PostgradMedJ(1990)66,304-306A)TheFellowshipofPostgraduateMedicine,1990 - PDF document

PostgradMedJ(1990)66,304-306A)TheFellowshipofPostgraduateMedicine,1990ThyroidfunctiontestsinamyloidgoitreP.DuhraandJ.CassarWestMiddlesexUniversityHospital,Isleworth,MiddlesexTW76AF,UK.Summary:Wepresenttwopatientswthamyloidgoitreduetoprimarysystemicamyloidosiswhichwasconfirmedatpost-mortem.Bothwereclinicallyeuthyroidbuthadhyperthyroxinaemiaandotherthyroidfunctiontestssuggestiveofthyrotoxicosis.IntroductionWhereasminoramyloidinfiltrationofthethyroidglandisfoundin50-80%ofcasesofgeneralizedamyloidosis,'theinductionofagoitrebyamyloidinvasionisrare.2Amyloidisaninertsubstance3andinfiltrationofthethyroiddoesnotusuallyinterferewiththeendocrinefunctionofthegland.4'5Intwopreviousreportsofpossiblehyperthyroidisminamyloidgoitreanelevatedbasalmetabolicrate,onwhichthediagnosisofhyperthyroidismrested,couldinsteadhavebeenattributedtotheunderly-ingchronicinflammatorydiseaseproducingthesecondaryamyloidosis.6Apartfromthesetworeportsthyroidover-activityhasnotbeennotedinamyloidgoitre.Wedescribetwocaseswithamyloidgoitrewhowereclinicallyeuthyroidbuthadhyperthyrox-inaemia.CasereportsCaseIA50yearoldmanualworkerpresentedinFeb-ruary1984withanenlargingcervicalswelling,dysphagiaforsolids,changeinvoice,weightlossandfeelinggenerallyill.Physicalexaminationrevealedaeuthyroidmanwithpallor,asoftpitchedvoiceandalarge,diffuse,hardgoitre.Therewasnocervicallymphadenopathynordysthyroideyediseaseandapartfrommoderatehepato-splenomegalytherestoftheexaminationwasnormal.Investigationsshowedanormochromicnormo-cyticanaemiawithhaemoglobin8.7g/dl;meancorpuscularvolume86.4fl;erythrocytesedimenta-tionrate39mminonehour.Biochemicalprofilewasnormalexcepttotalprotein71g/l,albumin28g/l,plasmabicarbonate18mmol/l,urea25.9mmol/l,creatinine519p.mol/l.Creatinineclearancewas12ml/minandurinaryproteinexcre-tion0.3g/24hours.Assessmentofthyroidfunctiondisclosedaserumfreethyroxine(FT4)of32.5pmol/l(NR8.8-23),thyrotrophinreleasinghormone(TRH)testshowedthyroidstimulatinghormone(TSH)values)of1.2,0.6,0.6mU/Itakenattime0,30,60minutesafterintravenousTRHbolus.Atechnetiumthyroidscanshowedgeneralized'thyroidenlargementwithhomogenousdistribu-tion"ofradiaoactivity.Theoveralltechnetiumuptakewas5.1%ofthedoseat20minutes(normalupper.level3.5%).SerumTSHreceptorantibodyactivitywasdeterminedusingtheRapoportbioassaywhichutilizeshumanthyroidcellsinculture.Thethyroidstimulatingantibodylevelwas18bovineTSHequivalentsperml(normalrangeunder2.8).Thyroglobinandmicrosomalantibodieswereundetectableintheserum.CarbimazoletherapywasintroducedinApril1984andFT4threemonthslaterwasreducedto7.5pmol/l.InAugust1984carbimazolewasinadvertentlydiscontinuedfor10daysandFT4,measuredonthetenthday,hadrisento77.0pmol/l.Carbimazolewaspromptlyrecommenced.Serumimmunoelectrophoresisshowedaparaprotein,typedasIgGKappa.Serumimmunoglobulinswereassayed:IgG28g/l(NR5.3-16.5);IgA0.2g/l(NR0.8-4.0)andIgM0.3g/l(NR0.5-2.0).Askeletalsurveyshowednolyticdefectstypicalofmultiplemyeloma.Abonemarrowaspiratecon-tained15%plasmacellswithmanyabnormalforms.Athyroidneedlebiopsyshowedwidelyseparatedthyroidfolliclessomeofwhichwerefilledwithcolloid.Thethyroidstromastainedwithcongoredexhibitedthecharacteristicapple-greenbirefringenceofamyloidunderpolarizedlight.ArenalbiopsyperformedinMarch1985confirmedthediagnosis.ByFebruary1985hehadprogressedtoend-stagerenalfailurenecessitatingCorrespondence:J.Cassar,Ph.D,M.D.,F.R.C.P.Accepted:21September1989 CLINICALREPORTS305haemodialysis,andunderwentatotalthyroidec-tomyinApril1985forreliefofseveredysphagia.Apale,hardthyroidglandweighing167grammeswasremoved.Therewasgrossamyloidinfiltrationaccountingforapproximately90%ofthethyroidmass.Inadditiontoseparatingindividualfollicles,amyloidhadobliteratedmanycapillariesbyinvasionoftheirwall.Thefollicleswereatrophicwithnohypertrophyofthefollicularcells,andtheonlyevidenceofthyroidhyperactivitywassomepapillaryinfoldingandscantycolloid.Therewasnosignificantcellularinfiltrationoftheinterstitium.Hedevelopedrapidlyworseningcardiacfailureanddied3weeksafterthyroidectomy.Necropsyrevealedcardiacfailureduetoamyloidinvasionoftheheartasthemaincauseofdeath.TherewaswidespreadALamyloiddepositionandnoevidenceofanyunder-lyingchronicinflammatorydisease.Case2Thispatientwasaschoolsecretaryandwasfirstseenin1950whenshewas40yearsold.Shehadhadagoitresincetheageof12whichonexaminationwasmultinodular.Shewasclinicallyeuthyroid.In1978shewasseenagainbecauseofonsetofatrialfibrillation.TotalT4was140pmol/l(NR60-150).Totaltriiodothyronine(T3)was2.69nmol/l.(NR1.23-3.07).Overtheyears(1978-1982)hertotalT4fluctuatedbetween136to190nmol/l(n=14,mean162).FreeT4(1982-1984)fluctuatedbetween17.7to26.7pmol/l(n=13,mean21.7,NR8.8-23).T3wasalwayswithinnormallimits(n=15),exceptononeoccasion.Thyroidanti-bodieswerenegative.Duringatherapeutictrialofcarbimazoleatadoseof15mg/daybetweenJulytoNovember1985shequicklybecamehypothyroidwithafreeT4downto6.8pmol/l.TSHatthisstagewas2.4mU/l(NR0-5.5).AlsoatherlastvisittotheclinicfreeT4was7.6pmol/landTSH1.3mU/I.ATRHtestwascarriedoutin1981andTSHresponsewasbasal5.2mU/l,30minutes5.1mU/I,60minutes4.7mU/l.Thiswasrepeatedin1985andonthisoccasionTSHlevelswerebasal0.9mU/1,30minutes1.2mU/1,60minutes1.3mU/l.BasalTSHlevelsbetween1983to1986werebetween1.3to3mU/1.Thyroidstimulatingimmunoglobulinlevelswerewithinnormallimits.InMay1987shecomplainedofmalaiseandonexaminationshehadgeneralizedoedemabutwasclinicallyeuthyroid.Urinalysisshowed++++proteinuria,fullbloodcountwasnormal,bloodurea7.9mmol/l,creatinine96Lmol/l,24hoururineproteinwas3.6g.NoBenceJonesproteinswerenotedintheurine.Serumalbuminwas17g/l.Renalbiopsyshowedfeaturesofamyloidosis.Plasmaproteinelectrophoresisdidnotshowpara-proteinaemia.Trephinebiopsyrevealedanexcessofmononucl-earcellsstainingpositivelyforimmunoglobulinlambdalightchains.Onlysomecellswererecog-nizablyplasmacytoid.FreeT4was8.7pmol/l,TSH0.6mU/l.Therewasarapiddeteriorationinherclincialstateandshedied7weeksafteradmission.Post-mortemconfirmedthediagnosisofALamyloidosis.Therewasamyloidinthethyroid,adrenalandpancreas.Thethyroidweighed360g.Onsectionthereweremultiplenoduleswithoutcysticchangeorhaemorrhage.Histologyshowedamyloidosisoffollicularbasementmembranes,vessels,connectivetissueseptaandcapsule.DiscussionThepresenceofminoramyloiddepositsinthyroidglandinsystemicamyloidosiswasfirstrecordedin1855byVenRekitansky.Greateramyloidinvasionofthethyroid,sufficienttoproduceaclinicallydetectableenlargement,wasdescribedbyVonBeckmanin1858.Amyloidgoitreusuallymanifestsclinicallyasarapidlyenlargingcervicalswellingwithdysphagia,hoarsenessofvoiceanddyspnoea,duetocompres-sionoflocalstructures.Theremaybeadditionalsymptomsrelatedtoamyloiddepositioninotherorgans.Thegoitreisfirmtohardinconsistencyandthistogetherwithitsrapidgrowthusuallysuggestsmalignancy7andthissuspicionmaybestrengthenedbythefindingofregionallymph-adenopathy5alsoduetoamyloidinvasion.Thecorrectdiagnosisisonlyrevealedafterthyroidec-tomybutinsomecasesaneedlebiopsyofthethyroidhassatisfactorilyestablishedthediag-nosis.8Histologically,thethyroidparenchymaisvirtuallyreplacedbyamyloid,thefolliclesaredistorted,containingscantycolloidandtheirliningepitheliumisflattened.9Thelumenofbloodvesselsmaybenarrowedbyinfiltrationoftheirwallwithamyloid.Massivedepositionofamyloidinthethyroidmayincreaseitssizefromfivetotentimesnormal,anditsweightfrom150to250grammes.Theheaviestrecordedweightbeing573grammes.6Despitesuchextensiveamyloidinfiltrationtheendocrinefunctionoftheglandisremarkablywellpreserved.Inareviewof30casesofamyloidgoitre,Arien&Klein6foundnoinstanceofhypo-thyroidism.However,theydidfindtwocasesofpossiblehyperthyroidism,butthiswasbasedonanelevatedbasalmetabolicratewhichcouldinsteadbeattributedtotheunderlyingchronicinflammatorydisease.Jaimet°'claimstohavedescribedthefirstcaseofhypothyroidisminamyloidgoitreandanotherpossiblecaseof 306CLINICALREPORTShypothyroidismwasdescribedbyDanovitchetal."However,theirconclusionhingedoninade-quatethyroidfunctiontests.Inouropinion,thyroiddysfunctioninamyloidgoitrehasnotbeenconvincinglydemonstrated.TheobservationthatourpatientswereclinicallyeuthyroiddespitemarkedlyelevatedfreeT4raisestheinterestingquestionregardingitspathogenesis.AlthoughT3ismorepotentthanT4thelatterdoespossessintrinsichormonalactivity12anditseleva-tionalonecansustainthyrotoxicosis.13'14ThepresenceofanormalT3intheabovecasesdoesnotthereforefullyaccountfortheoccurrenceofclinicaleuthyroidisminthefaceofhyperthyroxin-aemia.AmoreprobableexplanationisthatthereispartialperipheralresistancetotheactionofT4.Theexactmechanismofthisresistanceisunclear15butadefectintheintracellulartransportofT416orreducedintracellularT45'deiodinationhasbeenproposed.17AnormalT3inthepresenceofanelevatedT4intheabovecasesmayalsobeduetotheeuthyroidsicksyndrome."8InthisconditiontheperipheralconversionofT4toT3isimpairedbythepresenceofanon-thyroidalillness.'9Inourpatientsgeneralizedamyloiddepositionandinthelaterstages,chronicrenalfailureandcardiacfailurewouldadequatelyexplainthissyndrome.ThepossibilityofacirculatingfactorinterferingwiththefreeT4assaycannotbeexcluded.Thereareseveralinterestingfeaturesaboutthesecases.Amyloidgoitreisitselfararitywithonlyabout80previouslyreportedcases.7Toourknowledgethesearethefirstcasesofhyperthy-roxinaemiainclinicallyeuthyroidpatientswithamyloidgoitreduetosystemicamyloidosis.AcknowledgementsWeacknowledgethehelpofMrJ.Fleming,DrG.Hughes,DrS.Kane,DrA.Knudsen,DrM.PhillipandDrP.Gowerinlookingafterthesepatients.TheTSAbassayswerecarriedoutbyDrAMacGregorandDrT.Weetman.References1.Kennedy,J.S.,Thomson,J.A.&Buchanan,W.M.Amyloidinthethyroid.QJMed1974,169:127-143.2.Shapiro,S.T.,Kohut,R.I.&Potter,J.M.AmyloidgoitreArchOtolaryngol1971,93:203.3.Hind,C.R.K&Pepys,M.B.Amyloidosis:classificationandpathogenesis(1).HospitalUpdate1984,10:593-598.4.James,P.D.Amyloidgoitre.JClinPathol1972,25:683-688.5.Kneebone,R.L.,Greeff,H.&Mannell,A.Amyloidgoitre:Acasereport.SAfrMedJ1984,65:931-932.6.Arean,V.M.&Klein,R.E.Amyloidgoitre:Reviewoftheliteratureandreportofacase.AmJClinPathol1961,36:341-355.7.Amado,J.A.,Palacios,S.,Mazanos,J.,Ondiviela,R.,Casanova,D.&Freijanes,J.Fastgrowinggoitreasthefirstclinicalmanifestationofsystemicamyloidosis.PostgradMedJ1982,58:171-172.8.Gharib,N.&Goellner,J.R.Diagnosisofamyloidosisbyfineneedleaspirationbiopsyofthethyroid.NEnglJMed1981,305:586.9.Walker,G.A.Amyloidgoitre.SurgGynecolObstet1942,75:374-378.10.Jaimet,C.H.Amyloidgoitre.CanMedAssocJ1951,64:158-159.11.Danovitch,G.M.,LeRoith,D.,Sobel,R.Sikuler,E.&Straus,R.Amyloidgoitreinfamilialmediterraneanfever.ClinEndocrinol1979,11:595-601.12.Ingbar,S.H.&Braverman,L.Activeformofthethyroidhormone.AnnRevMed1975,26:443-449.13.Turner,T.G.,Brownlie,B.E.W.&Sadder,W.A.DoesT4toxicosisexist?Lancet1975,i:407-408.14.Birkhaser,M.,Busset,R.,Burer,T.&Burger,A.Diagnosisofhyperthyroidismwhenserumthyroxinealoneisraised.Lancet1977,u:53-56.15.Borst,G.C.,Eil,C.&Burman,K.D.Euthyroidhyperthyroxinaemia.AnnInternMed1983,98:366-378.16.Wortsman,J.,Premachandra,B.N.&Hays,I.Euthyroidhyperthyroxinaemiaduetodecreasedintracellulartransportofthyroxine.In:Programandabstractsof57thmeetingoftheAmericanThyroidAssociation.Worcester,Massachusetts,1981.17.Kleinnaus,N.,Faber,J.,Kanana,L.,Schneer,J.&Scheinfeld,M.Euthyroidhyperthyroxinaemiaduetoageneralised5'-deiodinasedefect.JClinEndocrinolMetab1988,66:684-688.18.Wartofsky,L.&Burman,K.D.Alterationsinthyroidfunctioninpatientswithsystemicillness:the'euthyroidsicksyndrome'.EndocrRev1982,3:164-217.19.Cavalieri,R.R.&Rapoport,B.Impairedperipheralconver-sionofthyroxinetotriiodothyronine.AnnRevMed1977,28:57-65.