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ClinicalReview&Education
JAMA | Review
AcutePancreatitis
AReview
MichaelA.Mederos,MD;HowardA.Reber,MD;MarkD.Girgis,MD
Multimedia
IMPORTANCE IntheUnitedStates,acutepancreatitisisoneoftheleadingcausesofhospital Relatedarticlepage391
admissionfromgastrointestinaldiseases,withapproximately300000emergency
departmentvisitseachyear.Outcomesfromacutepancreatitisareinfluencedbyrisk Supplementalcontent
stratification, fluid and nutritional management,andfollow-upcareandrisk-reduction CMEQuizat
strategies,whicharethesubjectofthisreview. jamacmelookup.com
OBSERVATIONSMEDLINEwassearchedviaPubMedaswastheCochranedatabasesforEnglish-
languagestudiespublishedbetweenJanuary2009andAugust2020forcurrent
recommendationsforpredictivescoringtools,fluidmanagementandnutrition,andfollow-up
andrisk-reductionstrategiesforacutepancreatitis.Severalscoringsystems,suchastheBedside
IndexofSeverityinAcutePancreatitis(BISAP)andtheAcutePhysiologyandChronicHealth
Evaluation(APACHE)IItools,havegoodpredictivecapabilitiesfordiseaseseverity(mild,moderately
severe,andseverepertherevisedAtlantaclassification)andmortality,butnoonetoolworkswell
forallformsofacutepancreatitis.Earlyandaggressivefluidresuscitationandearlyenteralnutrition
areassociatedwithlowerratesofmortalityandinfectiouscomplications,yettheoptimaltypeand
rateoffluidresuscitationhaveyettobedetermined.Theunderlyingetiologyofacutepancreatitis
shouldbesoughtinallpatients,andrisk-reductionstrategies,suchascholecystectomyandalcohol AuthorAffiliations:Departmentof
cessationcounseling,shouldbeusedduringandafterhospitalizationforacutepancreatitis. Surgery,DavidGeffenSchoolof
MedicineatUCLA,LosAngeles,
CONCLUSIONSANDRELEVANCEAcutepancreatitisisacomplexdiseasethatvariesinseverity California.
andcourse.Promptdiagnosisandstratificationofseverityinfluencepropermanagement. CorrespondingAuthor:MarkD.
Scoringsystemsareusefuladjunctsbutshouldnotsupersedeclinicaljudgment.Fluid Girgis, MD,UniversityofCalifornia,
LosAngeles,10833LeConteAve,
managementandnutritionareveryimportantaspectsofcareforacutepancreatitis. 14-174CHS,LosAngeles,CA90095
(mdgirgis@mednet.ucla.edu).
JAMA.2021;325(4):382-390.doi:10.1001/jama.2020.20317 SectionEditors:EdwardLivingston,
CorrectedonJune15,2021. MD,DeputyEditor,andMaryMcGrae
McDermott,MD,DeputyEditor.
cutepancreatitisisoneofthemostcommongastrointestinal 2020forrandomizedclinicaltrials(RCTs),meta-analyses,system-
conditions that results in hospital admission in the United aticreviews,andobservationalstudies.Manualsearcheswereper-
AStates.Theincidenceofacutepancreatitisisestimatedat110 formed of the references of selected articles, reviews, meta-
to140per100000population,withanestimatedmorethan300000 analyses,andpracticeguidelines.Selectstudiespriorto2009were
1,2 includedforhistoricalcontext.EmphasiswasgiventoRCTsandmeta-
USemergencydepartmentvisitsperyear. Admissionsduetoacute
pancreatitishaveincreasedfrom9.48casesper1000hospitalizations analyses. All publications and citations included were mutually
in2002to12.19in2013,withamedianhospitalcostofnearly$7000 agreedonbytheauthorsandselectedforclinicalimportanceand
3,4
perhospitalization. relevancewithconsiderationtothegeneralmedicalreadershipof
Acutepancreatitisisacomplexdiseasewithavariablecourse JAMA.Sixty-six articles were included, which contained 8 RCTs,
thatisoftendifficulttopredictearlyinitsdevelopment(eBoxinthe 12meta-analyses,and5clinicalguidelines.
Supplement).Approximately80%ofpatientsdevelopmildtomod-
eratelyseveredisease(absenceoforganfailure>48hours).5,6How- PathogenesisandEtiology
ever,one-fifthofpatientsdevelopseveredisease,withamortality Acutepancreatitisischaracterizedbydamagetotheacinarcells,the
5,7
rateofapproximately20%. Thepurposeofthisreviewistosum- functionalunitsoftheexocrinepancreas,precipitatinginappropriate
marizeevidenceregardingtherecognitionofdiseaseseverity,fluid releaseandactivationoftrypsinogentotrypsinwithintheacini.This
andnutritionmanagement,andrisk-reductionmethodsforthepre- triggerstheactivationofotherdigestiveenzymes,thekininsystem,
ventionofrecurrentdisease. andthecomplementcascaderesultinginautodigestionofthepancre-
8,9
aticparenchyma. Pancreaticductobstruction(eg,gallstonepancre-
atitis)isoneofthemorecommoncausesofacinardamage,causingan
Methods increase in ductal pressure, interstitial edema, and accumulation of
10
enzyme-richfluidwithinthepancreatictissue. Alternatively,primary
PubMedandtheCochranedatabasesweresearchedforEnglish- acinarinjurymaybecausedbyavarietyofotherfactors,suchascal-
language studies published from January 2009 through August cium, which regulates trypsin activation. Inappropriate release of
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AcutePancreatitis:AReview Review ClinicalReview&Education
Box1.EtiologiesofAcutePancreatitis Box1.(continued)
A.EtiologiesofAcutePancreatitis Tetracycline
15a Trimethoprim/sulfamethoxazole
Gallstones(21%-33%)
15a Valproicacid
Alcohol(16%-27%)
4,16a
Triglyceridemia(2%-5%) Abbreviations:ERCP,endoscopicretrogradecholangiopancreatography;
Iatrogrenic(ERCP/EUS) EUS,endoscopicultrasound.
Hypercalcemia a Percentagesforthe3mostcommonetiologiesintheUnitedStatesare
Infection shownonly.
Hereditary
Autoimmune intracellularcalcium,enhancedentryofextracellularcalcium,ordefec-
Medications tive calcium extrusion/reuptake mechanismscausesasustainedin-
Structural creaseincytosoliccalciumintheacini.Thiselevationleadstoprema-
Pancreasdivisum tureactivationoftrypsinogentotrypsin,resultinginacinarinjuryand
Tumorsorcysticlesions death.11,12 Ethanol is a common cause of acute pancreatitis, but its
17,18 pathogenesisremainsunknown;thereisevidencethatitmaydisrupt
B.SelectMedicationsImplicatedinAcutePancreatitis multiplebiochemicalpathwayswithinacinarcells.
Acetaminophen
Acetaminophen/codeine Gallstone disease and alcohol are the 2 leading causes of acute
5-Aminosalicylate(mesalamine,sulfasalazine) pancreatitis. Other causes include hypertriglyceridemia (typically
Amiodarone >1000mg/dL),hypercalcemia,familial(hereditary)pancreatitis,and
viral infections. Periampullary tumors,pancreaticheadmasses,and
Androgenicanabolicsteroids cystic lesions of the pancreas can cause obstruction of the pancre-
Azathioprine aticduct,impedingtheflowofpancreaticenzymes,whichmaylead
Cannabis toinappropriateenzymeactivationwithinthepancreas.Pancreasdi-
Carbamazepine visumandpancreaticstricturescanalsoobstructthepancreaticduct
Carbimazole andcausepancreatitis.Acutepancreatitiscanresultfrominstrumen-
Cimetidine tation of the ampulla andpancreaticductfollowingendoscopicret-
13
Cisplatin rograde cholangiopancreatography (ERCP) and endoscopic ultra-
sound(EUS),14withariskof5%to10%andlessthan1%,respectively
Clomiphene (Box1).Morethan500medicationshavebeenimplicatedasacause
Didanosine ofacutepancreatitisandatleast30ofthemhavebeenshowntohave
Enalapril adefiniteassociation,meaningthattheycauseacutepancreatitison
Estrogenandrelatedproducts repeated administration of the medications when other possible
Furosemide causesareexcluded(Box1B).17,18Theetiologyofacutepancreatitis
Isoniazid isnotidentifiedinmanycases.Additionalriskfactorsassociatedwith
Lamivudine acute pancreatitis include obesity, older age, smoking, and HIV-
positive status.5 The etiology of acute pancreatitis also varies
Losartan geographically.16Forexample,inarecentmeta-analysis,gallstonepan-
Methyldopa creatitis represented 26% of acute pancreatitis cases in the United
Metronidazole 15
Statescomparedwith68%inLatinAmerica.
Nadolol Acute pancreatitis is classified as 2 subtypes: interstitial
Pravastatin edematouspancreatitis and necrotizing pancreatitis (Box 2A).
Perindopril Interstitial edematouspancreatitisischaracterizedbyinflammation
Procainamide andedemaofthepancreaticparenchymaandperipancreatictis-
Pyritinol sues. Necrotizing pancreatitis occurs when this process progresses
Ranitidine to pancreatic or peripancreatic tissue death. Both forms of acute
pancreatitis may be associated with the local complications of pan-
Rosuvastatin creatic fluid and solid collections. Acute peripancreatic fluid collec-
Saxagliptin tions (APFCs) develop within 4 weeks of disease onset and contain
Simvastatin mostly fluid; acute necrotic collections (ANCs) develop in necrotiz-
Sulindac ing pancreatitis and contain solid and fluid components. Acute
Tamoxifen intrapancreatic collections are a result of necrotizing pancreatitis
andarereferredtoasANCs.19APFCsandANCsthatpersistafter4
Telaprevir weeksfromonsetofdiseasearereferredtoaspseudocystsand
(continued) walled-off necrosis, respectively (Box 2A and Figure). Peripancre-
atic and pancreatic collections may be secondarily infected and
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Clinical Review&Education Review AcutePancreatitis:AReview
Box2.RevisedAtlantaClassificationDefinitions
A.MorphologicClassificationofAcutePancreatitis Involvesthepancreaticparenchymaorperipancreatictissues
andPancreaticCollections Heterogenousandnonliquiddensityofvaryingdegreesin
Interstitial EdematousPancreatitis differentlocations
Diffuseorlocalizedenlargementofthepancreaswithhomogenous >4wk
enhancementofthepancreaticparenchyma WON
Inflammatorychangesoftheperipancreaticfat Mature,encapsulatedcollectionofpancreaticand/or
±Peripancreaticfluid(see“Collections”below) peripancreaticnecrosiswithawell-definedwall
Collections Heterogeneouswithliquidandnonliquiddensitywithvary-
<4wk ingdegreesofloculations
APFC
Adjacenttothepancreas(nointrapancreaticextension) B.DiagnosticCriteria(2of3)
Singleormultiple 1. Abdominalpainconsistentwithacutepancreatitis
Homogenouscollectionwithfluiddensity 2. Elevatedserumamylaseorlipase>3timestheupperlimit
ofnormal
Noassociatedperipancreaticnecrosis 3. Characteristicfindingsofacutepancreatitisonimaging
Confinedtonormalfascialplanes (eg,contrast-enhancedcomputedtomography,magneticreso-
>4wk nanceimaging,and,lessfrequently,ultrasound)
Pseudocyst C.GradesofSeverity
Mature,encapsulatedcollection(s)offluidwith Mild
awell-definedwalloutsidethepancreas 1. Noorganfailure
Homogenousfluiddensity 2. Nolocalorsystemiccomplications
Nosolidcomponent ModeratelySevere
NecrotizingPancreatitis 1. Organfailurethatresolveswithin48h(transientorganfailure)
Necrosisofteninvolvingboththepancreaticparenchyma and/or
andperipancreatictissue 2. Localorsystemiccomplicationswithoutpersistentorganfailure
Variablecontrastenhancementpatterninthefirstfewdays Severe
Nonenhancingareasshouldbeconsiderednecrosisafterthefirst 1. Persistentorganfailure(>48h)
weekofdisease Singleorganfailure
Multipleorganfailure
Maybecomesecondarilyinfected
Collections Abbreviations:ANC,acutenecroticcollection;APFC,acuteperipancreaticfluid
<4wk collection;WON,walled-offnecrosis.
ANC
describedasinfectedANCandinfectedwalled-offnecrosis.Inaddi- stoneinthecommonbileduct(ie,choledocholithiasis)orthatastone
tion to pancreatic collections, local complications also include recently passed. Additional testing with transabdominal ultra-
gastric outlet dysfunction, splenic or portal vein thrombosis, and soundtoevaluateforgallstonesandserumtriglyceridelevelsshould
20 alsobeobtained.IgG4levelsarehelpfulwhenautoimmunepancre-
colonicnecrosis.
atitis is suspected. Computed tomography (CT) or magnetic reso-
ClinicalPresentationandDiagnosis nanceimaging(MRI)maybeindicatedtoevaluateforstructural
Abdominalpainisthemostcommonpresentingsymptom.Thepain causesofacutepancreatitis,butthisisnotmandatoryduringinitial
isusuallydescribedasconstantandoftenwithradiationtotheback managementofthediseaseprocess.Patientswithrecurrentacute
that may be exacerbated by eating, drinking, or lying supine. pancreatitisorfamilyhistoryofacutepancreatitis/chronicpancre-
Accompanyingsymptomsoftenincludenausea,vomiting,andlow- atitiswithoutanidentifiableetiologywiththeaforementionedlabs
tomoderate-gradefever.Evaluationofsuspectedacutepancreati- orimagingshouldbereferredforgenetictestingtoevaluateforhe-
tis beginswithacomprehensivehistoryandphysicalexamination. reditarypancreatitis.
Assessmentshouldfocusonahistoryofepisodesofacutepancre- Todiagnoseacutepancreatitis, the revised Atlanta classifica-
atitis andriskfactors,includingbiliarycolic/gallstonedisease,alco- tion (RAC) requires 2 of the 3 following criteria be present: (1) ab-
holuse,familyhistoryofacuteorchronicpancreatitis,recentinfec- dominalpainsuggestiveofpancreatitis,(2)serumamylaseand/or
tions,trauma,insectbites,andnewmedications.Thisfocusedhistory lipasegreaterthan3timestheupperlimitofnormal,(3)andcross-
canassistinidentifyingtheunderlyingetiology. sectional imaging (CT or MRI) findings consistent with acute pan-
Physicalexaminationoftenrevealsabdominaldistentionandde- creatitis (Box 2B).20 Acute pancreatitis can be diagnosed in about
creased bowel sounds. Rebound tenderness is uncommon. Stan- 80%ofpatientsbasedonthepresenceofabdominalpainandel-
dardchemistrieswithamylase,lipase,andliverpaneltestscanhelp evatedpancreaticenzymesonly.21However,CTisausefuladjunct
confirm the diagnosis of acute pancreatitis as well as identify un- toconfirmacutepancreatitiswhenthediagnosisisinquestionand
derlying etiology (ie, hypercalcemia). An elevated direct bilirubin toruleoutotherintra-abdominalconditionsthatcanmimicacute
and/oralkalinephosphataselevelmayindicatethepresenceofagall- pancreatitissuchasaperforatedduodenalulcer.
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AcutePancreatitis:AReview Review ClinicalReview&Education
Figure.Timeline,Manifestations,andManagementofAcutePancreatitis
y Interstitial Rapid resolution of pain
MILDedematous
erit pancreatitis
v Y Acute peripancreatic luid collection Pseudocyst
TEL or transient organ failure
SEVERENecrotizing Acute necrotic luid collection Sterile necrosis Walled-off necrosis
MODERA pancreatitis or transient organ failure Infected necrosis Infected walled-off
necrosis
Manifestations by se Persistent organ failure
SEVERE
Symptom onset Admisson 24 h 48 h 72 h 2 wk 4 wk >4 wk
Initiation of fluid resuscitation for all levels of severity
Initiation of solid oral diet once tolerable without exacerbation of pain
y MILD
erit Cholecystectomy for gallstone pancreatitis prior to discharge (preferably within 24-48 h)
v
Initiation of oral diet or nasoenteral nutrition
Contrast-enhanced computed tomography (CT)
if there is persistent SIRS, worsening clinical
Y SEVERE status, or high suspicion of infected necrosis
Management by seTEL Antibiotics for infected necrosis conirmed
AND SEVERE by CT or ine-needle aspiration
MODERA Procedural management of local
complications via step-up approach
SIRSindicatessystemicinflammatoryresponsesyndrome.
Table1.ModifiedMarshallScoringSystemforOrganDysfunction Abbreviations:FIO ,fractionof
2
inspiredoxygen;PaO ,partial
a 2
Score pressureofarterialoxygen.
Organsystem 012 3 4 aScore2foranysystemdefinesthe
b presenceoforganfailure.
Respiratory(PaO /FIO ) >400 301-400 201-300 101-200 <101
2 2
Kidney(serumcreatinine),μmol/L <134 134-169 170-310 311-439 >439 bFornonventilatedpatients,FIO2can
Kidney(serumcreatinine),mg/dL <1.4 1.4-1.8 1.9-3.6 3.7-4.9 >4.9 beestimatedbytherateof
supplementaloxygen(roomair,
Cardiovascular(systolic >90 <90,fluid <90,notfluid <90,pH<7.3 <90,pH<7.2 21%,2L/min,25%;4L/min,30%;
bloodpressure),mmHg responsive responsive 6-8L/min,40%;9-10L/min,50%).
DiseaseSeverityandRiskStratification mentbasedonthepredictedseverityofdisease.22Thoughtheyare
TheRACgradesacutepancreatitisseveritybythepresenceanddu- useful adjuncts for decision-making in acute pancreatitis, scoring
rationoforganfailure(ie,respiratory,kidney,andcardiovascularas toolsshouldnotreplaceclinicaljudgment.Theearliestscoringsys-
23,24
determinedbythemodifiedMarshallscoringsystem;Table1)and temwaspublishedbyRansonetal in 1974 and 1977 and an-
thepresenceoflocalcomplications.Patientswithoutlocalcompli- otherbyImrieetal25,26in1978and1984.However,bothofthese
cationsororganfailurehavemildacutepancreatitis.Patientswith scoringsystemsrequireinformationacquiredinthefirst48hours
transientorganfailure(recoverywithin48hours)and/orlocalcom- ofhospitalpresentationandarecumbersometocalculate.In1985,
plications have moderatelysevereacutepancreatitis,andpatients theAPACHEIImodel27wasdevelopedasacomprehensivetoolde-
withpersistentorganfailurebeyond48hourswithorwithoutlocal signedtopredictdiseaseseverityandmortalityinpatientsadmit-
complicationshavesevereacutepancreatitis(Box2C).Mildpancre- tedtotheICU.APACHEIIrequires12variables(Table2)thatarenot
atitis is the most common form of acute pancreatitis and is self- routinelyobtainedinpatientswhoarenotcriticallyill.Additionally,
limiting;patientsaretypicallydischargedwithinaweek.Patientswith theBedsideIndexforSeverityinAcutePancreatitis(BISAP)score28
moderatelysevereandseverediseaseoftenhaveaprotractedcourse wasdevelopedin2008anddesignedasapredictorofmortality
over weeks to months due to local complications and organ dys- basedon5variables:bloodureanitrogen(BUN)levelgreaterthan
function(Figure). 25mg/dL,impairedmentalstatus, systemic inflammatory re-
Giventhevariableclinicalcourseinacutepancreatitisandthe sponsesyndrome(SIRS),ageolderthan60years,orradiographic
significantmortalityrateinseverecases,severalriskscoreshavebeen evidenceofpleuraleffusionwithinthefirst24hoursofadmission.
developedtopredictoutcome(Table2).Theseclassification sys- Thelowestscorewasassociatedwithalessthan1%mortalityrate
temsmayassistindeterminingtheappropriatelevelofcare(inten- andthehighestwithagreaterthan20%mortalityrate.Inaddition
sive care unit [ICU] vs non-ICU) and guide anticipatory manage- tomortality,earlystudiesdemonstratedaBISAPscoreof3orgreater
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