caledonian society for endocrinology - Edinburgh Diabetes

caledoniansocietyforendocrinologyanddiabetes

www.calsoc.org

CalSoc2017

CrieffHydroNovember24th/25th

@CalSocEndo

@CalSocEndo

#CalSoc2017

Contents

1CalSoc2017

PageProgrammeofevents 2Welcome 4AHendeelist 5

InvitedspeakersProfRebeccaReynolds 6ProfSimonPearce 10DrPetrosPerros 14DrPaulNewey 18ProfRobertSemple 21

Abstractpresenta1onsDrDhruOBhaH 23DrLauraReid 26DrSharonMackin 29DrNyoNyoTun 32DrCatrionaFarrell 35DrMarcusLyall 37DrCatrionaKyle 40

ProgrammeofEvents

13.00–14.30 RegistraOon

Friday24thNovember

Session1

Chair:DrAnnaDoverConsultantPhysician/HonorarySeniorLecturerRoyalInfirmaryofEdinburgh/UniversityofEdinburgh

14.30–15.15 Obesity&DiabetesinPregnancy:Highlightsin2017ProfessorRebeccaReynoldsProfessorofMetabolicMedicineUniversityofEdinburgh

15.15–16.00 Addison’sDiseaseUpdateProfessorSimonPearceProfessorofEndocrinologyNewcastleUniversity

16.00–16.15 Coffee

16.15–17.00 HypothyroidismgoestotheScoKshParliamentDrPetrosPerrosConsultantEndocrinologist/HonorarySeniorLecturerRoyalVictoriaInfirmary,Newcastle/NewcastleUniversity

17.00–17.30 DevelopingaScoKshEndocrineITsystem

19.30 Dinner

2 CalSoc2017

13.15–14.00 MeettheExpert–Traineesession–ThyroidDrPetrosPerros/ProfSimonPearce

ProgrammeofEvents

08.45–09.00 CalSocAnnualGeneralMeeOng

Saturday25thNovember

Session2

DrMarieFreelConsultantEndocrinologist/HonoraryAssociateClinicalProfessorQueenElizabethUniversityHospital,Glasgow/UniversityofGlasgow

09.00–09.45 U1lityandChallengesofGene1cTes1nginEndocrinologyDrPaulNeweySeniorLecturerinEndocrinologySchoolofMedicine,UniversityofDundee

09.45–10.45 AbstractPresenta1onsDrDhruOBhaHDrLauraReidDrSharonMackinDrNyoNyoTun

10.45–11.00 Coffee

11.00–11.45 AbstractPresenta1onsDrCatrionaFarrellDrMarcusLyallDrCatrionaKyle

11.45–12.30 UpdateoninsulinresistanceProfessorRobertSempleProfessorofTranslaOonalMolecularMedicineUniversityofEdinburgh

Chair:

3CalSoc2017

WelcometoCalSoc2017WelcometoCrieffforthe37thwintermeeOngoftheCaledonianSocietyforEndocrinology.Thisyear’smeeOngpromisestocoverawiderangeofclinicallyrelevanttopicsacrossbothdiabetesandendocrinology,deliveredbyinternaOonallyrecognisedexpertsintheirfield.ArecurringquesOonatrecentmeeOngshasbeen‘HowcanweuseCalSoctoharnesstheenthusiasmandexperOseoftheScofshendocrinecommunitytodeliveranaOonalprogrammeofclinicalresearch?’Thishasinvolvedexploringthepossibilityofdevelopinganendocrineequivalentofourworld-leadingSCI-Diabetessystem.Partofthisyear’smeeOngwillbedevotedtoprovidinganupdateonprogressandcanvassingopinionaboutwhatsuchasystemwouldlooklikeandhowwemightachieveit.ManythankstoourgrowingnumberofsupportersfromthepharmaceuOcalindustry.ThisyearwewelcomeNAPPandPfizer,aswellaslong-termsponsorsNovoNordisk,Lilly,Sanofi,MSDandIpsen.ThemeeOngcouldnottakepartwithouttheircontribuOonandIwouldencourageyoutovisittheirstandsbetweensessions.DrFraserGibbOnbehalfoftheCalSocCommiHee

ProfessorGrahamLeeseConsultantPhysicianandHonoraryProfessorNinewellsHospital/UniversityofDundee

DrRussellDrummondConsultantPhysicianandHonoraryClinicalAssociateProfessorGlasgowRoyalInfirmary/UniversityofGlasgow

DrFraserGibb(Secretary-Treasurer)ConsultantPhysicianandHonorarySeniorClinicalLecturerRoyalInfirmaryofEdinburgh/UniversityofEdinburgh

DrSamPhilipConsultantPhysicianandHonoraryClinicalLecturerAberdeenRoyalInfirmary/UniversityofAberdeen

CalSocCommi\ee

'CaledonianSocietyforEndocrinology&DiabetesAnnualMeeOng'hasbeensubmiHedtotheFederaOonoftheRoyalCollegesofPhysiciansoftheUnitedKingdomfor6category1(external)CPDcredits.Approvalpending.

4 CalSoc2017

DrLouiseClarkConsultantPhysicianDumfriesandGallowayRoyalInfirmary

AHendees

5CalSoc2017

Firstname SecondName Grade Loca1on Role

Prakash Abraham Cons Aberdeen AHendee

Melisande Addison Trainee Edinburgh AHendee

Ganesh Arungirinathan Cons Edinburgh AHendee

MohammedAzharuddin Cons Greenock AHendee

DhruO BhaH Trainee Aberdeen Oral

Chad Bisambar Trainee Ayr AHendee

Luke Boyle Trainee Edinburgh AHendee

Geraldine Brennan Cons Monklands AHendee

Linda Buchanan Cons ForthValley AHendee

David Carty Cons Glasgow AHendee

Tom Chambers Trainee Edinburgh AHendee

Louise Clark Cons Dumfries AHendee

Catriona Clarke Biochemist Edinburgh AHendee

Alan Connacher Cons Perth AHendee

Jenna Cowan Cons Crosshouse AHendee

Marion Devers Cons Monklands AHendee

Anna Dover Cons Edinburgh AHendee

Jane DymoH Cons Aberdeen AHendee

Catriona Farrell Trainee Dundee Oral

Marie Freel Cons Glasgow AHendee

Priya George Trainee Dundee AHendee

Fraser Gibb Cons Edinburgh AHendee

Saket Gupta Cons Fife AHendee

Kate Hughes Cons Glasgow AHendee

Emma Johns Trainee Glasgow AHendee

Chris Jones Cons Greenock AHendee

Pauline Jones Cons Edinburgh AHendee

Brian Kennon Cons Glasgow AHendee

Chris Kueh Trainee Glasgow AHendee

Catriona Kyle Trainee Edinburgh Oral

Graham Leese Cons Dundee AHendee

Robert Lindsay Cons Glasgow AHendee

Rachel Livingstone Trainee Glasgow AHendee

Marcus Lyall Trainee Edinburgh Oral

Firstname SecondName Grade LocaOon Role

Alison MacEwen Cons Ayrshire AHendee

David Macfarlane Cons Inverness AHendee

ScoH Mackenzie Cons Edinburgh AHendee

Alasdair Mackie Cons Dundee AHendee

Sharon Mackin Trainee Glasgow Oral

Hannah Macpherson Trainee Edinburgh AHendee

Iqbal Malik Cons Dundee AHendee

Susan McGeoch Cons Aberdeen AHendee

Louise McKenna Trainee Glasgow AHendee

Frances McManus Cons Glasgow AHendee

Emily McMurray Cons Edinburgh AHendee

Kenneth Muir Cons Inverness AHendee

Paul Newey Cons Dundee Speaker

Rose Norton Student Edinburgh AHendee

Mo Oroko Trainee Glasgow AHendee

Simon Pearce Cons Newcastle Speaker

Petros Perros Cons Newcastle Speaker

Colin Perry Cons Glasgow AHendee

Sam Philip Cons Aberdeen AHendee

Laura Reid Trainee Edinburgh Oral

Rebecca Reynolds Cons Edinburgh Speaker

Robert Semple Cons Edinburgh Speaker

Anne Sillars Trainee Glasgow AHendee

Lee Sit Trainee Edinburgh AHendee

Karen Smith Biochemist Glasgow AHendee

Alison Stewart Cons Glasgow AHendee

Roland SOmson Cons Edinburgh AHendee

Mark Strachan Cons Edinburgh AHendee

Sandeep Thekkepat Cons Monklands AHendee

Chris Thompson Cons Dublin AHendee

Joe Timmons Trainee Glasgow AHendee

NyoNyo Tun Trainee Edinburgh Oral

Liesbeth VanLook Cons Livingston AHendee

MinChong Zhuo Trainee Glasgow AHendee

ProfRebeccaReynoldsBiographyProfessorReynoldsisProfessorofMetabolicMedicine,UniversityofEdinburghandHonoraryConsultantPhysicianinDiabetes&Endocrinology,NHSLothianandDeputyHeadoftheCentreforCardiovascularSciences,UniversityofEdinburgh.HermainresearchinterestisintheearlylifeoriginsofhealthanddiseaseandshewasawardedtheNickHalesAwardin2011bytheInternaOonalSocietyfortheDevelopmentalOriginsofHealthandDiseaseandtheCurtRichterAwardin2012bytheInternaOonalSocietyofPsychoneuronendocrinologyinrecogniOonofthiswork.SheisChairoftheDiabetesUKClinicalStudiesGroup‘CausesofDiabetes’.Herresearchspans‘processtopopulaOon’egexperimentalmedicinestudiesinpregnantwomenandtheirchildren,detailedmechanisOcstudiesusingplacentalOssue,randomisedcontrolledtrialstesOngintervenOonsinpregnancytoimproveoutcomesandepidemiologicaldata-linkagestudiesusing‘bigdata’inScotland.Herclinicalworkincludesgeneralandantenataldiabetesandendocrinology,andreproducOveendocrinology.SheismoduleleadforUniversityofEdinburghMBChBEndocrinology&Diabetes.

AbstractObesityandDiabetesinPregnancy:Highlightsin2017ObesityanddiabetesrepresentthemostcommonpregnancycomplicaOonsindevelopedcountries.BothofthesecondiOonshaveshorttermrisksduringpregnancyforbothmotherandchild(1),withincreasingevidencedemonstraOngthattherearealsolongertermrisksoftheseexposuresinpregnancyimpacOngonhealthacrossthelifespan(2,3).ResearchersandcliniciansinScotlandhavecontributedtosomeofthelandmarkclinicaltrialspublishedin2017.Allthesetrialsaimedtoimprovetreatmentandclinicaloutcomesforwomenwithobesityand/ordiabetesinpregnancy.ThispresentaOonwilldiscusstheresultsofthesekeytrialsincludingtheCONCEPTTtrialtesOngtheuOlityofconOnuousglucosemonitoringinpregnantwomenwithtype1diabetes(4),theGRACEStrial,tesOngwhetherthecombinaOonoforalhypoglycaemicagentsmepormin+glibenclamidewouldbepreferabletostandardcareofmepormin+insulinforwomenwithgestaOonaldiabetes(5)andtrialsofintervenOonsinobesepregnancywithmepormin(EMPOWARandMOPS)(6,7),diet/lifestyleintervenOons(8),orbariatricsurgery(9).ParOcipaOoninthesestudieshasdemonstratedourabilitytoparOcipatein/and/orleadimportantclinicaltrialsinpregnancy,chimingwiththeChiefMedicalOfficerforEngland’svisiontoopOmisewomen’shealth.ReferencesKallialaIetalObesityandgynaecologicalandobstetriccondiOons:umbrellareviewoftheliterature.BMJ.2017Oct26;359:j4511.doi:10.1136/bmj.j4511.LeeKetalMaternalObesityDuringPregnancyAssociatesWithPrematureMortalityandMajorCardiovascularEventsinLaterLife.Hypertension.2015Nov;66(5):938-44.doi:10.1161/HYPERTENSIONAHA.115.05920ReynoldsRMetalMaternalobesityduringpregnancyandprematuremortalityfromcardiovasculareventinadultoffspring:follow-upof1323275personyears.BMJ.2013Aug13;347:f4539.doi:10.1136/bmj.f4539.FeigDSetalConOnuousglucosemonitoringinpregnantwomenwithtype1diabetes(CONCEPTT):amulOcentreinternaOonalrandomisedcontrolledtrial.Lancet.2017Sep15.pii:S0140-6736(17)32400-5.doi:10.1016/S0140-6736(17)32400-5ReynoldsRMetalGlibenclamideandmepoRminversusstAndardcareingEstaOonaldiabeteS(GRACES):afeasibilityopenlabelrandomisedtrial.BMCPregnancyChildbirth.2017Sep22;17(1):316.doi:10.1186/s12884-017-1505-3.ChiswickCetalEffectofmeporminonmaternalandfetaloutcomesinobesepregnantwomen(EMPOWaR):arandomised,double-blind,placebo-controlledtrial.LancetDiabetesEndocrinol.2015Oct;3(10):778-86.doi:10.1016/S2213-8587(15)00219-3.Epub2015Jul9.SyngelakiAetalMeporminversusPlaceboinObesePregnantWomenwithoutDiabetesMellitus.NEnglJMed.2016Feb4;374(5):434-43.doi:10.1056/NEJMoa1509819.RogozińskaEetalEffectsofantenataldietandphysicalacOvityonmaternalandfetaloutcomes:individualpaOentdatameta-analysisandhealtheconomicevaluaOon.HealthTechnolAssess.2017Aug;21(41):1-158.doi:10.3310/hta21410.JohanssonKetalOutcomesofpregnancyawerbariatricsurgery.NEnglJMed.2015Feb26;372(9):814-24.doi:10.1056/NEJMoa1405789.

6 CalSoc2017

ProfRebeccaReynolds

7CalSoc2017

Primary outcome

*

CGMControl

*mean difference -0.19%; 95% CI -0.34—0.03; p = 0.0207

• LGA 53% CGM vs 69% control; Odds ratio 0.51; 95%CI 0.28—0.90, p=0.0210

• Neonatal hypoglycaemia requiring iv treatment 15% vs 28%;Odds ratio 0.45; 95%CI 0.22—0.89, p=0.0250

• NICU admission>24hrs; 27% CGM vs 43% control;Odds ratio 0.48; 95% CI 0.26-0.86; p=0.0157

Summary of neonatal outcomes

NNT 6

NNT 8

NNT 6

ProfRebeccaReynolds

8 CalSoc2017

Obesity and obstetric conditions: umbrella review of 144 meta-analyses of cohort studies

Strong evidence for increased risk of :Maternal adverse outcomes• Pre-eclampsia • Gestational Diabetes• Antenatal depression• Total and emergency caesarean sectionFetal adverse outcomes• Fetal macrosomia• Low Apgar score at 1 minute• Stillbirth Kalliala et al BMJ 2017; 359; j4511

Conclusions• A randomised trial of glibenclamide v insulin in

women with GDM and who need a second line therapy in addition to metformin would be “feasible” but would require 30-60 centres recruiting for 3 years

• In this small sample, no woman had a symptomatic hypoglycaemic episode

• Preference for glibenclamide over insulin is not universal

• Preliminary data suggests that insulin gives superior control, with fewer excursions < 3.3 mmol/l

ProfRebeccaReynolds

9CalSoc2017

Effect of diet and lifestyle interventions : IPD and meta-analysis and health economic evaluation

Evidence from 36 RCTs of over >12,000 women shows that lifestyle interventions have :

– 0.70 kg (95% CI 0.92 to 0.48 kg) reduction in gestational weight gain

– No effect on birth weight– No effect on the incidence of large for gestational

age, or small for gestational age infants– No effect on maternal composite outcomes– No evidence of cost benefit

Rogozinska et al HTA 2017 21(41): 1-158

Metformin: bwt and GWG

Elmaraezy et al Int J Reprod Biomed 2017 15(8): 461

Birthweight

Gestational weight gain

ProfSimonPearceBiographySimonPearcequalifiedinMedicineMB,BS1stclasshonoursfromNewcastleUniversity.Followinginternalmedicinetraining,heundertookpostgraduateeducaOoninendocrinologyinRajThakker’slabatHammersmith,followedbyspellsatBrigham&Women’sHospital,Boston;andlaHerlybackinNewcastle,UK.HewasappointedasSeniorLecturerinEndocrinologyin2001atNewcastleUniversity,andpromotedtoProfessorin2007,affiliatedtotheInsOtuteofGeneOcMedicineandtheRoyalVictoriaInfirmary.Hehaspublishedmorethan170papersoverthelast25years,mainlyonparathyroidcalcium-sensing,thyroiddiseaseandAddison’sdisease.

Summaryoftalk•ThefirstpresentaOonofapaOentwithadrenalinsufficiencyisfrequentlyoverlookedbyhealthcareprofessionals.•FoodpoisoningandgastroenteriOsarethecommonestcauseofAddisoniancrisis.•SaltdepleOondueto(relaOve)mineralocorOcoiddeficiencyisresponsibleformuchofthepathophysiologyofadrenalcrisis.•ExcellentpaOentengagementandsteroideducaOoniskeytoallowingpeoplewithAddison’sdiseasetosafelymanagetheircondiOon,day-to-day.•SmallandowendosesofhydrocorOsonegivebeHersteroidexposureprofiles.•Fine-tuningofmineralocorOcoidreplacementandsaltintakeinAddison’spaOentsisimportantforadrenalcrisisprevenOonandopOmalwellbeing,andisowenneglectedbyphysicians.•Bothmodified-releasehydrocorOsonetabletsandconOnuoussubcutaneoushydrocorOsoneinfusionsoffercloserapproximaOonstohealthyplasmacorOsolrhythmsthanmulOdose,immediate-releaseoralhydrocorOsone.•Greaterclinicalexperiencewiththesenovelreplacementtherapiesneedstobegainedfortheirroleinthemanagementofadrenalinsufficiencytobeestablished.•ThereisdurableresidualadrenalfuncOoninaproporOonofpaOentswithAddison’sdisease,andthisisafuturetherapeuOctarget.References:PazderskaA,PearceSH.Adrenalinsufficiency-recogniOonandmanagement.ClinMed(Lond)2017;17:258-262.doi:10.7861/clinmedicine.17-3-258.GanEH,PearceSH.RegeneraOvetherapiesinautoimmuneAddison'sdisease.EurJEndocrinol2017;176:R123-R135.doi:10.1530/EJE-16-0581.HusebyeES,AllolioB,ArltW,BadenhoopK,BensingS,BeHerleC,FalorniA,GanEH,HulOngAL,Kasperlik-ZaluskaA,KämpeO,LøvåsK,MeyerG,PearceSH.Consensusstatementonthediagnosis,treatmentandfollow-upofpaOentswithprimaryadrenalinsufficiency.JInternMed2014;275:104-15.doi:10.1111/joim.12162.GanEH,MacArthurK,MitchellAL,HughesBA,PerrosP,BallSG,JamesRA,QuintonR,ChenS,FurmaniakJ,ArltW,PearceSH.ResidualadrenalfuncOoninautoimmuneAddison'sdisease:improvementawertetracosacOde(ACTH1-24)treatment.JClinEndocrinolMetab2014;99:111-8.doi:10.1210/jc.2013-2449

10 CalSoc2017

ProfSimonPearce

11CalSoc2017

•  67%$of$pa)ents$had$3$or$more$encounters$with$features$of$adrenal$failure$before$Δ$

•  50%$of$men,$70%$of$women$had$complained$of$symptoms$>$6$months$

•  68%$had$a$different$ini)al$diagnosis$– Mental$health$– Gastrointes)nal$

Bleicken$B$et$al.$Am$J$Med$Sci$2010$

Pa3ent,Educa3on,•  Steroid$card$&$Medical$alert$jewellery$

•  iPhone$medic$alert$home$screens$

•  �Sick$day$rules�$–  Fever,$diarrhoea$– Minor$procedures$(den)st,$gastroscopy)$

–  Vomi)ng$

•  How$&$when$to$inject$with$IM$hydrocor)sone$

•  www.addisons.org.uk$

ProfSimonPearce

12 CalSoc2017

Pa3ent,Educa3on,•  Steroid$card$&$Medical$alert$jewellery$

•  iPhone$medic$alert$home$screens$

•  �Sick$day$rules�$–  Fever,$diarrhoea$– Minor$procedures$(den)st,$gastroscopy)$

–  Vomi)ng$

•  How$&$when$to$inject$with$IM$hydrocor)sone$

•  www.addisons.org.uk$

Ask the patient 10 questions 1.  Do you have low spots during the day? 2.  Are you clock-watching for one particular dose? 3.  Do you often miss a dose because you haven�t

noticed the time? 4.  What time is bedtime? 5.  Do you sleep okay? 6.  How do you feel first thing in the morning? 7.  How are your general energy levels/ get up & go? 8.  Are you napping during the day? 9.  Changes in pigmentation? 10.  Changes in weight?

ProfSimonPearce

13CalSoc2017

Chronic,Management:,mineralocor3coid,

•  Fludrocor)sone$50`500mcg$daily$

•  Younger$people$need$more$

•  Discuss$salt$cravings,$including$typical$foods$

•  Consider$salt$tablets$(NaCl$1.8`3.6$g/d)$

•  Titrate$according$to$Na+/K+,$BP,$renin$

Model of evolving Addison�s disease

•  Insidious onset of disease •  ACTH vs Immune destruction

ACTH

Immune system attack Failure to make steroids Adrenal becomes dormant

ACTH stimulation Adrenal cells proliferate

Regeneration

DrPetrosPerrosBiographyPetrosPerrosisaconsultantendocrinologistattheRoyalVictoriaInfirmary,Newcastleandhonoraryseniorlecturer,NewcastleUniversity.HequalifiedfromNewcastleUniversityandtrainedinNewcastle,GlasgowandEdinburgh.Hisclinicalandresearchinterestsincludethyroidcancer,thyroideyediseaseandneuroendocrinetumours.HeisapastpresidentoftheEuropeanGrouponGraves’OrbitopathyandiscurrentlyconvenoroftheSocietyforEndocrinologythyroidnetwork.

AbstractHypothyroidismgoestotheScofshParliamentSomaOcandcogniOvesymptomsarefoundabout10%ofthegeneralpopulaOonandinpaOentswithhypothyroidism.ClaimsthattreatmentwithT3-containingpreparaOonsincombinaOonwithT4aresuperiortoT4alonehavenotbeenconfirmedbyseveralrandomisedclinicaltrials.SomepaOentgroupsarecampaigningforwideuseofT3incombinaOonwithT4ordesiccatedanimalthyroidextract.TwoplausiblehypotheseshavebeenputforwardtoexplainpersistentsymptomsintreatedhypothyroidpaOents:funcOonalsomatoformdisorder,andinabilityofavailablethyroidhormonereplacementtherapiestorestorenormalphysiology.Concernsaboutlong-termsafetyofcombinaOontherapiespersist.

14 CalSoc2017

•  T4 alone resulted in normal TSH but low serum and tissue T3 levels

•  Serum T3, T4 and TSH and tissue T3 were only restored with continuous T4 + T3 administration

•  Patterns of gene expression in tissues were only restored with continuous T4 + T3 administration

Biological basis Pathophysiology of OTAST

Moreales-Escobar et al, 1996, Werneck de Castro et al, 2015)

Thyroidectomised rats treated with: -T4 alone -T4 + boluses of T3 -T4 + continuous T3 infusion

DrPetrosPerros

15CalSoc2017

Biological basis MCT10 and D2 Gene Polymorphisms:

preference for T4+T3 treatment

Carle et al, 2017

Pathophysiology of OTAST

% Responsers

100 80 60 40 20 0

Neither n=19

One n=19

Both n=7

p<0.05

Taylor et al, 2014

TSH threshold for starting treatment

10% 51%

Trends in diagnosis and treatment of hypothyroidism


DrPetrosPerros

16 CalSoc2017

Prescriptions 2001-2013 (PCA)

10

8

6

4

2

0

Fold increase

T4 T3 Animal thyroid extract

TFTs


Mean FT3 Values

2.80

3.60

4.40

5.20

6.00

6.80

0.00 4.00 8.00 12.00 16.00 20.00 24.00

Hours Post-Dose

FT

3 -

No

rmal

Ran

ge

(pm

ol/L

)

P atientsC ontro ls

Potential harm of T3 + T4 treatments

Biochemical thyrotoxicosis almost inevitable in T3 treated patients

DrPetrosPerros

17CalSoc2017

Risk of future AF

Cappola et al 2006

HR =1.98 (1.29-3.03)


Extrapolations from subclinical hyperthyroidism paradigm

Haemtkens et al 2008


Mortality

Extrapolations from subclinical hyperthyroidism paradigm

DrPaulNewey

18 CalSoc2017

BiographyDrPaulNeweyisaSeniorLecturerinEndocrinologyandHonoraryConsultantPhysicianattheUniversityofDundee,Scotland.HeundertookhismedicalstudiesattheUniversityofEdinburghbeforemovingtoOxfordforhisSpecialtyTraining.DuringthisperiodhewasawardedaDPhilforhisstudiesonhereditaryendocrinedisordersincludingMulOpleEndocrineNeoplasiaType1(MEN1).HewassubsequentlyappointedaNIHRClinicalLecturerinOxfordundertakingpost-doctoralresearchinthefieldofendocrinetumourigenesis.In2014,DrNeweymovedtotheUniversityofDundeetoestablishhisownresearchgroupconOnuinghisinterestinendocrinetumourigenesis.In2015,hewasawardedaNRSScofshSeniorClinicalFellowship.DrNewey’smainareaofresearchisunderstandingthegeneOcbasisofendocrinediseasewithafocusonneuroendocrinetumoursanddisordersofcalciumhomeostasis.

AbstractUOlityandChallengesofGeneOcTesOnginEndocrinologyTheadventofhigh-throughputDNAsequencingtechnologyhasacceleratedtheidenOficaOonofgenesresponsibleforbothhereditaryandsporadicendocrinediseasesandisincreasinglyappliedintheclinicalsefngtoguidepaOentmanagement.However,thisaccessibilityandscopeofgeneOctesOngbringsmanychallenges,includinginherentdifficulOesindatainterpretaOon.Thesechallenges,whichincludeestablishingaccurateesOmatesofvariantpathogenicityandpenetrance,mayresultindiagnosOcconfusion.ThistalkwillprovideanoverviewofthecurrentapproachestoclinicalgeneOctesOnginendocrinologyandhighlightmanyofthecontemporarychallengesfaced.

DrPaulNewey

19CalSoc2017

TheGene'cTes'ngWorkflow–WhichTest?

TheGene'cTes'ngWorkflow–Pre-TestConsidera'ons

DrPaulNewey

20 CalSoc2017

TheGene'cTes'ngWorkflow–Communica'ngResults

TheGene'cTes'ngWorkflow–Intepreta'on

ProfRobertSempleBiographyRobertSempleisanerrantScotwho,unOlOctober,hadspenthisenOreprofessionalcareerinEngland.HereadNaturalSciencesandthenMedicineattheUniversityofCambridgebeforeinternalmedicalpostsinLondon.HereturnedtoCambridgeforspecialisttraininginDiabetesandEndocrinology,interruptedbydoctoralstudieswithProfSirStephenO'Rahilly,focusingontranscripOonalregulaOonofadiposeOssuemetabolism.Forthepast12yearshisresearchhasfocusedonrarehumandisordersofinsulinacOonand/orgrowth,withtheaimofidenOfyingnovelacquiredorgeneOcdefectsunderlyinginsulinresistanceandrelatedcondiOons,bothtoacceleratediagnosisandtreatmentofaffectedpaOents,andtogaininsightsintodiseasemechanism.InOctoberhetookupachairofTranslaOonalMolecularMedicineattheUniversityofEdinburgh,andaswellasre-establishingaresearchgroupfocusingoncausesandconsequencesofinsulinresistance,heaimstoprovideaclinicalrouteofreferralinScotlandforpaOentswithrelatedproblems.

AbstractAcquiredandgeneOcdisordersofadiposeOssuedevelopmentorfuncOonand/orsevereinsulinresistanceareaheterogenousgroupofcondiOonswhichareunderdiagnosedyetimposeahugeburdenofprematuremorbidityandmortalityonaffectedpaOents.Drawingonexperienceof15yearsofresearch,translaOonalandclinicalexperienceinCambridge,encompassingtheEnglishNHSSevereInsulinResistanceService,apracOcalaccountwillbegivenofthecondiOonsmostlikelytobeseeninendocrine/diabetespracOce,withafocusontherequirementsforspecificdiagnosisandmanagement.

21CalSoc2017

ProfRobertSemple

22 CalSoc2017

DrDhruOBhaH

23CalSoc2017

BiographyIgraduatedfromtheUniversityofSheffieldin2009andmovedtoNorthofScotlandforfoundaOonandcoremedicaltraining.IcommencedspecialisttraininginDiabetesandEndocrinologyin2014andamcurrentlyinmypenulOmateyearoftrainingatAberdeenRoyalInfirmary.

AbstractIs11C-methioninePETco-registeredwithMRIagamechangerforchallengingfunc1oningpituitarytumours–AberdeenexperienceinAcromegalyandCushing’sdisease.DhruOBhaH1,JackStraiton2,MahmoudKamel3,AlexGraveling1,SamPhilip1,PrakashAbraham1.DepartmentofEndocrinology1,DepartmentofClinicalRadiologyandNuclearMedicine2,DepartmentofNeurosurgery3,AberdeenRoyalInfirmary,Aberdeen,U.K.Aims:11C-methioninepositronemissiontomographyco-registeredwithMRI(met-PET/MRI)isanewimagingtechniqueusedforfuncOoningpituitaryadenomas.InpaOentswithpersistentacromegalyawerprimarytherapyandotherfuncOoningpituitaryadenomas,met-PET/MRIcanhelpidenOfythesite(s)ofresidualpituitaryadenomawhenMRIappearancesareinconclusiveanddirectfurthertargetedintervenOon(Trans-sphenoidalsurgery-TSSorradiotherapy).Methods:ProspecOvestudyofpaOentswithacromegalyunderacOvefollow-upinateachinghospital.Datawascollectedfrompaperandelectronicrecords(2009onwards).Anarbitraryagecut-offof75wasusedwhenconsideringsuitabilityforrepeatTSS.RemainingpaOentsweredividedintothreecategories.P1:poorlycontrolledonsomatostaOnanalogue(SSA)therapyand/orpegvisomant.P2:wellcontrolledonSSA.P3:poorlycontrolledondopamineagonist(DA)therapy.ForCushing’sdiseasetargetedpaOentswerereferredfromothercentres.Results:Acromegalycohort:Outofthefiwy-onepaOentsincluded,twenty-threepaOentsundertheageof75wereonacOvetreatment(P1:10,P2:8andP3:3).Annualcost(BNF2017)ofmedicalendocrinetherapyforP1categorypaOentswas£150,829andP2categorypaOentswas£73,466.NineP1categorypaOents,willingforfurtherintervenOon,haveagreedtomet-PET/MRIand2paOentshaveundergoneTSS.IllustraOvecase:AyoungfemalepaOentwithacromegalyonSSA+DA(P1)andDM(diabetesmellitus)on120unitsofinsulin/day,bothpoorlycontrolled,underwentredoTSSinfluencedbymet-PET/MRI(fusedimages).Shewasdischargedoffinsulinandwithintactsteroidaxis.Cushing’sdiseasecohort:Sofar3paOents(1eachfromAberdeen/Dundee/Inverness)withCushing’sdiseasehavehadposiOveoutcomesfollowingTSSinfluencedbymet-PET/MRI.IllustraOvecases1:A67yearoldwomanwithpreviousrightadrenalectomyandsubsequentACTHdependantCushing’ssyndromeviasuppressionandCRHtests.BIPSSandMRIx2negaOve,met-PET/MRIconfirmedanadenomaandunderwentsurgery;2A28yearoldmanwithrecurrentCushing’sdiseaseandType2DMunderwentTSSawerthemet-PET/MRIclarifiedthefuncOoningareafrompostsurgicalchange.Comment:Sofar,ourpaOentswhohaveundergonemet-PET/MRIhaveshownidenOfiableresidualfuncOoningpituitaryadenoma.IthasinfluencedourdecisiontoputthesepaOentsforwardforTSS.TherearepotenOalcostsavingsinvolvediftheyareabletocomeoffmedicaltherapiesorevendecreasefrequencyoftheseinjecOons.Acknowledgements–Cambridgeteamforassistancesefngupmet-PET/MRI.EurJEndocrinol.2016Nov;175(5):485-498.ProfGrahamLeese,DundeeandDrSaOnderBal,InvernessforreferralandinformaOonabouttheirpaOents.

DrDhruOBhaH

24 CalSoc2017

Outline

•  MET-PET•  Poten+alapplica+ons

– Cambridgeexperiencesince2011–200+– AberdeenstartupDec2016–9cases(6pipeline)

•  Acromegaly–4(2illustra+vecasesdiscussed)•  Cushings–3(1eachfromAberdeen/Dundee/Inverness–2illustra+vecasesdiscussed)

•  TSHoma-1•  EctopicACTH-1

•  Poorlycontrolledonsomatosta0nanalogue(SSA)therapyand/orpegvisomant

•  10pa0ents•  Meanannualcostoftherapy-£15,083

P1• WellcontrolledonSSA•  8pa0ents•  Meanannualcostoftherapy-£9,183P2•  Poorlycontrolledondopamineagonist(DA)therapy•  3pa0ents•  Meanannualcostoftherapy-£455P3

• Poorlycontrolledonsomatosta0nanalogue(SSA)therapyand/orpegvisomant

• 10pa0ents• Meanannualcostoftherapy-£15,083

P1

• WellcontrolledonSSA• 8pa0ents• Meanannualcostoftherapy-£9,183

P2

• Poorlycontrolledondopamineagonist(DA)therapy

• 3pa0ents• Meanannualcostoftherapy-£455

P3

Figure1:Pa0entcategoryandtotalannualcost

Acromegaly–Illustra1vecase-1•  26,F,presentedin2011•  IGF1-150(9-42nmol/l)atdiagnosis,OGTTlowestGH83mcg/l

andnewdiagnosisofDM•  TSS-2011–Improvedvision,butremnant•  Radiotherapy–2013;Pegvisamontallergy,OnLanreoSde

120mg4weeklyandCabergoline•  Singleparent,Smoker,Poorcompliance•  2016:IGF145-60(15-40nmol/L);HBA1c:127-151mmol/molonHumalogMix25–60unitsbd

DrDhruOBhaHBiographyXX

25CalSoc2017

Case1:-

Radiology–PreandPost-op

CoronalMRI-Pre-op CoronalT1wMRI+Gd–Pre-op/met-PETMRI

CoronalMRI-Post-op

Biochemicalprofile Pre-op(Feb’17)

Post-op(Jul’17)

IGF-1(15-40nmol/L) 63.2 16.9GHug/L 1.55 1.31Cor<sol,nmol/L - 894HbA1c(20-42mmol/mol) 120 88

Prolac<n(59-619mu/l) <40 <40

FT4(10-25pmol/L) 17 22

Case1:resultscon=nued

DrLauraReid

26 CalSoc2017

BiographyLaurastudiedmedicineatClareCollege,Cambridge,graduaOngin2010.ShecompletedherfoundaOonandcoremedicaltraininginNorthernIreland,beforespendingayearworkinginMelbourne,Australia.ShemovedtoEdinburghin2015tocommencetrainingindiabetesandendocrinology.ShehasrecentlystartedworkonanMD,focusingonglycaemicvariabilityanddiabeOcreOnopathyprogressioninpeoplewithtype1diabetespreandpostcommencementofinsulinpumptherapyortreatmentwithisletcelltransplantaOon.

AbstractPredictorsofnephrolithiasis,osteoporosisandmortalityinprimaryhyperparathyroidismLauraJReid,BalaMuthukrishnan,FraserWGibbIntroduc1on:Primaryhyperparathyroidism(PHPT)isoneofthecommonestendocrinedisorderswithaprevalenceofatleast1in1000.Nephrolithiasisandosteoporosisaremorecommoninpeoplewithprimaryhyperparathyroidism,althoughtheclinicalfactorsassociatedwiththisriskarenotwellcharacterised.RecentevidencehassuggestedparathyroidhormoneconcentraOon,butnotcalcium,isassociatedwithmortalityinPHPT.Objec1ves:ToreviewprevalenceofnephrolithiasisandosteoporosisinpaOentswithPHPTinEdinburgh,andassessfactorsassociatedwiththesecomplicaOons.ToassessfactorsassociatedwithmortalityinPHPT.Methods:AllpaOentsassessedattheEdinburghCentreforEndocrinology&Diabetes,between2006–2014,withadiagnosisofPHPTwereidenOfied(n=611).PresenOngclinicalfeatures,biochemistryresultsandimagingresultswereobtainedfromtheelectronicpaOentrecord.Results:Intotal,85/611(13.9%)ofpaOentshadadiagnosisofnephrolithiasis.Adjustedcalciumatdiagnosis(2.76[2.65–2.91]vs.2.72[2.65–2.82],p=0.08)andPTH(12.7[9.9–19.6]vs.12.0[9.3–16.7],p=0.07)werenotsignificantlydifferentinthosewithahistoryofrenalstonescomparedtothosewithnorenalstones.Onlyage(OR0.97,p<0.001)andmalegender(OR2.32,p=0.003)weresignificantlyassociatedwithnephrolithiasisinlogisOcregressionanalysis.BoneMineralDensity(BMD)datawasavailablein461paOentsofwhom223hadosteoporosis;184osteopeniaand54normalBMD.Age(p<0.001),BMI(p<0.001),Gender(p=0.044)andPTHatdiagnosis(p=0.047)weresignificantlyassociatedwithosteoporosis.Parathyroidsurgery(HR0.25,p=0.005),VitaminDdeficiency(HR1.23,p=0.007)adjustedcalciumatdiagnosis(HR1.15,p=0.03)wereindependentlyassociatedwithmortality;PTHwasnot(HR0.99,p=0.74).Conclusions:•  NephrolithiasisismostcommoninyoungermenwithPHPT.•  OsteoporosisiscommoninPHPTbutthisis,inpart,aconsequenceoftheageandgenderofthosepresenOng

withthiscondiOon.•  PTH,ratherthancalcium,ismorestronglycorrelatedwithbonemineraldensity.•  ParathyroidsurgeryisassociatedwithlowerratesofmortalitybutthisisalmostcertainlyareflecOonofselecOon

bias(i.e.lesssurgeryinfrailpaOents).•  HigherPTHisassociatedwithhighermortality,butthisismostlikelyareflecOonoflowervitaminDlevels,which

aremorerobustlyassociatedwithmortality.•  Contrarytoearlierreports,thesedatasuggestadjustedcalciumandnotPTHisthemostsignificantbiochemical

signalformortalityriskinPHPT.

DrLauraReid

27CalSoc2017

DrLauraReid

28 CalSoc2017

DrSharonMackin

29CalSoc2017

BiographyIgraduatedfromtheUniversityofDundeein2009andthereawermovedtoGlasgowformyclinicaltraining,progressingthroughthetradiOonalfoundaOonandcoretrainingroutes.ItookupmyspecialtypostinDiabetesandEndocrinologybackin2013andamnowST6.Morerecently,IhavebeenawardedapersonalfellowshipfromtheGlasgowChildren’sHospitalCharitytoresearchtheroleofglucose-loweringonmaternalandplacentalvascularfuncOoningestaOonaldiabetes.MyresearchisbeingconductedattheUniversityofGlasgow’sInsOtuteofCardiovascularandMedicalSciencesunderthesupervisionofDrRobertLindsayandProfessorChrisOanDelles,andIhavebeeninpostsinceAugust2017.

AbstractKenneyCaffeySyndrome2:AnextremelyrarecaseofhypoparathyroidismandrecurrenthypomagnesaemiaSharonTMackin,RhianMTouyz,ColinPerryWepresentadiagnosOcallychallengingcaseofa22-yearoldfemalewithshortstatureandcongenitalhypoparathyroidismwithrecurrentadmissionsforseverehypocalcaemia,hypokalaemiaandhypomagnesaemia.CaseOurpaOentwasbornat38weeksgestaOontounrelated,healthyparentsofaverageheight,followingapregnancycomplicatedbyintrauterinegrowthrestricOon.Shewasasmallinfantwithabirthweightof2.4kg(-1.7SD),alengththatwasalmost4SDbelowexpectedandasmallheadcircumferenceof31cm(-2.2SD).Shehadfacialdysmorphicfeaturesoffrontalbossing,microphthalmiaandmid-facialhypoplasia.GrowthfailurewasapersistentproblemduringchildhooddespitenormalsOmulatedGHandIGF-1levels.SkeletalsurveysrevealedgracileboneswithcorOcalthickening,hypoplasOcmandiblesandaj-shapedsella.Pituitaryimagingandbiochemistrywerenormal.GHtherapywastrialledseveralOmesbutcomplicatedpre-exisOnghypermetropiawithmacularoedema.Recurrentseverehypocalcaemia,hypomagnesaemiaandhypokalaemiahasresultedinfrequenthospitalisaOonsinceinfancy.BiochemicaltesOngconfirmspersistenthypoparathyroidism,highurinarymagnesiumandpotassiumexcreOonbutnormalcalcium:creaOnine,reninandaldosterone.Sheistreatedwithalfacalcidol1microgramdailyandvaryingdosesofcalciumcarbonate,magnesiumandpotassiumreplacement.DespiteextensiveinvesOgaOon,nounifyingdiagnosiswasachievedunOlattheageof21years,wholegenomicsequencingconfirmedade-novoheterozygousc.1706G>AtransiOonintheFAM111AgenediagnosOcofKenny-CaffeySyndrome2.Kenny-CaffeySyndrome2(KCS2)KCS2isextremelyrarewithlessthan60casesreportedintheEnglishliterature.Theclinicalfeaturesofshortstature,skeletalabnormaliOesandhypoparathyroidismwerefirstdescribedinamotherandsonin1966byKennyandLinarelli.1In2013,genomicsequencingoffiveunrelated,affectedindividualsidenOfiedamutaOonintheFAM111Agenelocatedonchromosome11.2FAM111Acodesfora611aminoacidproteinwhichbearshomologytotrypsinbutitsfuncOonisunclear.3ExisOngclinicalcaseseries’hypothesiseanimportantroleinparathyroidhormoneregulaOonandbonegrowth.TherecurrenthypomagnesaemiaandhypokalaemiaseeninourcasesuggestsapotenOalmechanisminvolvingmagnesiumregulaOon.WeareconducOngfurtherresearchintounderstandingtheroleofFAM111Ainmagnesiumhomeostasis.KennyFM,LinarelliL(1966).DwarfismandcorOcalthickeningoftubularbones:transienthypocalcemiainamotherandson.AmJDisChild111:201–207UngerS,GornaMW,LeBechecAetal(2013).FAM111AmutaOonsresultinhypoparathyroidismandimpairedskeletaldevelopment.AmJHumGenet92:990–995FineDA,RozenblaH-RozenO,PadiMetal(2012)IdenOficaOonofFAM111AasanSV40hostrangerestricOonandadenovirushelperfactor.PLoSPathog.8(10):e1002949

DrSharonMackin

30 CalSoc2017

DrSharonMackin

31CalSoc2017

DrNyoNyoTun

32 CalSoc2017

AbstractTestosteroneDeficiencyinT2DMisaCondi1onofRela1veEstrogenExcess,ElevatedAdiposeAromataseExpressionandHighLep1nDrNyoNyoTun,DrDawnLivingstone&DrFraserWGibbBackground:Androgendeficiency(AD)isobservedinupto50%ofmenwithT2DM.IthasbeenproposedthisisaconsequenceofelevatedaromataseacOvityfromanexpandedadiposecompartment,howeverthishasbeencalledintoquesOonaslowerestradiolconcentraOonshavebeenreportedinmenwithT2DMrelatedhypogonadism.Acomplementaryhypothesispositsthepro-inflammatorystateassociatedwithT2DMasapotenOalcontributor.WesoughttoinvesOgatepredicOvefactorsforADinalargecohortofmenwithT2DM.Methods:228menwithT2DMundertheageof65wererecruitedandunderwent:fasOngbloodsampling,anthropometricmeasurements,bioimpedancebodyfatesOmaOon,AMSandSF-36quesOonnairesandsubcutaneousadiposeneedlebiopsy(n=150).Sexsteroids(includingTandE2)weremeasuredbyLCMS/MS.15geneOcvariantsrelatedtosex-steroidswereanalysedandsubcutaneousadiposemRNAexpressionof23genesofinterestwasassessedbyRT-PCR.TandE2wereconvertedtoz-scoresandthedifferencebetweenz-scoresusedasameasureofdivergence.Results:AD(definedastotalT<10nM)waspresentin34.3%.IndividualfactorsassociatedwithADincludedBMI(33.2vs.30.5mg/kg2,P<0.001),HbA1c(58vs.51mmol/mol,P<0.001),HOMA-IR(6.2vs.4.6,P=0.008),differencebetweenTandE2z-score(-0.6,vs.0.40,P<0.001–lessthan0indicatesrelaOveE2excess),plasmalepOn(21350vs.14600pg/ml,P<0.001)andadiposearomataseexpression(2.45vs.1.87,P<0.05).Age,smoking,alcoholconsumpOon,IL-6,IL-8,MCP-1andTNF-αwerenotassociatedwithtestosteronedeficiency.ModestassociaOonswithADwereobservedin5ofthe15geneOcvariantsassessed.LogisOcregressionidenOfiedT–E2z-scoredifference(P<0.001),insulinresistance(P=0.03)andplasmalepOn(P0.05)asthestrongestindependentpredictorsofAD.Conclusions:PreviousdemonstraOonoflowerE2levelsinhypogonadalmenwithT2DMisconfoundedbyfailuretoadjustforlowersubstrateandrogenlevels.Ourfindingssupportthehypothesisthatadiposity(highlepOn),higheraromataseexpressionandrelaOveestrogenexcessarekeydeterminantsofhypogonadisminT2DM.IncontrastcirculaOngandadiposemeasuresofinflammaOonwerenotassociatedwithhypogonadism.

BiographyIgraduatedfromUniversityofEdinburghin2007.MyfoundaOonandcoremedicaltrainingyearswerespentinGlasgowandAberdeen.IreturnedtoEdinburghin2013toundertakespecialtytrainingandtookOmeoutofprogrammetoundertakeanMDlookingintopredicOvefactorsofandrogendeficiencyinmenwithtype2diabetesunderthesupervisionofDr.DawnLivingstoneandDr.FraserGibb.

DrNyoNyoTun

33CalSoc2017

Δ=-3

Lessthan0=rela0veestradiolexcess

EdinburghEndocrinology

Rela0veTandE2balanceDifferencebetweenz-scores

Rela%veTandE2balanceDifferencebetweenz-scores


Rela%veestrogenexcess

Rela%veandrogenexcess

Limitedton=196menwithnormalrangeLH

DrNyoNyoTun

34 CalSoc2017

HbA1cLowerTassociatedwithhigherHbA1c


Totaltestosterone

R-0.287,P<0.001

P<0.001

Freetestosterone

R–0.173,P=0.016

P=0.108

Estradiol

R0.085,P=0.239

Lep$nAssociatedwithlowerTandhigherE2


Totaltestosterone

R-0.351,P<0.001

P=0.002

Freetestosterone

R-0.331,P<0.001

P=0.002

Estradiol

R0.143,P0.046

CYP19expressionAssociatedwithlowerCFTandhigherE2


Totaltestosterone

R-0.100,P=0.308

P=0.090

Freetestosterone

R-0.205,P=0.035

P=0.266

Estradiol

R0.301,P=0.002

HOMA-IRInsulinresistanceassociatedwithlowT


Totaltestosterone

R-0.272,P<0.001

P=0.011

Freetestosterone

R-0.167,P=0.019

P=0.025

Estradiol

R0.086,P=0.232

AgeAssociatedwithE,CFTbutnottotalT


Totaltestosterone

R-0.023,P=0.744

P=0.820

Freetestosterone

R-0.218,P=0.002

P=0.019

Estradiol

R-0.157,P=0.028

BMIDivergentassocia1onwithTandE2


Totaltestosterone

R-0.291,P<0.001

P=0.002

Freetestosterone

R-0.332,P<0.001

P<0.001

Estradiol

R0.257,P<0.001

DrCatrionaFarrell

35CalSoc2017

BiographyCatrionaFarrellgraduatedinmedicinefromGlasgowUniversityin2010whereshewentontocompleteFoundaOonandCoreMedicalTraining.ShemovedtotheEastofScotlandin2015tocommencehigherspecialtytraininginDiabetesandEndocrinology.In2017CatrionawasawardedtheDiabetesUKSirGeorgeAlberOResearchFellowshiptoundertakeaPhD,shewillbelookingintotheuseofhighintensityexerciseasanoveltreatmentofimpairedawarenessofhypoglycaemiaintype1diabetesunderthesupervisionofProfRoryMcCrimmonattheUniversityofDundee.

AbstractPancrea1cNeuroendocrineTumourassociatedwithHypoglycaemia;Tumour,TreatmentorTransforma1on?CatrionaFarrell,AsaDahle-Smith,GrahamLeese,PaulNeweyPancreaOcneuroendocrinetumours(PanNETs)occurinfrequently,withanannualincidenceof~1/100,000andaretypicallyclassifiedintofuncOoningandnon-funcOoningsubgroupsdependingonthesecretoryprofileofthetumour.ForindividualspresenOngwithadvancedfuncOonaltumours(e.g.insulinoma,gastrinoma,glucagonoma)treatmentstrategiesneednotonlyaddresscontrollingdiseaseprogressionbutmustalsocontrolsymptomsassociatedwithhormoneexcess.FailuretorecogniseoradequatelytreatsuchhormonesecreOonmayresultinsignificantmorbidityand/ormortality.Here,weillustratesomeofthesechallengesinapaOentdiagnosedwithanadvancedPanNET,whosubsequentlydevelopedmarkedhypoglycaemia.The57-yearoldmalepaOentiniOallypresentedwithweightlossandjaundice.Imagingrevealedthepresenceofahead-of-pancreasmassassociatedwithmulOplelivermetastases.SubsequentpancreaOcbiopsyindicatedalow-gradepancreaOcneuroendocrinetumour,whilstfurtherevaluaOonindicatedmarkedelevaOonofserumchromograninA,modestelevaOonofglucagon(X2ULN),andaviduptakeonoctreoOdescanning.Inviewofdiseaseburden,medicalmanagementwasrecommendedandhecommencedlong-acOngsomatostaOnanalogue(SSA)therapy.ThreemonthsawercommencingSSAtherapy,thepaOentdevelopedsymptomssuggesOveofhypoglycaemiaculminaOnginaroadtrafficaccidentassociatedwithlossofconsciousness.SubsequentreferraltoendocrinologyconfirmedendogenoushyperinsulinaemichypoglycaemiaanddiazoxidewasstartedwithparOalamelioraOonofsymptoms.Inviewofminordiseaseprogressiononimaging,SSAtherapywasdisconOnuedandeverolimuscommenced,withexcellentcontrolofhypoglycaemia.Diseaseburdenhasremainedstableoncurrenttherapy.InthispresentaOonwewillreviewtheuseofeverolimusasaninsulinomatreatmentandconsiderthethreepossibiliOesforthepresentaOonofhypoglycaemiainthiscase:(1)misseddiagnosisofmetastaOcinsulinomaatpresentaOon;(2)precipitaOonofhypoglycaemiabySSAtherapy;or(3)tumourtransformaOontoasecretoryphenotype.

DrCatrionaFarrell

36 CalSoc2017

Background–Pancrea/cNeuroendocrineTumours(PanNETs)

1

•  PanNETSareaheterogeneousgroupofneoplasmsarisingfromendocrinecellsofthepancrea9cislets

•  Incidenceandprevalenceincreasingover

past20years•  Func9oningvsnon-func9oning•  Advanceddiseaseisfrequentlyevidentat

the9meofdiagnosis•  Currenttherapiesaimtocontroldisease

progressionandsymptomsrelatedtoexcesshormonesecre9on

Age-adjustedincidenceofPancrea3cNETS(DatafromSEERRegistry)

•  Surgical–shouldbeofferedtoallpa0entsifnonresectablemetasta0cdiseaseisnotpresent–  Laparoscopic–  Abla0on(percutaneous,endoscopic)

•  Medical–priortosurgery,ormalignantorrecurrentcases

–  Frequentsmallmeals–  Diazoxide–  Somatosta0nanalogues–  mTORinhibitor(Everolimus)–  Pep0deReceptorRadionuclideTherapy(PRRT)–  Chemoembolisa0on

Management–Insulinoma

0123456789

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Glucosemmol/l

0500

10001500200025003000

01/03/13

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01/09/13

Proinsulinpmol/l

00.51

1.52

2.53

3.54

4.5

01/03/13

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CPep1de(nmol/l)

0

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InsulinmU/l

ResponsetoEverolimus

DrMarcusLyallBiographyMarcusLyallisaClinicalLecturerattheBHFCentreforCardiovascularScienceattheUniversityofEdinburgh.HavinggraduatedinbiochemistryandthensubsequentlymedicinefromtheUniversityofDundee,hetookupaspecialtytrainingpostindiabetesandendocrinologyinLothianin2011beforeobtainingapositonontheEdinburghClinicalAcademicTraining(ECAT)Schemein2012.HisPhDresearchunderthesupervisionofDrMandyDrakeandProfessorRichardMeehan,focusedontheinteracOonbetweenglucosemetabolismandtheepigenomeinmetabolicliverdisease.OtherresearchinterestsincludeinvitrostemcellmodellingofNAFLDandsteroidinducedhyperglycaemiaincancertherapy.

AbstractIsReninaUsefulMarkerofMineralocorOcoidReplacementinAddison’sDisease?MarcusJLyall1,TarekMohamedElsayedSalem2,FraserWGibb31University/BHFCentreforCardiovascularScience,EndocrinologyUnit,UniversityofEdinburgh.2Alexandriauniversity,Egypt.3EdinburghCentreforEndocrinologyandDiabetes,RoyalInfirmaryofEdinburgh.IntroducOonTheuOlityofreninmeasurementinguidingmineralocorOcoidreplacementisunclear.Toaddressthis,weretrospecOvelyexaminedtheparametersandtreatmentof97paOentswithAddison’sdiseaseoverafiveyearperiod.MethodsAdrenalreplacement,bloodpressure(BP),orthostaOcbloodpressureresponse,urea,sodium,potassiumandreninlevelsof97paOentsaHendingourclinicwerecollectedovertheperiod2012-2016.DatawereanalysedandgraphicaloutputsgeneratedinRversion3.3.2.Results97paOentsaHendingfor397appointmentswerereviewed.Reninlevelwasmeasuredon227(57%)ofaHendancesatanesOmatedcostof£5500.68%ofreninmeasurementswereelevated(>45mU/L)with48%above90mu/Landamedianlevelof82mU/L.AweakbutsignificantnegaOveassociaOonwithplasmasodium(P<0.001,R20.072)wasnotedhowevernoassociaOonwaspresentbetweenreninlevelandpotassiumlevel,systolicordiastolicbloodpressureororthostaOcresponse.Areninlevel>90mu/Lwas63%sensiOveand57%specificfordetecOnganotherfeatureofmineralocorOcoiddeficiency(Na<135mmol/l,K>5.0mmol/l,orthostaOchypotension).Areninlevel>45ml/lwas76%sensiOvebutonly36%sensiOve.ReceiveroperaOngcharacterisOccurvedemonstratedthatelevatedreninwasavalidbutsubopOmaltestforidenOfyingotherfeaturesofmineralocorOcoiddeficiency(AUC0.649,pvalue<0.01).InpaOentswithnormalbiochemistryandorthostaOcbloodpressureresponse,derangedreninlevelalonesignificantlyinfluencedtheincidenceoffludrocorOsonedoseOtraOon(renin<5or>90mU/l,P<0.001chi-squaredtest).Conclusion.OurstudysuggeststhatserumreninminimallycorrelateswithclinicalandbiochemicalfeaturesofmineralocorOcoidstateandthathighreninlevelshaveonlymodestsensiOvityandlowspecificityfordetecOngfeaturesofmineralocorOcoiddeficiency.Despitethis,reninconOnuestobemeasuredrouOnelyatsignificantcostandtreatmentdecisionsconOnuetobemadebasedonlyonreninleveltheclinicaloutcomeofwhichremainsunclear.

37CalSoc2017

DrMarcusLyall

38 CalSoc2017

•  Renin level was measured on 227/397 (57%) of attendances

•  The majority of patients with PAI remain hyper-reninaemic despite fludrocortisone replacement (Median 82mu/l).

•  68% of measurements were above the reference range (45mU/L) with 48% greater than 90mU/l.

Renindistribu,onofpa,entsonmineralocor,coidreplacement.

SerumreninmU/l

45 82


Statistic >45mU/l >90mU/l

Sensitivity 76.47% 62.75%

Specificity 34.09 % 56.82 %

Positive Predictive Value 25.16% 29.63%

Negative Predictive Value 83.33 % 84.03 %

Disease prevalence 22.47% 22.47%

•  Reninreninisavalidbutsubop1maltestforiden1fyingotherfeaturesofmineralocor1coid

•  serumNa<135mmol/l,•  serumK+>5.0mmol/lor•  posturaldropof

≥10mmHgdiastolicor≥20mmHgsystolic

AUC = 0.649

P Value = 0.0012

Doeselevatedserumreninpredictotherfeaturesofmineralocor4coiddeficiency?


DrMarcusLyall

39CalSoc2017

not measured

**

*

**

ns

Changeinfludrocor/sonedoseinresponsetoreninlevelinpa/entswithnormalelectrolytes,bloodpressureandorthosta/cresponse,stra/fiedbyreninlevel.*P<0.01**P<0.001Chi squared test compared to ‘notmeasured’.

Arewemakingclinicaldecisionsbasedonreninlevelalone?

•  Inpa/entswithnormalbiochemistryandorthosta/cbloodpressureresponse,derangedreninlevelalonesignificantlyinfluencedtheincidenceoffludrocor/sonedose/tra/on.


Conclusions •  This study suggests that serum renin minimally correlates with

clinical and biochemical features of mineralocorticoid state.

•  Despite this, renin continues to be measured routinely, at significant cost, and treatment decisions continue to be made based on renin level alone

•  How this impacts on clinical outcomes is unclear.

•  Further work is required to investigate how renin level relates to incidence of hospital admission, antihypertensive treatment and cardiovascular outcome.


DrCatrionaKyleBiographyIgraduatedfromAberdeenUniversityin2008andcompletedmyfoundaOonandcoremedicaltraininginGlasgow.In2012,ImovedtoEdinburghtoundertakespecialisttraininginDiabetesandEndocrinology.Awer2years,ItookOmeoutofprogrammetoundertakeaPhDwithProfessorBrianWalkerandDrRolandSOmsoninvesOgaOngthecontribuOonsofcorOsolandcorOcosteronetometabolicregulaOoninhumans.IreturnedtoclinicaltraininginAugust2017andamcurrentlyworkingintheRoyalInfirmaryofEdinburgh.

AbstractContribu1onsofcor1solandcor1costeronetometabolicregula1oninhumansCatrionaJKyle1,MarkNixon1,AliceOstojic1,LukeBoyle1,NatalieZHomer1,RuthAndrew1,RolandHSOmson1,BrianRWalker1.1BHFCentreforCardiovascularScience,Queen’sMedicalResearchInsOtute,UniversityofEdinburgh,UKBackgroundBothcorOsolandcorOcosteronecirculateinhumanplasmahowevercorOcosteronehasbeenrelaOvelyneglectedinhumanresearchtodate.ThereisevidenceofdisOnctregulaOonwithindifferentOssues:thetransmembraneATP-bindingcasseHe(ABC)transporterABCB1,highlyexpressedinthebrain,exportscorOsolbutnotcorOcosterone,likelyaccounOngfortherelaOveaccumulaOonofcorOcosteroneinthecentralnervoussystem(CNS).Incontrast,ABCC1,highlyexpressedinadiposeOssueandskeletalmuscle,exportscorOcosteronebutnotcorOsol,suggesOngcorOsolhasadisproporOonatelygreatereffectintheseOssues.WehypothesizedthatcorOcosteroneplaysanimportantroleincentralhypothalamic-pituitary-adrenalaxisfeedbackandthatcorOcosteronemightbeabeHerglucocorOcoidforreplacementincongenitaladrenalhyperplasia(CAH)duetoanimprovedmetabolicsideeffectprofile.MethodsTodeterminewhethertheABCC1transporterisresponsiblefordifferenOalbindingofcorOsolandcorOcosteronetoGR/MRinadiposeOssueandskeletalmuscle,weexaminedcorOcosteroidreceptoroccupancyofglucocorOcoidscentrallyandperipherallywithandwithoutABCC1inhibiOonin14healthyindividualsinarandomisedcrossoverdesign.ToexploretheefficacyofcorOcosteroneasanoveltreatmentforCAHinhumans,wecomparedtheefficacyofcorOcosteronecomparedwithhydrocorOsoneandplaceboinsuppressingtheHPAaxisinpaOentswithCAH.ResultsABCC1inhibiOonincreasedHPAaxisacOvitybutdidnotincreaseadiposeOssueorskeletalmuscleglucocorOcoidreceptoroccupancyfollowingcombinedglucocorOcoidandmineralocorOcoidreceptorantagonism,highlighOngapreviouslyundiscoveredcentralroleforABCC1.CorOcosteroneinfusionsuppressedACTHandadrenalandrogenstoasimilarextentashydrocorOsoneinCAHpaOents,providingproof-of-conceptofitsefficacy.ConclusionsThesedatashowthatthereareimportantdifferencesbetweencorOcosteroneandcorOsolphysiologyinhumans.ThisisinpartduetotheeffectsofABCC1whichplaysanimportantroleinregulaOonoftheHPAaxisinaddiOontoregulaOngperipheralglucocorOcoidacOon.CorOcosteroneacutelysuppressestheHPAaxisinCAH,highlighOngitspotenOalasanalternaOvetohydrocorOsoneforglucocorOcoidreplacementtherapy.

40 CalSoc2017

DrCatrionaKyle

41CalSoc2017

Thealterna*veHPAaxis?Keyroleofcor+costeroneinHPAnega+vefeedback

DoesABCC1protectadipose+ssuefromexcesscor+costerone?

RaisedCSFandbrain*ssueconcentra*ons

Nixonetal.SciTransMed2016

•  Bloodwassampledregularlyfrom3sites:

Arterialised(retrogradecannulainhand,heatedto60°C)

Skeletalmuscle(deepvein,antecubitalfossa)

Adipose2ssue(superficialabdominalvein)

•  AdiposeCssuebloodflowwasmeasuredby133Xenonwashoutandinskeletalmuscleusing

venousocclusionplethysmography.

1.ABCC1inhibiConinadiposeandskeletalmuscle

2H-Cor2soneTracerBolusandInfusion

Time:060105120180240300360mins

PotassiumCanrenoate(MRantagonist)200mgIVbolus

Mifepristone/RU486(GRantagonist)400mgOral

DrCatrionaKyle

42 CalSoc2017

However, inhibi-on of ABCC1 with probenecid substan-ally enhanced thisresponse

Results:WholebodyArterialisedplasmacor6solandcor6costeroneconcentra6onsPlaceboandProbenecid

2.Cor'costeroneasanalterna'veglucocor'coidreplacementtherapy

DrCatrionaKyle

43CalSoc2017

Results:PlasmaACTHACTHsuppressionapparentwithbothglucocor:coids

%ACTHsuppressionagainstGCconcentra:on

PlaceboCor+solD8-cor+costerone

Cor:sol333.1±31.0nmol/LD8-cor:costerone:535.2±53.6nmol/L

Notes

44 CalSoc2017

Notes

45CalSoc2017

CalSoc2017registraOon,mealsandaccommodaOonwerecoveredbyoursponsors:

caledonian society for endocrinology - Edinburgh Diabetes

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