Secondary amyloidosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2] Shaghayegh Habibi, M.D.[3] Sabawoon Mirwais, M.B.B.S, M.D.[4]


AA amyloid is an abnormal insoluble extracellular protein derived from the spontaneous aggregation of fibrils composed of misfolded proteins, called amyloid precursors. In secondary amyloidosis, the amyloid precursor is SAA, an acute phase reactant, encoded by SAA 1&2 genes. In secondary amyloidosis, intermediate products of SAA metabolism tend to aggregate and form protofilaments that accumulate within extracellular space and form the insoluble amyloid deposits. Secondary amyloidosis is associated with chronic inflammation (such as tuberculosis or rheumatoid arthritis).


Increased production of IL-1/IL-6/TNF-α
Upregulation of hepatic serum amyloid A production
SAA production uptake by macrophages
C-terminal cleavage of SAA
β-sheet configuration of SAA
Fibril deposition in extracellular space
Binding of glycosaminoglycan, serum amyloid P, and lipid components
Resistant to proteolysis
The above algorithm is adopted from International Journal of Nephrology and Renovascular Disease[4]

Associated Conditions

Associated Conditions
Conditions Examples
Chronic infections
Monogenic periodic fever syndromes
Conditions predisposing to recurrent infections
Inflammatory Arthritis
Systemic Vasculitis

Gross Pathology

On gross pathology, the organs affected by amyloidosis can be characterized by the following features:

  • Porcelain like or waxy appearance
  • Enlargement


Nodular deposits of amyloid on the pleural surfaces.[8]
Cut section of an inguinal lymph node showing firm and waxy consistency.[9]
A slice of the affected node (left) has turned black after treatment with Lugol's solution. A piece of normal myometrium (right) treated similarly with no reaction is also shown.[10]

Microscopic Pathology

On microscopic histopathological analysis, aa amyloidosis is characterized by:[11][12]

  • Green birefringence under polarized light after Congo red staining (appears red under normal light)
  • Linear non-branching fibrils (indefinite length with an approximately same diameter)
  • Distinct X-ray diffraction pattern consistent with Pauling's model of a cross-beta fibril

On electron microscopy, amyloid fibrils have the following characteristics:[13]

  • 10 to 15 nm diameter
  • Straight, rigid, and nonbranching
  • Composed of twisted protofilaments


Small bowel duodenum with amyloid deposition Congo red.[14]
Amyloidosis (black arrows) in a lymph node after staining with Congo Red.[15]
Green birefringence under polarized light.[16]


  1. Jayaraman, Shobini; Gantz, Donald L.; Haupt, Christian; Gursky, Olga (2017). "Serum amyloid A forms stable oligomers that disrupt vesicles at lysosomal pH and contribute to the pathogenesis of reactive amyloidosis". Proceedings of the National Academy of Sciences. 114 (32): E6507–E6515. doi:10.1073/pnas.1707120114. ISSN 0027-8424.
  2. Kisilevsky, Robert; Raimondi, Sara; Bellotti, Vittorio (2016). "Historical and Current Concepts of Fibrillogenesis and In vivo Amyloidogenesis: Implications of Amyloid Tissue Targeting". Frontiers in Molecular Biosciences. 3. doi:10.3389/fmolb.2016.00017. ISSN 2296-889X.
  3. Wechalekar AD, Gillmore JD, Hawkins PN (June 2016). "Systemic amyloidosis". Lancet. 387 (10038): 2641–2654. doi:10.1016/S0140-6736(15)01274-X. PMID 26719234.
  4. Rumjon A, Coats T, Javaid MM (2012). "Review of eprodisate for the treatment of renal disease in AA amyloidosis". Int J Nephrol Renovasc Dis. 5: 37–43. doi:10.2147/IJNRD.S19165. PMC 3304340. PMID 22427728.
  5. Blank, Norbert; Hegenbart, Ute; Dietrich, Sascha; Brune, Maik; Beimler, Jörg; Röcken, Christoph; Müller-Tidow, Carsten; Lorenz, Hanns-Martin; Schönland, Stefan O. (2018). "Obesity is a significant susceptibility factor for idiopathic AA amyloidosis". Amyloid. 25 (1): 37–45. doi:10.1080/13506129.2018.1429391. ISSN 1350-6129.
  6. van der Hilst, J. C. H.; Yamada, T.; Op den Camp, H. J. M.; van der Meer, J. W. M.; Drenth, J. P. H.; Simon, A. (2008). "Increased susceptibility of serum amyloid A 1.1 to degradation by MMP-1: potential explanation for higher risk of type AA amyloidosis". Rheumatology. 47 (11): 1651–1654. doi:10.1093/rheumatology/ken371. ISSN 1462-0324.
  7. Papa, Riccardo; Doglio, Matteo; Lachmann, Helen J.; Ozen, Seza; Frenkel, Joost; Simon, Anna; Neven, Bénédicte; Kuemmerle-Deschner, Jasmin; Ozgodan, Huri; Caorsi, Roberta; Federici, Silvia; Finetti, Martina; Trachana, Maria; Brunner, Jurgen; Bezrodnik, Liliana; Pinedo Gago, Mari Carmen; Maggio, Maria Cristina; Tsitsami, Elena; Al Suwairi, Wafaa; Espada, Graciela; Shcherbina, Anna; Aksu, Guzide; Ruperto, Nicolino; Martini, Alberto; Ceccherini, Isabella; Gattorno, Marco (2017). "A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry". Orphanet Journal of Rare Diseases. 12 (1). doi:10.1186/s13023-017-0720-3. ISSN 1750-1172.
  8. By Yale Rosen from USA - Amyloidosis, CC BY-SA 2.0,
  9. By Ed Uthman, MD -, CC BY-SA 2.0,
  10. By Ed Uthman, MD -, CC BY-SA 2.0,
  11. Röcken C, Shakespeare A (February 2002). "Pathology, diagnosis and pathogenesis of AA amyloidosis". Virchows Arch. 440 (2): 111–122. doi:10.1007/s00428-001-0582-9. PMID 11964039.
  12. Close, William; Neumann, Matthias; Schmidt, Andreas; Hora, Manuel; Annamalai, Karthikeyan; Schmidt, Matthias; Reif, Bernd; Schmidt, Volker; Grigorieff, Nikolaus; Fändrich, Marcus (2018). "Physical basis of amyloid fibril polymorphism". Nature Communications. 9 (1). doi:10.1038/s41467-018-03164-5. ISSN 2041-1723.
  13. By Michael Feldman, MD, PhDUniversity of Pennsylvania School of Medicine -, CC BY 2.0,
  14. By Ed Uthman, MD -, CC BY-SA 2.0,
  15. By Ed Uthman, MD -, CC BY-SA 2.0,