Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis (primary amyloidosis)

S Vincent Rajkumar, MD
Section Editors
Richard J Glassock, MD, MACP
Robert A Kyle, MD
Deputy Editor
Rebecca F Connor, MD


Amyloidosis is a generic term that refers to the extracellular tissue deposition of fibrils composed of low molecular weight subunits of a variety of normal serum proteins. These fibrils have a predominantly antiparallel ß-pleated sheet configuration (noted on x-ray diffraction), and can be identified on biopsy specimens both by their characteristic appearance on electron microscopy, and by their ability to bind Congo red (leading to green birefringence under polarized light) and thioflavine T (producing an intense yellow-green fluorescence).

More than 20 distinct low molecular weight proteins are recognized to form amyloid fibrils. The two most common causes of systemic amyloid deposition are:

Immunoglobulin light chain (AL) amyloidosis (previously referred to as primary amyloidosis) in which the fibrils are composed of fragments of monoclonal light chains. Affected patients may have amyloidosis alone or in association with other plasma cell dyscrasias (multiple myeloma, Waldenstrom macroglobulinemia). All forms of systemic amyloidosis in which the fibrils are derived from monoclonal light chains, regardless of the nature of the underlying plasma cell disorder (eg, MGUS, multiple myeloma, or Waldenstrom macroglobulinemia) are considered AL amyloidosis.

AA amyloidosis in which the fibrils are composed of fragments of the acute phase reactant serum amyloid A. AA amyloidosis is typically reactive (secondary) to chronic inflammation. (See "Pathogenesis of secondary (AA) amyloidosis".)

AL amyloidosis is a systemic disorder that can present with a variety of symptoms or signs, including heavy proteinuria (usually in the nephrotic range), edema, hepatosplenomegaly, otherwise unexplained heart failure, and the carpal tunnel syndrome. Although virtually all patients have multisystem amyloid deposition, it is not uncommon to present with evidence of mainly one organ being affected. (See "Renal amyloidosis" and "Gastrointestinal amyloidosis: Clinical manifestations, diagnosis, and management" and "Clinical manifestations and diagnosis of amyloid cardiomyopathy".)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Dec 2016. | This topic last updated: Mon Jul 18 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Kyle RA, Linos A, Beard CM, et al. Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989. Blood 1992; 79:1817.
  2. Kyle RA, Greipp PR. Amyloidosis (AL). Clinical and laboratory features in 229 cases. Mayo Clin Proc 1983; 58:665.
  3. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995; 32:45.
  4. Kyle RA, Greipp PR, O'Fallon WM. Primary systemic amyloidosis: multivariate analysis for prognostic factors in 168 cases. Blood 1986; 68:220.
  5. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002; 346:564.
  6. Rajkumar SV, Gertz MA, Kyle RA. Primary systemic amyloidosis with delayed progression to multiple myeloma. Cancer 1998; 82:1501.
  7. Madan S, Dispenzieri A, Lacy MQ, et al. Clinical features and treatment response of light chain (AL) amyloidosis diagnosed in patients with previous diagnosis of multiple myeloma. Mayo Clin Proc 2010; 85:232.
  8. Alpers CE, Cotran RS. Neoplasia and glomerular injury. Kidney Int 1986; 30:465.
  9. Menke DM, Kyle RA, Fleming CR, et al. Symptomatic gastric amyloidosis in patients with primary systemic amyloidosis. Mayo Clin Proc 1993; 68:763.
  10. Eder L, Bitterman H. Image in clinical medicine. Amyloid purpura. N Engl J Med 2007; 356:2406.
  11. Yood RA, Skinner M, Rubinow A, et al. Bleeding manifestations in 100 patients with amyloidosis. JAMA 1983; 249:1322.
  12. Mumford AD, O'Donnell J, Gillmore JD, et al. Bleeding symptoms and coagulation abnormalities in 337 patients with AL-amyloidosis. Br J Haematol 2000; 110:454.
  13. Sucker C, Hetzel GR, Grabensee B, et al. Amyloidosis and bleeding: pathophysiology, diagnosis, and therapy. Am J Kidney Dis 2006; 47:947.
  14. Gertz MA, Kyle RA, Noel P. Primary systemic amyloidosis: a rare complication of immunoglobulin M monoclonal gammopathies and Waldenström's macroglobulinemia. J Clin Oncol 1993; 11:914.
  15. Gertz MA, Kyle RA. Amyloidosis with IgM monoclonal gammopathies. Semin Oncol 2003; 30:325.
  16. Terrier B, Jaccard A, Harousseau JL, et al. The clinical spectrum of IgM-related amyloidosis: a French nationwide retrospective study of 72 patients. Medicine (Baltimore) 2008; 87:99.
  17. Wechalekar AD, Lachmann HJ, Goodman HJ, et al. AL amyloidosis associated with IgM paraproteinemia: clinical profile and treatment outcome. Blood 2008; 112:4009.
  18. Sachchithanantham S, Roussel M, Palladini G, et al. European Collaborative Study Defining Clinical Profile Outcomes and Novel Prognostic Criteria in Monoclonal Immunoglobulin M-Related Light Chain Amyloidosis. J Clin Oncol 2016; 34:2037.
  19. Gertz MA, Buadi FK, Hayman SR, et al. Immunoglobulin D amyloidosis: a distinct entity. Blood 2012; 119:44.
  20. Duston MA, Skinner M, Shirahama T, Cohen AS. Diagnosis of amyloidosis by abdominal fat aspiration. Analysis of four years' experience. Am J Med 1987; 82:412.
  21. Duston MA, Skinner M, Meenan RF, Cohen AS. Sensitivity, specificity, and predictive value of abdominal fat aspiration for the diagnosis of amyloidosis. Arthritis Rheum 1989; 32:82.
  22. Sungur C, Sungur A, Ruacan S, et al. Diagnostic value of bone marrow biopsy in patients with renal disease secondary to familial Mediterranean fever. Kidney Int 1993; 44:834.
  23. Swerdlow SH, Campo E, Harris NL, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, IARC Press, Lyon 2008.
  24. Glenner GG. Amyloid deposits and amyloidosis. The beta-fibrilloses (first of two parts). N Engl J Med 1980; 302:1283.
  25. Fernández de Larrea C, Verga L, Morbini P, et al. A practical approach to the diagnosis of systemic amyloidoses. Blood 2015; 125:2239.
  26. Schönland SO, Hegenbart U, Bochtler T, et al. Immunohistochemistry in the classification of systemic forms of amyloidosis: a systematic investigation of 117 patients. Blood 2012; 119:488.
  27. Novak L, Cook WJ, Herrera GA, Sanders PW. AL-amyloidosis is underdiagnosed in renal biopsies. Nephrol Dial Transplant 2004; 19:3050.
  28. Anesi E, Palladini G, Perfetti V, et al. Therapeutic advances demand accurate typing of amyloid deposits. Am J Med 2001; 111:243.
  29. Herrera GA, Sanders PW, Reddy BV, et al. Ultrastructural immunolabeling: a unique diagnostic tool in monoclonal light chain-related renal diseases. Ultrastruct Pathol 1994; 18:401.
  30. Westermark P, Benson L, Juul J, Sletten K. Use of subcutaneous abdominal fat biopsy specimen for detailed typing of amyloid fibril protein-AL by amino acid sequence analysis. J Clin Pathol 1989; 42:817.
  31. Vrana JA, Gamez JD, Madden BJ, et al. Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood 2009; 114:4957.
  32. Sethi S, Theis JD, Leung N, et al. Mass spectrometry-based proteomic diagnosis of renal immunoglobulin heavy chain amyloidosis. Clin J Am Soc Nephrol 2010; 5:2180.
  33. Klein CJ, Vrana JA, Theis JD, et al. Mass spectrometric-based proteomic analysis of amyloid neuropathy type in nerve tissue. Arch Neurol 2011; 68:195.
  34. Brambilla F, Lavatelli F, Di Silvestre D, et al. Reliable typing of systemic amyloidoses through proteomic analysis of subcutaneous adipose tissue. Blood 2012; 119:1844.
  35. Fonseca R, Ahmann GJ, Jalal SM, et al. Chromosomal abnormalities in systemic amyloidosis. Br J Haematol 1998; 103:704.
  36. Hayman SR, Bailey RJ, Jalal SM, et al. Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis. Blood 2001; 98:2266.
  37. Harrison CJ, Mazzullo H, Ross FM, et al. Translocations of 14q32 and deletions of 13q14 are common chromosomal abnormalities in systemic amyloidosis. Br J Haematol 2002; 117:427.
  38. Bochtler T, Hegenbart U, Cremer FW, et al. Evaluation of the cytogenetic aberration pattern in amyloid light chain amyloidosis as compared with monoclonal gammopathy of undetermined significance reveals common pathways of karyotypic instability. Blood 2008; 111:4700.
  39. Bryce AH, Ketterling RP, Gertz MA, et al. Translocation t(11;14) and survival of patients with light chain (AL) amyloidosis. Haematologica 2009; 94:380.
  40. Kyle RA, Gertz MA, Greipp PR, 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.
  41. Palladini G, Russo P, Bosoni T, et al. Identification of amyloidogenic light chains requires the combination of serum-free light chain assay with immunofixation of serum and urine. Clin Chem 2009; 55:499.
  42. Paiva B, Vídriales MB, Pérez JJ, et al. The clinical utility and prognostic value of multiparameter flow cytometry immunophenotyping in light-chain amyloidosis. Blood 2011; 117:3613.
  43. Hawkins PN, Lavender JP, Pepys MB. Evaluation of systemic amyloidosis by scintigraphy with 123I-labeled serum amyloid P component. N Engl J Med 1990; 323:508.
  44. Gallo G, Wisniewski T, Choi-Miura NH, et al. Potential role of apolipoprotein-E in fibrillogenesis. Am J Pathol 1994; 145:526.
  45. Hawkins PN, Pepys MB. Imaging amyloidosis with radiolabelled SAP. Eur J Nucl Med 1995; 22:595.
  46. Jager PL, Hazenberg BP, Franssen EJ, et al. Kinetic studies with iodine-123-labeled serum amyloid P component in patients with systemic AA and AL amyloidosis and assessment of clinical value. J Nucl Med 1998; 39:699.
  47. Tan SY, Pepys MB, Hawkins PN. Treatment of amyloidosis. Am J Kidney Dis 1995; 26:267.
  48. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009; 23:3.
  49. Rajkumar SV. Multiple myeloma: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol 2011; 86:57.
  50. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014; 15:e538.
  51. Benson MD, Liepnieks JJ, Kluve-Beckerman B. Hereditary systemic immunoglobulin light-chain amyloidosis. Blood 2015; 125:3281.
  52. Lachmann HJ, Booth DR, Booth SE, et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med 2002; 346:1786.
  53. Gertz MA, Kyle RA, Edwards WD. Recognition of congestive heart failure due to senile cardiac amyloidosis. Biomed Pharmacother 1989; 43:101.
  54. Ng B, Connors LH, Davidoff R, et al. Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-associated amyloidosis. Arch Intern Med 2005; 165:1425.
  55. Nasr SH, Valeri AM, Cornell LD, et al. Renal monoclonal immunoglobulin deposition disease: a report of 64 patients from a single institution. Clin J Am Soc Nephrol 2012; 7:231.
  56. Pozzi C, D'Amico M, Fogazzi GB, et al. Light chain deposition disease with renal involvement: clinical characteristics and prognostic factors. Am J Kidney Dis 2003; 42:1154.
  57. Sayed RH, Wechalekar AD, Gilbertson JA, et al. Natural history and outcome of light chain deposition disease. Blood 2015; 126:2805.
  58. Guidelines Working Group of UK Myeloma Forum, British Commitee for Standards in Haematology, British Society for Haematology. Guidelines on the diagnosis and management of AL amyloidosis. Br J Haematol 2004; 125:681.
  59. Fujita Y, Tsuji-Abe Y, Sato-Matsumura KC, et al. Nail dystrophy and blisters as sole manifestations in myeloma-associated amyloidosis. J Am Acad Dermatol 2006; 54:712.
  60. Kyle RA, Gertz MA, Lacy MQ, Dispenzieri A. Localized AL amyloidosis of the colon: an unrecognized entity. Amyloid 2003; 10:36.
  61. Tirzaman O, Wahner-Roedler DL, Malek RS, et al. Primary localized amyloidosis of the urinary bladder: a case series of 31 patients. Mayo Clin Proc 2000; 75:1264.
  62. Domínguez S, Wienberg P, Clarós P, et al. Primary localized nasopharyngeal amyloidosis. A case report. Int J Pediatr Otorhinolaryngol 1996; 36:61.
  63. Zeiser R, Mikesch K, Fisch P, et al. Extramedullary plasmocytoma with local amyloidosis presenting as a lump on the lip. Br J Haematol 2004; 125:679.