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M S Petrov and M Basina of the exocrine 184:4 R151–R163 Review

DIAGNOSIS OF ENDOCRINE Diagnosing and classifying diabetes in of the exocrine pancreas

Correspondence Maxim S Petrov1 and Marina Basina2 should be addressed 1School of Medicine, University of Auckland, Auckland, New Zealand and 2Division of Endocrinology, Stanford to M S Petrov University, Stanford, USA Email [email protected]

Abstract

Diabetes in the setting of diseases of the exocrine pancreas has long existed as a known, but underdiagnosed or misdiagnosed, disorder. It currently finds itself in a state of taxonomic dereliction and requires a long overdue refurbishment. Correct conceptualisation is a key precondition for knowledge development in this disorder. This article lays out the epistemological foundation for diabetes of the exocrine pancreas (DEP) and presents a synthesis of the current interdisciplinary discourse on diagnosing and classifying DEP. A diagnosis of DEP in people with no medical records of pre-existing diabetes is generally based on the most up-to-date biochemical criteria endorsed by the American Diabetes Association and European Association for the Study of Diabetes. The presence of exocrine pancreatic dysfunction is not considered a mandatory diagnostic criterion for DEP but is rather a significant for developing DEP. DEP principally comprises post-pancreatitis diabetes mellitus, pancreatic cancer-related diabetes, and cystic fibrosis-related diabetes, which are mutually exclusive with autoimmune diabetes and . Other exclusions and stipulations apply. The DEP criteria will be instrumental in aiding optimal design and conduct of clinical studies, uniform collection of health utilisation data, meaningful comparison of scientific findings across countries, and clear communication among stakeholders (healthcare providers, patients, medical regulatory authorities, pharmaceutical industry). European Journal of Endocrinology

European Journal of Endocrinology (2021) 184, R151–R163

Introduction

The pancreas is composed of functionally diverse is different from type 2 diabetes in many regards. It is exocrine and endocrine compartments that uniquely associated with significantly worse short-term outcomes originate from a common progenitor. One facet of the such as control and glycaemic variability in predetermined interplay between the exocrine and the first few years after the diagnosis of diabetes (1, 4). It endocrine pancreas is the development of diabetes in is associated with significantly worse long-term outcomes diseases of the exocrine pancreas. Although dwarfed by such as from any cause in general and cancer type 2 diabetes, this type of diabetes is the second most mortality in particular (5, 6). It has a unique response common type of new-onset diabetes in adults (surpassing to common anti-diabetic (7, 8). Last, data ) (1). Its prevalence has nearly tripled in on distinct pathophysiological signatures in this type of the past decade and its incidence is projected to have a diabetes have emerged (9, 10, 11, 12). 2.8% annual growth and reach 15.8 per 100 000 general Although a wealth of knowledge on diabetes in population in 2050 (2, 3). Further, it is a valid taxon in its diseases of the exocrine pancreas has been accumulated, own right as diabetes in diseases of the exocrine pancreas classification of this type of diabetes has not kept pace.

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-20-0974 European Journal of Endocrinology https://eje.bioscientifica.com after theremovalofpancreas ( diabetes’ todenotethedevelopment ofdiabetesinanimals pancreas. In 1892, Harley coined the term ‘pancreatic initial termsstemmedfrom surgicalexplorationsofthe evolution, itsmeaninghas also changedovertime.The has undergonealongevolutionand,inparallelwiththe The notionofdiabetesindiseasestheexocrinepancreas Semantic evolution frameworks. in thetrialsofdiseaseswithoutdistinctnamesand pharmaceutical companiesarehesitanttobeinvolved from well-designedrandomisedcontrolledtrialswhereas optimal treatmentsforthesepeoplewithoutevidence major professionalbodiesinthefieldcannotrecommend diseases oftheexocrinepancreasinacatch-22situation: absence ofastandardisednomenclatureputsdiabetesin radiologists, andotherhealthcareprofessionals.Also,the care physicians, nurses, dieticians, oncologists, primary endocrinologists, gastroenterologists,surgeons, of thistypediabetesandresearch intoit,involving natureofmanagement of thehighlyinterdisciplinary for diabetesindiseasesoftheexocrinepancreasbecause regions, andtimeperiods).Thisisespeciallyimportant (to compare them impartially across studies, geographic promote standardisation for reporting research findings facilitate communicationbetweenkeystakeholdersand patient groupsinahierarchical fashionisessentialto classification systemthat defines fairly homogenous 20 that cannotbeencapsulatedbyasinglefeature( typically haveacomplexaetiologyandpathogenesis nosologically derelict.Diseasesoftheexocrinepancreas made diabetesindiseasesoftheexocrinepancreas in diseasesoftheexocrinepancreas( formally assessedthebodyofevidenceondiabetes of gastroenterology(UnitedEuropeanGastroenterology) first guidelinesbyamajorprofessionalbodyinthefield exocrine pancreas.Also,itwasnotuntil2017thatthe to theframeworkforclassifyingdiabetesindiseasesof Organization ( of the first classification of diabetes by the World Health sincethepublication that, inmorethanhalfacentury changed sincethe1990s( section ‘otherspecifictypesofdiabetes’thathashardly bodies merely include a 100-odd words text under the classification ofdiabetesissuedbymajorprofessional The 2019clinicalpracticeguidelinesondiagnosisand Review ), andsoisthediabetesthatfollowsthem.Amodern 17 ), there has been no progressin regards 13 , 14 , M SPetrovandBasina 15 21 , ). Itwasfollowedby 16 ). Itwouldappear 18 ). Thesehave 19 , secondary todiseasesoftheexocrinepancreasbutalso secondary it isnowrecognisedthatpeoplewithnotonlydiabetes term ‘pancreoprivicdiabetes’isnotspecificenoughas Given thattheLatinverb is ‘pancreatic’or ‘pancreatogenic’, atleast to someextent. pancreas. Thismeansthatvirtuallyanytypeofdiabetes involve dysfunctionoftheisletsLangerhansin exceptions, thedevelopmentandprogressionofdiabetes rare as nowadays it is well established that, with very into aseparatecategory, theseareratheranachronisms toaninsultthepancreas they putdiabetessecondary ( started tobecomewidelyusedbysurgeonsatthetime) of diabetesfollowingpancreaticoduodenectomy(which ‘pancreatogenic steatorrhea’)–todenotethedevelopment diabetes’ in the 1960s (as an adoption of the earlier term of theentirepancreas,andterm‘pancreatogenic the developmentofdiabetesfollowingacompleteremoval the term ‘pancreoprivic diabetes’ in the 1950s – to denote professional bodyinthefield ofdiabetologyorneurology, of diabetesthebrainnever gotrecognisedbyany selectively involvesthebrain ( distinct typeofdiabetes(dubbed ‘type3diabetes’)that formed abeliefthatAlzheimer’s diseaserepresents a new perturbations ininsulinsignallingmechanismsand some -specific of US neuroscientists who observed was coinedandpromulgatedin2006–2008byagroup 3c diabetes’( 1989) haveeverencouragedtheuseofterm‘type Association noritsearlierversions(annualupdatessince classification ofdiabetesby theAmericanDiabetes -related diabetes.Similarly, neither the2019 such asmonogenicdiabetes,drug-induced or always beensemanticallyindistinguishablefromentities under ‘otherspecifictypesofdiabetes’and,hence,has in diseasesoftheexocrinepancreashasinvariablybeen in diseases of theexocrine pancreas ( versions haseverdesignatedadistincttermfordiabetes diabetes bytheWorld HealthOrganizationnoritsearlier sobering truth isthat neither the 2019 classification of the topicaswellcountlesswebpages.However, the has beenperpetuatedbyseveralpublishedreviewson Organization and by the American Diabetes Association refrain that this term is endorsed by the World Health the use of the misnomer ‘type 3c diabetes’. The oft-cited notion ofdiabetesindiseasestheexocrinepancreaswas between theabovetermsiscounter-productive. exocrine pancreatic function ( type 1diabetesand2mayhave‘deprived’ pancreas Diabetes oftheexocrine 22 , The nextstageinthesemanticevolutionof 23 ). Althoughthesetermswereinitiallyusefulas 15 , 16 ). Actually, theterm‘type3diabetes’ Downloaded fromBioscientifica.com at10/01/202101:06:57AM privo 24 26 means‘todeprive’,the , , 25 27 ). Overall,vacillating 184 ). Whilethenotion 13 :4 , 14 ). Diabetes R152 via freeaccess European Journal of Endocrinology diabetes mellitus)infuture revisions ofclassifications a distinctniche(asis,forexample, thecaseforgestational 12 pancreatic cancer, andcysticfibrosisare notthesame( in mild acute pancreatitis, end-stage chronic pancreatitis, acknowledge thatthemechanismsunderliediabetes diabetes as one meaningful andsemanticallyaccuratetocallthistype of 37 pathogenesis oftype1diabetesor2 ( pancreatic cancer, andcysticfibrosis,butnotinthe to pancreatitis, the pathogenesisofdiabetessecondary externally totheisletsofLangerhans)playsakeyrole in that excessiveintra-pancreaticfatdeposition(located then ( in 2017( pancreas’, memorably anddistinctly acronymised toDEP, notion wastheintroductionof‘diabetesexocrine diabetes –undertheletter‘F’). was presentedundertheletter‘E’andinfection-related the letter‘C’(whereas,forexample,drug-induceddiabetes of theexocrinepancreashappenedtobepresentedunder Roman numeralIV).Further, undersectionIII,diseases for example,gestationaldiabeteswaspresentedunderthe to bepresentedundertheRomannumeralIII(whereas, of diabetes.‘Otherspecifictypesdiabetes’happened meant tobeinterpretedasdesignationsofdistincttypes The tableusedtheRomannumeralsI-IV, whichwerenot of theexocrinepancreasin2014document)( re-published with minor updates not related to diseases published inthe1998document(andsubsequently outlining theaetiologicalclassificationofdiabetes reference to‘type3c’orexocrinedysfunction( Association between1999and2008)didnotcontainany that matter, anyguidelinebytheAmericanDiabetes ( diseases with exocrine dysfunction as a cause for diabetes’ label (i.e.‘3c’–notetheArabicnumeral)to‘pancreatic classification ofdiabetesmellitus( 1998 reportoftheexpertcommitteeondiagnosisand Diabetes Associationadecadeearlier(specifically, the believed thatadocumentpublishedbytheAmerican sponsored conferences/workshops( (non-peer-reviewed) proceedings of two small industry- the groupintroducedterm‘type3cdiabetes’in recently marketed)intype1and2diabetes.In2008, interested intheuseoffaecalelastase-1test(thenonly it didattracttheattentionofagroupGermaninternists 28 Review , , ). However, thetextof1998document(or, for 19 The lateststageinthesemanticevolutionof the The confusionmighthavearisenfromanewtable 38 ). For these disorders to stand a chance of occupying 1 , , 39 32 31 , , ). Thetermhasbeenincreasinglyusedsince 40 33 of , , the exocrine pancreas. It is important to 41 34 ). Hence, it is pathophysiologically , 35 ). Accumulatingevidenceshows M SPetrovandBasina 16 28 )) hadassignedanew , 29 ). Theauthors 16 ). 16 , 30 10 36 ). , , with pancreaticcancer–adisorderinwhichitisoften ( widely used,andshouldremainapartoftheterminology related diabetes’(CFRD)issemanticallyaccurate,already ofacute pancreatitis. The term‘cystic fibrosis- a history (and should)bereadilydone,especiallyinpeoplewith not semanticallyruleoutprevalentdiabetes,whichcan related diabetes’ and such like because the latter does This termisconsideredsuperiortothe‘pancreatitis- be termed‘post-pancreatitisdiabetesmellitus’(PPDM). diabetes mellitusinthepost-pancreatitissettingisbestto to transplantation ( secondary both endocrinologistsandsurgeonstodescribediabetes diabetes mellitus’ is deeply ingrained in the lexicon of diabetes. Inparticular, theterm‘post-transplantation those bodiesforotherentitiesrepresentingsecondary aligned withtheterminologyalreadyendorsedby used bythestakeholdersinfieldshouldbelinguistically diabetes mellitusbymajorprofessionalbodies,thelexicon such astotalpancreasvolume (thatcanpotentiallybe have suggested that relatively simple measurements chronic pancreatitis.Recent high-qualityMRIstudies between termssuchas‘possible’, ‘probable’,and‘early’ to characteriseanintermediate statehavealternated states isclinicallychallenge( identifying individuals who transition between the two manner,are typicallydiagnosed in astraightforward acute pancreatitisandend-stagechronic a diseasecontinuum( studies haveestablishedthatpancreatitisoftenrepresents the early1990sandmorerecentmeta-analysisofclinical A seriesofcarefulhistopathologicalstudiesconducted in acronymised to PPDM-A and PPDM-C, correspondingly. chronic pancreatitisdiabetesmellitusarerecognised – post-acute pancreatitis diabetes mellitus and post- pancreatitis (acute pancreatitis and chronic pancreatitis), CFRD ( The core entities that makeup DEP are PPDM, PCRD, and Core entities distinguishing DEPfromothertypesofdiabetes. entities thatareunderthescope,thereforeunequivocally denotes aclearlydefined,uniform,andsuccinctsetof times, baseless)termsusedinthepast,DEPisatermthat replaces theoldones.Unlikeamorphous(and,at importantly, DEPisnotmerelyanewumbrellatermthat termed ‘pancreatic cancer-related diabetes’ (PCRD). Most uneasy toruleoutprevalentdiabetes–isbestbe pancreas Diabetes oftheexocrine 15 ). Forthepurposeofconsistency, diabetesassociated Table 1 ). Given that there are two main types of 42 Downloaded fromBioscientifica.com at10/01/202101:06:57AM , 43 15 ). Whilethefirstattackof 44 https://eje.bioscientifica.com ). Hence, newly diagnosed ). Historically, attempts 184 :4 R153 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com disorders accumulates, they should be labelled as PPDM-C on the burden and distinct features of these rather rare pancreatitis ( or fibrocalculouspancreatic diabetes),andautoimmune pancreatitis (alsoknownasfibrocalculous pancreatopathy pancreatitis,tropical of diabetesassociated with hereditary of chronicpancreatitis.Therearereportsintheliterature autoimmune pancreatitis are typically considered subtypes pancreatitis,tropicalcalcific and hereditary of acutenecrotisingpancreatitis( as PPDM-Athesyndromeistypicallyacomplication disconnected pancreaticductsyndromeshouldbelabelled as PPDM-A.Peoplewhodevelopdiabetesasequela of to theabovemorphologicalchanges,shouldbelabelled following anattackofpancreatitis,whichdidnotlead implication forPPDMisthatindividualswithdiabetes or from a surgically resected specimen ( samples undertakenbyendoscopicultrasonography or histologicalproofofchronicpancreatitisfrombiopsy cholangiopancreatography (Cambridgegrade3or4)and/ and/or themainpancreaticductonmagneticresonance evidence ofstricturesanddilatationsinsidebranches pancreatic calcificationsonCTorMRIand/orradiological changes inthepancreas:intraductaland/orparenchymal be diagnosedonlyinthepresenceoffollowing are determinedandvalidated,chronicpancreatitisshould However, until age- and sex-specific thresholds for them thepurpose( be leveraged)couldserve automated andthepowerofartificialintelligencecan New-onset diabetesinpre-symptomaticpancreaticductal Antecedent diabetesmellitusinpancreatitis(ADMP) Special entities Diabetes secondarytohereditaryhemochromatosis Diabetes secondarytopancreaticagenesis/hypoplasia Diabetes afterbluntpancreatic(abdominal)trauma Diabetes afterpancreaticsurgery Drug-induced diabetes Maturity-onset diabetesoftheyoung Diabetes withfirstrecognitionduringpregnancyafteran Autoimmune diabeteswithfirstrecognitionafteranattack hyperglycaemia General exclusions Cystic fibrosis-relateddiabetes(CFRD) Pancreatic cancer-relateddiabetes(PCRD) Post-chronic pancreatitisdiabetesmellitus(PPDM-C) Post-acute pancreatitisdiabetesmellitus(PPDM-A) Post-pancreatitis diabetesmellitus(PPDM) General inclusions Table 1 Review adenocarcinoma (NOD-PDAC) attack ofpancreatitis of pancreatitis Classification ofdiabetestheexocrinepancreas. 52 , 53 , 54 , 55 , 56 , 57 M SPetrovandBasina ). Untilfurtherevidence 50 , 51 ). Entitiessuchas 45 , 18 46 , , 49 47 ). The , 48 ). setting, glycatedhaemoglobinand/orfastingplasma inpatient setting)shouldbeacceptable.Inaclinical (but notintheemergencydepartment,urgentcare,or plasma glucosemeasuredinoutpatientsettingonly intravenous infusionofdextrose).Specifically, fasting management ofpancreatitis(e.g.parenteralnutrition, acute stressresponseandmayalsobeaconsequenceof after hospitalisation)asitselevatedlevelsmayreflectthe course ofpancreatitis(and,arbitrarily, within90days be usedforthepurposeofdiagnosingPPDMduring glucose (orrandomforthatmatter)shouldnot for diagnosingDEP( Diabetes Associationguidelinesshouldgenerallybeused diagnostic criteriafordiabetesoutlinedintheAmerican for thepurposeoftreatingdiabetes),biochemical known diagnosisand/oruseofantidiabeticmedications below andpresentedin (unless theexclusioncriteriaorstipulationsdescribed misclassification bias( should bediscouragedasit mayresultinaconsiderable never frozensample.The use ofpoint-of-caredevices and fastingplasmaglucose should bemeasuredonfresh, sites onhaemoglobin)( binding ofglucoseandothercarbohydratestovarious (that arechemicallydistinctmoietiesproducedbythe glycated haemoglobinfromotherglycohaemoglobins different studies,thisensuresaproperseparation of addition tostandardisationandcomparabilitybetween Control andComplicationsTrial referenceassay. In Standardisation ProgramandstandardisedtotheDiabetes a methodcertifiedbytheNationalGlycohaemoglobin that glycatedhaemoglobinshouldbemeasuredusing in thissetting( studies questionedthevalidityofglycatedhaemoglobin be amoresuitablediagnostictestforCFRDasearlier glucose tolerancetestisalsocurrentlyconsideredto and overlyrestrictivecriteriaforpancreatitis( because of the rather liberal inclusion criteria for diabetes diagnosing PPDM-A,thoughitsfindingsareinconclusive that oralglucosetolerancetestmaybebeneficialin control study of 52 people from Ireland suggested is thecasewithglycatedhaemoglobin).A2020case– plasma glucose)norrequiresthe90-daylagperiod(as by the acutestressresponse(as is thecase with fasting diagnosing ofPPDMasthetestneitherisconfounded glucose tolerancetestmay, intheory, enableanearlier patients. However, in a research setting, the use of oral because ofeaseuse,convenience,andacceptabilityto glucose areoftenpreferredtooraltolerancetest pancreas Diabetes oftheexocrine In peoplewithnomedicalrecordsofdiabetes(i.e. 15 , 58 Table 2 60 ). Itisimportanttounderscore Table 1 Downloaded fromBioscientifica.com at10/01/202101:06:57AM 59 ). ). ). Bothglycatedhaemoglobin ). However, fastingplasma aremet). 184 :4 33 ). Oral R154 via freeaccess European Journal of Endocrinology FPG, fastingplasmaglucose;NODAP,new-onsetdiabetesafterpancreatitis;PPDM,post-pancreatitismellitus. suspected in people with diabetes who haveunintentional imaging ofthepancreas( exocrine pancreasmayhave visuallyunremarkable because somepeoplewith diabetes anddiseasesofthe is notrequiredasadiagnosticcriterionforDEP. Thisis imaging (byMRI,CT, orendoscopicultrasound)initself pertinent tonotethatevidenceofpathologicalpancreatic standards ofpracticeforeachdisease( pancreas shouldbediagnosedinlinewithcurrent characteristic. viewed asastrongriskfactorforDEPbutnotitsdefining arguments, exocrinepancreaticdysfunctionshouldbe not materiallyaffecttheassociation.Basedonabove of acutepancreatitis(aetiology, severity, recurrence)did Type ofpancreatitis(acutevschronic)andcharacteristics for PPDM(adjustedhazardratio3.83; topancreatitishadasignificantlyhigherrisk secondary showed thatthosewithexocrinepancreaticdysfunction with acute or chronic pancreatitis from New Zealand pancreas ( often developsinpeoplewithdiseasesoftheexocrine acknowledged thatexocrinepancreaticdysfunctionalso ofdiseasestheexocrinepancreas.However,history itis ( indirect pancreaticfunctiontestsorpancreasvolumetry than 80clinicalstudiesthatemployedeitherdirect/ studies andthenconfirmedin3meta-analysesofmore This wasfirstdemonstratedinseveralhistopathological 2 diabetes(includingthoserequiringinsulintherapy). dysfunction oftendevelopsinpeoplewithtype1and characteristic ofPPDMorPCRD.Exocrinepancreatic as adiagnosticcriterionforDEPitisnotspecific NODAP PPDM Type 2diabetes interfering withtheaccuracyofmeasurements)values. refers tonocalorieintakeforatleast8h.'Notavailable'bothmissingandinconclusive(duechronicdisorders of unequivocalhyperglycaemia,diagnosisrequirestwoabnormaltestresultsonsimultaneousorconsecutivetesting.Fasting Table 2 25 Review

, Although theunderlyingdiseaseofexocrine Exocrine pancreatic dysfunction should not be used 61

, 62 Diagnostic criteriafordiabetesinindividualswithahistoryofpancreatitisbasedonlaboratoryworkup.Intheabsence 24 , , 63 64 ). Almostinvariably, thosepeoplehadno ). A2020cohortstudyof9124individuals AND/OR HbA1c FPG OR HbA1c Before FPG AND HbA1c FPG notavailable < ≥ 7.0 mmol/L(126mg/dL) 7.0 mmol/L(126mg/dL) < ≥ 48 mmol/mol(6.5%) 48 mmol/mol(6.5%) 66 ). Forexample,PCRDcanbe M SPetrovandBasina Timing ofdiabetesworkupinrelationtothefirstattackpancreatitis P 18 < 0.05) ( AND/OR AND AND/OR , 49

), itis

65 HbA1c HbA1c notavailable HbA1c During orwithin90days ). cancer becomesvisibleoncross-sectionalimaging( new-onset diabetesnotinfrequentlymanifestsbefore level andnormalpancreaticimaging.Itwasshownthat weight loss,anorexia,jaundice,elevatedserumCA19–9 symptomatic pancreaticcancer (especiallyifaccompanied new-onset diabetesisapromising earlymarkerinpre- (NOD-PDAC). Agrowingbody ofliteratureindicatesthat in pre-symptomaticpancreatic ductaladenocarcinoma in clinicalstudies.Thefirstentityisnew-onsetdiabetes to beawareofthemastheyarenotinfrequentlyreported be recognisedonly retrospectively ( Two diabetesentitiesindiseaseoftheexocrinepancreascan Special entities DEP outsidehigh-incomecountries. ultrasound wouldmakeitvirtuallyunfeasibletodiagnose are ubiquitous,therelianceonMRI,CT, orendoscopic but not least, given that diseases of the exocrine pancreas the timeofdiabetesdiagnosis( have visuallyunremarkableimagingofthepancreasat developing PPDM( necrotising) acutepancreatitisarealsoatahighriskof studies, hasestablishedthatindividualsaftermild(non- based studies,andprospectivelongitudinalcohort PPDM, aseriesofmodernmeta-analyses,population- for the development of of Langerhans is mandatory postulated that extensive structural damage of theislets (non-necrotising) pancreatitis. While the old dogma pancreatic imagingisthosewithPPDMfollowingmild ( associated with pancreatic tumour volume and grade Further, thedegreeofhyperglycaemiaissignificantly < ≥ pancreas Diabetes oftheexocrine 68 48 mmol/mol(6.5%) 48 mmol/mol(6.5%) ). Butthelargestfractionofpeoplewithnormal 69

AND AND AND , 70

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71 , 72 FPG AND/OR HbA1c FPG AND/OR HbA1c Any HbA1c/FPG More than90days https://eje.bioscientifica.com 73 ). Thesepeopletypically Table 1 ≥ ≥ , 7.0 mmol/L(126mg/dL) 7.0 mmol/L(126mg/dL) 74 184 ≥ ≥ 48 mmol/mol(6.5%) 48 mmol/mol(6.5%) , :4 75 ). It is important , 76 , 77 R155 ). Last 67 via freeaccess ). ). European Journal of Endocrinology https://eje.bioscientifica.com type 1autoimmunepancreatitis –abenignIgG4-related endocrine andexocrinepancreas. valuable insightsintotheintricate interplaybetweenthe investigations ofthisgroup ofpeoplecouldprovide the useofchemicalshift-encodedMRI)( pancreatic fatdeposition(robustlydeterminedwith partial lipodystrophyischaracterisedbyexcessintra- pancreatitis. Ofnote,a2018studyshowedthatfamilial on whetherornotdiabetespredatesthediagnosis of should be labelled as either ADMP or PPDM depending and hypertriglyceridaemia-inducedacutepancreatitis with co-existingdiagnosesoflipodystrophy, diabetes, at highriskofdevelopingacutepancreatitis.People have severehypertriglyceridaemia,whichputsthem diabetes mellitus. Peoplewith lipodystrophy alsooften resistance,theyareathighriskofdeveloping ADMP. Giventhatthesepeopleoftenhavemarked by absenceorlossofsubcutaneousfat–mayalsohave group ofgeneticoracquireddisorderscharacterised 84 may (ornot)relatetodiabeticketoacidosis( induced acutepancreatitisinpeoplewithdiabetes,which 82 of pancreatitisinpeoplewithpre-existingdiabetes( developing pancreatitisandworsein-hospitaloutcomes ( ‘antecedent diabetesmellitusinpancreatitis’(ADMP) that predates the diagnosis of pancreatitis, which we term the occurrenceofPPDMinstudypopulations. pancreatic cancermaybenefitfromtakingintoaccount which suggests that future studies on early detection of mutations inpancreaticcancerpredispositiongenes, ofpancreaticcancerandinheritedgenetic a history magnitude of risk was similar to that for families with (adjusted hazardratio6.94; ofpancreatitis those withtype2diabetesandnohistory had asignificantlyhigherriskofpancreaticcancerthan from NewZealandshowedthatindividualswithPPDM A 2020population-basedstudyof139843individuals NOD-PDAC mayoverlapwithPPDMinsomepeople. adenocarcinoma representdistinctphenomena.Ofnote, early-stage andcachexiainlate-stagepancreaticductal mice, itwashypothesisedthatperipheraltissuelossin in supplementation paradoxicallyledtoworsesurvival adenocarcinoma ( a driverofadiposetissuelossinearlypancreaticductal it wasshownthatexocrinepancreaticdysfunctionis by changeinbodycomposition)( Fig. 1 Review , ). A specific example is severe hypertriglyceridaemia- The second entity is diabetes (of any recognised type) Similar to people with lipodystrophy, people with 85 ). Onescenarioisasignificantlyincreasedriskof ). Peoplewithlipodystrophy–aheterogeneous 80 ). Giventhatpancreaticenzyme P < 0.05)( M SPetrovandBasina 68 , 78

, 6 79 ). The observed ). Theobserved ). Importantly, 86 ). Further 83 81 , , follow-up ofindividualswithpancreatitisisdeemedPPMD type 2diabetes.Diabeteswithfirstrecognitionduring diagnosed diabetesofanytype,althoughmostcommonlyitis pancreatitis isdeemedADMP.Thisentitymayinclude Diabetes withfirstrecognitionpriortotheattackof Terminology fordiabetesinthesettingofpancreatitis. Figure 1 post-pancreatitis diabetesmellitus. NODAP, new-onsetdiabetesafterpancreatitis;PPDM, data). ADMP,antecedentdiabetesmellitusinpancreatitis; available glycatedhaemoglobinand/orfastingplasmaglucose documented euglycaemiaatbaseline(asevidencedby pancreatitis andprediabetesduringfollow-upwhohad (NOPAP) isalsoadoptedtodescribeindividualswith diabetes, theterm‘new-onsetprediabetesafterpancreatitis’ isknownasoneofthestrongestriskfactorsfor haemoglobin and/orfastingplasmaglucosedata).Giventhat of diabetesatbaseline(asevidencedbyavailableglycated describe individualswithPPDMwhohaddocumentedabsence ‘new-onset diabetesafterpancreatitis’(NODAP)isadoptedto hospitalisation forpancreatitis(i.e.atbaseline),theterm diabetes mayremainundiagnosedpriortoandduring (unless thegeneralexclusions therapy butthenbecomeinsulin-independent ( negative autoimmunemarkers initiallyrequireinsulin individuals presentingwith diabeticketoacidosisand Another scenarioisketosis-prone diabetes,where diabetes shouldbelabelled asdrug-induceddiabetes. which mayleadtonew-onsetdiabetes( most effective treatment for autoimmune pancreatitis), the administrationoflargedosescorticosteroids(as complexity inthisgroupofpeopleisthattheymayrequire the diagnosisofpancreatitis.Theadditionalfacet of or PPDMdependingonwhethernotdiabetespredates absence ofislet-directedautoantibodies)mayhaveADMP ductal adenocarcinoma ( digestive diseasethatmaymasqueradeaspancreatic pancreas Diabetes oftheexocrine Downloaded fromBioscientifica.com at10/01/202101:06:57AM 55 ( , Table 1 87 ) –anddiabetes(inthe ) aremet).Because 184 :4 87 ). Inthatcase, 88 ). These R156 via freeaccess European Journal of Endocrinology Diabetes Association( diabetes recognised by the American a type of secondary should beconsideredaspart ofdrug-induceddiabetes– the timeofdiabetesdiagnosis ( or imagingfindingssuggestive ofacutepancreatitisat them, 42%havemarkedlyelevatedlipase,amylaseand/ cancer therapiesdevelopfulminantdiabetes( modern treatment for cancers resistant to conventional reported that around 1% of patients who receive this and PD-1(knownascheckpointinhibitors)( ligandsCTLA-4 antibodies thatblockimmuneinhibitory always) present in patientstreated with monoclonal of PPDM.Also,autoimmunemarkersareoften(butnot proteins, or zinc transporter-8) rules out the diagnosis acid decarboxylase,insulin,tyrosinephosphatase-like diabetes (i.e. isletcell antibody or antibodies toglutamic the presenceofautoimmunemarkersdiagnosticfortype1 the most cleanlydefined PPDM group( diagnosis ofPPDMasanoperationalmeansproducing hyperglycaemia inpeoplewithpancreatitisrulesoutthe to bepartoftheDEPcriteria( resulting inseveraldiabetesentitiesbeingconsiderednot other typesofdiabetes are viewed as mutually exclusive, subtypes ofdiabetesinquestion.ThatiswhyDEPand the majorityofpatientswhosharekeyfeatures of the universe ofpossiblepatientsbutrathertogrouptogether based research. Theyare notmeanttocapturetheentire well-defined cohortsofpatientsforclinicalorpopulation- intentofcreatingrelativelyhomogeneous with aprimary 2 Association areadvocatedinthepresentdiscourse( diagnostic criteriafordiabetesbytheAmericanDiabetes individuals withthediseaseaspossible.Thatiswhy intentofaccuratelyidentifyingasmany with aprimary reflect thedifferenttraitsofdiabetes(i.e.itsheterogeneity), are not the same ( The intentsofdiagnosticcriteriaandclassification Key exclusions dysfunction, skeletalmuscleloss)( need for insulin, development of exocrine pancreatic diabetes worsenfollowinganattackofpancreatitis(e.g. traits ofindividualswithclassicaluncomplicatedtype2 The last scenario worth noting here is when metabolic an attackofpancreatitisatanytimeafteronsetdiabetes. the need for long-term insulin therapy and they may have people canberecognisedonlyretrospectivelybasedon ). Classificationcriteriaarestandardiseddefinitions,used Review The presenceofseveralentitiescharacterisedby 89 ). Diagnostic criteria are broad and must 15 ). Also,stresshyperglycaemia Table 1 91 M SPetrovandBasina ). Thisformofdiabetes 69 ). , 76 Fig. 2 ). ). Specifically, 90 ). Itwas 91 ). Of Table did notchangeconsiderably:from6.7to8.0per1000 diagnosis ofdiabetesordiseasetheexocrinepancreas) in controlsfromthegeneralpopulation(whohadnoprior years ( density ofdiabetesfrom22.5to60.8per1000person- pancreatitis resultedinthemarkedinflationofincidence disregarding the90-daylagperiodinpeoplewithacute based study of 14 830 people from Taiwan when be helpful ( hospitalisation (orshortlyafterit)withPPDMwouldnot labelling themajorityofpancreatitispatientsduring of 10 patients with pancreatitis and indiscriminately important, stresshyperglycaemiaoccursinupto7out hyperglycaemia duringthecourseofpancreatitisis preceding 8–12weeks.Whileidentifyingtransientstress reflect averageplasmaglucoseconcentrationoverthe period isappliedbecauselevelsofglycatedhaemoglobin rules outthediagnosisofPPDM( during pancreatitis (or up to 90 days after pancreatitis) is blunt pancreatic trauma. Contrary toearlieranecdotal is bluntpancreatictrauma. Contrary estimates ofDEP. Arareindication forpancreaticresection therefore, wouldartificially inflatetheepidemiological result inalogicalfallacycalled inclusion ofpostoperativediabetes asapartofDEPwould pancreatic cancer(i.e.thecoreentitiesinDEPcriteria), indications for pancreaticresection are pancreatitis and ratio 1.6; 1.5; after pancreaticresectionwerepancreatitis(hazardratio showed thattheonlyindependentpredictorsofdiabetes preoperative patients withoutdiabetes from theUSA ( after pancreaticresection(oddsratio1.4; significantly associatedwiththedevelopmentofdiabetes showed thatpancreatitiswastheonlypre-existingdisease preoperative patientswithoutdiabetesfromTaiwan 101 ( (pancreaticoduodenectomy vsdistalpancreatectomy) associated withthetypeofpancreaticresectionperformed that thedevelopmentofdiabeteswasnotsignificantly but pre-existingdisease(s).Severalstudiesdemonstrated changes inglucosemetabolismareoftenduetonotsurgery postoperative diabetes( many as2outof5patientsduringfollow-updeveloped 1731 patientsafterpancreaticresection)showedthatas systematic reviewof26clinicalstudies(encompassing associated withanincreasedriskofdiabetes.A2015 person-years ( pancreas Diabetes oftheexocrine 102 96 , ). Further, a2015population-basedstudyof3914 It is well recognised that pancreatic surgery is It iswellrecognisedthatpancreaticsurgery ). Similarly, a2017population-basedstudy of678 97 P 70 = 0.03)andCharlsoncomorbidityindex(hazard ) orthevolumeofpancreasresected( ). Atthesametime,incidencedensityofdiabetes P 93 = 0.02)( , 70 94 ). ). This was shown in a 2015 population- 97 ). Giventhatthemostcommon Downloaded fromBioscientifica.com at10/01/202101:06:57AM 95 ). However, postoperative https://eje.bioscientifica.com circulus 81 , 184 92 in :4 ). The90-daylag probando 98 P , = 0.002) 99 R157 , and, 100 via freeaccess , European Journal of Endocrinology https://eje.bioscientifica.com glands inhumansandissecreted withthemilk( pancreas-specific: it is also expressed in lactating mammary in pancreaticacini( carboxyl-ester lipase–one of thefourlipasesexpressed dysfunction andcausedby heterozygousmutationsin of theyoung,characterisedbyexocrinepancreatic of monogenicdiabetesistype8maturity-onset the AmericanDiabetesAssociation( diabetes –asubtypeofmonogenicrecognisedby 106 mutations inthetranscriptionfactor 6 monthsofageandisoftenlinkedtoheterozygous malformation, diabetesoccursalmostinvariablyunder malformation ofthepancreas.Inpeoplewiththis rarecongenital criteria. Pancreaticagenesisisavery hypoplasia) isalsoconsiderednottobepartoftheDEP ( of injury trauma didnotleadtonew-onsetdiabeteswithin3years case reports,a2017cohortstudyshowedthatpancreatic obvious. HbA1c,glycatedhaemoglobin;FPG,fastingplasmaglucose. However, theclinicalimportanceofestablishingadiagnosischronicdiseasesuchasdiabetesearlierthan90daysisnot lag periodisarbitraryandsomeindividualsafterpancreatitismay,intheory,developnew-onsetdiabetessoonerthanthat. cytoplasm ofisletcells,insulin,glutamicaciddecarboxylase,insulinoma-associatedantigen-2,andzinctransporter-8.The 90-day Diagnostic algorithmtoidentifypost-pancreatitisdiabetesmellitus.Markersoftheautoimmuneprocessreferantibodies tothe Figure 2 Review ). Therefore,itshouldbeconsideredaspartofneonatal Diabetes secondary topancreaticagenesis(or Diabetes secondary 103 ). 107 ). However, theenzymeisnot M SPetrovandBasina 15 ). Anotherexample GATA6 ( 104 107 , 105 ). In , It is worth noting though that secondary alterationiniron It isworthnotingthoughthat secondary hemochromatosisaspartofDEP. tohereditary secondary no sufficient scientific evidence to consider diabetes (such astheliver, skeletalmuscle,gut, brain),thereis key organsinvolvedinthe pathogenesisofdiabetes to dysfunctionofnotonlythepancreasbutalsoother ( hemochromatosis common mutation in type1hereditary (1.26% vs0.25%)werehomozygousfor type 1diabetesthancontrolsfromthegeneralpopulation from Denmark showed that more people with late-onset on whattypeofdiabetesitis( around 20% but there is no consensus in the literature hemochromatosis is prevalence ofdiabetesinhereditary organs (includingbutnotlimitedtothepancreas).The iron absorptionandincreaseddepositioninseveral axis andischaracterisedbyanunregulatedintestinal of anumbergenesinvolvedinthehepcidin–ferroportin hemochromatosis.Itiscausedbymutations is hereditary addition, genetic disease that is not part of the DEP criteria pancreas Diabetes oftheexocrine 109 ). Given that hereditary hemochromatosis canlead ). Giventhathereditary Downloaded fromBioscientifica.com at10/01/202101:06:57AM 108 ). Alarge2001study 184 C282Y :4 –themost R158 via freeaccess European Journal of Endocrinology people withPPDM,PCRD,and CFRD. The DEPcriteria will help filltheapparentevidence gapandtargetstudying this article will encourage pharmaceutical companies to reimbursement lessintricate. Itisalsoanticipatedthat insurance companieswill make medicalbillingand complex (yetwell-ordered)notionsuchasDEPbyhealth of hypo-andhyperglycaemia.Further, appreciationofa satisfaction, andreduceburnoutfromfrequentepisodes counsel peopleontherapyoptions,improveindividuals’ diagnosing and classifyingofDEPwillmakeiteasierto article publishedinthisissueoftheJournal( pares outcomes and management of PPDM –the complications andmortality. Bestrecent evidenceon with diabetesandmitigatinglong-termriskfordiabetic normal glycaemicprofilesoonafterpatientsarediagnosed early inthecourseofDEPwithaviewtoachievingnear- underscores theneedtoofferappropriatemanagement the awarenessandearlyrecognitionofDEP( vascular complicationsanddeath,itisimportanttoraise effect ofearlyglycaemiccontrolonmicro-andmacro- diabetes andtakingintoaccountthewell-knownlegacy few years after the diagnosis in comparison with type 2 by a significantly poorer glycaemic control in the first as type1diabetes)( and often misdiagnosed as type 2 diabetes (and sometimes being thecaseforDEPbecauseitistypicallydiagnosedlate that isbothtimelyandaccurate( provision ofqualityhealthcaretoadiagnosticprocess The NationalAcademyofMedicine(USA)linksthe Conclusion a characteristic of DEP, in particular PPDM ( hemochromatosis–canbe leading totype1–4hereditary – unrelated to one of the genetic mutations PPDM-C PPDM-A PPDM PCRD NOPAP NOD-PDAC NODAP DEP CFRD ADMP Abbreviation Table 3 Review in the DEP criteria – are overviewed inthe companion intheDEPcriteria–areoverviewed Key termsandabbreviations(inalphabeticalorder). Post-acute pancreatitisdiabetesmellitus Post-pancreatitis diabetesmellitus Pancreatic cancer-relateddiabetes New-onset prediabetesafterpancreatitis New-onset diabetesinpre-symptomatic New-onset diabetesafterpancreatitis Diabetes oftheexocrinepancreas Cystic fibrosis-relateddiabetes Antecedent diabetesmellitusinpancreatitis Term Post-chronic pancreatitisdiabetesmellitus pancreatic ductaladenocarcinoma 1 ). GiventhatDEPischaracterised M SPetrovandBasina 113 ). Thisisfarfrom 110 115 primus inter , 114 111 ). Correct ). This , 112 ). the public,commercialornot-for-profitsector. This research did not receive any specific grant from any funding agency in Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisreview. no is there that declare authors The Declaration ofinterest practice andresearch. and justificationtoapplytheDEPcriteriainbothclinical is gathered.But,atthistime,theresufficientevidence be requiredinthefuture,whennewhigh-qualityevidence to evolve( and evidence-based. 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Accepted 18January2021 Revised versionreceived1December2020 Received 25August2020 115 114 113 112 111 110 pancreas Diabetes oftheexocrine Petrov MS. Post-pancreatitisdiabetesmellitus:primetimefor Jivanji CJ, Soo DH&Petrov MS.Towards reducingtheriskof The NationalAcademiesofSciences,Engineering,andMedicine; Chand SK, Singh RG,Pendharkar SA,Bharmal SH&Petrov MS. Chand SK, Singh RG,Pendharkar SA&Petrov MS.Iron:astrong Kimita W &Petrov MS.Ironmetabolismandtheexocrinepancreas. R137–R149. disease. secondary 421X.16.02365-5) e Dietologica new onsetdiabetesafterpancreatitis. Care InstituteofMedicine. Care Services; Committee onDiagnosticErrorinHealthCare,Board cyto.2017.09.014) pancreatitis. Interplay betweeninnateimmunityandironmetabolismafteracute (https://doi.org/10.1007/s12011-017-1131-y) pancreatitis. element inthepathogenesisofchronichyperglycaemiaafteracute cca.2020.10.013) Clinica ChimicaActa 6736(01)06526-6) Lancet in late-onsettype1diabetesmellitus:aretrospectivestudy. Tybjaerg-Hansen A, . Washington, DC:NationalAcademiesPress,2015. 2001 2017 358 (https://doi.org/10.1530/EJE-20-0468) Cytokine Biological Trace ElementResearch 1405–1409. 63 European Journal ofEndocrinology European Journal et al 2020 270–284. 2018 . Prevalence of hereditary haemochromatosis . Prevalenceofhereditary 511 Downloaded fromBioscientifica.com at10/01/202101:06:57AM 103 (https://doi.org/10.1016/S0140- 167–176. (https://doi.org/10.23736/S1121- 90–98. https://eje.bioscientifica.com Improving DiagnosisinHealth Minerva GastroenterologicaMinerva (https://doi.org/10.1016/j. (https://doi.org/10.1016/j. 184 2018 :4 183 2021 71–79. 184 R163 via freeaccess