AdrenalDiseases:Clinical OverviewandManagement DeepikaReddy,March7,2012 10:30AM DepartmentofEndocrinology
ObjecFves Understandbasicadrenalphysiology (steroidogenesis) UnderstandthefuncFonofvariousadrenal hormones Reviewcommonformsofcongenitaladrenal hyperplasia Reviewhormonaldeficiencyandhormonal excessstates.
HistologyoftheAdrenalGland
TheAdrenalGland OuterZoneofCortex:Glomerulosa Siteofaldosterone(mineralocorFcoid)producFon MiddleZoneofCortex:Fasciculata SiteofcorFsol(glucocorFcoid)producFon InnerZoneofCortex:ReFcularis SiteofandrogenproducFon AdrenalMedulla siteofcatecholamineproducfon
FuncFonofAdrenalHormones Aldosterone EffectisonrenalcollecFngtubuleandpartofthe distalconvolutedtubule.itservestoincrease sodium,waterreabsorpfonandpotassium excrefon. Aldosteroneisthereforeinvolvedinmaintenance ofextracellularfluidvolume,naandk concentrafon AcFvatedbytherenin angiotensinsystem
GlucocorFcoidFuncFon Figfrom Endocrinologyanintegratedapproach :S.S.NusseyandS.A.Whitehead
GlucocorFcoidFuncFon Liver:Raisebloodglucose:ByincreasinghepaFcglucoseproducFonandreduced peripheraluflizafon Muscle:Aminoacidreleasefrommuscleforgluconeogenesis,chronicusecauses musclewasfng AdiposeTissue:Lipolysis,o`encounteredbythelipogenesisinducedbyinsulin Bone:DecreasedosteoblastaciFvity,increasedosteoclastacFvity,decreased calciumabsorpfonfromgutanddecreasedresponsivenesstovitamind ImmuneSystem:AnF inflammatoryproperfes/immunesuppressionbymulfple mechanisms Skin:affectsfibroblastfuncFon Cardiovascular:potenFatestheaffectofcatecholaminesandAngiotensinIIonthe vasculature. CNS:maybeassociatedwithdepression,psychosis Kidney:IncreasesrenalbloodflowandincreasesGFR. (InhighconcentraFons,canhavemineralocorFcoideffect)
AdrenalAndrogens Playasignificantroleingonadaldevelopmentinuteroand youngchildren. Inadultmales,adrenalglandnotasignificantsourceof androgens Inadultfemales,adrenalandrogenexcesscancause symptomsofandrogenexcesssuchashirsuifsm.deficiency maycauselossofsomesecondarysexualcharacterisfcs.in thepostmenopausalstatemaybeanimportantsourceof androgens.
Effectsofcatecholamines Cardiovascular Increase in heart rate and force Increased venous return Increased peripheral resistance Visceral Smooth muscle relaxation via β 2 actions and contraction via α mediated actions Modulation of fluid and electrolyte transport in the gut, kidney, gall bladder via α receptors Metabolic β receptor mediated glycogenolysis, lipolysis Increases in diet induced and non shivering thermogenesis via β receptors Water and electrolyte metabolism Decreased sodium excretion and glomerular filtration due to direct effects on the kidney β receptor mediated effects on renin secretion leads to increased aldosterone production with effects on distal sodium handling Serum potassium may be increased as a result of α mediated effects on the liver but decreased as a result of β 2 receptormediated effects on muscle Hormone secretion The sympatho adrenal part of the autonomic nervous system modulates the responses of a number of endocrine systems, including: The renin angiotensin aldosterone system Increased secretion of glucagon and insulin
ADRENAL STEROID PRODUCTION 1 : 17 hydroxylase (CYP17, P450c17); 17,20: 17,20 lyase (also mediated by CYP17); 3 : 3 hydroxysteroid dehydrogenase; 21: 21 hydroxylase (CYP21A2, P450c21); 11 : 11 hydroxylase; (CYP11B1, P450c11); 18 refers to the two step process of aldosterone synthase (CYP11B2, P450c11as), resulting in the addition of an hydroxyl group that is then oxidized to an aldehyde group at the 18 carbon position; 17 R: 17 reductase; 5 R: 5 reductase; DHEA: dehydroepiandrostenedione; DHEAS: DHEA sulfate; A: aromatase (CYP19). Source: UPTODATE
Case1 A26 year oldwomanwasreferredbecauseofincreasingfacialhair.she hadhermenarcheat11yearsofagebuthadalwaysnotedirregular periods.shewas154cmtallwithaweightof87kg.onexaminafon,she wasobesebuthadnoclinicalevidenceofglucocorfcoidor mineralocorfcoidexcessandherbloodpressurewasnormal.shehad, however,excessfacialhair,areolarhairsonthebreasts,malepagern pubichairwithanextensionupthelineaalbainthemidlineofthelower abdomen.therewashairontheinnerthighsbutnoneonherback.there wasnoclitoralhypertrophy,breastatrophyorothersignsof masculinizafonsuchasdeepvoiceandmusculardevelopment. Herserumtestosteronewasmildlyelevatedaswasher17OH progesteronelevel.therewasasignificantincreasein17ohprogestrone levelfollowingacthsfmulafon
CongenitalAdrenalHyperplasia(CAH):duetoCYP21A2 Deficiencyofanyoftheenzymesintheadrenalsteroidsynthesispathway cancausespecificclinicaldisorders ThemostcommonisCYP21A2(21hydroxylase)deficiency.Itisassociated with: ImpairedsynthesisofcorFsol impairedsynthesisofaldosterone IncreasedACTHandincreasedprecursorhormones.Asaconsequence thereisincreasedandrogenproducfonthatcancausevirilizafon. ItmaybeseenininfancywithoutorwithoutsaltwasFng. MayalsobepickedupfirstinadultswithahistoryofhirsuiFsm,o`en inferflity,possiblecliteromegaly TreatwithglucocorFcoids
ADRENAL STEROID PRODUCTION 1 : 17 hydroxylase (CYP17, P450c17); 17,20: 17,20 lyase (also mediated by CYP17); 3 : 3 hydroxysteroid dehydrogenase; 21: 21 hydroxylase (CYP21A2, P450c21); 11 : 11 hydroxylase; (CYP11B1, P450c11); 18 refers to the two step process of aldosterone synthase (CYP11B2, P450c11as), resulting in the addition of an hydroxyl group that is then oxidized to an aldehyde group at the 18 carbon position; 17 R: 17 reductase; 5 R: 5 reductase; DHEA: dehydroepiandrostenedione; DHEAS: DHEA sulfate; A: aromatase (CYP19). Source: UPTODATE
CAHduetoCYP17deficiency MostpaFentspresentatabouttheFmeofexpectedpubertybecauseof hypertension,hypokalemia,andhypogonadism. Theremayormaynotbeadrenalinsufficiency,dependinguponthe degreeofthecorfsolsecretorydefect. FemalepaFents Female(46,XX)paFentshaveprimaryamenorrheaand absentsecondarysexualcharacterisfcs. MalepaFents Male(46,XY)paFentsusuallyhavecompletemale pseudohermaphrodifsm,withfemaleexternalgenitalia,ablindvagina,no uterusorfallopiantubes,andintraabdominaltestes. Source:UPTODATE
CAHfrom3 BETA HYDROXYSTEROIDDEHYDROGENASE deficiency MostpaFentspresentasneonatesorinearlyinfancywithclinical manifestafonsofbothcorfsolandaldosteronedeficiency. TheyhavewithfeedingdifficulFes,vomiFng,volumedepleFon, hyponatremia,andhyperkalemia. FemalesmayhavemildvirilizaFonoftheirexternalgenitalia,presumably duetoexcessdhea,aligleofwhichisconvertedperipherallyto testosterone. Maleshavevaryingdegreesoffailureofnormalgenitaldevelopment, rangingfromhypospadiastomalepseudohermaphrodifsmwithnearly normalfemaleexternalgenitalia.
Case2 A33 year oldwomanpresentedwithincreasingskin pigmentafonandweightloss.shealsohadnauseaand abdominaldiscomfort.therewasnoobtainablefamilyhistory ofanyillnessand,apartfromlethargy,shedeniedanyother problem.shehadtwohealthychildren.shewastakingno medicafon.shehadasupinesystolicbloodpressureof50 mmhg(thatbecameunrecordablewhenstanding) HerbaselinecorFsollevelat8AMwas3mcg/dL.Shewas given250mcgofcosyntropin.corfsolrecheckedat30min was7mcg/dlandat60minwas9mcg/dl.
ClinicalfeaturesofAdrenalInsufficiency Weakness FaFgue Anorexia Weightloss HyperpigmentaFon Hypotensionandposturalsymptoms,shockacute. Nausea/vomiFng SaltCraving
EFology:PrimaryvsSeondary AnACTHsFmulaFontestisusedtodiagnoseadrenalinsufficiency BaselinecorFsolandACTHchecked.FollowingthisthepaFentreceives 250mcgofcosyntropin.CorFsollevelsarerechecked30minand60min later.thetestisadequateifeitherthe30minor60minlevelis18 20 mcg/dlorgreater. Iftheresponseisinadequate,theACTHlevelhelpsdetermineifitis primaryadrenalorsecondarytopituitarydysfuncfon. AhighACTHsuggestsprimaryadrenalinsufficiencyandalowACTHlevel suggestssecondaryadrenalinsufficiency.
CausesofPrimaryAdrenalInsufficiency Autoimmune MetastaFcmalignancy Adrenalhemorrage InfecFonssuchasTB Adrenoleukodystrophy InfilteraFvedisorderssuchasamyloidosis CongenFaladrenalhyperplasia FamilialglucocorFcoiddeficiency(unresponsivetoACTH) Drugssuchasketoconazole,mitotane,etomadateetc.
CausesofSecondaryAdrenalInsufficiency ExogenousSteroids PituitaryDysfuncFon/Hypothalamic dysfuncfon TumorcompressingcorFcotrophs Bleed(Sheehans) Immune(LymphocyFchypophysiFs) Hemochromatosis InfiltaraFve(sarcoidosis)
TreatmentofAdrenalInsufiiciency InPrimaryAdrenalInsufficiency ReplaceGlucocorFcoidandPossibly MineralocorFcoid InSecondaryAdrenalInsufficiency ReplaceGlucocorFcoid InformallpaFentsof sickdayrules Takex2 3 Fmesmaintenancedoseinacuteillness.
Case3 A25yearoldfemalepaFentwaspresented with50lbweightgainover1year.shehad fafgue,hirsuifsmandincreasingabdominal striae.shealsousedtohaveregularperiods unflabouttwoyearsagowhenthecycles becomeirregular. A24hrurinefreecorFsolwasx5theupper limitofnormalrange
ClinicalFeaturesofcorFsolexcess(Cushing ssyndrome inthiscase) Obesity Hypertension HirsuFsm Striae Acne EasyBruising Osteopenia MuscleWeakness Depression(someFmespsychosis) Menstrualdisorders Glucoseintolerance ElevatedLipids Kidneystones
EFologyofCushing ssyndrome Adrenalhyperplasia.CanbeduetoACTH oversfmulafon.acthcanbefromanectopic sourcesuchassmallcelllungcancer. WhentheACTHcomesfromthepituitarythat iscushing sdisease Adrenaladenomas Adrenalcarcinomas Iatrogenic
IniFalDiagnosis IfCorFsolexcessissuspected,thefollowingtestcanbedone 24hrurinefreecorFsolvaluesoverx4theupperlimitofnormalare thoughttobesignificant. Suppresionwith1mgdexamethasone.At11PM,1mgof dexamethasoneisgivenandcorfsolischeckedat8am.innormal pafents,thecorfsolsuppressesbelow1.8mcg/dl.falseposifvemay beseeninpafentsonanfseizuremedicafonandinrenalfailure. MidnightsalivarycorFsol.ThereisdiurnalvariaFonincorFsol release.pafentswithcushingslosethisvariafon.salivarycorfsolis checkedonthreeconsecufvedays.posifveifthemajorityare abnormal.thistestmayalsohelpdisfnguishcushing sfrompseudo cushing sdisease.
IniFalDiagnosis ThenextstepistoassessACTHlevels WhenthecorFsolexcessisduetoprimary adrenalover producfon(eg.adrenal Adenoma),ACTHlevelsarelow. IfACTHlevelsarehigh,thesourceiseitherthe pituitaryorotherfssue(ectopicsource)
Treatment SurgeryistheprimarytreatmentforCushing s Syndrome IfthepaFentisnotacandidateforsurgery/ hasextensivediseasedrugsthatblockadrenal steroidsynthesissuchasmetyrapone, ketoconazolecanbetried.
EndocrineReasonsforHypertension AdrenalDependent Pheochromocytoma Primaryaldosteronism CushingsSyndrome HyperdeoxycorFcosteronism CongenitalAdrenalHyperplasia 11b hydroxylasedeficiency 17a hydroxylasedeficiency Deoxycortocosterone producingtumor Source:Endocrinehypertension:WilliamYoungfromCleveland ClinicEndocrinereview
Pheochromocytomas: Pheochromocytomasaretumorsofneuroectodermalorigin TheyresultinincreasedcatecholamineproducFono`enfromtheadrenal medulla 2 8cases/million Male:FemaleraFois1:1 Usuallypresentsin3 5 th decadeoflife CLINICALMANIFESTATIONS HTNin90 100%o`enlabile ParoxysmalepisodesincludeClassicTriad:Headache,sweaFngand palpitafons ChronicvolumedepleFon Cardiomyopathy/MI Source:WilliamsTextbookofEndocrinology.10thediFonpg555
SynthesisofCatecholamines
MetabolismofCatecholamines
DiagnosisofPheochromocytoma 24hrUrineStudies: Urinemetanephrinesandcatecholaminesaremostreliabletestfor pheochromocytoma Ifsuspicionishighurinefreemetanephrinesmaybeuseful CheckcreaFninewiththeurinestudiestoensureadequacyofthesample PlasmaStudies: FracFonatedplasmafreemetanephrinesmaybeused:HighpredicFvevalueofa negafvetest
LocalizaFonofthePheochromocytoma Sporadicpheochromocytomasarelarge(o`en 2 5cm)ThoseassociatedgeneFcsyndromes canbesmaller. 95%areintraabdominal 90%withintheadrenalgland CTorMRIcanbeusedforiniFalevaluaFon. MIBGscan(sensiFvity80%,specificity99%) canbeconfirmatory. UseMRIinpregnantwomen
ManagementofpaFentswith Pheochromocytoma PaFentsneedtohaveadrenergicblockade7 10dayspriorto surgery.sooneriftheyhavehadrecentmiorcardiomyopathy Canstartwithalphablocker.Phenoxybenzamineisusedstart at10mgandraiseq2 3daysFllSBParound100./warn pafentaboutorthostasisandfafgue. Mayalsousecalciumchannelblocker/nicardipine30mgBID DONOTuseonlybetablockersmaymakecondiFonsworse duetounopposedalphaadrenergicsfmulafon Onceadequatelyblocked,paFentcanhavePheoresected.
Ruleof10withPheochromocytomas 10%areextraadrenal 10%occurinchildren 10%aremulFple 10%recura`ersurgicalremoval.PaFentsshouldhavetesFng yearlyfollowingsurgery 10%aremalignant 10%arefamilial(orpartofsyndromesuchasMEN) Mayneedscreeningforthesesyndromes. 10%arefoundasadrenalincidentalomas
PrimaryAldosteronism DuetooverproducFonofaldosteroneinthezona glomerulosa PaFentspresentwithhypertensionando`enhave hypokalemia. MayalsohavenonspecificfindingssuchasfaFgue, headaches,increasedthirst. Maybduetoadrenaladenomaorhyperplasia
Diagnosis MeasureserumaldosteroneandplasmareninacFvityinAM SuggesFveifaldosterone/PRAacFvityisgreaterthan30ANDtheabsolute aldoteroneofgreaterthan15ng/dl. ConfirmwithSaltloadingtests(canuseeitheroralorIV.UsewithcauFonin pafentswithseverehypertensionandchf) Oralsaltloading,andadequatepotassiumreplacementfor3days. Thendo24hrurineforaldosterone.Normalvaluesare5 20mcgin24hours CanalsodoIVsalineloading(2litersover4hours.CheckcorFsoland aldosteronebeforeanda`ertheload.postsalinerafoofaldosteroneto corfsolgreaterthan3seenwithaldosteroneproducingadenoma.
LocalizaFon CTorMRIcanbeusedasiniFalstudy Canconfirmwithadrenalveinsampling. Rightandle`adrenalveinandvenacavacorFsoland aldosteronemeasured Catheterplacementisaccurateiftheadrenalveinto venacavacorfsolrafois5:1. Aldosteronelevelsfromle`andrightadrenalveins arecomparedandgreaterthan4:1rafobetween thetwosuggestunilateralaldosteoneproducing adenoma.
Treatment Dependsondiagnosis Ifanadenomaisdetected,treatmentissurgery. ShouldbepreppedpreoperaFvelywithspironolactone Bloodpressureandpotassiumarenormal. Ifduetohyperplasia,treatedwithanFhypertensives specificallyaldosteroneantogonists(spironolactone, eplerenone)