Overview of systemic and localized amyloidosis

Saulius Girnius

DOI: https://doi.org/10.7175/rhc.v4i4.662


Amyloidosis is a family of protein misfolding disorders, in which insoluble fibrillar proteins deposit extracellularly and cause end organ damage. Depending on the precursor protein, clinical manifestations in amyloidosis vary significantly. In systemic amyloidosis, the heart, kidneys, and nerves are most commonly affected, resulting in congestive heart failure, arrhythmia, nephrotic syndrome, renal failure, and peripheral and autonomic neuropathies. In localized amyloidosis, amyloid deposits at the site of production, so only one organ is disrupted. Once amyloidosis is confirmed histologically, the precursor subtype must be identified using immunohistochemistry, immunofixation, electron microscopy, or laser microdissection and mass spectrometry. Treatment should not be initiated prior to the identification of the type of amyloidosis. Currently, treatment focuses on the suppression of the precursor protein: in AL amyloidosis, chemotherapy or autologous stem cell transplants suppress production of immunoglobulin light chains; in AA amyloidosis, anti-microbial and anti-inflammatory agents suppress amyloid A production; and in AF amyloidosis, a liver transplantation removes the source of mutant transthyretin protein production. Newer drugs are being developed to target amyloidosis at an epigenetic level or stabilize folding intermediates, but there are currently in development.


Localized amyloidosis; Rare disease; Systemic amyloidosis

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  • Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med 1997; 337: 898-909; http://dx.doi.org/10.1056/NEJM199709253371306
  • Leung N, Nasr SH, Sethi S. How I treat amyloidosis: the importance of accurate diagnosis and amyloid typing. Blood 2012; 120: 3206-13; http://dx.doi.org/10.1182/blood-2012-03-413682
  • Dember LM. Amyloidosis-associated kidney disease. J Am Soc Nephrol 2006; 17: 3458-71; http://dx.doi.org/10.1681/ASN.2006050460
  • Brenner DA, Jain M, Pimentel DR, et al. Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress. Circ Res 2004; 94: 1008-10; http://dx.doi.org/10.1161/01.RES.0000126569.75419.74
  • Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002; 297: 353-6; http://dx.doi.org/10.1126/science.1072994
  • Berk JL, O’Regan A, Skinner M. Pulmonary and tracheobronchial amyloidosis. Semin Respir Crit Care Med 2002; 23: 155-65; http://dx.doi.org/10.1055/s-2002-25304
  • Charlot M, Seldin DC, O’Hara C, et al. Localized amyloidosis of the breast: a case series. Amyloid 2011; 18: 72-5; http://dx.doi.org/10.3109/13506129.2011.570817
  • O’Regan A, Fenlon HM, Beamis JF, et al. Tracheobronchial amyloidosis. The Boston University experience from 1984 to 1999. Medicine (Baltimore) 2000; 79: 69-79; http://dx.doi.org/10.1097/00005792-200003000-00001
  • Dische FE, Wernstedt C, Westermark GT, et al. Insulin as an amyloid-fibril protein at sites of repeated insulin injections in a diabetic patient. Diabetologia 1988; 31: 158-61; http://dx.doi.org/10.1007/BF00276849
  • 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: 1817-22
  • Hurle MR, Helms LR, Li L, et al. A role for destabilizing amino acid replacements in light-chain amyloidosis. Proc Natl Acad Sci U S A 1994; 91: 5446-50; http://dx.doi.org/10.1073/pnas.91.12.5446
  • Joss N, McLaughlin K, Simpson K, et al. Presentation, survival and prognostic markers in AA amyloidosis. Qjm 2000; 93: 535-42; http://dx.doi.org/10.1093/qjmed/93.8.535
  • Lachmann HJ, Goodman HJ, Gilbertson JA, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med 2007; 356: 2361-71; http://dx.doi.org/10.1056/NEJMoa070265
  • Gertz MA, Kyle RA. Secondary systemic amyloidosis: response and survival in 64 patients. Medicine (Baltimore) 1991; 70: 246-56; http://dx.doi.org/10.1097/00005792-199107000-00002
  • Verine J, Mourad N, Desseaux K, et al. Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response. Hum Pathol 2007; 38: 1798-809; http://dx.doi.org/10.1016/j.humpath.2007.04.013
  • Girnius S, Dember L, Doros G, et al. The changing face of AA amyloidosis: a single center experience. Amyloid 2011; 18 Suppl 1: 226-8; http://dx.doi.org/10.3109/13506129.2011.574354085
  • Bunker D, Gorevic P. AA amyloidosis: Mount Sinai experience, 1997-2012. Mt Sinai J Med 2012; 79: 749-56; http://dx.doi.org/10.1002/msj.21342
  • Buxbaum JN, Tagoe C, Gallo G, et al. Why are some amyloidoses systemic? Does hepatic “chaperoning at a distance” prevent cardiac deposition in a transgenic model of human senile systemic (transthyretin) amyloidosis? Faseb J 2012; 26: 2283-93; http://dx.doi.org/10.1096/fj.11-189571
  • Rapezzi C, Quarta CC, Riva L, et al. Transthyretin-related amyloidoses and the heart: a clinical overview. Nat Rev Cardiol 2010; 7: 398-408; http://dx.doi.org/10.1038/nrcardio.2010.67
  • 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: 1425-9; http://dx.doi.org/10.1001/archinte.165.12.1425
  • Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation 2012; 126: 1286-300; http://dx.doi.org/10.1161/CIRCULATIONAHA.111.078915
  • Tanskanen M, Peuralinna T, Polvikoski T, 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: 232-9; http://dx.doi.org/10.1080/07853890701842988
  • Obayashi K, Ueda M, Oshima T, et al. Pathological changes long after liver transplantation in a familial amyloidotic polyneuropathy patient. BMJ Case Rep 2012; 2012. http://dx.doi.org/10.1136/bcr-2012-006593
  • Evenepoel P, Bammens B, Verbeke K, et al. Superior dialytic clearance of beta(2)-microglobulin and p-cresol by high-flux hemodialysis as compared to peritoneal dialysis. Kidney international 2006; 70: 794-9; http://dx.doi.org/10.1038/sj.ki.5001640
  • Tsai SB, Seldin DC, Wu H, et al. Myocardial infarction with “clean coronaries” caused by amyloid light-chain AL amyloidosis: a case report and literature review. Amyloid 2011; 18: 160-4; http://dx.doi.org/10.3109/13506129.2011.571319
  • Pinney JH, Whelan CJ, Petrie A, et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc 2013; 2: e000098; http://dx.doi.org/10.1161/JAHA.113.000098
  • Feng D, Syed IS, Martinez M, et al. Intracardiac thrombosis and anticoagulation therapy in cardiac amyloidosis. Circulation 2009; 119: 2490-7; http://dx.doi.org/10.1161/CIRCULATIONAHA.108.785014
  • Porciani MC, Lilli A, Perfetto F, et al. Tissue Doppler and strain imaging: a new tool for early detection of cardiac amyloidosis. Amyloid 2009; 16: 63-70; http://dx.doi.org/10.1080/13506120902879681
  • Maceira AM, Joshi J, Prasad SK, et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2005; 111: 186-93; http://dx.doi.org/10.1161/01.CIR.0000152819.97857.9D
  • Rapezzi C, Quarta CC, Guidalotti PL, et al. Role of (99m)Tc-DPD scintigraphy in diagnosis and prognosis of hereditary transthyretin-related cardiac amyloidosis. JACC Cardiovasc Imaging 2011; 4: 659-70; http://dx.doi.org/10.1016/j.jcmg.2011.03.016
  • Kristen AV, Haufe S, Schonland SO, et al. Skeletal scintigraphy indicates disease severity of cardiac involvement in patients with senile systemic amyloidosis. Int J Cardiol 2013; 164: 179-84; http://dx.doi.org/10.1016/j.ijcard.2011.06.123
  • Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol 2004; 22: 3751-7; http://dx.doi.org/10.1200/JCO.2004.03.029
  • Kumar S, Dispenzieri A, Lacy MQ, 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; http://dx.doi.org/10.1200/JCO.2011.38.5724
  • Suhr OB, Anan I, Backman C, et al. Do troponin and B-natriuretic peptide detect cardiomyopathy in transthyretin amyloidosis? J Intern Med 2008; 263: 294-301; http://dx.doi.org/10.1111/j.1365-2796.2007.01888.x
  • Carone FA, Epstein FH. Nephrogenic diabetes insipidus caused by amyloid disease. Evidence in man of the role of the collecting ducts in concentrating urine. Am J Med 1960; 29: 539-44; http://dx.doi.org/10.1016/0002-9343(60)90050-4
  • Rikitake O, Sakemi T, Yoshikawa Y, et al. Adult Fanconi syndrome in primary amyloidosis with lambda light-chain proteinuria. Jpn J Med 1989; 28: 523-6; http://dx.doi.org/10.2169/internalmedicine1962.28.523
  • Wang AK, Fealey RD, Gehrking TL, et al. Patterns of neuropathy and autonomic failure in patients with amyloidosis. Mayo Clin Proc 2008; 83: 1226-30; http://dx.doi.org/10.4065/83.11.1226
  • Rao J, Yang J, Liu Z, et al. Right retrocaval ureter and left nutcracker syndrome: a case report. Urology 2008; 71: 1226 e9-11; http://dx.doi.org/10.1016/j.urology.2007.11.108
  • Cowan AJ, Skinner M, Seldin DC, et al. Amyloidosis of the gastrointestinal tract: a 13-year, single-center, referral experience. Haematologica 2013; 98: 141-6; http://dx.doi.org/10.3324/haematol.2012.068155
  • Lehmann TG, Scheble V, Miller S, et al. Spontaneous hepatic rupture in amyloidosis - report of a case. Z Gastroenterol 2012; 50: 1296-301; http://dx.doi.org/10.1055/s-0032-1325340
  • Tam M, Seldin DC, Forbes BM, et al. Spontaneous rupture of the liver in a patient with systemic AL amyloidosis undergoing treatment with high-dose melphalan and autologous stem cell transplantation: a case report with literature review. Amyloid 2009; 16: 103-7; http://dx.doi.org/10.1080/13506120902879574
  • Gertz MA, Kyle RA, Greipp PR. Hyposplenism in primary systemic amyloidosis. Ann Intern Med 1983; 98: 475-; http://dx.doi.org/10.7326/0003-4819-98-4-475
  • Renzulli P, Schoepfer A, Mueller E, et al. Atraumatic splenic rupture in amyloidosis. Amyloid 2009; 16: 47-53; http://dx.doi.org/10.1080/13506120802676922
  • Vieira IG, Marchiori E, Zanetti G, et al. Pulmonary amyloidosis with calcified nodules and masses - a six-year computed tomography follow-up: a case report. Cases J 2009; 2: 6540; http://dx.doi.org/10.4076/1757-1626-2-6540
  • Dubrey SW, Cha K, Anderson J, et al. The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement. Qjm 1998; 91: 141-57; http://dx.doi.org/10.1093/qjmed/91.2.141
  • Ohmori H, Ando Y, Makita Y, et al. Common origin of the Val30Met mutation responsible for the amyloidogenic transthyretin type of familial amyloidotic polyneuropathy. J Med Genet 2004; 41: e51; http://dx.doi.org/10.1136/jmg.2003.014803
  • Jacobson DR, Pastore R, Pool S, et al. Revised transthyretin Ile 122 allele frequency in African-Americans. Hum Genet 1996; 98: 236-8; http://dx.doi.org/10.1007/s004390050199
  • Buxbaum J, Alexander A, Koziol J, et al. Significance of the amyloidogenic transthyretin Val 122 Ile allele in African Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. Am Heart J 2010; 159: 864-70; http://dx.doi.org/10.1016/j.ahj.2010.02.006
  • Rogers DR. Screening for Amyloid with the Thioflavin-T Fluorescent Method. Am J Clin Pathol 1965; 44: 59-61
  • Libbey CA, Skinner M, Cohen AS. Use of abdominal fat tissue aspirate in the diagnosis of systemic amyloidosis. Arch Intern Med 1983; 143: 1549-52; http://dx.doi.org/10.1001/archinte.1983.00350080055015
  • Simmons Z, Blaivas M, Aguilera AJ, et al. Low diagnostic yield of sural nerve biopsy in patients with peripheral neuropathy and primary amyloidosis. J Neurol Sci 1993; 120: 60-3; http://dx.doi.org/10.1016/0022-510X(93)90025-T
  • 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: 4957-9; http://dx.doi.org/10.1182/blood-2009-07-230722
  • Rowczenio D, Dogan A, Theis JD, et al. Amyloidogenicity and clinical phenotype associated with five novel mutations in apolipoprotein A-I. Am J Pathol 2011; 179: 1978-87; http://dx.doi.org/10.1016/j.ajpath.2011.06.024
  • Connors LH, Ericsson T, Skare J, et al. A simple screening test for variant transthyretins associated with familial transthyretin amyloidosis using isoelectric focusing. Biochim Biophys Acta 1998; 1407: 185-92; http://dx.doi.org/10.1016/S0925-4439(98)00037-4
  • Jaccard A, Moreau P, Leblond V, et al. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med 2007; 357: 1083-93; http://dx.doi.org/10.1056/NEJMoa070484
  • Cibeira MT, Sanchorawala V, Seldin DC, et al. Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients. Blood 2011; 118: 4346-52; http://dx.doi.org/10.1182/blood-2011-01-330738


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