AutoantibodiesAutoantibodies inin ThyroidThyroid DiseaseDisease andand DiabetesDiabetes

DrDr KetanKetan DhatariyaDhatariya Consultant in Diabetes and Endocrinology Norfolk and Norwich University Hospital NHS Trust WhatWhat ’’ss anan Autoantibody?Autoantibody?

 AnAn autoantibodyautoantibody isis anan antibodyantibody manufacturedmanufactured byby thethe immuneimmune systemsystem thatthat isis directeddirected againstagainst oneone oror moremore ofof thethe individual'sindividual's ownown proteinsproteins AA ListList ofof aa FewFew ofof thethe MedicallyMedically ImportantImportant AutoantibodiesAutoantibodies

 Anti - antibodies  Antinuclear antibody (ANA)  Anti - antibodies  Anti -p62 antibodies in primary biliary cirrhosis  Anti -GD3 ( Guillain -Barr é syndrome )  Anti -sp100 antibodies in primary biliary  Anti -GM1 (travellers diarrhoea) cirrhosis  Anti -GQ1b  Anti -glycoprotein210 antibodies in  Anti -gastric parietal cell antibody primary biliary cirrhosis primary biliary cirrhosis  Anti -glomerular basement membrane  antibody antibody  Anti -extractable nuclear antigen  Anti -Hu antibody antibodies (Anti -ENA antibodies) antibodies (Anti -ENA antibodies)  Anti -Jo 1 antibody  Anti -Ro antibody Anti -Ro antibody  Anti -liver/kidney microsomal 1 antibody  Anti -La antibody (anti -LKM 1 antibodies )  Anti -PM/ Scl (anti -exosome ) antibody  Anti -Ku antibody  Anti -Scl 70 antibody (in sclerosis and  Anti -mitochondrial antibody scleroderma) scleroderma)  Anti -neutrophil cytoplasmic antibody  Anti - antibodies (ANCA)  Anti - antibodies  Rheumatoid factor  Anti -smooth muscle antibody  Lupus anticoagulant  Anti - antibodies  Anti - antibodies  Anti -tTG coeliac disease  Anti -eTG dermatitis herpetiformis  etc, etc etc …… . ThyroidThyroid TheThe 22 ClassicClassic AutoimmuneAutoimmune ThyroidThyroid DiseasesDiseases

 GravesGraves ’’ diseasedisease –– autoimmuneautoimmune hyperthyroidismhyperthyroidism

 HashimotoHashimoto ’’ss diseasedisease // thyroiditisthyroiditis –– autoimmuneautoimmune hypothyroidismhypothyroidism

Females Males Hypothyroidism 4.1 0.6 Hyperthyroidism 0.8 <0.1

Incidence per 1000 per year Vanderpump et al Clin Endo 1995;43:55-68 TheThe MainMain ThyroidThyroid AntibodiesAntibodies

 AntiAnti –– TSHTSH receptorreceptor antibodiesantibodies (( TRAbTRAb ))

 AntiAnti --thyroidthyroid peroxidaseperoxidase antibodiesantibodies (TPO)(TPO)

 (Anti(Anti thyroglobulin)thyroglobulin) TheThe TSHTSH receptorreceptor

 TheThe primaryprimary targettarget forfor thethe autoantibodyautoantibody isis thethe TSHTSH receptorreceptor

 ThisThis isis aa classicclassic glycopeptideglycopeptide 77 transmembranetransmembrane GG-- proteinprotein linkedlinked receptorreceptor GravesGraves ’’ DiseaseDisease

 TSHTSH receptorreceptor antibodiesantibodies (( TRAbTRAb )) bindbind toto thethe TSHTSH receptorreceptor

 ActivatingActivating thethe GG --proteinprotein coupledcoupled mechanismmechanism

 IncreasingIncreasing cAMPcAMP andand adenylateadenylate cyclase,cyclase, triggeringtriggering thethe intracellularintracellular signallingsignalling cascadecascade

 UltimatelyUltimately leadingleading toto thethe inappropriateinappropriate secretionsecretion onon thyroxinethyroxine GravesGraves ’’ DiseaseDisease

 TSHTSH receptorreceptor antibodiesantibodies areare presentpresent inin 8080 --100%100% ofof allall casecase ofof GravesGraves ’’ –– theirtheir presencepresence isis essentiallyessentially diagnosticdiagnostic ofof GravesGraves ’’

 LevelsLevels decreasedecrease withwith treatmenttreatment

 LevelsLevels afterafter treatmenttreatment areare predictivepredictive ofof relapserelapse GravesGraves ’’ DiseaseDisease

 TRAbTRAb isis usuallyusually stimulatingstimulating

 TheyThey cancan occasionallyoccasionally bebe blockingblocking –– butbut thesethese havehave nono effecteffect onon thethe receptorreceptor

 TheyThey maymay bebe responsibleresponsible forfor continuingcontinuing pituitarypituitary TSHTSH suppressionsuppression despitedespite normalisationnormalisation ofof thethe fT4/fT3fT4/fT3 levelslevels withwith drugsdrugs // RAIRAI // surgerysurgery AntiAnti TPOTPO antibodiesantibodies

 FarFar moremore commonlycommonly performedperformed thanthan TSHTSH receptorreceptor antibodiesantibodies

 ButBut farfar lessless specificspecific

 UsefulUseful asas aa diagnosticdiagnostic markermarker

 IsIs anan indicatorindicator ofof thyroidthyroid injuryinjury –– thusthus notnot aa causecause ofof thethe condition,condition, butbut aa resultresult ofof thethe conditioncondition PrevalencePrevalence ofof ThyroidThyroid AutoantibodiesAutoantibodies

Group TRAb (%) TgAb (%) TPOAb (%) General 0 5-20 8-27 population Graves ’ 80 -95 50 -70 50 -80

Hashimoto ’s 10 -20 80 -90 90 -100

Relatives 0 40 -50 40 -50 Those with 0 40 40 T1DM Pregnant 0 14 14 women AntiAnti TPOTPO antibodiesantibodies

 HighHigh titrestitres inin subclinicalsubclinical diseasedisease (i.e.(i.e. raisedraised TSHTSH butbut normalnormal fT4/fT3)fT4/fT3) areare moremore likelylikely toto bebe associatedassociated withwith thethe developmentdevelopment ofof overtovert hypothyroidismhypothyroidism overover timetime (3(3 --5%5% perper year)year) AntiAnti --thyroglobulinthyroglobulin antibodiesantibodies

 VeryVery rarelyrarely donedone atat thethe N&N.N&N. TheThe onlyonly timetime thisthis isis reallyreally usefuluseful isis inin patientspatients withwith thyroidthyroid cancercancer

 ThyroidThyroid cancercancer releasesreleases thyroglobulin,thyroglobulin, andand isis thusthus aa makermaker forfor tumourtumour bulkbulk

 PostPost surgerysurgery // RAIRAI isis itit isis measuredmeasured toto assessassess tumourtumour recurrencerecurrence

 HighHigh levelslevels ofof AntiTgAntiTg negatesnegates thethe TgTg report,report, andand diseasedisease progressionprogression needsneeds toto bebe mademade clinicallyclinically // usingusing imagingimaging DiabetesDiabetes TheThe ClassicClassic ModelModel ofof thethe PathogenesisPathogenesis ofof T1DMT1DM

Atkinson MA et al. Lancet 2001;358:221-229 AutoantibodiesAutoantibodies inin TypeType 11 DiabetesDiabetes

 ThereThere areare 33 mainmain autoantibodiesautoantibodies

 Anti islet cell (ICA512/IA -2)  Anti glutamic acid decarboxylase (GAD65)  Anti -insulin (IAA) AutoantibodiesAutoantibodies inin TypeType 11 DiabetesDiabetes

 InIn relativesrelatives ofof peoplepeople withwith establishedestablished T1DM,T1DM, overover 90%90% ofof peoplepeople whowho gogo onon toto developdevelop T1DMT1DM havehave oneone oror bothboth ofof thesethese antibodiesantibodies

 ItIt isis thusthus aa reasonablereasonable predictorpredictor toto seesee ifif someonesomeone isis atat riskrisk ofof developingdeveloping thethe conditioncondition

 TheThe moremore antibodiesantibodies presentpresent simultaneously,simultaneously, thethe greatergreater thethe riskrisk HoweverHowever

 UpUp toto 3%3% ofof thethe populationpopulation hashas thesethese antibodies,antibodies, andand 90%90% ofof childrenchildren whowho developdevelop T1DMT1DM dodo notnot havehave aa familyfamily membermember withwith thethe conditioncondition PrevalencePrevalence ofof GADGAD

Group Autoantibody Frequency (%)

Healthy control group 0.3 –0.6 First -degree relatives of patients 3–4 with type 1 diabetes Patients with other autoimmune 1–2 endocrine disorders Patients with newly diagnosed 55 –85 type 1 diabetes Patients with type 2 diabetes 10 –15

Patients with gestational diabetes 10 HopeHope withwith RituximabRituximab ??

 8787 peoplepeople withwith newlynewly diagnoseddiagnosed typetype 11 diabetesdiabetes

 GivenGiven 44 dosesdoses ofof rituximabrituximab overover 33 weeksweeks

 FollowedFollowed upup forfor aa yearyear

Pescovitz MD et al NEJM 2009;361(22):2143-2152 ThyroidsThyroids andand DiabetesDiabetes areare RelatedRelated

 IfIf aa personperson presentspresents withwith one,one, looklook outout forfor thethe samesame personperson havinghaving anotheranother autoimmuneautoimmune disease,disease, oror forfor oneone ofof theirtheir familyfamily toto havehave somethingsomething elseelse Autoimmune Polyendocrinopathy-Candidiasis- Ectodermal Dystrophy (APECED) PAS II(A) (Schmidt's PAS I PAS IIB (or III) syndrome) Central Clinical Autoimmune adrenal failure Autoimmune adrenal failure Autoimmune thyroid disease Feature: (Addison's disease) (Addison's disease) (Hashimoto, Graves)

Other clinical Autoimmune thyroid disease Hypoparathyroidism Pernicious anaemia features (one or (Hashimoto, Graves) more): Chronic candidiasis Pernicious anaemia Vitiligo Gondal failure Vitiligo Alopecia Immune mediated diabetes Hypopituitarism Alopecia (T1DM) Immune mediated diabetes Coaliac disease Coeliac disease (T1DM) Pernicious anaemia Coeliac disease Gonadal failure Vitiligo Gonadal failure Alopecia Immune mediated diabetes (T1DM) Autoimmune thyroid disease

Likely to be an autosomal Likely to be an autosomal Autosomal recessive dominant, with variable dominant, with variable Genetics: expression expression CTLA-4 gene CTLA-4 gene Defect of AIRE gene HLA-DR3 and/or HLA-DR4 HLA-DR3 and/or HLA-DR4 haplotypes, chromosome 6 haplotypes, chromosome 6 Prevelence: Rare More common More common Onset: Childhood onset Adult onset Adult onset ThankThank youyou forfor youryour attentionattention