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

Pathogenesis of secondary (AA) amyloidosis

Peter D Gorevic, MD
Section Editor
Peter H Schur, MD
Deputy Editor
Paul L Romain, MD


Amyloidosis is a generic term that refers to the predominantly extracellular tissue deposition of fibrils composed of low molecular weight subunits (5 to 25 kD) derived from any of a variety of serum proteins. These fibrils have a predominantly antiparallel beta-pleated sheet configuration; they can be identified on biopsy specimens by tinctorial properties that result from the binding of specific dyes, such as Congo red (leading to green birefringence under polarized light) and thioflavine T (producing an intense yellow-green fluorescence), and by electron microscopy [1].

All forms of amyloidosis are characterized by co-deposition of other substances, including [1,2]:

Serum amyloid P component (SAP), a member of the pentraxin family that includes C-reactive protein

Glycosaminoglycans, notably heparan sulfate

Apolipoproteins (E and J)


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: Mar 2017. | This topic last updated: Dec 02, 2015.
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. Westermark GT, Fändrich M, Westermark P. AA amyloidosis: pathogenesis and targeted therapy. Annu Rev Pathol 2015; 10:321.
  2. Alexandrescu AT. Amyloid accomplices and enforcers. Protein Sci 2005; 14:1.
  3. Gallo G, Wisniewski T, Choi-Miura NH, et al. Potential role of apolipoprotein-E in fibrillogenesis. Am J Pathol 1994; 145:526.
  4. Kisilevsky R, Ancsin JB, Szarek WA, Petanceska S. Heparan sulfate as a therapeutic target in amyloidogenesis: prospects and possible complications. Amyloid 2007; 14:21.
  5. Husby G, Stenstad T, Magnus JH, et al. Interaction between circulating amyloid fibril protein precursors and extracellular tissue matrix components in the pathogenesis of systemic amyloidosis. Clin Immunol Immunopathol 1994; 70:2.
  6. Tennent GA, Lovat LB, Pepys MB. Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer disease and systemic amyloidosis. Proc Natl Acad Sci U S A 1995; 92:4299.
  7. Kisilevsky R, Manley PN. Acute-phase serum amyloid A: perspectives on its physiological and pathological roles. Amyloid 2012; 19:5.
  8. O'Hara R, Murphy EP, Whitehead AS, et al. Local expression of the serum amyloid A and formyl peptide receptor-like 1 genes in synovial tissue is associated with matrix metalloproteinase production in patients with inflammatory arthritis. Arthritis Rheum 2004; 50:1788.
  9. Thorn CF, Lu ZY, Whitehead AS. Regulation of the human acute phase serum amyloid A genes by tumour necrosis factor-alpha, interleukin-6 and glucocorticoids in hepatic and epithelial cell lines. Scand J Immunol 2004; 59:152.
  10. Ray A, Shakya A, Kumar D, et al. Inflammation-responsive transcription factor SAF-1 activity is linked to the development of amyloid A amyloidosis. J Immunol 2006; 177:2601.
  11. Yoshizaki K. Pathogenic role of IL-6 combined with TNF-α or IL-1 in the induction of acute phase proteins SAA and CRP in chronic inflammatory diseases. Adv Exp Med Biol 2011; 691:141.
  12. Sipe J. Revised nomenclature for serum amyloid A (SAA). Nomenclature Committee of the International Society of Amyloidosis. Part 2. Amyloid 1999; 6:67.
  13. Obici L, Raimondi S, Lavatelli F, et al. Susceptibility to AA amyloidosis in rheumatic diseases: a critical overview. Arthritis Rheum 2009; 61:1435.
  14. van der Hilst JC, Yamada T, Op den Camp HJ, et al. Increased susceptibility of serum amyloid A 1.1 to degradation by MMP-1: potential explanation for higher risk of type AA amyloidosis. Rheumatology (Oxford) 2008; 47:1651.
  15. van der Westhuyzen DR, de Beer FC, Webb NR. HDL cholesterol transport during inflammation. Curr Opin Lipidol 2007; 18:147.
  16. Poitou C, Divoux A, Faty A, et al. Role of serum amyloid a in adipocyte-macrophage cross talk and adipocyte cholesterol efflux. J Clin Endocrinol Metab 2009; 94:1810.
  17. Ancsin JB, Kisilevsky R. Characterization of high affinity binding between laminin and the acute-phase protein, serum amyloid A. J Biol Chem 1997; 272:406.
  18. Mullan RH, Bresnihan B, Golden-Mason L, et al. Acute-phase serum amyloid A stimulation of angiogenesis, leukocyte recruitment, and matrix degradation in rheumatoid arthritis through an NF-kappaB-dependent signal transduction pathway. Arthritis Rheum 2006; 54:105.
  19. Lee HY, Kim SD, Shim JW, et al. LL-37 inhibits serum amyloid A-induced IL-8 production in human neutrophils. Exp Mol Med 2009; 41:325.
  20. He RL, Zhou J, Hanson CZ, et al. Serum amyloid A induces G-CSF expression and neutrophilia via Toll-like receptor 2. Blood 2009; 113:429.
  21. Urieli-Shoval S, Shubinsky G, Linke RP, et al. Adhesion of human platelets to serum amyloid A. Blood 2002; 99:1224.
  22. Ye RD, Sun L. Emerging functions of serum amyloid A in inflammation. J Leukoc Biol 2015; 98:923.
  23. Ancsin JB, Kisilevsky R. The heparin/heparan sulfate-binding site on apo-serum amyloid A. Implications for the therapeutic intervention of amyloidosis. J Biol Chem 1999; 274:7172.
  24. Vallon R, Freuler F, Desta-Tsedu N, et al. Serum amyloid A (apoSAA) expression is up-regulated in rheumatoid arthritis and induces transcription of matrix metalloproteinases. J Immunol 2001; 166:2801.
  25. Migita K, Koga T, Torigoshi T, et al. Serum amyloid A protein stimulates CCL20 production in rheumatoid synoviocytes. Rheumatology (Oxford) 2009; 48:741.
  26. Connolly M, Mullan RH, McCormick J, et al. Acute-phase serum amyloid A regulates tumor necrosis factor α and matrix turnover and predicts disease progression in patients with inflammatory arthritis before and after biologic therapy. Arthritis Rheum 2012; 64:1035.
  27. Connolly M, Rooney PR, McGarry T, et al. Acute serum amyloid A is an endogenous TLR2 ligand that mediates inflammatory and angiogenic mechanisms. Ann Rheum Dis 2016; 75:1392.
  28. Migita K, Koga T, Komori A, et al. Influence of Janus kinase inhibition on interleukin 6-mediated induction of acute-phase serum amyloid A in rheumatoid synovium. J Rheumatol 2011; 38:2309.
  29. Lachmann HJ, Goodman HJ, Gilbertson JA, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med 2007; 356:2361.
  30. Bunker D, Gorevic P. AA amyloidosis: Mount Sinai experience, 1997-2012. Mt Sinai J Med 2012; 79:749.
  31. Gruys E, Snel FW. Animal models for reactive amyloidosis. Baillieres Clin Rheumatol 1994; 8:599.
  32. Landman WJ. Amyloid arthropathy in chickens. Vet Q 1999; 21:78.
  33. Sevimli A, Misirlioğlu D, Yağci A, et al. The role of chicken IL-1beta, IL-6 and TNF-alpha in the occurrence of amyloid arthropathy. Vet Res Commun 2008; 32:499.
  34. Murakami T, Ishiguro N, Higuchi K. Transmission of systemic AA amyloidosis in animals. Vet Pathol 2014; 51:363.
  35. Grateau G. Musculoskeletal disorders in secondary amyloidosis and hereditary fevers. Best Pract Res Clin Rheumatol 2003; 17:929.
  36. van der Hilst JC. Recent insights into the pathogenesis of type AA amyloidosis. ScientificWorldJournal 2011; 11:641.
  37. Röcken C, Menard R, Bühling F, et al. Proteolysis of serum amyloid A and AA amyloid proteins by cysteine proteases: cathepsin B generates AA amyloid proteins and cathepsin L may prevent their formation. Ann Rheum Dis 2005; 64:808.
  38. Kinkley SM, Bagshaw WL, Tam SP, Kisilevsky R. The path of murine serum amyloid A through peritoneal macrophages. Amyloid 2006; 13:123.
  39. Westermark GT, Engström U, Westermark P. The N-terminal segment of protein AA determines its fibrillogenic property. Biochem Biophys Res Commun 1992; 182:27.
  40. Yamada T, Kluve-Beckerman B, Liepnieks JJ, Benson MD. Fibril formation from recombinant human serum amyloid A. Biochim Biophys Acta 1994; 1226:323.
  41. Ray A, Schatten H, Ray BK. Activation of Sp1 and its functional co-operation with serum amyloid A-activating sequence binding factor in synoviocyte cells trigger synergistic action of interleukin-1 and interleukin-6 in serum amyloid A gene expression. J Biol Chem 1999; 274:4300.
  42. Lee HY, Kim MK, Park KS, et al. Serum amyloid A stimulates matrix-metalloproteinase-9 upregulation via formyl peptide receptor like-1-mediated signaling in human monocytic cells. Biochem Biophys Res Commun 2005; 330:989.
  43. Gillmore JD, Lovat LB, Persey MR, et al. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet 2001; 358:24.
  44. Gertz MA, Skinner M, Sipe JD, et al. Serum amyloid A protein and C-reactive protein in systemic amyloidosis. Clin Exp Rheumatol 1985; 3:317.
  45. De Beer FC, Mallya RK, Fagan EA, et al. Serum amyloid-A protein concentration in inflammatory diseases and its relationship to the incidence of reactive systemic amyloidosis. Lancet 1982; 2:231.
  46. Ajiro J, Narita I, Sato F, et al. SAA1 gene polymorphisms and the risk of AA amyloidosis in Japanese patients with rheumatoid arthritis. Mod Rheumatol 2006; 16:294.
  47. Utku U, Dilek M, Akpolat I, et al. SAA1 alpha/alpha alleles in Behçet's disease related amyloidosis. Clin Rheumatol 2007; 26:927.
  48. Ombrello AK, Aksentijevich I. AA amyloidosis. In: Amyloid and Related Disorders: Surgical Pathology and Clinical Correlations, Pickens MM. (Ed), Springer, 2012. p.31.
  49. Kluve-Beckerman B, Liepnieks JJ, Wang L, Benson MD. A cell culture system for the study of amyloid pathogenesis. Amyloid formation by peritoneal macrophages cultured with recombinant serum amyloid A. Am J Pathol 1999; 155:123.
  50. Migita K, Eguchi K, Tsukada T, et al. Increased circulating serum amyloid A protein derivatives in rheumatoid arthritis patients with secondary amyloidosis. Lab Invest 1996; 75:371.
  51. Westermark GT, Westermark P, Sletten K. Amyloid fibril protein AA. Characterization of uncommon subspecies from a patient with rheumatoid arthritis. Lab Invest 1987; 57:57.
  52. Westermark GT, Sletten K, Westermark P. Massive vascular AA-amyloidosis: a histologically and biochemically distinctive subtype of reactive systemic amyloidosis. Scand J Immunol 1989; 30:605.
  53. Senthilkumar S, Chang E, Jayakumar R. Diffusible amyloid oligomers trigger systemic amyloidosis in mice. Biochem J 2008; 415:207.
  54. Westermark GT, Westermark P. Serum amyloid A and protein AA: molecular mechanisms of a transmissible amyloidosis. FEBS Lett 2009; 583:2685.
  55. Gorevic PD. Amyloid and inflammation. Proc Natl Acad Sci U S A 2013; 110:16291.