Avoiding Catastrophe

HomeCirculation: Heart FailureVol. 14, No. 4Avoiding Catastrophe Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree CommentaryPDF/EPUBAvoiding CatastropheUnderstanding Light Chain Testing in the Evaluation of ATTR Amyloidosis Ronald M. Witteles, MD and Michaela Liedtke, WittelesRonald Witteles Correspondence to: MD, Division Cardiovascular Medicine, Stanford Amyloid Center, 300 Pasteur Dr, Lane Building #158, University School Stanford, CA 94305. Email E-mail Address: [email protected] https://orcid.org/0000-0002-3043-1472 (R.M.W., M.L.). Medicine (R.M.W.), CA. Search for more papers by this author LiedtkeMichaela Liedtke Hematology (M.L.), Originally published19 Mar 2021https://doi.org/10.1161/CIRCHEARTFAILURE.120.008225Circulation: Failure. 2021;14:e008225Over last decade, we have witnessed a true paradigm shift amyloid cardiomyopathy (ATTR-CM)—with development effective therapies occurring concomitantly with major advance ability make diagnosis noninvasively.1From diagnostic standpoint, fundamental occurred acceptance bone scintigraphy as means achieving noninvasive diagnosis. Such testing takes advantage fortuitous discovery that multiple nuclear tracers (99mtechnetium pyrophosphate United States) are taken up myocardium patients ATTR-CM, little no uptake other forms cardiomyopathy. This simple-to-perform, relatively inexpensive scan has directly contributed surge ATTR-CM diagnoses.Perhaps issue which created most confusion risk false-positive false-negative diagnoses been interpretation serum free light chains (FLC) evaluation ATTR-CM. report aims clear confusion, propose simple mechanism accurate FLC interpretation.Understanding Laboratory TestsSystemic AL amyloidosis almost always arises consequence clonal plasma cell disorder, resulting production circulate bloodstream deposit extracellularly.2 In evaluating patient possibility amyloidosis, therefore, one key principles is evaluate presence disorder.Plasma cells produce antibodies, composed heavy chains. can be subdivided into 2 broad categories, ? ?. Clonal antibody (eg, IgG-?), chain ? chain), or both. As such, goal laboratory discover evidence either chain, implies disorder.Two tests—serum protein electrophoresis immunofixation (SPIE) urine (UPIE)—directly assess clonality. With each these tests, an performed looking abnormal spike; if present, identifies what IgM-? antibody, etc). Because antibodies commonly present at higher concentration than chains, SPIE used primarily identify antibodies; because concentrated urine, UPIE If tests positive, monoclonal definitively proven, cannot establish amyloidosis.By contrast, assay not direct assessment test, all unbound (free) measured, categorized subtypes. measures both normal (abnormal) FLC. ratio ?:? far off direction other, it (whichever level). detect lower concentrations UPIE, many ways valuable test searching disorder.What Level Ratio Serum Is Normal?To understand levels, must clearance. The marrow produces approximately twice Clearance occurs mechanisms: kidneys reticuloendothelial system. While system clears same rate, much efficiently ?, due dimerization FLC.3, 4In setting truly kidney function, kidneys’ predominates, overcoming extra marrow. typically <1, range low 0.26. However, glomerular filtration rate drops, renal clearance contributes progressively less levels. setting, rise, increasingly reflective levels marrow, rather efficient kidneys.3, 4Therefore, even modest reductions >1, near end 0.26–0.49) decidedly abnormal— should raise suspicion production. advanced dysfunction, such low-normal ratios greater suspicion. On contrary, elevations encountered dysfunction CKD stage 3–5). settings, slightly above upper-limit-of-normal (as defined young, healthy population) 1.65 downright common, often 1.66 2.25 range.3, 4Failure recognize mild elevation finding common. Indeed, biologically implausible gammopathy undetermined significance rates 42% population reported, largely driven isolated abnormalities outside range.5Why Does Matter Amyloidosis?In landmark study, 1217 underwent detection (SPIE, FLC).1 combination positive negative yielded 100% specificity ATTR-CM—correctly diagnosing 391 out patients.Crucially, however, on well; 22% had scans.1 Misdiagnosing having catastrophe, missed opportunity institute potentially life-saving chemotherapy/immunotherapy. result occur from failure check misinterpreting ratio. catastrophic mistake, mildly elevated lead unnecessary endomyocardial biopsies delays proper just important correctly establishing being evaluated ATTR-CM.GuidanceWe recommend following when interpreting context ATTR-CM:Bone without assessment.Monoclonal include SPIE, testing. any 3 abnormal, cardiac biopsy required.Normal ranges viewed degree CKD. Failure adjust results. Based known effects reduction clearance, adjustments (Figure).Download figureDownload PowerPointFigure. Differences At (GFR) (in ml/min/1.73 m2), leads ratios. GFR excess mistakes suspected ATTR-CM.Sources FundingThis study was supported Krauss Charitable Foundation.Disclosures Dr reports personal fees Pfizer, Alnylam, Eidos, Ionis/Akcea submitted work. conflicts.FootnotesThe opinions expressed article necessarily those editors American Association.For Sources Funding Disclosures, see page 522.Correspondence protected]eduReferences1. Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, Wechalekar AD, Berk JL, Quarta CC, Grogan M, et al.. Nonbiopsy transthyretin amyloidosis.Circulation. 2016; 133:2404–2412. doi: 10.1161/CIRCULATIONAHA.116.021612LinkGoogle Scholar2. RM, cardiologist oncologist: Epidemiology, diagnosis, management.JACC CardioOncology. 2019; 1:117–130.CrossrefGoogle Scholar3. Abadie JM, van Hoeven KH, Wells JM. Are reference intervals required screening disorders electrophoresis?Am J Clin Pathol. 2009; 131:166–171. 10.1309/AJCPR2M4EUYNHLGMCrossrefMedlineGoogle Scholar4. Hutchison CA, Harding S, Hewins P, Mead GP, Townsend J, Bradwell AR, Cockwell P. Quantitative urinary polyclonal chronic disease.Clin Am Soc Nephrol. 2008; 3:1684–1690. 10.2215/CJN.02290508CrossrefMedlineGoogle Scholar5. Phull Sanchorawala V, Connors LH, Doros Ruberg FL, Sarosiek S. Monoclonal systemic (ATTR).Amyloid. 2018; 25:62–67. 10.1080/13506129.2018.1436048CrossrefMedlineGoogle Scholar Previous Back top Next FiguresReferencesRelatedDetails April 2021Vol Issue 4Article InformationMetrics Download: 415 © 2021 Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.120.008225PMID: 33736459 publishedMarch 19, Keywordsamyloidosisplasma cellsglomerular ratemyocardiumcardiomyopathyPDF download SubjectsHeart