insufficiency in the outpatient and inpatient 在门诊和住院病人的肾上腺功能不全课件

Adrenalinsufficiency Howtodiagnose treatandmanage TheodoreC Friedman M D Ph D ProfessorofMedicine UCLAChief DivisionofEndocrinology MolecularMedicineandMetabolismCharlesR DrewUMagicConventionChicagoJune13 2010 Case 1961 44y omalePMH PSH Age23 Episodeofhypotension Age28 frail 150lbs lookedtired hollowed eyedandanemic thencollapsed Age37 backsurgery Age38 diagnosedwithhypothyroidism metabolicrateof 15 low liiothyroninestarted lifelonghistoryofGIsymptoms cramping diarrhea inabilitytogainweight age38 43intentional35lbsweightgain includingincreasedmusclemass Familyhx Sister Addison sdiseaseSon Graves disease Medications ascorbicacid 500mgtwicedailyhydrocortisone 10mgdailyprednisone 2 5mgtwicedailymethyltestosterone 10mg dliothyroninesodium 25mcgtwicedailyfludrocortisone 0 1mg ddiphenoxylatehydrochloride opioidagonist atropinesulfate 2tabletsasneeded Lomotil PE 6feet 175lbsAppearedpaleandanemicAppearedbronze beforetreatment ImpairedvibrationsenseLabs Hgb15 5g dL hematocrit41 Otherwisenoneavailable Case Whatisthediagnosis Whoisit Whythemedications PresidentJohnF Kennedy Dx Polyglandularfailuresyndrome Type2 MandelLR EndocrineandautoimmuneaspectsofthehealthhistoryofJohnF Kennedy AnnInternMed 2009 151 350 4 JohnF Kennedy 1944 27year oldJFKatreunionwithfellownavymates JohnF MandelLRAnnInternMed2009 151 350 354 2009byAmericanCollegeofPhysicians PresidentKennedy sMedications ascorbicacid 500mgtwicedaily Why hydrocortisone 10mgdailyprednisone 2 5mgtwicedailyWhyboth methyltestosterone 10mg dOralnolongergiven Suggestshypogonadismsecondarytosteroidreplacmentvsprimaryhypogonadismvshypophysitis Helpedwithmusclemassandweight liothyroninesodium 25mcgtwicedailyWhynotdesiccatedthyroid Levothyroxinefirstintroducedin1962fludrocortisone 0 1mg dGood checkreninleveldiphenoxylatehydrochloride atropinesulfate testforCeliacdiseaseinstead PolyglandularFailureSyndromes TypeIautoimmunepolyglandularsyndrome children mucocutaneouscandidiasishypoparathyroidismadrenalinsufficiencyTypeIIautoimmunepolyglandularsyndrome Schmidtsyndrome adults Addison sdiseaseautoimmunethyroiddisease GravesdiseaseorHashimoto sthyroiditis insulin dependentdiabetesmellitusPerniciousanemiaGonadalfailureHypophysitisCeliacdiseaseVitilgo AdrenalGlands Theadrenalglandslieatthesuperiorpoleofeachkidney Theyarecomposedoftwodistinctregions thecortexandthemedulla AdrenalHormones Glucocorticoids CortisolMineralocorticoids AldosteroneAndrogens DHEA S testosterone androstenedioneEstrogensCatecholamines Epinephrine Dopamine Cortisol Dailysecretion10 15mgCircadiancycleHasthreeforms Free 5 physiologicallyactiveboundtoCBG albuminCortisolmetabolites Cortisol Brain Hypothalamic Pituitary AdrenalAxis Renin Angiotensin AldosteroneAxis Angiotensinogen 452A A Liver Prorenin Renin Kidney AngiotensinI 10A A AngiotensinII 8A A AngiotensinIIreceptor Aldosterone Angiotensin convertingenzyme Adrenal Lung Plasma Adrenal Vascular Site ActionsofGlucocorticoids MaintainsmetabolichomeostasisRegulatesbloodglucoselevelsRaisesinsulinlevelsIncreasescatabolism decreasesanabolismInhibitsreproductive thyroidandgrowthhormoneaxesMineralocorticoidactivityofcortisolAffectsconnectivetissueCauseslossofcollagenLossofconnectivetissueInhibitsfibroblastsInhibitsboneformation incr resorption ActionsofGlucocorticoids 2 MaintainscardiovascularfunctionIncreasescardiacoutputIncreasesvasculartonePermissiveeffectsonpressorhormonesIncreasessodiumretentionAffectsbehaviorandcognitivefunctionAffectsimmunesystemDecrease ofcirculatinglymphocytes monocytes andeosinophilsdecreasemigrationofPMNstositesofinjuryRegulatesabout25 ofhumangenome Renin Angiotensin AldosteroneActions AngiotensinIIvasopressorstimulatesaldosteroneAldosteroneActivatessodium potassiumpumpIncreasesplasmasodiumDecreasesplasmapotassiumDecreasesplasmahydrogen DailyACTH CortisolTrends PrimaryAdrenalInsufficiencyGlucocorticoidandMineralocorticoidInsufficiencyCompensatoryIncreaseinPOMC hyperpigmentation Secondary Central AdrenalInsufficiencyGlucocorticoidInsufficiencyOnlyGlucocorticoidWithdrawalGlucocorticoidInsufficiencyOnly DifferentTypesofGlucocorticoidInsufficiency CausesofPrimaryAdrenalInsufficiency Autoimmune Addison sDisease TuberculosisFungalDiseaseAIDS HIV CMV MAI MetastaticCancerAdrenalHemorrhageBilateralAdrenalectomyAgentswhichinhibitcortisolbiosynthesis ketoconazole Sepsis CausesofSecondaryAdrenalInsufficiency corticotropesarethemostpreservedcellsinthepituitary PituitaryTumorsRadiationSurgeryPituitaryApoplexy Sheehan sSyndromeInfiltrativeDiseasesAfterCureofCushing sSyndromeGlucocorticoidWithdrawal SymptomsofGlucocorticoidInsufficiency FatigueVomitingDiarrheaAnorexiaMalaiseMuscleandjointpainAbdominalpainWeightlossHypoglycemiaHyponatremia SIADH SymptomsofMineralocorticoidInsufficiency DecreasedintracellularvolumeHypotensionDehydrationShockHyponatremiaHyperkalemiaArrhythmiasAcidosisSalt craving LaboratoryFindingsofPrimaryAdrenalInsufficiency HyponatremiaHyperkalemiaHypoglycemiaLymphocytosisEosinophiliaMildnormochromicAnemia SymptomsofPrimaryAdrenalInsufficiency HypotensionDehydrationHyponatremiaHyperkalemiaSalt cravingAmenorrheaDecreasedlibidoHyperpigmentation FatigueGI vomiting diarrhea abdominalpainAnorexia weightlossMalaiseMuscleandjointpainHypoglycemiaHyponatremiaDepression Hyperpigmentation SymptomsofSecondaryAdrenalInsufficiency AmenorrheaDecreasedlibido FatigueGI vomiting diarrhea abdominalpainAnorexia weightlossMalaiseMuscleandjointpainHypoglycemiaHyponatremiaDepression StagesinDevelopmentofPrimaryAdrenalInsufficiency Stage1 reninrises aldosteronenormalStage2 ACTHrises cortisolnormalStage3 impairedcortisolresponsetoACTHStage4 aldosteronelevelsdropStage5 cortisollevelsdrop Copyright 2001TheEndocrineSociety Ten S etal JClinEndocrinolMetab2001 86 2909 2922 StagesinDevelopmentofPrimaryAdrenalInsufficiency DiagnosisofAdrenalInsufficiency Goals Demonstrateinappropriatelylowcortisolandaldosterone ifprimary DeterminewhetherthecortisoldeficiencyisdependentorindependentofACTHdeficiency IstheCortisolLevelLow AQuickApproach Checkingan8AMfastingcortisollevelcanusuallymakeorexcludethediagnosisinapatientlevelsofcortisol12ug dlrespectively Shouldonlybedoneinsubjectswithsigns symptomsofadrenalinsufficiencyorhistoryconsistentwithit Canbeusedinthosepatientswithamoderateindexofsuspicion MeasurementofACTHlevelscandifferentiatebetweenprimaryandsecondaryinsufficiencyConsistentlyhighACTHcanbeasignofearlyadrenalinsufficiency Roy R andFriedman T C 2004 SubclinicalAdrenalInsufficiency ADisease LikeSubclinicalHypothyroidism WhoseTimeHasCome EndoTrends11 3 14 15 ProblemswithJustCheckingMorningCortisolLevels Erturketal Evaluationofhypothalamic pituitaryadrenalaxisbyinsulinhypoglycemiatestJ Clin J ClinEndocrinolMet 1998 83 2350FoundthatsomepatientswithanAMcortisolbetween12 18mg dLhadaITT inducedcortisol 17andwouldbeclassifiedasbeingadrenally insufficient IdoubtthesehaveclinicallysignificantcortisoldefiencyandneedreplacementMayneedcoverageduringsurgeryormajorillness CosyntropinStimulationTest 250ugIVbolusofcosyntropin synth ACTH inmorningorafternoonPlasmacortisolattime0 30 60minutesCortisol 18ug dlfrombaselinerulesoutprimaryadrenalinsufficiencyand90 secondaryinsufficiencyifpeakresponseislessthan10mg dl glucocorticoidreplacementisrequiredifpeakresponseisbetween10and20mg dl glucocorticoidreplacementisrecommendedduringstressesandmaybeduringeverydayIncrementalincreaseincortisolnotrecommendedNeedtohavecentralhypocortisolismforabout1month somearticlessay12days priortoenoughadrenalatrophyandfailedcosyntropintest 1mcgCosyntropinStimulationTest ProposedtobemorephysiologicalBydefinitionwillpickupmorecasesofadrenalinsufficiency LoraiuxandFleseiru pointourseveralproblemswiththistestAlowerdoseisonthesteeperpartofthedose responsecurveresultinginmorevariation normals willhavealowerresponseto1mcgcosyntropin butwedon tknowthecutoffforthistest Callingsomeoneabnormalbasedonabluntedresponseto1mcgcosyntropinandputtingthemonlifelongglucocorticoidsmaybetheworsethingwecandotoapatient LoraiuxandFleseiruCur Opin Endocrinol DiabetesObe16 392 400 2009 SalivarycortisoltestingAdvantages AvoidanticipatorystressofblooddrawsMeasuresfreecortisolNotaffectedbyCBGvariationsEasytocollectMorepleasantTwostudiessuggestitwassimilartoserumcortisoltodiagnoseadrenalinsufficiency Onelookedatbaselinecortisollevelsandonelookedatduringcosyntropintesting SalivarycortisoltestingDisadvantages Cut offsarenotknown Lowlevelsofcortisol accuracymightbeaproblemMostcortisolinthemorningisbound ArticlesshowednotasmuchdifferencesinsalivaryvsserumcortisolbetweenadrenalinsufficientpatientsandnormalsReliableatstandardlabs Esoterix Labcorp Quest ACLLessreliableatlabsdealingdirectlytotheconsumer Diagnos tech Geneva GreatSmokie HormoneSalivaTestsAlmostalwayslow IhavehadCushing spatientswithlowlevelswhoreceivedsteroids BigdivideonthisbetweenEndosandAlternativeDocs Naturopaths Insulin InducedHypoglycemia 0 1units kginsulininmorning moreifinsulin resistant Checkglucoseattime0 15 30 45 60 90Cortisolshouldriseabove18ug dLandglucoseshouldfallbelow40mg dLPatientsanddocsdonotlikeit Ifhypopit missingcounter regulatoryhormones cortisolandGH hardtogetoutofhypoglycemia Manyhypopitpatientsareinsulinresistant havetogivemoreinsulin Literaturesuggestsgivingaseconddoseofinsulinif1stonedoesn tachievehypoglycemia butthatalreadystimulatescortisol soonthe2ndinsulindose cortisoldoesn trespond falsepositives Urinecortisol Urinaryfreecortisoland17 OHcorticosteroidsNotgreatatseparatinglownormalfromlow Mightgiveyouahint Reminder ACTHisthelasthormonetobeaffectedinpituitaryinsufficiency GH TSH gonadotropinshavetobeinvariablylost Symptomsofglucocorticoidinsufficiencyareunique weightloss nausea abdominalpain Primaryadrenalinsufficiencyisrelativelyrareandalsohasauniquesymptomandlabcomplex Oncestarted glucocorticoidsmaybehardtostopandareoftenverydetrimental Itsprobablyafalse positivetest unlessitsintherightcontext Thinktwicebeforegoingonglucocorticoids Glucocorticoidsstimulatemood sothefactthatyoufeelbetteronglucocorticoidsdoesnotmeanyouhaveadrenalinsufficiency AdrenalFatigue Fiction Wildlyproposedbyalternativeandanti agingdoctorsLotsofinternetdiscussiononitOftenbasedonsalivarycortisolassays sometimesmarketeddirectlytopatients whichlackbothprecisionandaccuracy Theoryisthat stress leadstheadrenalstoworkharderandmakemorecortisol thenitburnsout petersout andmakeslesscortisol It slikeahormonefactoryanditwanesinitsproduction oneofthewayitwanesisjustbystress Dr ToriHudson NaturopathicPhysician AlternativedoctorsmaygiveherbsandsupplementstostimulatetheadrenalglandbutalsogiveIsocort groundupsheepadrenals orhydrocortisone Eatlean greenandclean onealternativedoctorsaidisthetreatmentforadrenalfatigue AdrenalFatigue Fact Theadrenalsareup regulatedduringstressandmakecortisol notlesscortisol Mommersteegetal Psychoneuroendocrinology 2006 31 216 225 studied74clinicallydiagnosedburnoutindividualsmostlyonsick leaveandcomparedwith35healthycontrols Theyfoundsimilarsalivarycortisolafterawakeningandatdifferenttimesofthedayandafteranovernightdexamethasonesuppressiontestinthe2groups Patientsshouldnotbeputoncortisolunlesstheyareshowntobeadrenallyinsufficient Isocortcontains2 5mgofhydrocortisone often6ormorepillsadayaregiven plusaldosteroneandDHEA DHEASandisdangerous AdrenalInsufficiencyandHypothyroidism Addison sDiseaseandHashimoto s autoimmune hypothyroidismco existaspartofTypeIIautoimmunepolyglandularsyndrome Schmidtsyndrome Inhypopituitarism adrenalinsufficiencyandcentralhypothyroidismoftenco existPatientswithfull blownadrenalinsufficiencyandhypothyroidismdoneedtohaveglucocorticoidreplacementpriortothyroidreplacement Thatisbecauseinhypothyroidism cortisolmetabolismisdecreased 11b HSD1favoringcortisonetocortisolconversion Treatmentofhypothyroidismcausesthelowlevelsofcortisoltobebrokendownandwillleadtoanadrenalcrisis Probablynottrueinborderlineadrenalinsufficiencyor adrenalfatigue Statementsofneedingcortisoltosupportthyroidreplacementaremyths AdrenalCrisis UsuallyinPatientswithPrimaryAdrenalInsufficiencyPrecipitatedbyStressNewlydiagnosedvs establishedpatientstoppedmedicinesillnessvomiting PresentationofAdrenalCrisis usuallyprimaryadrenalinsufficiency Hypotension shock 90 Abdominalpain 80 Fever 65 Anorexia nausea vomiting 60 Confusion 40 Hyponatremia hyperkalemia acidosis 80 Hypoglycemia 20 Workup TreatmentforSuspectedAdrenalCrisis EstablishIVaccessDrawbloodforelectrolytes glucose cortisol ACTH aldosteroneandplasmareninactivityInfuseupto3litersofnormalsalineFollowfluidstatusGive100mgofIVhydrocortisoneSupportiveMeasures SubacuteMeasuresforSuspectedAdrenalCrisis ContinueIVfluidsSearchforaninfectioussourceDetermineifprimaryorcentraladrenalinsufficiencyGivefludrocortisoneifprimaryinsufficiency notrequiredinitiallyifhydrocortisonedoseismorethan50mg day ContinueIVhydrocortisone MaintenanceTherapyforAdrenalInsufficiency Dailycortisolproductionrateinman Estebanetal JCEM 72 39 1991 measureddailycortisolproductionratesinnormalvolunteerswithastablecortisolisotopemethod 9 9 2 7mg day 5 7mg m2day Notalloforalcortisolisabsorbed needtotake12 15mg dayMostglucocorticoidreplacementissupraphysiological Leadstoosteoporosis glucoseintoleranceandincreasedinfections Truephysiologicalreplacementislikelytobebenign GlucocorticoidReplacement Mostpatientsareover treatedEarliestmanifestationofexcesstreatmentiseasybruisabilityWeightgain centralobesity etc Earliestmanifestationofinadequatetreatmentisjointpain ReasonabletomimiccircadianrhythmwithmostorallcortisolgivenfirstthinginthemorningWanttoavoidnighttimeadministrationasitcouldleadtosleepdisturbances But somepatientsneedabitofcortisoltogointodeepsleepNostudiescomparingdifferenttreatmentregimens GlucocorticoidReplacement 2 MyapproachistousehydrocortisonemainlyinAM aimfordosebetween15and20mg dayinawomenandslightlyhigherinaman Hydrocortisone10 20mgonawakeningHydrocortisone2 5 5mginmid afternoonOccasionallya3rddoseisneededMorephysiologicalthanprednisoneordexamethasoneDecreasedoseslowlyuntilsomesymptomsdevelop thengobackadose SmallchangesmakeabigdifferenceIncreasedosewithillness shorttermitsbettertoerrongivingmore longtermitsbettertogivelessCortefisbrandname hydrocortisoneisgeneric mostofmypatientsprefergeneric Modified ReleaseHydrocortisone Investigational DuoCorthydrocortisonedual releasetabletcombinesbotharapidreleasedoseandanextendedreleasedose DesignedtobettermimiccircadianrhythmofcortisolWebsitestates Existingadministrationformscannotadequatelymimicthe24hourcircadianpatternofcortisol Probablybestusewillbeincongenitaladrenalhyperplasia Notsurereplacementisabigprobleminadrenalinsufficientpatientsduetocortisol cortisoneshuttleManypatientsdofineonasingledoseofhydrocortisoneinAMeventhoughbloodcortisollevelsarealmost0 Thisisduetotheconversionofcortisoltocortisone whichgoesbacktocortisolinthetissues 30mgofmodifiedhydrocortisonemayover replaceindividuals Modified ReleaseHydrocortisone circadianrhythm Debono M etal JClinEndocrinolMetab2009 94 1548 1554 Modified ReleaseHydrocortisone onlylong lasting Debono M etal JClinEndocrinolMetab2009 94 1548 1554 MaintenanceTherapyforPrimaryAdrenalInsufficiency PrimaryadrenalinsufficiencymayneedabitmoreglucocorticoidsthansecondaryMineralocorticoidReplacementFludrocortisone0 05mgto0 5mgdaily 0 05mgtwiceaday Shouldbegiventwiceaday half lifeis3 5hrsFludrocortisoneisgeneric brand Florinef isnotavailable ProbablywillneedmorefludrocortisoneinthesummerMed AlertBracelet canalsobegiveninsecondary butlesscrucial Solucortef 100mginAct O vial Monitoringglucocorticoidreplacement Signsandsymptoms24hrUFCover estimatecortisolasitreflectsamountintheurinerightafterdosingthatexceeds11b HSD2capacity 17 OHS canbecorrectedforcreatinineexcretioning day reflectscortisolmetabolismandismoreintegratedthroughouttheday Daycurvesunder estimatecortisolastheignorecortisone cortisolshuttleACTHishighunlessover replaced Monitoringglucocorticoidreplacement LW Sheehan ssyndrome veryathleticandhealthconsciousHCtaperedfrom20mg dayto17 5mg day 12 5mginAM 5mginPM lessbruising slightweightlossOn17 5mgaday UFC191mg day 10 34 17 OHS4 7mg day 2 6 17 OHS gmCr3 5mg day 1 6 3 6 Wentdownto15mg dayofHC hadanadrenalcrisiswhenhadtheflu Monitoringmineralocorticoidreplacementinprimaryadrenalinsufficiency Plasmareninactivityisveryaccurateandprobablyshouldbemeasuredevery2 3monthsIfitshigh morefludrocortisoneisgiven ifitslow lessfludrocortisoneisgivenElectrolytesarerelativelyinsensitiveandarenotasubstituteforfrequentreninmonitoring HormonalInteractions Treatingadrenalinsufficiencymayunmaskdiabetesinsipidus HormonalInteractions IncreasedGH IGF Ileadstolowerlevelsofcortisol 11 HSD1 Thus treatingapatientwithhypopituitarismwithGHwilldecreasecortisollevels Similarly treatingapatientwithhypopituitarismwiththyroidhormonewilldecreasecortisollevels Wehadonepatientthatwasover replacedonglucocorticoids under replacedonthyroidhormoneandnottreatedwithGH WestartedGH decreasedherglucocorticoidsandincreasedherL thyroxine shewentintoadrenalcrisis Makechangesslowly Monitorfrequently GlucocorticoidsareNeededforSleep Garc a BorregueroD etal JClinEndocrinolMetab 200085 4201 6 InAddison spatients cortisolplaysapositive permissiveroleinREMsleepregulationandmayhelptoconsolidatesleep Suggestsaneedforalowdoseofhydrocortisone 2 5mg atnight PhysiologicalEquivalentsofGlucocorticoids 20mgofhydrocortisone5mgofprednisone4mgofmethylprednisolone0 75mgofdexamethasone TreatmentofMinor