4 182

Y Takahashi Mechanism of autoimmune 182:4 R59–R66 Review hypopituitarism

MECHANISMS IN ENDOCRINOLOGY Autoimmune hypopituitarism: novel mechanistic insights Correspondence should be addressed Yutaka Takahashi to Y Takahashi Division of Diabetes and Endocrinology, Kobe University, Graduate School of Medicine, Kobe, Japan Email [email protected]

Abstract

Hypopituitarism is caused by various insults to the pituitary, such as hypothalamic and pituitary tumors, inflammation, autoimmunity, vascular injury, genetic abnormalities, irradiation, and trauma. Recently, it has been found that autoimmunity to the pituitary involves many pathological conditions associated with specific or non-specific hormone deficiencies in the gland. This review discusses the recent findings on the underlying mechanism of autoimmune hypopituitarism particularly of lymphocytic hypophysitis, IgG4-related hypophysitis, immune checkpoint inhibitor- induced hypophysitis, anti-PIT-1 hypophysitis, and isolated ACTH deficiency.

European Journal of Endocrinology (2020) 182, R59–R66

Introduction

Hypopituitarism is defined as the deficiency of one or hypophysitis, and necrotizing hypophysitis on the basis

European Journal of Endocrinology more pituitary hormones. Although a pituitary tumor of histological features (2, 3). Lymphocytic hypophysitis is the most common cause, a tumor or cyst in the (autoimmune hypophysitis) is an autoimmune pituitary hypothalamus or infundibulum, infiltrative, vascular, disease and is caused by immune-mediated diffuse and other disorders, and pituitary or cranial radiation infiltration of lymphocytes and plasma cells. IgG4- therapy may also cause hypopituitarism (1). Recently, it related hypophysitis is a recently discovered subtype has emerged that autoimmunity to the pituitary involves of autoimmune hypophysitis associated with multi- many pathological conditions associated with specific or organ IgG4-related systemic disease (IgG4-RD). Pituitary non-specific hormone deficiencies. involvement of IgG4-RD had initially been considered Hypophysitis can occur as a primary entity or rare, but recent studies (4, 5) have suggested that its secondary to local or systemic disorders. Primary prevalence is underestimated. In these conditions, mostly hypophysitis is further classified as lymphocytic non-specific anterior pituitary hormone deficiencies and/ hypophysitis, granulomatous hypophysitis, xanthomatous or central diabetes mellitus are observed.

Invited Author’s profile Yutaka Takahashi, MD, PhD, is Associate Professor of Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan. His research activities focus on pituitary diseases. He has researched and reported on the association between adult GH deficiency and NASH, a novel clinical entity ‘anti-PIT-1 antibody syndrome’. More recently, he has reported the application of induced pluripotent stem cells on the pathophysiology of congenital pituitary hypoplasia.

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-19-1051 European Journal of Endocrinology https://eje.bioscientifica.com tissue. pituitary considered tobeproducedas aresultofdisruptionsinthe (HCS) ( factor Tpit,andhumanchorionic somatomammotrophin 166 (C14orf166),corticotroph-specific transcription secretogranin II, chromosome 14 open reading frame gland(PC1/3,PC2, CPE, and7B2), in thepituitary prohormone-processing enzymescommonlyproduced specific factors1aand2(PGSF1aPGSF2),regulatory autoantibodies against has beenstronglysuggestedbecauseofthepresence of in upto50%ofthepatients. The autoimmuneetiology autoimmune diseases,suchasthyroiditis, hypophysitis isfrequentlyassociatedwithother do notshowsexpredominance( infundibulo-neurohypophysitis andpanhypophysitis pregnancy or postpartum. ( adenohypophysitis developsin30–70%ofpatientsduring associated withpregnancy. Lymphocytic hypophysitis andlymphocyticadenohypophysitis of Lymphocytic hypophysitisisthemostcommonform (autoimmune hypophysitis) Lymphocytic hypophysitis hypopituitarism. findings ontheunderlyingmechanismofautoimmune induced hypophysitis ( hypophysitis andinACTHPD-1/PDL-1inhibitor- in ACTH,LH/FSH,andTSHCTLA-4inhibitor-induced induced hypophysitisshowsapredominantdeficiency in GH,PRL,andTSH( PIT-1 antibody syndrome) involves specific deficiency prevalent. Anti-PIT-1 hypophysitis (also called as anti- ( hormonehavebeendetected type ofanteriorpituitary been reported,wherespecificautoantibodiesagainsteach deficiencies includingACTH,LH/FSH,GH,andPRLhave hormone several conditionsofisolatedanteriorpituitary defectshavebeenreported.Forexample, anterior pituitary been detectedinICI-inducedhypophysitis. Interestingly, relativelyspecifichormonedeficiencyhas has emergedasanimmune-relatedadverseevent(IrAE). check pointinhibitor-induced(ICI-induced)hypophysitis of immunotherapy for manykindsofcancers,immune hypophysitis havebeenreported,withtheinduction of drugs.Althoughvariousformsdrug-induced 6 ), althoughisolatedACTHdeficiencyisfoundtobe Review In other autoimmune pituitary diseases,specific In otherautoimmunepituitary Hypophysitis isalsoassociatedwithseveralkinds 10 ). However, mostoftheseantibodies are 2 7 α , ). Asmentionedpreviously, ICI- -enolase, GH, pituitary gland- -enolase, GH,pituitary 3 ). This review discusses recent 8 ). Incontrast, lymphocytic Y Takahashi 9 ). Lymphocytic

diabetes. Proliferation of T cells in the pituitary wasalso diabetes. ProliferationofTcellsinthepituitary disease suchasthyroiditis,multiplesclerosis,andtype-1 are involvedinthepathogenesisofotherautoimmune infiltrating cellsexpressed IFN- gland( T andBcellswithinthepituitary demonstrated continuousgenerationofautoreactive cause infundibulo-neurohypophysitis. breakdown ofimmunetolerancetorabphilin-3Amight the neurohypophysis( mononuclear cells and that of CD3 cells that reacted with rabphilin-3A in peripheral blood there wasalinearassociationbetweenthenumberofT with rabphilin-3Aproteinledtoneurohypophysitis,and nucleus inthehypothalamus.Immunizationofmice the neurohypophysisandAVP neuronsinthesupraoptic neurohypophysitis ( found tobeabiomarkerforlymphocyticinfundibulo- subtype of hypophysitis that forms part of an emerging pseudotumors. and inflammatory aortic aneurysm, lymphadenopathy, retroperitoneal fibrosis, inflammatory interstitial pneumonitis, nephritis,prostatitis, autoimmune pancreatitis,hypophysitis,Riedelthyroiditis, of awidevarietyorgans,includingMikulicz’s disease, cells withfibrosis( organs withabundantinfiltrationofIgG4-positiveplasma and mass-formingornodular/thickenedlesionsofvarious metachronously, show diffuse or focal organ enlargement Patients with IgG4-RD, either synchronously or IgG4-related hypophysitis development oflymphocytichypophysitis. suggest thatactivatedTcellsplayanimportantroleinthe autoimmune hypophysitis.Collectively, thesedata antigen presentationtoTcellsinthepathogenesisof ( than thatofapatientwithanothertypesellarmass expressing theHLA-DQ8markerwas23-foldhigher odds ratioofapatientwithautoimmunehypophysitis strongly associatedwithautoimmunehypophysitis.The reported thattheHLAmarkers,DQ8andDR53,were activated phenotype(granzymeB with hypophysitisshowedabundantCD8 ( reported inpatientswithautoimmunehypophysitis hypopituitarism Mechanism ofautoimmune 15 13 ). Theseassociationssuggesttheimportanceof ). It has also been reported that pregnant patients Other animalmodelsofautoimmunehypophysitis Recently, anti-rabphilinantibodieshavebeen IgG4-related hypophysitis is anewlydiscovered In termsofgeneticpathophysiology, ithasbeen 16 ). IgG4-RD plays a role in the disorders ). IgG4-RDplaysaroleinthedisorders 11 ). Rabphilin-3Aisexpressedin 12 Downloaded fromBioscientifica.com at10/01/202112:02:12AM ). Thesedatasuggestthatthe γ and IL-17, both of which + ) in the pituitary ( ) inthepituitary 182 + T cells infiltrating :4 + Tcellswith 13 ). These R60 14 ). via freeaccess European Journal of Endocrinology inhibitory FC inhibitory only FCGRfamilymember expressed inBcellsandisan ( IgE levelsarefrequentlyobserved rhinitis, andatopicdermatitis, andelevatedlevelsofserum ofatopicdiseaseincludingasthma,allergic have ahistory such as asthma.Indeed,one-third of IgG4-RD patients in theonsetlikeotherautoiimmuneorallergicdiseases, have highlightedthefundamentalroleofHLAlocus The geneticassociationsbetween FCGR2B involving Japanese individuals revealed IgG4-RD ( 3 ( and potassium voltage-gated channel subfamily A member ( pancreatitis. Involvementof has beenreportedtobeassociatedwithautoimmune MHC classIIallelesHLA-DRB1*04:05andDQB1*04:01 genetic factorsinIgG4-RD.Ahaplotypeconsistingof involved intissue-specificinjury. questioned ( that autoantibodiesplayamajorroleinIgG4-RDhasbeen been detectedinpatientswithIgG4-RD.Thus,theidea a pathogenicrole,IgG4-typeautoantibodieshavenot 511 E8;althoughsomeoftheseautoantibodiesmayplay against prohibitin,galectin-3,annexinA11,andlaminin detected inpatientswithIgG4-RD,includingthose disease. Forexample,variousautoantibodieshavebeen accumulating evidenceonIgG4-RDindicatesautoimmune for IgG4-relatedhypophysitishaverarelybeenreported, solely exhibitedhypophysitis( swelling (18%).Asmallproportionofpatients(14%) autoimmune pancreatitis(AIP;24%),andlymphnode by interstitialpneumonia(28%),Mikulicz’s diseaseand fibrosis beingthemostcommonform(38%),followed course ofIgG4-relatedhypophysitis,withretroperitoneal of various organs was noted throughout the clinical pancreatitis) may beunderestimated( of IgG4-relatedhypophysitisinIgG4-RD(autoimmune a rarecondition,ithasbeenreportedthattheprevalence response tosteroidtherapy( either theanteriororposteriorpituitary, andshowsgood levels. Itgenerallyoccursinelderlymen,involving with a‘storiform’pattern,andincreasedserumIgG4 withlymphocytes,fibrosis infiltration ofthepituitary stalk,diffuse gland,thickeningofthepituitary pituitary dense infiltrationofIgG4-positiveplasmacellsintothe group ofIgG4-RDscharacterizedbyacombination FCRL3 Review KCNA3 Several studies have suggested the involvement of Several studieshavesuggestedtheinvolvementof Regarding the pathogenesis, although data specific ), cytotoxicT-lymphocyte-associated 4 ( regionsasthesusceptibilitylociforIgG4-RD( ) locus has also been suggested to play a role in ) locushasalsobeensuggestedtoplayarolein 20 ). Recently, agenome-wideassociationstudy 19 γ receptor. Itplays animportantroleinthe ), butsomeoftheautoantibodiesmaybe 4 , 18 17 HLA Y Takahashi ). HLA-DRB1 ). Althoughconsidered , Fc receptor-like 3 , Fcreceptor-like3 18 22 ). Theinvolvement ). FC HLA-DRB1 and IgG4-RD andIgG4-RD γ R2B is the R2B isthe CTLA4 and and 21 ). ). ), of inhibitory cytokinessuchasIL-10andTGF- of inhibitory (e.g. increasednumberofTreg cellsandaugmentation inpatientswithotherautoimmunediseases observed with IgG4-RD often have phenotypes opposite to those cells ( follicular helper (Tfh) cells ( ( stimulating cytokineTGF- cytokineIL-10,andfibroblast- and IL-13),regulatory and theproductionofTh2-typecytokines(IL-4,IL-5, demonstrated thatTh2-dominantimmuneresponses related pancreatitisandcholangitis( cells playsanimportantroleinthedevelopmentofIgG4- T(Treg)number ofThelper2(Th2)cellsandregulatory reported inpatientswithIgG4-RD.Theincreasethe that theSNPisinvolvedinpathogenesis( regions hadanimpactonFC elimination ofautoreactiveBcells.TheSNPinthe T-lymphocyte antigen-4(CTLA-4),anti-programmedcell Immune checkpointinhibitors (ICIs),suchasanti-cytotoxic ICI-induced hypophysitis important inthepathogenesisofIgG4-RD( isotype switchingofimmunoglobinstoIgG4/IgEmaybe investigation isrequired,themechanismunderlying reported in patients with IgG4-RD ( galectin-3 producedbyplasmablastscloneshavebeen Recently, bothIgG4- and IgE-iso-type antibodies against allergy ( hyperproduction ofIgG4isfrequentlyassociatedwith of thepathogenesisIgG4-RD,namelythat ( through anIgG4-specificclass-switchrecombination factors maybeinvolvedinthepathogenesisofIgG4-RD class-switch recombinations,overexpressionofthese as wellTh2cytokinescaninduceIgG4-andIgE-specific syndrome andinthecontrols( in patientswithIgG4-RDthanSjogren’s activation-induced cytidinedeaminase(AID)washigher cells, ithasbeenreportedthattheexpressionofIL-10and of IgG4andtissueinfiltrationIgG4-positiveplasma IL-33 productionhasbeensuggested( fibrosis, theinvolvementofelevatedIFN-I-dependent allergic phenotypes( response,sinceIgG4isknowntoinhibit is asecondary suggesting thattheincreaseinserumIgG4concentrations hypopituitarism Mechanism ofautoimmune 24 31 , ). These observations suggestanimportantaspect ). Theseobservations Various immunological abnormalities have been With respecttotheincreasedserumconcentration 25 27 ). FunctionalabnormalitiesinCD4 32 ) havealsobeenreported.Interestingly, patients ), suggesting a characteristic of allergic disease. 28 Downloaded fromBioscientifica.com at10/01/202112:02:12AM ). Regardinginflammationand β areincreasedinIgG4-RD γ 26 R2B expression, suggesting R2B expression,suggesting https://eje.bioscientifica.com ), and CD4 30 ). SinceAIDandIL-10 33 182 23 29 ). Although further :4 ). Severalreports ). 19 + cytotoxic T 21 + Tcells, ). ). FCGR2B β ) ( R61 23 via freeaccess ),

European Journal of Endocrinology https://eje.bioscientifica.com as T-cell activity against antigens present in tumors and unclarified; however, severalpotential mechanismssuch CTLA-4 andPD-1/PDL-1inhibitors. suggest thedifferenceinunderlyingmechanisms of use ofPD-1/PDL-1inhibitors( israre withthe and obviousenlargementofthepituitary permanent andexclusiveACTHdeficiencyisobserved with CTLA-4 inhibitor-induced hypophysitis. In contrast, inpatients contrast administration is typically observed either homogenousorheterogenousenhancementafter gland,with moderate diffuseenlargementofthepituitary thyroid andgonadalaxishasbeenreported.Mid-to- of ACTH deficiencyispermanent,andtherecovery deficiency withtheuseofCTLA-4inhibitors.Generally, hormoneabnormalitiesfollowedbyLHandFSH pituitary ( those oncombinationtreatment(30daysaverage) up to1yearwithPDL-1inhibitors( with CTLA-4inhibitors,3–6monthsPD-1 hormone. The median time to occurrence is 2–4 months the onsetofhypophysitisandprofileimpaired hypophysitis ( with hypophysitistreatedipilimumab-induced werenotedinpatients For example,theseobservations and the incidence and severity of irAE. patient survival Interestingly, acorrelationseemstoexistbetweenoverall combination ofCTLA4andPD1inhibitorswasused( ( predominant andhypophysitisisrelativelyrare(0.1–0.4%) 39 in8–13%of the patients( is predominantlyobserved 3 ICI-induced hypophysitishaverecentlybeenreviewed( topics, the underlying mechanisms and management for with combinationtherapy).Becauseoftheemerging depending oneachICIthatwasused(asinisolationor ( parathyroid ( organs, includingthethyroid,pituitary, adrenal,pancreas, In termsofendocrinopathies,theinvolvementvarious gastrointestinal tract,endocrineglands,skin,andliver( organ systemcanbeaffected,irAEcommonlyinvolvesthe toxicity profile,oftentermedasanirAE( system, treatmentwithICIs is associatedwitha specific cancers ( (PDL-1), havebecomethemainstayoftreatmentforvarious death 1(PD-1),andanti-programmedligand 40 39 40 , Review ). In contrast, with PD-1/PDL-1 inhibitors, thyroiditis is ). Incontrast,withPD-1/PDL-1inhibitors,thyroiditisis 40 ). Importantly, theprofileofendocrineirAEisdifferent ). The incidence of hypophysitis was 8.5–9.0% when a ). The incidence of hypophysitis was 8.5–9.0% when a ). ACTH and/or TSH deficiency are the most common The otherimportantissueisthedifferencein The mechanisms that lead to irAE are still largely ). With theuseofCTLA-4inhibitors,hypophysitis 34 ). By increasing the activity of the immune ). Byincreasingtheactivityofimmune 37 42 ), andadiposetissue( ) andinpatientswiththyroiditis( 40 Y Takahashi ). Thesedatastrongly 38 44 ), has been reported ), hasbeenreported 35 ), andearlierfor ). Although any ). Althoughany 43 ). 36 41 2 2 ). ). ). ). , , subclass ofipilimumabisIgG1andthattremelimumab Importantly, withtheuseofCTLA-4 inhibitors, the levels, whichmayexplaintheriskofhypophysitis( adenomas,withdifferentexpression and pituitary CTLA-4 isalsoexpressedinnormalhumanpituitary biomarker forICI-inducedhypophysitis ( autoantibody hasthepotential toactasanon-treatment for ICI-inducedhypophysitis, whereastheanti-ITM2B act as both apredictive and an on-treatment biomarker that the anti-GNAL autoantibody has the potential to of theseantibodiesisstillunclarified,ithasbeensuggested hypophysitis ( membrane protein 2B (ITM2B)antibody in ICI-induced activity polypeptide (GNAL) antibody and anti-integral typeG-protein alpha-activating identified anti-olfactory using cDNAexpressionlibrariesoftheplasmasamples with ipilimumab-induced hypophysitis ( ACTH-producing cellshavebeendetectedinpatients hypophysitis. AutoantibodiesagainstTSH-,FSH-, or cells havebeenreportedinpatientswithICI-induced inhibitors ( with theuseofCTLA4inhibitorsthanPD-1/PDL-1 may alsoexplainthehigherprevalenceofhypophysitis for PD-1/PDL-1 inhibitors. These different mechanisms therefore, differentmechanismshavebeensuggested that cannotactivatetheclassicalcomplementpathway; PD-1 andPDL-1inhibitorsfallundertheIgG4subclass In contrast,PD-1isnotexpressedinthepituitary, and similar featuresastypeIIhypersensitivityreactions( cells and expression of CTLA-4 in the anterior pituitary CTLA-4 inhibitor-inducedhypophysitisrevealedastrong cytotoxicity ( pathway andleadtoantibody-dependentcell-mediated is IgG2,whichcanactivatetheclassicalcomplement binding ofanti-CTLA-4antibodiestothecells( occurredafterthe complement-dependent cellinjury inananimalmodel,where hypophysitis wasobserved II hypersensitivityinCTLA-4inhibitor-induced cells,andasimilarfeatureoftype anterior pituitary have beenproposed( expressed onnormaltissue(directactionoftheantibody) direct bindingoftheantibodywithCTLA4 enhanced complement-mediated inflammation dueto cytokines (activationofimmuneresponse),and autoimmunity), increasing levels ofinflammatory preexisting autoantibodies(enhancementof increasinglevelsof healthy tissue(molecularmimicry), hypopituitarism Mechanism ofautoimmune Several autoantibodies against anterior pituitary Several autoantibodiesagainstanteriorpituitary Interestingly, CTLA4isexpressedinthe 39 ). 40 48 ). An autopsy study of a patient with ). Althoughthepathophysiologicalrole 35 ). Downloaded fromBioscientifica.com at10/01/202112:02:12AM 182 :4 45 48 ). A screening ). R62 47 46 45 via freeaccess ). ). ). European Journal of Endocrinology of corticotrophs; however, this antibody is not specific to Tpit is anessentialtranscriptionfactorforthedevelopment lymphocytic hypophysitis has beenspeculatedbecause involvement of anti-Tpit antibody in the development of in somepatients.Amongtheseautoantibodies,thecausal Indeed, anti-corticotrophantibodieshavebeendetected has stronglybeensuggestedasthepathogenesis( polyglandular syndrome,autoimmunitytocorticotrophs are relatedtoautoimmunediseasesincluding hypophysitis andthatsomecasesofisolatedACTHdeficiency are oftenthefirstcelltypetobeaffectedinlymphocytic diagnostic criteriahavebeenproposed( and isaformofparaneoplasticsyndrome.Recently, the associated autoimmunediseaselikemyastheniagravis indicated that anti-PIT-1 hypophysitis is athymoma- to playacausalrole( producing cells,autoimmunitytoPIT-1 isconsidered differentiation andmaintenanceofGH-,PRL-,TSH- Because PIT-1 isanessentialtranscriptionfactorinthe (CTLs) playapivotalroleindiseasedevelopment( is adiseasemarker, andPIT-1-reactive cytotoxicTcells the PIT-1 protein( with athymomaorneoplasmthatectopicallyexpresses and TSHdeficiencies( disease characterizedbyacquiredandspecificGH,PRL, autoimmune syndrome) isanewlydescribedpituitary antibodies havenotbeenclarified. the pathologicalsignificanceandcausalroleofthese deficiency, bothinadultsandchildren( has beenreportedinsomecasesofidiopathicGH Furthermore, thepresenceofanti-somatotrophantibodies somatotrophs, andgonadotrophs,respectively( these antibodiesweretargetedagainstcorticotrophs, and hypogonadotropichypogonadism,respectively, and 21% ofthepatientswithACTHdeficiency, GHdeficiency, antibodies werepresentathightitersin15%,20%,and hypogonadotropic hypogonadism( cells havebeendetectedinpatientswithidiopathic antibodiesagainstgonadotropin-secreting anti-pituitary mechanisms hasstronglybeensuggested.Forexample, are rare.Intheseconditions,theroleofautoimmune hormonedeficiencieswithoutgeneticdefects pituitary Except foranisolatedACTHdeficiency, isolatedanterior with pituitaryautoimmunity Specific hormonedeficienciesassociated Review In isolatedACTHdeficiency, giventhatcorticotrophs Anti-PIT-1 hypophysitis(anti-PIT-1 antibody 54 ). Circulating anti-PIT-1 antibody 7 54 , 53 ). Accumulatingevidencehas ). Thisdisorderisassociated Y Takahashi 49 54 51 ). Anti-pituitary ). Anti-pituitary ). , 52 ). However, 50 55 56 ). ). ). ). deficiency remainunknown. may be related, the underlying mechanisms in ACTH immunodeficiency (CVID);althoughautoimmunity impaired Bcellfunctionleadingtocommonvariable mechanism, the mutation in mutations affectingtheC-terminalpartof Whole exomeanalysisrevealedgermlineheterozygous early-onset ACTH deficiency, whichisarare condition. infections. Inthissyndrome,patientsmanifestisolated preceded byhypogammaglobulinemiaandrecurrent kindreds presentingwithsymptomaticACTHdeficiency described in2012( immune deficiency)syndromeisararedisorderfirst anti-Tpit antibody( to elucidate the significance of investigation is necessary in otherautoimmuneendocrinediseases( lymphocytic hypophysitis,asithasalsobeendetected autoimmune diseases( of paraneoplasticsyndrome asthecauseofpituitary been proposed,theseresults suggesttheimportance autoimmunity have underlying mechanismsofpituitary hormone deficiencies. Although various anterior pituitary deficiency ascomparedtoconditionswithotherisolated behind therelativelyhighprevalenceofisolatedACTH expression isnotrareintumorsmayexplainthereason that especially silent ectopic POMC these observations corticotrophs, butnothormoneexcess.Furthermore, an immunereactiontoPOMC-expressingcellsincluding or bioinactiveectopicexpressionofPOMCmaycause that silentectopicACTHexpressionisnotrare.Limited tumors withoutectopicACTHsyndrome( with non-small-celllungcancer( POMC manifests as Cushing’s syndrome. Interestingly, silent ectopic ACTHsyndromewithexcessivethat ectopic ACTHexpressioninatumorisassociatedwith least in part with paraneoplastic syndrome ( suggested thatisolatedACTHdeficiencyisassociatedat in anothercaseofectopicACTHsyndrome,ithasbeen CTL infiltrationaroundcorticotrophswasalsoobserved POMC-reactive CTLswerealsodetected.Giventhat in thelungandcirculating anti-POMCantibodies; with ectopicallyexpressedproopiomelanocortin(POMC) the patientshadlarge-cellneuroendocrinecarcinoma paraneoplastic syndromewasreported( in severalunrelatedpatients( hypopituitarism Mechanism ofautoimmune DAVID withvariable (deficientanteriorpituitary Recently, acaseofisolatedACTHdeficiencyasform expression was observed in48%ofthepatients expressionwasobserved 6 58 ). ). Thepatientsfromthreedistinct 54 Downloaded fromBioscientifica.com at10/01/202112:02:12AM ). https://eje.bioscientifica.com 59 NFKB2 61 ). Astheunderlying ) andwithcarcinoid 182 60 :4 resulted in an ). Interestingly, 62 54 ), suggesting 57 ). Generally, ). Further ). Further NFKB2 R63 via freeaccess

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