medigraphic.com
ISSN 2500-7106 (Electronic)
ISSN 0123-2576 (Print)
Medicina & Laboratorio

2022, Number 2

<< Back Next >>

Medicina & Laboratorio 2022; 26 (2)

AL amyloidosis: current concepts

Lacouture-Fierro JA, Mejía-Buriticá L, Ribero-Vargas DA

Language: Spanish
References: 74
Page: 119-139
PDF size: 304.66 Kb.


ABSTRACT

Systemic amyloidosis constitutes a group of diseases with diverse etiologies characterized by the synthesis of proteins with defective folding, capable of aggregating and depositing in the extracellular matrix of different organs and tissues, altering their structure and function. More than 14 forms of systemic amyloidosis are known, of which the most frequent is AL amyloidosis, the subject of this review, in which the precursor proteins are unstable immunoglobulin light chains, secreted by a clone of plasma cells or, to a lesser extent, often due to lymphoplasmacytic or mantle cell lymphoma. AL amyloidosis can lead to a wide range of clinical manifestations and organ involvement, such as the heart and kidney. Early recognition of the disease and timely diagnosis are crucial to improve patient survival. Treatment should be individualized according to the condition of each patient, which requires a properly classification of individuals according to their prognosis. Amyloidosis-targeted therapy is essentially focused on reducing organ involvement, and therefore prolonging survival with improvement in symptoms. In this review, important aspects of the pathophysiology, epidemiology, clinical manifestations, diagnosis, and treatment of AL amyloidosis are discussed.


REFERENCES

  1. Vaxman I, Dispenzieri A, Muchtar E, GertzM. New developments in diagnosis, risk assessmentand management in systemic amyloidosis.Blood Rev 2020;40:100636. https://doi.org/10.1016/j.blre.2019.100636.

  2. Al Hamed R, Bazarbachi AH, Bazarbachi A,Malard F, Harousseau JL, Mohty M. Comprehensivereview of AL amyloidosis: somepractical recommendations. Blood Cancer J2021;11:97. https://doi.org/10.1038/s41408-021-00486-4.

  3. Merlini G. AL amyloidosis: from molecularmechanisms to targeted therapies. HematologyAm Soc Hematol Educ Program2017;2017:1-12. https://doi.org/10.1182/asheducation-2017.1.1.

  4. Palladini G, Milani P, Merlini G. Management ofAL amyloidosis in 2020. Hematology Am Soc HematolEduc Program 2020;2020:363-371. https://doi.org/10.1182/hematology.2020006913.

  5. Muchtar E, Dispenzieri A, Gertz MA, KumarSK, Buadi FK, Leung N, et al. Treatment of ALamyloidosis: Mayo stratification of myelomaand risk-adapted therapy (mSMART) consensusstatement 2020 update. Mayo Clin Proc2021;96:1546-1577. https://doi.org/10.1016/j.mayocp.2021.03.012.

  6. Quock TP, Yan T, Chang E, Guthrie S, BroderMS. Epidemiology of AL amyloidosis: a realworldstudy using US claims data. Blood Adv2018;2:1046-1053. https://doi.org/10.1182/bloodadvances.2018016402.

  7. Palladini G, Milani P, Merlini G. Novel strategiesfor the diagnosis and treatment of cardiacamyloidosis. Expert Rev Cardiovasc Ther2015;13:1195-1211. https://doi.org/10.1586/14779072.2015.1093936.

  8. Hasib-Sidiqi M, Gertz MA. Immunoglobulinlight chain amyloidosis diagnosis and treatmentalgorithm 2021. Blood Cancer J 2021;11:90.https://doi.org/10.1038/s41408-021-00483-7.

  9. Merlini G, Bellotti V. Molecular mechanisms ofamyloidosis. N Engl J Med 2003;349:583-596.https://doi.org/10.1056/NEJMra023144.

  10. Tahir UA, Doros G, Kim JS, Connors LH, SeldinDC, Sam F. Predictors of mortality in lightchain cardiac amyloidosis with heart failure.Sci Rep 2019;9:8552. https://doi.org/10.1038/s41598-019-44912-x.

  11. Kumar S, Dispenzieri A, Lacy MQ, HaymanSR, Buadi FK, Colby C, et al. Revised prognosticstaging system for light chain amyloidosisincorporating cardiac biomarkersand serum free light chain measurements.J Clin Oncol 2012;30:989-995. https://doi.org/10.1200/jco.2011.38.5724.

  12. Muchtar E, Kumar SK, Gertz MA, Grogan M,AbouEzzeddine OF, Jaffe AS, et al. Stagingsystems use for risk stratification of systemicamyloidosis in the era of high-sensitivity troponinT assay. Blood 2019;133:763-766. https://doi.org/10.1182/blood-2018-10-875252.

  13. Khurana R, Gillespie JR, Talapatra A, MinertLJ, Ionescu-Zanetti C, Millett I, et al. Partiallyfolded intermediates as critical precursors oflight chain amyloid fibrils and amorphous aggregates.Biochemistry 2001;40:3525-3535.https://doi.org/10.1021/bi001782b.

  14. Ami D, Lavatelli F, Rognoni P, Palladini G, RaimondiS, Giorgetti S, et al. In situ characterizationof protein aggregates in human tissuesaffected by light chain amyloidosis: a FTIR microspectroscopystudy. Sci Rep 2016;6:29096.https://doi.org/10.1038/srep29096.

  15. Selkoe DJ, Hardy J. The amyloid hypothesisof Alzheimer's disease at 25 years. EMBO MolMed 2016;8:595-608. https://doi.org/10.15252/emmm.201606210.

  16. Guan J, Mishra S, Qiu Y, Shi J, Trudeau K,Las G, et al. Lysosomal dysfunction and impairedautophagy underlie the pathogenesisof amyloidogenic light chain-mediated cardiotoxicity.EMBO Mol Med 2014;6:1493-1507.https://doi.org/10.15252/emmm.201404190.

  17. Falk RH, Comenzo RL, Skinner M. Thesystemic amyloidoses. N Engl J Med1997;337:898-909. https://doi.org/10.1056/nejm199709253371306.

  18. Kyle RA, Linos A, Beard CM, Linke RP, GertzMA, O'Fallon WM, et al. Incidence and naturalhistory of primary systemic amyloidosis in OlmstedCounty, Minnesota, 1950 through 1989.Blood 1992;79:1817-1822.

  19. Kyle RA, Larson DR, Kurtin PJ, Kumar S,Cerhan JR, Therneau TM, et al. Incidenceof AL amyloidosis in Olmsted County, Minnesota, 1990 through 2015. Mayo Clin Proc

  20. 2019;94:465-471. https://doi.org/10.1016/j.mayocp.2018.08.041.20. Duhamel S, Mohty D, Magne J, Lavergne D,Bordessoule D, Aboyans V, et al. Incidenceand prevalence of light chain amyloidosis: Apopulation-based study. Blood 2017;130:5577.https://doi.org/10.1182/blood.V130.Suppl_1.5577.5577.

  21. Peña C, González JT, López-Vidal H, DonosoJ, Contreras C, Vergara CG, et al. AL amyloidosisin the Chilean public health system: a pendingdebt. Multicenter study of the Chilean MonoclonalGammopathies Cooperative Group.Rev Med Chil 2019;147:1239-1246. https://doi.org/10.4067/s0034-98872019001001239.

  22. Funcolehf. Amiloidosis hereditaria en Colombia.Bogotá D. C.: Fundación Colombiana paraEnfermedades Huérfanas (Funcolehf); 2021.Acceso 03 de junio de 2022. Disponible enhttp://www.enfermedadeshuerfanas.org.co/amiloidosishereditaria/generalidades.

  23. McCausland KL, White MK, Guthrie SD,Quock T, Finkel M, Lousada I, et al. Lightchain (AL) amyloidosis: The journey to diagnosis.Patient 2018;11:207-216. https://doi.org/10.1007/s40271-017-0273-5.

  24. Gertz MA LM, Dispenzieri A, Buadi FK. Immunoglobulinlight-chain (AL) amyloidosis. In:Greer JP RG, Glader B, Arber DA, Means RT, ListAF, et al., ed. Wintrobe’s Clinical Hematology.14th ed. Philadelphia, USA: Lippincott Williams& Wilkins; 2018. p. 6543–6624.

  25. Hawkins PN. Amyloid fibril formation and classicfacial features of AL amyloidosis. jpg. SanFrancisco, California: Wikimedia Commons;2008. Acceso 10 de junio de 2022. Disponibleen https://commons.wikimedia.org/w/index.php?search=Classic+facial+features+of+AL+amyloidosis+with+purpura+around+the+eyes&title=Special:MediaSearch&go=Go&type=image.

  26. Deshpande P, Guledgud MV, Patil K, HegdeU, Sahni A, Huchanahalli-Sheshanna S. Macroglossiawith crenations along the marginsand loss of papillae on dorsum surface of thetongue.png. San Francisco, California: WikimediaCommons; 2015. Acceso 10 de enero de2022. Disponible en https://commons.wikimedia.org/w/index.php?search=Macroglossia+with+crenations+along+the+margins+and+loss+of+papillae+on+dorsum+surface+of+the+tongue&title=Special:MediaSearch&go=Go&type=image.

  27. Muchtar E, Gertz MA, Kyle RA, Lacy MQ, DingliD, Leung N, et al. A modern primer on lightchain amyloidosis in 592 patients with massspectrometry-verified typing. Mayo Clin Proc2019;94:472-483. https://doi.org/10.1016/j.mayocp.2018.08.006.

  28. Muchtar E, Gertz MA, Kumar SK, Lacy MQ,Dingli D, Buadi FK, et al. Improved outcomesfor newly diagnosed AL amyloidosis between2000 and 2014: cracking the glass ceiling of earlydeath. Blood 2017;129:2111-2119. https://doi.org/10.1182/blood-2016-11-751628.

  29. Gertz MA, Comenzo R, Falk RH, Fermand JP,Hazenberg BP, Hawkins PN, et al. Definitionof organ involvement and treatment responsein immunoglobulin light chain amyloidosis (AL):a consensus opinion from the 10th InternationalSymposium on Amyloid and Amyloidosis,Tours, France, 18-22 April 2004. Am J Hematol2005;79:319-328. https://doi.org/10.1002/ajh.20381.

  30. Wechalekar AD, Gillmore JD, HawkinsPN. Systemic amyloidosis. Lancet2016;387:2641-2654. https://doi.org/10.1016/s0140-6736(15)01274-x.

  31. Falk RH, Quarta CC. Echocardiography in cardiacamyloidosis. Heart Fail Rev 2015;20:125-131. https://doi.org/10.1007/s10741-014-9466-3.

  32. Zhao L, Tian Z, Fang Q. Diagnostic accuracy ofcardiovascular magnetic resonance for patientswith suspected cardiac amyloidosis: a systematicreview and meta-analysis. BMC CardiovascDisord 2016;16:129. https://doi.org/10.1186/s12872-016-0311-6.

  33. Fontana M, Pica S, Reant P, Abdel-Gadir A,Treibel TA, Banypersad SM, et al. Prognosticvalue of late gadolinium enhancement cardiovascularmagnetic resonance in cardiac amyloidosis.Circulation 2015;132:1570-1579. https://doi.org/10.1161/circulationaha.115.016567.

  34. Kuria IM, Gitau SN, Makhdomi KB. Bonescintigraphy imaging of cardiac amyloidosis.World J Nucl Med 2019;18:314-316. https://doi.org/10.4103/wjnm.WJNM_9_19.

  35. Gillmore JD, Wechalekar A, Bird J, CavenaghJ, Hawkins S, Kazmi M, et al. Guidelines onthe diagnosis and investigation of AL amyloidosis.Br J Haematol 2015;168:207-218. https://doi.org/10.1111/bjh.13156.

  36. Rajkumar SV, Dimopoulos MA, Palumbo A,Blade J, Merlini G, Mateos MV, et al. InternationalMyeloma Working Group updatedcriteria for the diagnosis of multiple myeloma.Lancet Oncol 2014;15:e538-548. https://doi.org/10.1016/s1470-2045(14)70442-5.

  37. Gertz MA. Immunoglobulin light chain amyloidosis:2020 update on diagnosis, prognosis,and treatment. Am J Hematol 2020;95:848-860. https://doi.org/10.1002/ajh.25819.

  38. Mollee P, Merlini G. Free light chain testingfor the diagnosis, monitoring and prognosticationof AL amyloidosis. Clin Chem Lab Med2016;54:921-927. https://doi.org/10.1515/cclm-2015-0938.

  39. El-Meanawy A, Mueller C, Iczkowski KA. Improvingsensitivity of amyloid detection by Congored stain by using polarizing microscopeand avoiding pitfalls. Diagn Pathol 2019;14:57.https://doi.org/10.1186/s13000-019-0822-4.

  40. Sara JDS, Khodadadi R, Barth D, Burton MC.Amyloidosis: a unifying diagnosis for nephroticsyndrome and congestive cardiac failure. BMJCase Rep 2018;2018:bcr2018224317. https://doi.org/10.1136/bcr-2018-224317.

  41. Palladini G, Milani P, Merlini G. Managementof AL amyloidosis in 2020. Blood2020;136:2620-2627. https://doi.org/10.1182/blood.2020006913.

  42. Lebovic D, Hoffman J, Levine BM, HassounH, Landau H, Goldsmith Y, et al. Predictorsof survival in patients with systemic light-chainamyloidosis and cardiac involvement initiallyineligible for stem cell transplantation and treatedwith oral melphalan and dexamethasone.Br J Haematol 2008;143:369-373. https://doi.org/10.1111/j.1365-2141.2008.07327.x.

  43. Gertz MA, Kyle RA. Primary systemic amyloidosis--a diagnostic primer. Mayo Clin Proc1989;64:1505-1519. https://doi.org/10.1016/s0025-6196(12)65706-1.

  44. Dispenzieri A, Gertz MA, Kumar SK, LacyMQ, Kyle RA, Saenger AK, et al. High sensitivitycardiac troponin T in patients with immunoglobulinlight chain amyloidosis. Heart2014;100:383-388. https://doi.org/10.1136/heartjnl-2013-304957.

  45. Kristen AV, Giannitsis E, Lehrke S, HegenbartU, Konstandin M, Lindenmaier D, et al. Assessmentof disease severity and outcome inpatients with systemic light-chain amyloidosisby the high-sensitivity troponin T assay. Blood2010;116:2455-2461. https://doi.org/10.1182/blood-2010-02-267708.

  46. Palladini G, Barassi A, Klersy C, Pacciolla R,Milani P, Sarais G, et al. The combination ofhigh-sensitivity cardiac troponin T (hs-cTnT) atpresentation and changes in N-terminal natriureticpeptide type B (NT-proBNP) after chemotherapybest predicts survival in AL amyloidosis.Blood 2010;116:3426-3430. https://doi.org/10.1182/blood-2010-05-286567.

  47. Palladini G, Campana C, Klersy C, Balduini A,Vadacca G, Perfetti V, et al. Serum N-terminalpro-brain natriuretic peptide is a sensitive markerof myocardial dysfunction in AL amyloidosis.Circulation 2003;107:2440-2445. https://doi.org/10.1161/01.Cir.0000068314.02595.B2.

  48. Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ,Burritt MF, Therneau TM, et al. Serum cardiactroponins and N-terminal pro-brain natriureticpeptide: a staging system for primary systemicamyloidosis. J Clin Oncol 2004;22:3751-3757.https://doi.org/10.1200/jco.2004.03.029.

  49. Palladini G, Sachchithanantham S, Milani P,Gillmore J, Foli A, Lachmann H, et al. A Europeancollaborative study of cyclophosphamide,bortezomib, and dexamethasone in upfronttreatment of systemic AL amyloidosis. Blood2015;126:612-615. https://doi.org/10.1182/blood-2015-01-620302.

  50. Hammerer-Lercher A, Ploner T, Neururer S,Schratzberger P, Griesmacher A, PachingerO, et al. High-sensitivity cardiac troponin Tcompared with standard troponin T testing onemergency department admission: how muchdoes it add in everyday clinical practice? JAm Heart Assoc 2013;2:e000204. https://doi.org/10.1161/jaha.113.000204.

  51. Dispenzieri A, Kyle RA, Gertz MA, TherneauTM, Miller WL, Chandrasekaran K, et al. Survivalin patients with primary systemic amyloidosisand raised serum cardiac troponins. Lancet2003;361:1787-1789. https://doi.org/10.1016/s0140-6736(03)13396-x.

  52. Muchtar E, Therneau TM, Larson DR, GertzMA, Lacy MQ, Buadi FK, et al. Comparativeanalysis of staging systems in AL amyloidosis.Leukemia 2019;33:811-814. https://doi.org/10.1038/s41375-018-0370-z.

  53. Lilleness B, Ruberg FL, Mussinelli R, Doros G,Sanchorawala V. Development and validationof a survival staging system incorporating BNPin patients with light chain amyloidosis. Blood2019;133:215-223. https://doi.org/10.1182/blood-2018-06-858951.

  54. White JA, Kim HW, Shah D, Fine N, Kim KY,Wendell DC, et al. CMR imaging with rapidvisual T1 assessment predicts mortality in patientssuspected of cardiac amyloidosis. JACCCardiovasc Imaging 2014;7:143-156. https://doi.org/10.1016/j.jcmg.2013.09.019.

  55. Sidana S, Tandon N, Brady PA, Grogan M,Gertz MA, Dispenzieri A, et al. Prognostic significanceof holter monitor findings in patientswith light chain amyloidosis. Mayo Clin Proc2019;94:455-464. https://doi.org/10.1016/j.mayocp.2018.08.039.

  56. Palladini G, Kyle RA, Larson DR, TherneauTM, Merlini G, Gertz MA. Multicentre versussingle centre approach to rare diseases:the model of systemic light chain amyloidosis.Amyloid 2005;12:120-126. https://doi.org/10.1080/13506120500107055.

  57. Muchtar E, Dispenzieri A, Kumar SK, Buadi FK,Lacy MQ, Zeldenrust S, et al. Immunoparesis innewly diagnosed AL amyloidosis is a marker forresponse and survival. Leukemia 2017;31:92-99.https://doi.org/10.1038/leu.2016.140.

  58. Puig N, Paiva B, Lasa M, Burgos L, PerezJJ, Merino J, et al. Flow cytometry for fastscreening and automated risk assessment insystemic light-chain amyloidosis. Leukemia2019;33:1256-1267. https://doi.org/10.1038/s41375-018-0308-5.

  59. Kourelis TV, Kumar SK, Gertz MA, Lacy MQ,Buadi FK, Hayman SR, et al. Coexistent multiplemyeloma or increased bone marrow plasmacells define equally high-risk populationsin patients with immunoglobulin light chainamyloidosis. J Clin Oncol 2013;31:4319-4324.https://doi.org/10.1200/jco.2013.50.8499.

  60. Bochtler T, Hegenbart U, Kunz C, GranzowM, Benner A, Seckinger A, et al. Translocationt(11;14) is associated with adverse outcomein patients with newly diagnosed AL amyloidosiswhen treated with bortezomib-basedregimens. J Clin Oncol 2015;33:1371-1378.https://doi.org/10.1200/jco.2014.57.4947.

  61. Muchtar E, Dispenzieri A, Kumar SK, KetterlingRP, Dingli D, Lacy MQ, et al. Interphasefluorescence in situ hybridization in untreatedAL amyloidosis has an independent prognosticimpact by abnormality type and treatment category.Leukemia 2017;31:1562-1569. https://doi.org/10.1038/leu.2016.369.

  62. Wong SW, Hegenbart U, Palladini G, ShahGL, Landau HJ, Warner M, et al. Outcomeof patients with newly diagnosed systemiclight-chain amyloidosis associated with deletionof 17p. Clin Lymphoma Myeloma Leuk2018;18:e493-499. https://doi.org/10.1016/j.clml.2018.07.292.

  63. Palladini G, Hegenbart U, Milani P, KimmichC, Foli A, Ho AD, et al. A staging system for renaloutcome and early markers of renal responseto chemotherapy in AL amyloidosis. Blood2014;124:2325-2332. https://doi.org/10.1182/blood-2014-04-570010.

  64. Kastritis E, Palladini G, Minnema MC,Wechalekar AD, Jaccard A, Lee HC, et al.Daratumumab-based treatment for immunoglobulinlight-chain amyloidosis. N Engl J Med2021;385:46-58. https://doi.org/10.1056/NEJMoa2028631.

  65. Dispenzieri A, Lacy MQ, Zeldenrust SR, HaymanSR, Kumar SK, Geyer SM, et al. Theactivity of lenalidomide with or without dexamethasonein patients with primary systemicamyloidosis. Blood 2007;109:465-470. https://doi.org/10.1182/blood-2006-07-032987.

  66. Manwani R, Mahmood S, SachchithananthamS, Lachmann HJ, Gillmore JD,Yong K, et al. Carfilzomib is an effectiveupfront treatment in AL amyloidosis patientswith peripheral and autonomic neuropathy.Br J Haematol 2019;187:638-641. https://doi.org/10.1111/bjh.16122.

  67. Sidana S, Milani P, Binder M, Basset M, TandonN, Foli A, et al. A validated composite organand hematologic response model for earlyassessment of treatment outcomes in lightchain amyloidosis. Blood Cancer J 2020;10:41.https://doi.org/10.1038/s41408-020-0306-5.

  68. Batalini F, Econimo L, Quillen K, Sloan JM,Sarosiek S, Brauneis D, et al. High-dosemelphalan and stem cell transplantation inpatients on dialysis due to immunoglobulinlight-chain amyloidosis and monoclonal immunoglobulindeposition disease. Biol Blood MarrowTransplant 2018;24:127-132. https://doi.org/10.1016/j.bbmt.2017.08.031.

  69. Scully MS, Wessman DE, McKee JM, FranciscoGM, Nayak KR, Kobashigawa JA. Totalartificial heart implantation as a bridge toheart transplantation in an active duty servicemember with amyloid cardiomyopathy.Mil Med 2017;182:e1858-1860. https://doi.org/10.7205/milmed-d-16-00122.

  70. Kristen AV, Kreusser MM, Blum P, SchönlandSO, Frankenstein L, Dösch AO, et al. Improvedoutcomes after heart transplantation forcardiac amyloidosis in the modern era. J HeartLung Transplant 2018;37:611-618. https://doi.org/10.1016/j.healun.2017.11.015.

  71. Huh JY, Seo S, Suh C, Huh J, Yoon DH, KimJ-J. Sequential heart and autologous stem celltransplantation for light-chain cardiac amyloidosis.Blood Res 2017;52:221-224. https://doi.org/10.5045/br.2017.52.3.221.

  72. Sousa M, Monohan G, Rajagopalan N,Grigorian A, Guglin M. Heart transplantationin cardiac amyloidosis. Heart Fail Rev2017;22:317-327. https://doi.org/10.1007/s10741-017-9601-z.

  73. Grogan M, Gertz M, McCurdy A, Roeker L,Kyle R, Kushwaha S, et al. Long term outcomesof cardiac transplant for immunoglobulinlight chain amyloidosis: The Mayo Clinic experience.World J Transplant 2016;6:380-388.https://doi.org/10.5500/wjt.v6.i2.380.

  74. Lin G, Dispenzieri A, Kyle R, Grogan M, BradyPA. Implantable cardioverter defibrillators inpatients with cardiac amyloidosis. J CardiovascElectrophysiol 2013;24:793-798. https://doi.org/10.1111/jce.12123.




2020     |     www.medigraphic.com