Paraproteinaemia (PP)€¦ · monoclonal an7bodies or Immunoglobulins in serum, CSF and urine. •...

Paraproteinaemia(PP)PresentedbyMohsenAl-Saleh

StaffID#6837SeniorBMS,BScinMLS2004,MScinClin.Chem.2013

Outline

•  Defini3on•  Incidenceofparaproteinemia•  Disordersthatassociatedwithparaproteinemia•  Indica3onofscreeningforparaproteinemia•  Inves3ga3onofparaproteinemia•  MGUS,mul3plemyeloma

Defini3on

•  A paraprotein is a monoclonal immunoglobulin orimmunoglobulin light chain (Bence Jones protein)presentinthebloodorurineandarisingfromclonalprolifera7on of mature B-cells, most commonlyplasmacellsorB-lymphocytes.

•  Alterna7vetermsincludemonoclonalproteinorM-band.

Immunoglobulins

•  HeavyChains:-IgG,IgA-IgM,IgD•  LightChains:-Kappa(Κ)-Lambda(λ)

Immunoglobulins

Immunoglobulins

IincidenceofParaproteinaemia

•  Elderly>Young•  Inindividualsaged>50yrstheoverallincidenceis(3.2%)•  Thosewithage>70yrsis(5.3%)

•  Men>women(4.0%:2.7%)

•  AfricanAmericans>Caucasians

Consequences of paraproteinemia

•  Increasedserumviscosity•  Highserumproteins(>TP)concentra:on•  Pseudo-hyponatraemia•  BenceJonesprotein:

•  foundintheurineofpaJentwithB-cellmalignancy•  ConsistsoffreemonoclonalL-chainsortheirfragments•  LowMW(20-40kDa)

•  Amyloidosiscanalsooccur

Disordersassociatedwithparaproteinemia

MayoClinicReports:•  Experience•  1684ptwithPP•  KyleandKumar,Bri3sh•  JournalofHaematology

2007;139,730–743

1.  MalignantB-celldisorder:

•  Mul7plemyeloma(IgG,IgA,IgD,IgMor,λ,Κfreelightchains)

2.  MGUS:

•  ParaproteindetectedwithnoevidenceofotherB-celldisorder

Disorderassociatedwithaparaprotein

Indica3onoftes3ngofPP

•  Mul7plemyelomasuspected•  Bothurineandbloodshouldbescreened•  Pa7entshouldbescreenedforpresenceofM-proteinwhenpresen7ngwithanyoftheclinicalfindingslistedbelow:

ClinicalIndica3onsforscreeningforM-protein

Inves3ga3onofparaproteinemia

•  Serumproteinelectrophoresis(SPE)•  Serumimmunofixa7onelectrophoresis(IFE)•  Serumfreelightchain(SFLCA)•  Quan7ta7veImmunoglobulins

Serum&urineproteinelectrophoresis

SPE:•  Semi-Quan7ta7ve•  M-bandquan7fica7onUPE:•  Qualita7ve•  Requires24hrsurinecollec7on

Immunoglobulinlevels:•  IgA,IgG,IgM,IgD

Serum&urineproteinelectrophoresis

Advantages:•  Simple,cheap•  Commerciallyproducedgels

•  Mul7plesamplesinparallelonthesamegel

•  Lowamountofsample

Disadvantages:•  Lowresolu7on•  Notfullyautomated•  Timeconsuming•  Gelmustbestainedtovisualize

•  Semi-quan7ta7ve•  Maxi.Voltsused100v

Immunofixa3on(IFE)

•  Permitsthedetec7onandtypingofmonoclonalan7bodiesorImmunoglobulinsinserum,CSFandurine.

•  Principle:•  Themethoddetectsbyprecipita7on:whensolubleAgisbroughtincontactwithcorrespondingAb,precipita7onoccurs,whichmaybevisibleonlyaaerstaining.

IFE:•  Qualita7ve

•  Iden7fiesheavychain(IgG,IgA,IgM,IgD,IgE)

•  Iden7fieslightchain(λ,κprotein)type

Immunofixa3on(IFE)

Immunofixa3ontendstoreplaceproteinelectrophoresis

•  Itisfaster•  Itissomewhatmoresensi7veandrevealanimmunoglobulinesatlowerconcentra7on(lessthan1gm/L)

•  Itcanbepar7allyautomated•  Itismoreeasilyreadandinterpreted

SerumFreelightchain(SFLC)

•  Dailyproduc7on0.5-1gm•  Freelyfilteredbyglomeruli•  Reabsorbedbyproximaltubules•  Halflife3-6hrs

SerumFreeLightChain(SFLC)

•  AssaydetectsonlyfreeLC•  Quan7ta7ve•  CandetectmildlyincreasedlevelsofFLCevenwhentheselevelsareundetectablebySPEPandIFE

•  ExcellentforfollowingdiseaseprogressioninMGUS,anddiseaseresponseinmyeloma

TheKappa/LambdaRa3o

•  Whenthelevelofeitherkappaorlambdaisveryhighandtheotherchainisnormalorlow,thenthera7oisabnormalàmyelomaisac7ve

•  Iflevelsofbothkappaandlambdaareincreased,thera7omaybewithinthenormalrangeàindicatesadiseaseotherthanmyeloma,suchaspoorkidneyfunc7on

•  Ifthekappaandlambdalevelsarebothwithinthenormalrange,some7mesthera7omaybeabnormalàpersistentlowlevelofac7vemyelomawithexcessproduc7onoftheabnormallightchains.

•  Normalkappa/lambdara7oaaertreatmentàgoodremission

TheKappa/LambdaRa3o

OnceaPPisfoundwhatfurtherworkup

shouldbeperformed?•  DependingonclinicalsingsandsymptomsandontypesofM-

protein(IgG,IgA,IgM,IgD)inden7fiedbyIFE:DifferenJalDxIgM:•  Waldenstromsmacroglobulinaemia(WM)•  Chroniclymphoidleukemia(CLL)•  Non-hodgkinslymphoma(NHL)•  Monoclonalgammopathyofundeterminedsignificance(MGUS)•  Amyloidosis

DxofhighIgA:•  GammaAmyloma•  Chronicinfec7on•  Chronicliverdisease•  Sarcoidosis•  RA•  SLE

DxofhighIgG:•  IgGmyloma•  Chronicinfec7on•  Chronicliverdiseases•  Sarcoidosis•  Autoimmunedisease•  Parasi7cdiseases

OnceaPPisfoundwhatfurtherworkup

shouldbeperformed?

DisordersassociatedwithM-protein

Pa7entswithplasmacelldisorderandacircula7ngparaproteinissubdivideintothreegroups:

•  MGUS•  Asymptoma7cmyeloma(previouslytermedindolentorequivocalmyeloma)

•  Symptoma7cmyeloma

Threevariablesdefinethesegroups:(1)M-proteinlevel(2)bonemarrowplasmacellpercentage(3)thepresenceorabsenceofmyelomarelatedorganor7ssueimpairment(ROTI)

DisordersassociatedwithM-protein

Monoclonalgammopathyofundeterminedsignificant(MGUS)

•  Usualpresenta7onisasymptoma7celeva7onoftotalprotein

Diagnosisofexclusion:•  R/OMyeloma•  R/Ootherplasmacellabnormali7es•  theriskofprogressionofMGUStomyelomaorrelateddisorderis1%peryear

•  Notfoundinchildren•  Commonovertheageof50yrs•  Riskincreased3.7foldshigherforindividualswith1stdegreerelaJvewithdisease

Monoclonalgammopathyofundeterminedsignificant(MGUS)

Mul3pleMyloma(MM)

•  1%ofallmalignancies•  10%ofhematologicalmalignancies(2ndmostcommon)•  3-4per100,000populaJon•  16,000newcases/yr;11,000deaths/yr•  M>F•  Risk:radiaJonexposure

Mul3pleMyeloma

Symptoms

•  Bonepain(70%)•  Hypercalcaemia(30%)•  Fever(15%)•  Renalfailure(20%)•  InfecJon(10%)•  normochromicnormocyJcanemia(66%)•  Peripheralneuropathy•  Hyperviscosity•  ImpairedcoagulaJon•  ItcanbesummariesasCRAB

Paraprotein picture in MM

•  Serum/urineparaproJneseenin97%ofMMatdiagnosis

•  75%ofMMpaJenthaveBJPsintheirurine•  80%haveaserumM-protein&canbeidenJfiedonSPE•  >90%haveanM-proteinidenJfiedviaserumIFE(somearehiddeninothernormalbands)

•  15-20%ofMMproducelightchainsonly,whichmaynotbepresentinserumandpresentedonlyinurine

TypesofmonoclonalproteinsinMM

•  BasedonIGisotypeswithfrequencyparalleltonormalserumpercentages–  IgGkappa(30%)orlambda(18%)–  IgAkappa(10%)orlambda(6%)–  Freekappaorlambda(15%to20%)

•  Bence-Jonesproteins–  IgM(<1%)–  IgD(<1%)–  IgE(<1%)

RxofMul3pleMyeloma

•  NocureforMM•  Mediansurvival7me:– StageI

•  60months– StageII

•  45months– StageIII

•  30months

Treatmentop3onforMul3pleMyeloma•  Chemotherapy:

•  Immunotherapy:

–  Thalidomide(Thalomid)–  Lenalidomide(Revlumid)–  Bortezomib(Velcade)

•  Cor3costeroids:

–  Prednizone

•  Stemcelltransplanta3on:

–  Autologous–  Allogenic

•  Radia3ontherapy:

Cases

•  Case1:•  71yrsmalehas•  targetorgandamage(anemia,renalfailureandbonylyJclesion

•  MRIshowedinfiltraJonofT5,T12,L5•  BM:plasmacellof30%

IFEElectrophoresis

Case2:•  37yrsoldfemalediagnosedonMay2013tohaveplasmacellmyeloma.presentedtohospitalhavinglowerbackpain.MRIdoneshowedmulJplesacrallesion.

•  BMdoneshowed20%plasmacellwithCD138expression

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