AdrenalDiseases:ClinicalOverviewandManagement

DeepikaReddy,March7,201210:30AM

DepartmentofEndocrinology

ObjecFves

•  Understandbasicadrenalphysiology(steroidogenesis)

•  UnderstandthefuncFonofvariousadrenalhormones

•  Reviewcommonformsofcongenitaladrenalhyperplasia

•  Reviewhormonaldeficiencyandhormonalexcessstates.

HistologyoftheAdrenalGland

TheAdrenalGland

  OuterZoneofCortex:Glomerulosa  Siteofaldosterone(mineralocorFcoid)producFon

  MiddleZoneofCortex:Fasciculata

  SiteofcorFsol(glucocorFcoid)producFon  InnerZoneofCortex:ReFcularis

  SiteofandrogenproducFon  AdrenalMedulla

  siteofcatecholamineproducFon

FuncFonofAdrenalHormones

•  Aldosterone– EffectisonrenalcollecFngtubuleandpartofthedistalconvolutedtubule.Itservestoincreasesodium,waterreabsorpFonandpotassiumexcreFon.

– Aldosteroneisthereforeinvolvedinmaintenanceofextracellularfluidvolume,NaandKconcentraFon

– AcFvatedbytherenin‐angiotensinsystem

GlucocorFcoidFuncFonFigfrom‘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

•  Playasignificantroleingonadaldevelopmentinuteroandyoungchildren.

•  Inadultmales,adrenalglandnotasignificantsourceofandrogens

•  Inadultfemales,adrenalandrogenexcesscancausesymptomsofandrogenexcesssuchashirsuiFsm.DeficiencymaycauselossofsomesecondarysexualcharacterisFcs.Inthepostmenopausalstatemaybeanimportantsourceofandrogens.

EffectsofcatecholaminesCardiovascular 

Increase in heart rate and force Increased venous return Increased peripheral resistance  Visceral Smooth muscle relaxation via β2 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 β2 receptor‐mediated 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

hadhermenarcheat11yearsofagebuthadalwaysnotedirregularperiods.Shewas154cmtallwithaweightof87kg.OnexaminaFon,shewasobesebuthadnoclinicalevidenceofglucocorFcoidormineralocorFcoidexcessandherbloodpressurewasnormal.Shehad,however,excessfacialhair,areolarhairsonthebreasts,malepagernpubichairwithanextensionupthelineaalbainthemidlineofthelowerabdomen.Therewashairontheinnerthighsbutnoneonherback.Therewasnoclitoralhypertrophy,breastatrophyorothersignsofmasculinizaFonsuchasdeepvoiceandmusculardevelopment.

•  Herserumtestosteronewasmildlyelevatedaswasher17OHprogesteronelevel.Therewasasignificantincreasein17OHprogestronelevelfollowingACTHsFmulaFon

CongenitalAdrenalHyperplasia(CAH):duetoCYP21A2

•  Deficiencyofanyoftheenzymesintheadrenalsteroidsynthesispathwaycancausespecificclinicaldisorders

•  ThemostcommonisCYP21A2(21hydroxylase)deficiency.Itisassociatedwith:

•  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

•  MostpaFentspresentatabouttheFmeofexpectedpubertybecauseofhypertension,hypokalemia,andhypogonadism.

•  Theremayormaynotbeadrenalinsufficiency,dependinguponthedegreeofthecorFsolsecretorydefect.

•  FemalepaFents—Female(46,XX)paFentshaveprimaryamenorrheaandabsentsecondarysexualcharacterisFcs.

•  MalepaFents—Male(46,XY)paFentsusuallyhavecompletemalepseudohermaphrodiFsm,withfemaleexternalgenitalia,ablindvagina,nouterusorfallopiantubes,andintraabdominaltestes.

•  Source:UPTODATE

CAHfrom3‐BETA‐HYDROXYSTEROIDDEHYDROGENASEdeficiency

•  MostpaFentspresentasneonatesorinearlyinfancywithclinicalmanifestaFonsofbothcorFsolandaldosteronedeficiency.

•  TheyhavewithfeedingdifficulFes,vomiFng,volumedepleFon,hyponatremia,andhyperkalemia.

•  FemalesmayhavemildvirilizaFonoftheirexternalgenitalia,presumablyduetoexcessDHEA,aligleofwhichisconvertedperipherallytotestosterone.

•  Maleshavevaryingdegreesoffailureofnormalgenitaldevelopment,rangingfromhypospadiastomalepseudohermaphrodiFsmwithnearlynormalfemaleexternalgenitalia.

Case2

•  A33‐year‐oldwomanpresentedwithincreasingskinpigmentaFonandweightloss.Shealsohadnauseaandabdominaldiscomfort.Therewasnoobtainablefamilyhistoryofanyillnessand,apartfromlethargy,shedeniedanyotherproblem.Shehadtwohealthychildren.ShewastakingnomedicaFon.Shehadasupinesystolicbloodpressureof50mmHg(thatbecameunrecordablewhenstanding)

HerbaselinecorFsollevelat8AMwas3mcg/dL.Shewasgiven250mcgofCosyntropin.CorFsolrecheckedat30minwas7mcg/dLandat60minwas9mcg/dL.

ClinicalfeaturesofAdrenalInsufficiency

•  Weakness•  FaFgue•  Anorexia•  Weightloss•  HyperpigmentaFon•  Hypotensionandposturalsymptoms,shockacute.•  Nausea/vomiFng•  SaltCraving

EFology:PrimaryvsSeondary

•  AnACTHsFmulaFontestisusedtodiagnoseadrenalinsufficiency•  BaselinecorFsolandACTHchecked.FollowingthisthepaFentreceives

250mcgofcosyntropin.CorFsollevelsarerechecked30minand60minlater.Thetestisadequateifeitherthe30minor60minlevelis18‐20mcg/dLorgreater.

•  Iftheresponseisinadequate,theACTHlevelhelpsdetermineifitisprimaryadrenalorsecondarytopituitarydysfuncFon.

•  AhighACTHsuggestsprimaryadrenalinsufficiencyandalowACTHlevelsuggestssecondaryadrenalinsufficiency.

CausesofPrimaryAdrenalInsufficiency

•  Autoimmune•  MetastaFcmalignancy•  Adrenalhemorrage•  InfecFonssuchasTB•  Adrenoleukodystrophy•  InfilteraFvedisorderssuchasamyloidosis•  CongenFaladrenalhyperplasia•  FamilialglucocorFcoiddeficiency(unresponsivetoACTH)•  Drugssuchasketoconazole,mitotane,etomadateetc.

CausesofSecondaryAdrenalInsufficiency

•  ExogenousSteroids•  PituitaryDysfuncFon/HypothalamicdysfuncFon– TumorcompressingcorFcotrophs– Bleed(Sheehans)–  Immune(LymphocyFchypophysiFs)– Hemochromatosis–  InfiltaraFve(sarcoidosis)

TreatmentofAdrenalInsufiiciency

•  InPrimaryAdrenalInsufficiency– ReplaceGlucocorFcoidandPossiblyMineralocorFcoid

•  InSecondaryAdrenalInsufficiency– ReplaceGlucocorFcoidInformallpaFentsof‘sickdayrules’–Takex2‐3Fmesmaintenancedoseinacuteillness.

Case3

•  A25yearoldfemalepaFentwaspresentedwith50lbweightgainover1year.ShehadfaFgue,hirsuiFsmandincreasingabdominalstriae.ShealsousedtohaveregularperiodsunFlabouttwoyearsagowhenthecyclesbecomeirregular.

•  A24hrurinefreecorFsolwasx5theupperlimitofnormalrange

ClinicalFeaturesofcorFsolexcess(Cushing’sSyndromeinthiscase)

•  Obesity•  Hypertension•  HirsuFsm•  Striae•  Acne•  EasyBruising•  Osteopenia•  MuscleWeakness•  Depression(someFmespsychosis)•  Menstrualdisorders•  Glucoseintolerance•  ElevatedLipids•  Kidneystones

EFologyofCushing’sSyndrome

•  Adrenalhyperplasia.CanbeduetoACTHoversFmulaFon.ACTHcanbefromanectopicsourcesuchassmallcelllungcancer.

•  WhentheACTHcomesfromthepituitarythatisCushing’sDisease

•  Adrenaladenomas•  Adrenalcarcinomas•  Iatrogenic

IniFalDiagnosis

•  IfCorFsolexcessissuspected,thefollowingtestcanbedone•  24hrurinefreecorFsolvaluesoverx4theupperlimitofnormalare

thoughttobesignificant.•  Suppresionwith1mgdexamethasone.At11PM,1mgof

dexamethasoneisgivenandcorFsolischeckedat8AM.InnormalpaFents,thecorFsolsuppressesbelow1.8mcg/dL.FalseposiFvemaybeseeninpaFentsonanFseizuremedicaFonandinrenalfailure.

•  MidnightsalivarycorFsol.ThereisdiurnalvariaFonincorFsolrelease.PaFentswithCushingslosethisvariaFon.SalivarycorFsolischeckedonthreeconsecuFvedays.PosiFveifthemajorityareabnormal.ThistestmayalsohelpdisFnguishCushing’sfrompseudocushing’sdisease.

IniFalDiagnosis

•  ThenextstepistoassessACTHlevels•  WhenthecorFsolexcessisduetoprimaryadrenalover‐producFon(eg.AdrenalAdenoma),ACTHlevelsarelow.

•  IfACTHlevelsarehigh,thesourceiseitherthepituitaryorotherFssue(ectopicsource)

Treatment

•  SurgeryistheprimarytreatmentforCushing’sSyndrome

•  IfthepaFentisnotacandidateforsurgery/hasextensivediseasedrugsthatblockadrenalsteroidsynthesissuchasmetyrapone,ketoconazolecanbetried.

EndocrineReasonsforHypertension

•  AdrenalDependent–  Pheochromocytoma–  Primaryaldosteronism–  CushingsSyndrome–  HyperdeoxycorFcosteronism

•  CongenitalAdrenalHyperplasia11b‐hydroxylasedeficiency17a‐hydroxylasedeficiency•  Deoxycortocosterone‐producingtumor•  Source:Endocrinehypertension:WilliamYoungfromClevelandClinicEndocrinereview

Pheochromocytomas:•  Pheochromocytomasaretumorsofneuroectodermalorigin•  TheyresultinincreasedcatecholamineproducFono`enfromtheadrenal

medulla•  2‐8cases/million•  Male:FemaleraFois1:1•  Usuallypresentsin3‐5thdecadeoflife•  CLINICALMANIFESTATIONS

HTNin90‐100%o`enlabileParoxysmalepisodesincludeClassicTriad:Headache,sweaFngand

palpitaFonsChronicvolumedepleFonCardiomyopathy/MISource:WilliamsTextbookofEndocrinology.10thediFonpg555

SynthesisofCatecholamines

MetabolismofCatecholamines

DiagnosisofPheochromocytoma

•  24hrUrineStudies:•  Urinemetanephrinesandcatecholaminesaremostreliabletestfor

pheochromocytoma•  Ifsuspicionishighurinefreemetanephrinesmaybeuseful•  CheckcreaFninewiththeurinestudiestoensureadequacyofthesample•  PlasmaStudies:•  FracFonatedplasmafreemetanephrinesmaybeused:HighpredicFvevalueofa

negaFvetest

LocalizaFonofthePheochromocytoma

•  Sporadicpheochromocytomasarelarge(o`en2‐5cm)ThoseassociatedgeneFcsyndromescanbesmaller.

•  95%areintraabdominal•  90%withintheadrenalgland•  CTorMRIcanbeusedforiniFalevaluaFon.MIBGscan(sensiFvity80%,specificity99%)canbeconfirmatory.

•  UseMRIinpregnantwomen

ManagementofpaFentswithPheochromocytoma

•  PaFentsneedtohaveadrenergicblockade7‐10dayspriortosurgery.SooneriftheyhavehadrecentMIorcardiomyopathy

•  Canstartwithalphablocker.Phenoxybenzamineisusedstartat10mgandraiseq2‐3daysFllSBParound100./warnpaFentaboutorthostasisandfaFgue.

•  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

•  DuetooverproducFonofaldosteroneinthezonaglomerulosa

•  PaFentspresentwithhypertensionando`enhavehypokalemia.

•  MayalsohavenonspecificfindingssuchasfaFgue,headaches,increasedthirst.

•  Maybduetoadrenaladenomaorhyperplasia

Diagnosis

•  MeasureserumaldosteroneandplasmareninacFvityinAM•  SuggesFveifaldosterone/PRAacFvityisgreaterthan30ANDtheabsolute

aldoteroneofgreaterthan15ng/dL.•  ConfirmwithSaltloadingtests(canuseeitheroralorIV.UsewithcauFonin

paFentswithseverehypertensionandCHF)–  Oralsaltloading,andadequatepotassiumreplacementfor3days.–  Thendo24hrurineforaldosterone.Normalvaluesare5‐20mcgin24hours–  CanalsodoIVsalineloading(2litersover4hours.CheckcorFsoland

aldosteronebeforeanda`ertheload.PostsalineraFoofaldosteronetocorFsolgreaterthan3seenwithaldosteroneproducingadenoma.

LocalizaFon

•  CTorMRIcanbeusedasiniFalstudy•  Canconfirmwithadrenalveinsampling.•  Rightandle`adrenalveinandvenacavacorFsolandaldosteronemeasured

•  CatheterplacementisaccurateiftheadrenalveintovenacavacorFsolraFois5:1.

•  Aldosteronelevelsfromle`andrightadrenalveinsarecomparedandgreaterthan4:1raFobetweenthetwosuggestunilateralaldosteoneproducingadenoma.

Treatment

•  Dependsondiagnosis•  Ifanadenomaisdetected,treatmentissurgery.

ShouldbepreppedpreoperaFvelywithspironolactoneBloodpressureandpotassiumarenormal.

•  Ifduetohyperplasia,treatedwithanFhypertensivesspecificallyaldosteroneantogonists(spironolactone,eplerenone)