petruzziello F, Zeppa P, Catalano L, et al. Amyloid in bone marrow smears of patients affected by multiple myeloma. Ann Hematol. 2010;89:469-74.
15. Ohno F, Numata Y, Yamano T, et al. Gastroscopic biopsy of the stomach for the diagnosis of amyloidosis. Gastroenterol Jpn. 1982;17:415-21.
16. Fernandez-Flores A. Comparative study of Congo red fluorescence and immunohistochemistry in cutaneous amyloidosis. Rom J Morphol Embryol. 2010;51:683-6.
17. Foli A, Palladini G, Caporali R, et al. The role of minor salivary gland biopsy in the diagnosis of systemic amyloidosis: results of a prospective study in 62 patients. Amyloid. 2011;18(Suppl 1):75-7.
18. Tam M, Seldin DC, Forbes BM, et al. Spontaneous rupture of the liver in a patient with systemic AL amyloidosis undergoing treatment with high-dose melphalan and autologous stem cell transplantation: a case report with literature review. Amyloid. 2009;16:103-7.
19. Shidham VB, Hunt B, Jardeh SS, et al. Performing and processing FNA of anterior fat pad for amyloid. J Vis Exp. 2010; 44: pii 1747.
20. Siragusa S, Morice W, Gertz MA, et al. Asymptomatic immunoglobulin light chain amyloidosis (AL) at the time of diagnostic bone marrow biopsy in newly diagnosed patients with multiple myeloma and smoldering myeloma. A series of 144 cases and a review of the literature. Ann Hematol. 2011;90:101-6.
21. Shah KB, Inoue Y, Mehra MR. Amyloidosis and the heart: a comprehensive review. Arch Intern Med. 2006;166:1805-13.
22. Liu D, Niemann M, Hu K, et al. Echocardiographic evaluation of systolic and diastolic function in patients with cardiac amyloidosis. Am J Cardiol. 2011;108:591-8.
23. Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol. 2004;22:3751-7.
24. Dispenzieri A, Gertz MA, Kyle RA, et al. Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood. 2004;104:1881-7.
25. Palladini G, Barassi A, Klersy C, et al. The combination of high-sensitivity cardiac troponin T (hs-cTnT) at presentation and changes in N-terminal natriuretic peptide type B (NT-proBNP) after chemotherapy best predicts survival in AL amyloidosis. Blood. 2010;116:3426-30.
26. Gertz M, Lacy M, Dispenzieri A, et al. Troponin T level as an exclusion criterion for stem cell transplantation in light-chain amyloidosis. Leuk Lymphoma. 2008;49:36-41.
27. Dispenzieri A, Lacy MQ, Katzmann JA, et al. Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood. 2006;107:3378-83.
28. Gertz MA, Lacy MQ, Dispenzieri A, et al. Trends in day 100 and 2-year survival after auto-SCT for AL amyloidosis: outcomes before and after 2006. Bone Marrow Transplant. 2011;46:970-5.
29. Kumar S, Dispenzieri A, Lacy MQ, et al. Serum uric acid: novel prognostic factor in primary systemic amyloidosis. Mayo Clin Proc. 2008;83:297-303.
30. Palladini G, Dispenzieri A, Gertz MA, et al. Validation of the criteria of response to treatment in AL amyloidosis. ASH Annual Meeting Abstracts 2010;116:1364.
31. Kumar SK, Gertz MA, Lacy MQ, et al. Recent improvements in survival in primary systemic amyloidosis and the importance of an early mortality risk score. Mayo Clin Proc. 2011;86:12-8.
32. Wall JS, Kennel SJ, Stuckey AC, et al. Radioimmunodetection of amyloid deposits in patients with AL amyloidosis. Blood. 2010;116:2241-4.
33. Bodin K, Ellmerich S, Kahan MC, et al. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature. 2010;468:93-7.
34. Hovey BM, Ward JE, Soo Hoo P, et al. Preclinical development of siRNA therapeutics for AL amyloidosis. Gene Ther. 2011;18:1150-6.
35. Jones NF, Hilton PJ, Tighe JR Hobbs JR. Treatment of "primary" renal amyloidosis with melphalan. Lancet. 1972;2:616-9.
36. Dhodapkar MV, Hussein MA, Rasmussen E, et al. Clinical efficacy of high-dose dexamethasone with maintenance dexamethasone/alpha interferon in patients with primary systemic amyloidosis: results of United States Intergroup Trial Southwest Oncology Group (SWOG) S9628. Blood. 2004;104:3520-6.
37. Comenzo RL. Who knows how to treat systemic light chain amyloidosis? Oncology (Williston Park). 2011;25:626, 28-9, 32-3.
38. Cavo M, Rajkumar SV, Palumbo A, et al. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood. 2011;117:6063-73.
39. Gertz MA, Ansell SM, Dingli D, et al. Autologous stem cell transplant in 716 patients with multiple myeloma: low treatment-related mortality, feasibility of outpatient transplant, and effect of a multidisciplinary quality initiative. Mayo Clin Proc. 2008;83:1131-8.
40. Madan S, Kumar S, Lacy MQ, et al. Pre-stem cell transplant induction therapy does not affect post-transplant survival in light chain (AL) amyloidosis. ASH Annual Meeting Abstracts. 2010;116:370.
41. Chow LQ, Bahlis N, Russell J, et al. Autologous transplantation for primary systemic AL amyloidosis is feasible outside a major amyloidosis referral centre: the Calgary BMT Program experience. Bone Marrow Transplant. 2005;36:591-6.
42. Gertz MA, Lacy MQ, Dispenzieri A, et al. Autologous stem cell transplant for immunoglobulin light chain amyloidosis: a status report. Leuk Lymphoma. 2010;51:2181-7.
43. Cibeira MT, Sanchorawala V, Seldin DC, et al. Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients. Blood. 2011;118:4346-52.
44. Seldin DC, Choufani EB, Dember LM, et al. Tolerability and efficacy of thalidomide for the treatment of patients with light chain-associated (AL) amyloidosis. Clin Lymphoma. 2003;3:241-6.
45. Palladini G, Perfetti V, Perlini S, et al. The combination of thalidomide and intermediate-dose dexamethasone is an effective but toxic treatment for patients with primary amyloidosis (AL). Blood. 2005;105:2949-51.
46. Wechalekar AD, Goodman HJ, Lachmann HJ, et al. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007;109:457-64.
47. Specter R, Sanchorawala V, Seldin DC, et al. Kidney dysfunction during lenalidomide treatment for AL amyloidosis. Nephrol Dial Transplant. 2011;26:881-6.
48. Sanchorawala V, Wright DG, Rosenzweig M, et al. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007;109:492-6.
49. Sanchorawala V, Finn KT, Fennessey S, et al. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010;116:1990-1.
50. Palladini G, Russo P, Foli A, et al. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012;91:89-92.
51. Moreau P, Jaccard A, Benboubker L, et al. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010;116:4777-82.
52. Kumar S, Hayman SR, Buadi F. A phase II trial of lenalidomide, cyclophosphamide and dexamethasone (RCD) in patients with light chain amyloidosis [abstract 3853]. Blood. 2009;114:1482.
53. Dispenzieri A, Gertz MA Hayman SR. A pilot study of pomalidomide and dexamethasone in previously treated light chain amyloidosis patients [abstract 3854]. Blood. 2009;114:1482-3.
54. Wechalekar AD, Lachmann HJ, Offer M, et al. Efficacy of bortezomib in systemic AL amyloidosis with relapsed/refractory clonal disease. Haematologica. 2008;93:295-8.
55. Kastritis E, Anagnostopoulos A, Roussou M, et al. Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone. Haematologica. 2007;92:1351-8.
56. Reece DE, Hegenbart U, Sanchorawala V, et al. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011;118:865-73.
57. Landau H, Hassoun H, Bello C, et al. Consolidation with bortezomib and dexamethasone following risk-adapted melphalan and stem cell transplant in systemic AL amyloidosis. Amyloid. 2011;18(Suppl 1):130-1.
58. Kastritis E, Wechalekar AD, Dimopoulos MA, et al. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010;28:1031-7.
59. Sanchorawala V, Quillen K, Sloan JM, et al. Bortezomib and high dose melphalan conditioning for stem cell transplantation for AL amyloidosis: a pilot study. Haematologica. 2011;96:1890-2.
60. Lamm W, Willenbacher W, Lang A, et al. Efficacy of the combination of bortezomib and dexamethasone in systemic AL amyloidosis. Ann Hematol. 2011;
61. Kumar SK, Dispenzieri A, Lacy MQ, et al. Changes in serum-free light chain rather than intact monoclonal immunoglobulin levels predicts outcome following therapy in primary amyloidosis. Am J Hematol. 2011;86:251-5.
62. Herrera GA, Teng J, Turbat-Herrera EA. Renal amyloidosis: current views on pathogenesis and impact on diagnosis. Contrib Nephrol. 2011;169:232-46.
63. Sikkink LA Ramirez-Alvarado M. Cytotoxicity of amyloidogenic immunoglobulin light chains in cell culture. Cell Death Dis. 2010;1:e98.