The term amyloid, or amylum in Latin, was first adopted by Rudolf Virchow in 1854 (11. Kyle RA. Amyloidosis: a convoluted story. Br J Haematol. 2001;114:529-38. [PMID: 11552976]) to describe extracellular deposits of a beta-pleated protein that resembled starch when dyed with iodine. It was not until the 1920s that Congo red stain was used to elicit the classic apple-green birefringence of the protein when examined under light microscopy. Amyloidosis refers to a heterogeneous group of diseases caused by normally available soluble proteinaceous particles forming into insoluble aggregates (22. Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med. 2003; 349:583-96. [PMID: 12904524]); these present with myriad symptoms, depending on organ involvement.
This review will provide an overview of amyloidosis for the hospitalist, focusing primarily on systemic amyloidosis.
Types of amyloidosis
Amyloidosis can be classified depending on the type of protein composing the amyloid, on whether the disease is localized or systemic, or on whether disease is occurring secondary to other medical conditions (33. Real de Asúa D, et al. Systemic AA amyloidosis: epidemiology, diagnosis, and management. Clin Epidemiol. 2014;6:369-77. [PMID: 25378951] doi:10.2147/CLEP.S39981). The main types of amyloidosis are primary amyloid amyloidosis (AL), heavy-chain (AH) amyloidosis, secondary amyloid A (AA) amyloidosis, familial amyloidosis, senile amyloidosis, and dialysis-related amyloidosis.
AL amyloid is composed of immunoglobulin light chains as part of plasma-cell dyscrasias and is the most common form of systemic disease, with an incidence of 1 per 100,000 person-years in Western countries (44. Kyle RA, et al. Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989. Blood. 1992;79:1817-22. [PMID: 1558973]). Serum amyloid P (SAP) is a nonfibrillary component derived from a normal circulating plasma protein that binds to all amyloid precursors (Table 1) and stabilizes their tertiary structure, facilitating their pathogenesis (55. Obici L, Perfetti V, Palladini G, Moratti R, Merlini G. Clinical aspects of systemic amyloid diseases. Biochim Biophys Acta. 2005;1753:11-22. [PMID: 16198646]).
There are 4 steps in establishing the diagnosis (Table 2): 1) clinical suspicion, 2) visualization of the protein, 3) characterization of the precursor, and 4) identification of the extent of disease.
Proteinuria leading to nephrotic syndrome is the earliest and most common clinical manifestation of systemic amyloidosis (66. Lachmann HJ, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med. 2007;356:2361-71. [PMID: 17554117]). However, as in multiple myeloma, amyloidosis can be detected earlier if there is a “protein-albumin” dissociation in the urine, that is, evidence of heavy proteinuria in a random urine sample with negative (or minimal) protein on dipstick. This is because regular urine dipstick detects only albumin but not light chains.
Left ventricular hypertrophy, low-voltage electrocardiogram, and restrictive cardiomyopathy are some of the cardiac manifestations (77. Cueto-Garcia L, et al. Echocardiographic findings in systemic amyloidosis: spectrum of cardiac involvement and relation to survival. J Am Coll Cardiol. 1985;6:737-43. [PMID: 4031287]). Pleural infiltration with amyloid can lead to persistent pleural effusion (88. Berk JL, et al. Persistent pleural effusions in primary systemic amyloidosis: etiology and prognosis. Chest. 2003;124:969-77. [PMID: 12970025]). Gastrointestinal manifestations like diarrhea, malabsorption, and pseudo-obstruction are less common. Hepatosplenomegaly and hepatic failure can also occur. Orthostatic hypotension occurs due to autonomic neuropathy; peripheral neuropathy causes paresthesias. Amyloid arthropathy is present in approximately 2% of patients, while carpal tunnel syndrome is more common, affecting approximately 25% of patients (99. Gertz MA, Kyle RA. Primary systemic amyloidosis—a diagnostic primer. Mayo Clin Proc. 1989;64:1505-19. [PMID: 2513459]). Periorbital purpura and macroglossia, although pathognomonic, are rare.
If amyloidosis is suspected, then testing for paraproteins should be prompted. Serum and urine protein electrophoresis (SPEP and UPEP) along with serum and urine immunofixation (SIF and UIF) should be obtained in search for the monoclonal protein (1010. Dispenzieri A, et al. International Myeloma Working Group. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia. 2009;23:215-24. [PMID: 19020545] doi:10.1038/leu.2008.307). In patients who display clonality with no identifiable monoclonal protein on immunofixation, quantification of serum free light chains can be useful (1111. Kumar S, et al. Serum immunoglobulin free light-chain measurement in primary amyloidosis: prognostic value and correlations with clinical features. Blood. 2010;116:5126-9. [PMID: 20798235] doi:10.1182/blood-2010-06-290668). The sensitivity of SPEP is only 66%, while that of SIF is 74% and that of serum immunoglobulin free light-chain assay is 88%. The sensitivity for detecting a monoclonal protein further increases to 94% if all 3 serum tests are combined and rises to 98% if urine immunofixation is added (1212. Katzmann JA, et al. Screening panels for detection of monoclonal gammopathies. Clin Chem. 2009;55:1517-22. [PMID: 19520758] doi:10.1373/clinchem.2009.126664). It is important to keep in mind that the presence of a serum or urine monoclonal protein does not confirm the diagnosis of AL amyloidosis and may lead to a misdiagnosis in as many as 10% of cases (1313. Lachmann HJ, et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med. 2002;346:1786-91. [PMID: 12050338]).
Direct visualization of the amyloid deposits is mandatory (1414. Vrana JA, et al. Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood. 2009;114:4957-9. [PMID: 19797517] doi:10.1182/blood-2009-07-230722). Biopsies from the affected organs, like the heart or kidney, have a higher yield than those from more accessible yet unaffected organs, like subcutaneous abdominal fat (1515. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol. 1995;32:45-59. [PMID: 7878478]). Subcutaneous abdominal fat aspiration or biopsy is noninvasive and has now become the preferred initial diagnostic method in many centers, with a specificity of 93% to 100% but a sensitivity of only 57% to 82% (1616. van Gameren II, et al. Diagnostic accuracy of subcutaneous abdominal fat tissue aspiration for detecting systemic amyloidosis and its utility in clinical practice. Arthritis Rheum. 2006;54:2015-21. [PMID: 16732553]); sensitivity decreases in patients with single-organ disease. Rectal mucosa biopsy has shown variable results, with some reports showing similar sensitivity and specificity to subcutaneous abdominal fat aspiration (1717. Hachulla E, Grateau G. Diagnostic tools for amyloidosis. Joint Bone Spine. 2002; 69:538-45. [PMID: 12537260]). Minor salivary gland biopsy has a sensitivity of approximately 83% to 100% (1818. Caporali R, et al. Safety and usefulness of minor salivary gland biopsy: retrospective analysis of 502 procedures performed at a single center. Arthritis Rheum. 2008;59:714-20. [PMID: 18438907] doi:10.1002/art.23579).
Amyloid aggregates appear homogeneous and eosinophilic on hematoxylin-eosin staining. Congo red has high sensitivity and specificity in differentiating amyloid from other protein deposits and therefore remains the gold standard dye. It should be noted that certain related diseases don't stain positive for this dye as the fibril formation does not occur; examples include light- and heavy-chain deposit diseases. These diseases involve mainly the kidneys causing nephrotic syndrome but can rarely involve the heart and liver. Some of these patients will develop overt multiple myeloma necessitating meticulous follow-up and clinical evaluation.
While many methods are available for typing the precursor, including direct sequencing, immunogold, immunofluorescence, or immunohistochemistry, mass spectrometry remains the method of choice (1919. Vrana JA, et al. Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood. 2009;114:4957-9. [PMID: 19797517] doi:10.1182/blood-2009-07-230722).
Establishing disease extent starts with history and physical exam. Defining the extent of disease is important because the course of therapy differs based on whether disease is localized or systemic. Because the systemic form of amyloidosis can affect multiple organs, a thorough review of systems is crucial (2020. Gertz MA, Kyle RA. Primary systemic amyloidosis—a diagnostic primer. Mayo Clin Proc. 1989;64:1505-19. [PMID: 2513459]). Screening for cardiac involvement is important for prognostication as well as for identifying the window for therapy. A basic tool, the electrocardiogram, is one of the most important tests in the workup of amyloidosis, and with the increasing utility of serum cardiac markers, like troponins and N-terminal pro B-type natriuretic peptide (NT-proBNP), echocardiography is becoming less essential. Typical findings on echocardiogram include normal-size ventricles with disproportionate biatrial enlargement. Patients with normal echocardiography can benefit from Doppler myocardial images to further identify early systolic dysfunction (2121. Oh JK, et al. Dynamic left ventricular outflow tract obstruction in cardiac amyloidosis detected by continuous-wave Doppler echocardiography. Am J Cardiol. 1987;59:1008-10. [PMID: 3565277]).
Recently, speckle tracking modality in echocardiography has demonstrated abnormal radial strain pattern despite normal ejection fraction. A sparkling pattern of myocardium is a nonspecific echocardiographic marker for cardiac amyloidosis and occurs in only a minority of patients. The presence of delayed diffuse gadolinium enhancement subendocardially on T1-weighted images is sensitive for amyloid; however, the role of cardiac magnetic resonance is still evolving (2222. Ruberg FL, et al. Diagnostic and prognostic utility of cardiovascular magnetic resonance imaging in light-chain cardiac amyloidosis. Am J Cardiol. 2009;103:544-9. [PMID: 19195518] doi:10.1016/j.amjcard.2008.09.105). 18F-florbetapir, the positron emission tomography imaging agent approved for identifying amyloid B deposits in the brain in Alzheimer's disease, is currently under investigation for use in targeting cardiac amyloid (2323. Chen W, Dilsizian V. Molecular imaging of amyloidosis: will the heart be the next target after the brain? Curr Cardiol Rep. 2012;14:226-33. [PMID: 22193845] doi:10.1007/s11886-011-0239-5) (Table 3).
The prognosis of amyloidosis is related to the number and extent of organ involvement. Two major determinants of prognosis are the presence and severity of cardiac involvement (2626. Dispenzieri A, et al. Survival in patients with primary systemic amyloidosis and raised serum cardiac troponins. Lancet. 2003;361:1787-9. [PMID: 12781539]) and the presence of concurrent myeloma (2727. Pardanani A, et al. Circulating peripheral blood plasma cells as a prognostic indicator in patients with primary systemic amyloidosis. Blood. 2003;101:827-30. [PMID: 12393530]).
Multiple prognostic models are available that take into account troponin T as well as NT-proBNP. One model also utilizes serum uric acid (2828. Kumar S, et al. Serum uric acid: novel prognostic factor in primary systemic amyloidosis. Mayo Clin Proc. 2008;83:297-303. [PMID: 18315995] doi:10.4065/83.3.297). The Revised Mayo Stage classifies disease as stage I, II, III, or IV based on the presence of 0, 1, 2, or 3 of the following risk factors: NT-proBNP level ≥1,800 ng/L, cardiac troponin T level ≥0.025 μg/L, and a difference between the involved and uninvolved serum light chains of ≥18 mg/dL (2929. Kumar S, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol. 2012;30:989-95. [PMID: 22331953] doi:10.1200/JCO.2011.38.5724). Median overall survival is 96, 40, 14, and 6 months, respectively, for stages I, II, III, and IV.
We will focus on the treatment of AL amyloidosis. The initial step in therapy is to decide whether the patient is eligible for autologous hematopoietic stem-cell transplant (AHSCT) (Table 4), bearing in mind that there is no evidence to suggest the superiority of AHSCT over chemotherapy. The meta-analysis by Mhaskar and colleagues (3131. Mhaskar R. et al. Role of high-dose chemotherapy and autologous hematopoietic cell transplantation in primary systemic amyloidosis: a systematic review. Biol Blood Marrow Transplant. 2009;15:893-902. [PMID: 19589478] doi:10.1016/j.bbmt.2009.01.022), which showed superior overall survival for patients who received chemotherapy alone compared to those who received AHSCT, excluded a study that showed the opposite (3232. Mehta J, Dispenzieri A, Gertz MA. High-dose chemotherapy with autotransplantation in AL amyloidosis: a flawed meta-analysis [Letter]. Biol Blood Marrow Transplant. 2010;16:138-40; author reply 140-1. [PMID: 19761864] doi:10.1016/j.bbmt.2009.09.005). There was also no risk stratification. This suggests that the lower overall survival in the AHSCT group was related to more advanced disease.
In another study, a 10-year survival rate of up to 53% was reported for patients who achieved complete response following AHSCT (3333. Sanchorawala V, et al. Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem-cell transplantation. Blood. 2007;110:3561-3. [PMID: 17673601]). Transplant-related mortality rate was 4% to 7%, lower than previous reports (3434. Gertz MA, 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. [PMID: 20935685] doi:10.1038/bmt.2010.234, 3535. Tsai SB, et al. High-dose melphalan and stem cell transplantation for patients with AL amyloidosis: trends in treatment-related mortality over the past 17 years at a single referral center [Letter]. Blood. 2012;120:4445-6. [PMID: 23175664] doi:10.1182/blood-2012-09-457341), and further decreased when patients with high-risk disease were excluded (3636. Gertz MA, et al. Refinement in patient selection to reduce treatment-related mortality from autologous stem cell transplantation in amyloidosis. Bone Marrow Transplant. 2013;48:557-61. [PMID: 22964596] doi:10.1038/bmt.2012.170). The most important predictor of outcome before transplant is disease stage; after transplant, the most important predictor is hematologic response (Table 5) (3737. Gertz MA, et al. Effect of hematologic response on outcome of patients undergoing transplantation for primary amyloidosis: importance of achieving a complete response. Haematologica. 2007;92:1415-8. [PMID: 17768110]).
Conventional lines of chemotherapy
Melphalan and prednisone were first shown to be superior to placebo in 1978 (3838. Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978;52:818-27. [PMID: 356916]). The same regimen further doubled the overall survival when compared to colchicine (3939. Skinner M, et al. Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only. Am J Med. 1996;100:290-8. [PMID: 8629674], 4040. Kyle RA, et al. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997;336:1202-7. [PMID: 9110907]). In 2004, Palladini and colleagues reported that the combination of melphalan and dexamethasone is another feasible option for patients who were not eligible for AHSCT (4141. Palladini G, et al. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004;103:2936-8. [PMID: 15070667]). In a median follow-up of 5 years in their study, they reported median progression-free survival and overall survival were 3.8 and 5.1 years, respectively (4242. Palladini G, et al. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis [Letter]. Blood. 2007;110:787-8. [PMID: 17606766]). Furthermore, both melphalan and dexamethasone are available in oral formulations and continue to be standard treatment for patients who are not candidates for AHSCT.
Novel lines of therapy
Bortezomib is a proteasome inhibitor that has been studied as single-agent therapy, with dexamethasone, and in combination with cyclophosphamide and dexamethasone (CyBorD) (4343. Kastritis E, et al. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010;28:1031-7. [PMID: 20085941] doi:10.1200/JCO.2009.23.8220-4646. Reece DE, et al. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014;124:2498-506. [PMID: 25202139] doi:10.1182/blood-2014-04-568329). Toxicities include thrombocytopenia, fatigue, vomiting, and syncope.
Oral thalidomide was studied in combination with dexamethasone (4747. Palladini G, 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. [PMID: 15572585]), with melphalan and dexamethasone (4848. Palladini G, et al. Treatment of patients with advanced cardiac AL amyloidosis with oral melphalan, dexamethasone, and thalidomide. Ann Hematol. 2009;88:347-50. [PMID: 18779964] doi:10.1007/s00277-008-0600-y), and with cyclophosphamide and dexamethasone (4949. Wechalekar AD, et al. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007;109:457-64. [PMID: 16990593]). Thalidomide carries a boxed warning for venous thromboembolism. Other toxicities include edema, fatigue, sensory neuropathy, constipation, and hypocalcemia.
Oral lenalidomide has been studied plus dexamethasone, with or without cyclophosphamide (5050. Dispenzieri A, et al. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007;109:465-70. [PMID: 17008538]-5252. Kumar S, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol. 2012;30:989-95. [PMID: 22331953] doi:10.1200/JCO.2011.38.5724), and with melphalan and dexamethasone (5353. Moreau P, 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. [PMID: 20724537] doi:10.1182/blood-2010-07-294405). Toxicities include edema, fatigue, nausea, vomiting, change in bowel habits, and rash.
An oral derivative of thalidomide, pomalidomide, has been studied in combination with dexamethasone in patients with previously treated AL amyloidosis (5454. Dispenzieri A, et al. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012;119:5397-404. [PMID: 22493299] doi:10.1182/blood-2012-02-413161). Side effects include edema, fatigue, cytopenia, gastrointestinal, and back pain.
Amyloidosis refers to the deposition of abnormal protein from different precursors that collectively lead to multiorgan dysfunction. Early detection is key because the disease is associated with high morbidity and mortality. Most of the initial workup can be done by the primary care clinician or the hospitalist. Cardiac involvement is associated with worse prognosis. Stage can predict outcomes prior to therapy, and hematologic response is the best predictor of outcomes with therapy. Autologous hematopoietic stem-cell transplantation is a viable option for those who are eligible. For those who are not, systemic chemotherapy, with melphalan-based regimens or more novel agents, is indicated.