• Michael Voulgarelis
  • Ioannis Mitroulis
  • Athanasios G. TzioufasEmail author


The term amyloidosis refers to a family of heterogeneous diseases characterized by extracellular deposition of an abnormal protein-based material, called amyloid. Amyloidosis is caused by the production of misfolded insoluble proteins in increased amounts [1]. The proteins undergo partial proteolytic cleavage resulting in the formation of peptides, in an abnormal β-pleated sheet non-branching fibrillary conformation, which are resistant to further proteolysis and form linear, rigid, and 7.5–10 mm wide amyloid fibrils. Peptide P, apolipoprotein E, basement membrane components, as well as glycosaminoglycans, proteoglycans, and protease inhibitors are added to the fibrils, resulting to stabilization and deposition of amyloid [2] (Fig. 22.1). At least 30 different amyloidogenic proteins have been identified in humans, and they can be differentiated by mass spectroscopy after laser capture microdissection and genetic testing [3]. The physicochemical characteristics of amyloid will determine in which organs the amyloid will be deposited and therefore what lesions will occur. Although the amyloid composition changes according to the amyloidogenic protein, it has some common features: (i) It consists of protein fibrils, (ii) it is insoluble and resistant to proteolysis, and (iii) after Congo red staining, it gives an apple-green birefringence under cross-polarized light microscopy.


  1. 1.
    Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med. 2003 Aug 7;349(6):583–96.CrossRefGoogle Scholar
  2. 2.
    Kisilevsky R. The relation of proteoglycans, serum amyloid P and apo E to amyloidosis current status, 2000. Amyloid Int J Exp Clin Investig Off J Int Soc Amyloidosis. 2000;7(1):23–5.CrossRefGoogle Scholar
  3. 3.
    Sipe JD, Benson MD, Buxbaum JN, Ikeda S, Merlini G, Saraiva MJM, et al. Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis. Amyloid Int J Exp Clin Investig Off J Int Soc Amyloidosis. 2012 Dec;19(4):167–70.CrossRefGoogle Scholar
  4. 4.
    Hazenberg BPC. Amyloidosis: a clinical overview. Rheum Dis Clin N Am. 2013 May;39(2):323–45.CrossRefGoogle Scholar
  5. 5.
    Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol. 1995 Jan;32(1):45–59.PubMedGoogle Scholar
  6. 6.
    Kyle RA, Linos A, Beard CM, Linke RP, Gertz MA, O’Fallon WM, et al. Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989. Blood. 1992;79(7):1817–22.PubMedGoogle Scholar
  7. 7.
    Comenzo RL, Zhang Y, Martinez C, Osman K, Herrera GA. The tropism of organ involvement in primary systemic amyloidosis: contributions of Ig V(L) germ line gene use and clonal plasma cell burden. Blood. 2001;98(3):714–20.CrossRefGoogle Scholar
  8. 8.
    Lachmann HJ, Goodman HJB, Gilbertson JA, Gallimore JR, Sabin CA, Gillmore JD, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med. 2007;356(23):2361–71.CrossRefGoogle Scholar
  9. 9.
    Bunker D, Gorevic P. AA amyloidosis: Mount Sinai experience, 1997–2012. Mt Sinai J Med N Y. 2012;79(6):749–56.CrossRefGoogle Scholar
  10. 10.
    Westermark GT, Fändrich M, Westermark P. AA amyloidosis: pathogenesis and targeted therapy. Annu Rev Pathol. 2015;10:321–44.CrossRefGoogle Scholar
  11. 11.
    Andrade C. A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain J Neurol. 1952 Sep;75(3):408–27.CrossRefGoogle Scholar
  12. 12.
    Pomerance A. Senile cardiac amyloidosis. Br Heart J. 1965;27(5):711–8.CrossRefGoogle Scholar
  13. 13.
    Tanskanen M, Peuralinna T, Polvikoski T, Notkola I-L, Sulkava R, Hardy J, et al. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med. 2008;40(3):232–9.CrossRefGoogle Scholar
  14. 14.
    Liao R, Jain M, Teller P, Connors LH, Ngoy S, Skinner M, et al. Infusion of light chains from patients with cardiac amyloidosis causes diastolic dysfunction in isolated mouse hearts. Circulation. 2001;104(14):1594–7.CrossRefGoogle Scholar
  15. 15.
    Wechalekar AD, Gillmore JD, Hawkins PN. Systemic amyloidosis. Lancet Lond Engl. 2016;387(10038):2641–54.CrossRefGoogle Scholar
  16. 16.
    Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation. 2005;112(13):2047–60.CrossRefGoogle Scholar
  17. 17.
    Dember LM. Emerging treatment approaches for the systemic amyloidoses. Kidney Int. 2005;68(3):1377–90.CrossRefGoogle Scholar
  18. 18.
    Rapezzi C, Lorenzini M, Longhi S, Milandri A, Gagliardi C, Bartolomei I, et al. Cardiac amyloidosis: the great pretender. Heart Fail Rev. 2015;20(2):117–24.CrossRefGoogle Scholar
  19. 19.
    Park MA, Mueller PS, Kyle RA, Larson DR, Plevak MF, Gertz MA. Primary (AL) hepatic amyloidosis: clinical features and natural history in 98 patients. Medicine (Baltimore). 2003;82(5):291–8.CrossRefGoogle Scholar
  20. 20.
    Giancane G, Haar NMT, Wulffraat N, Vastert SJ, Barron K, Hentgen V, et al. Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever. Ann Rheum Dis. 2015;74(4):635–41.CrossRefGoogle Scholar
  21. 21.
    Twig G, Livneh A, Vivante A, Afek A, Shamiss A, Derazne E, et al. Mortality risk factors associated with familial Mediterranean fever among a cohort of 1.25 million adolescents. Ann Rheum Dis. 2014;73(4):704–9.CrossRefGoogle Scholar
  22. 22.
    Touitou I, Sarkisian T, Medlej-Hashim M, Tunca M, Livneh A, Cattan D, et al. Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever. Arthritis Rheum. 2007;56(5):1706–12.CrossRefGoogle Scholar
  23. 23.
    Akpolat T, Özkaya O, Özen S. Homozygous M694V as a risk factor for amyloidosis in Turkish FMF patients. Gene. 2012;492(1):285–9.CrossRefGoogle Scholar
  24. 24.
    Zemer D, Pras M, Sohar E, Modan M, Cabili S, Gafni J. Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med. 1986;314(16):1001–5.CrossRefGoogle Scholar
  25. 25.
    Ozen S, Demirkaya E, Erer B, Livneh A, Ben-Chetrit E, Giancane G, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis. 2016;75(4):644–51.CrossRefGoogle Scholar
  26. 26.
    Hentgen V, Grateau G, Kone-Paut I, Livneh A, Padeh S, Rozenbaum M, et al. Evidence-based recommendations for the practical management of familial Mediterranean fever. Semin Arthritis Rheum. 2013;43(3):387–91.CrossRefGoogle Scholar
  27. 27.
    ter Haar NM, Oswald M, Jeyaratnam J, Anton J, Barron KS, Brogan PA, et al. Recommendations for the management of autoinflammatory diseases. Ann Rheum Dis. 2015;74(9):1636–44.CrossRefGoogle Scholar
  28. 28.
    Lane T, Loeffler JM, Rowczenio DM, Gilbertson JA, Bybee A, Russell TL, et al. AA amyloidosis complicating the hereditary periodic fever syndromes. Arthritis Rheum. 2013;65(4):1116–21.CrossRefGoogle Scholar
  29. 29.
    Lachmann HJ, Papa R, Gerhold K, Obici L, Touitou I, Cantarini L, et al. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. Ann Rheum Dis. 2014;73(12):2160–7.CrossRefGoogle Scholar
  30. 30.
    Libbey CA, Skinner M, Cohen AS. Use of abdominal fat tissue aspirate in the diagnosis of systemic amyloidosis. Arch Intern Med. 1983;143(8):1549–52.CrossRefGoogle Scholar
  31. 31.
    Rapezzi C, Quarta CC, Guidalotti PL, Pettinato C, Fanti S, Leone O, et al. Role of (99m)Tc-DPD scintigraphy in diagnosis and prognosis of hereditary transthyretin-related cardiac amyloidosis. JACC Cardiovasc Imaging. 2011;4(6):659–70.CrossRefGoogle Scholar
  32. 32.
    Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016;133(24):2404–12.CrossRefGoogle Scholar
  33. 33.
    Abraham RS, Katzmann JA, Clark RJ, Bradwell AR, Kyle RA, Gertz MA. Quantitative analysis of serum free light chains. A new marker for the diagnostic evaluation of primary systemic amyloidosis. Am J Clin Pathol. 2003;119(2):274–8.CrossRefGoogle Scholar
  34. 34.
    Perugini E, Rapezzi C, Piva T, Leone O, Bacchi-Reggiani L, Riva L, et al. Non-invasive evaluation of the myocardial substrate of cardiac amyloidosis by gadolinium cardiac magnetic resonance. Heart. 2006;92(3):343–9.CrossRefGoogle Scholar
  35. 35.
    Booth DR, Booth SE, Gillmore JD, Hawkins PN, Pepys MB. SAA1 alleles as risk factors in reactive systemic AA amyloidosis. Amyloid. 1998;5(4):262–5.CrossRefGoogle Scholar
  36. 36.
    Kisilevsky R, Manley PN. Acute-phase serum amyloid a: perspectives on its physiological and pathological roles. Amyloid Int J Exp Clin Investig Off J Int Soc Amyloidosis. 2012;19(1):5–14.CrossRefGoogle Scholar
  37. 37.
    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;691:141–50.CrossRefGoogle Scholar
  38. 38.
    Solomon A, Weiss DT, Schell M, Hrncic R, Murphy CL, Wall J, et al. Transgenic mouse model of AA amyloidosis. Am J Pathol. 1999;154(4):1267–72.CrossRefGoogle Scholar
  39. 39.
    Courties A, Grateau G, Philippe P, Flipo R-M, Astudillo L, Aubry-Rozier B, et al. AA amyloidosis treated with tocilizumab: case series and updated literature review. Amyloid Int J Exp Clin Investig Off J Int Soc Amyloidosis. 2015;22(2):84–92.CrossRefGoogle Scholar
  40. 40.
    Okuda Y, Takasugi K. Successful use of a humanized anti-interleukin-6 receptor antibody, tocilizumab, to treat amyloid A amyloidosis complicating juvenile idiopathic arthritis. Arthritis Rheum. 2006 Sep;54(9):2997–3000.CrossRefGoogle Scholar
  41. 41.
    Ugurlu S, Hacioglu A, Adibnia Y, Hamuryudan V, Ozdogan H. Tocilizumab in the treatment of twelve cases with aa amyloidosis secondary to familial mediterranean fever. Orphanet J Rare Dis. 2017;12(1):105.CrossRefGoogle Scholar
  42. 42.
    Gillmore JD, Lovat LB, Persey MR, Pepys MB, Hawkins PN. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet. 2001;358(9275):24–9.CrossRefGoogle Scholar
  43. 43.
    Sun L, Ye RD. Serum amyloid A1: structure, function and gene polymorphism. Gene. 2016;583(1):48–57.CrossRefGoogle Scholar
  44. 44.
    Stix B, Kähne T, Sletten K, Raynes J, Roessner A, Röcken C. Proteolysis of AA amyloid fibril proteins by matrix metalloproteinases-1, −2, and −3. Am J Pathol. 2001;159(2):561–70.CrossRefGoogle Scholar
  45. 45.
    Chronopoulos S, Laird DW, Ali-Khan Z. Immunolocalization of serum amyloid A and AA amyloid in lysosomes in murine monocytoid cells: confocal and immunogold electron microscopic studies. J Pathol. 1994;173(4):361–9.CrossRefGoogle Scholar
  46. 46.
    Noborn F, O’Callaghan P, Hermansson E, Zhang X, Ancsin JB, Damas AM, et al. Heparan sulfate/heparin promotes transthyretin fibrillization through selective binding to a basic motif in the protein. Proc Natl Acad Sci U S A. 2011;108(14):5584–9.CrossRefGoogle Scholar
  47. 47.
    Bodin K, Ellmerich S, Kahan MC, Tennent GA, Loesch A, Gilbertson JA, et al. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature. 2010;468(7320):93–7.CrossRefGoogle Scholar
  48. 48.
    Inoue S, Kawano H, Ishihara T, Maeda S, Ohno S. Formation of experimental murine AA amyloid fibrils in SAP-deficient mice: high resolution ultrastructural study. Amyloid Int J Exp Clin Investig Off J Int Soc Amyloidosis. 2005;12(3):157–63.CrossRefGoogle Scholar
  49. 49.
    Merlini G, Seldin DC, Gertz MA. Amyloidosis: pathogenesis and new therapeutic options. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(14):1924–33.CrossRefGoogle Scholar
  50. 50.
    Dispenzieri A, Kyle RA, Gertz MA, Therneau TM, Miller WL, Chandrasekaran K, et al. Survival in patients with primary systemic amyloidosis and raised serum cardiac troponins. Lancet Lond Engl. 2003;361(9371):1787–9.CrossRefGoogle Scholar
  51. 51.
    Kumar S, Dispenzieri A, Katzmann JA, Larson DR, Colby CL, Lacy MQ, et al. Serum immunoglobulin free light-chain measurement in primary amyloidosis: prognostic value and correlations with clinical features. Blood. 2010;116(24):5126–9.CrossRefGoogle Scholar
  52. 52.
    Palladini G, Campana C, Klersy C, Balduini A, Vadacca G, Perfetti V, et al. Serum N-terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis. Circulation. 2003;107(19):2440–5.CrossRefGoogle Scholar
  53. 53.
    Wechalekar AD, Gillmore JD, Bird J, Cavenagh J, Hawkins S, Kazmi M, et al. Guidelines on the management of AL amyloidosis. Br J Haematol. 2015;168(2):186–206.CrossRefGoogle Scholar
  54. 54.
    Esatoglu SN, Hatemi G, Ugurlu S, Gokturk A, Tascilar K, Ozdogan H. Long-term follow-up of secondary amyloidosis patients treated with tumor necrosis factor inhibitor therapy: a STROBE-compliant observational study. Medicine (Baltimore). 2017 Aug;96(34):e7859.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Michael Voulgarelis
    • 1
  • Ioannis Mitroulis
    • 2
  • Athanasios G. Tzioufas
    • 1
    Email author
  1. 1.Department of Pathophysiology, Medical SchoolNational University of AthensAthensGreece
  2. 2.Institute of Clinical Chemistry and Laboratory MedicineTechnische Universität DresdenDresdenGermany

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