Drug-Induced Acute Pancreatitis and Pseudoaneurysms: An Ominous Combination

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www.elsevier.pt/ge

CLINICAL

CASE

Drug-Induced

Acute

Pancreatitis

and

Pseudoaneurysms:

An

Ominous

Combination

Diogo

Branquinho

∗

,

Daniel

Ramos-Andrade,

Luís

Elvas,

Pedro

Amaro,

Manuela

Ferreira,

Carlos

Soﬁa

GastroenterologyDepartment,CentroHospitalareUniversitáriodeCoimbra,Coimbra,Portugal Received15March2016;accepted6June2016

Availableonline12August2016

KEYWORDS Aneurysm,False; Embolization, Therapeutic; Pancreatitis/chemically induced

Abstract Ruptureofpseudoaneurysms israre but canbelife-threatening complicationsof acuteorchronicpancreatitis,usuallyduetoenzymaticdigestionofvesselwallscrossing peri-pancreatic ﬂuidcollections.Wereportthecaseofa40year-oldfemale,withmultisystemic lupus and anticoagulated for prior thrombotic events, admitted for probable cyclosporine-inducedacutepancreatitis.Hemodynamicinstabilityoccurredduetoabdominalhemorrhage fromtwopseudoaneurysmsinsideanacuteperi-pancreaticcollection.Selectiveangiography successfullyembolizedthegastroduodenalandpancreatoduodenalarteries.Thehemorrhage recurredtwoweekslaterandanothersuccessfulembolizationwasperformedandthepatient remainswelltodate.Thedecisiontorestartanticoagulantsandtosuspendcyclosporinewas challengingandrequiredamultidisciplinaryapproach.Despiterare,bleedingfroma pseudoa-neurysm shouldbeconsidered when facingapatient with pancreatitisandsudden signs of hemodynamicinstability.

©2016SociedadePortuguesadeGastrenterologia.PublishedbyElsevierEspa˜na,S.L.U.Thisis anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/ by-nc-nd/4.0/). PALAVRAS-CHAVE FalsoAneurisma; Embolizac¸ão Terapêutica; Pancreatite/induzida quimicamente

PancreatiteAgudaMedicamentosaePseudoaneurismas:UmaCombinaçãoTenebrosa Resumo Ospseudoaneurismas sãocomplicações rarasmas gravesdapancreatite agudaou crónica. Sãocausadospela digestãoenzimática deartériasque atravessamcolecções infla-matórias.Descreve-seocasodeumadoentedosexofeminino,de40anos,comlúpussistémico eanticoaguladaportrombosevenosaprofunda,admitidaporpancreatiteagudaassociadaà ciclosporina.Apresentousinaisdehemorragiaabdominalcausadapordoispseudoaneurismas

∗_{Corresponding}_author.

E-mailaddress:diogofbranquinho@yahoo.com(D.Branquinho). http://dx.doi.org/10.1016/j.jpge.2016.06.002

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1. Introduction

Most cases of pancreatitis are mild and have a favor-able prognosis. However they can also be present with a severe form and have ominous complications. Vascu-larevents rangefromasymptomaticvenous thrombosisto severelife-threateningarterialbleeding.1_Hemorrhage_from

pseudoaneurysms is considered a quite rare complication

ofacuteor morecommonly chronicpancreatitis,which is

thought to be caused by leakage of pancreatic enzymes

thaterodethewallofadjacentvisceralarteries.The

ves-selwallmayalsobedamagedbyischemiaandcompression

byinﬂammatoryornecroticcollections.Apseudoaneurysm

mayalsooccurafterbiliopancreaticsurgery.2_The_most

fre-quently involved vessels are the splenic artery in about

30---60%, the gastroduodenal artery in 20---25% and the

pancreatoduodenalarteryin10---15%ofthecases.

Involve-ment of the hepatic or left gastric arteries is even less

common.3_Bleeding_may_occur_into_the_{gastrointestinal}_tract

andpresent asmelena orhematochezia throughthemain

pancreaticduct(hemosuccuspancreaticus),intoa

pseudo-cyst/peripancreaticcollectionorintotheperitonealcavity.

Pseudoaneurysmhemorrhagemayoccurfromafewdaysto

severalyearsaftertheonsetofpancreatitis.4

Whenthisdiagnosisissuspected,contrast-enhancedCT

angiography is an excellent modality for identifying and

locatingthepseudoaneurysmaswellasitcandemonstrate

featuresofchronicpancreatitis.Itmayshowsimultaneous

opaciﬁcationofananeurysmalarteryandpseudocystor

pen-etrationofcontrastwithinapseudocyst afterthearterial

phase.5 _This _is _necessary _for _subsequent_selective

angiog-raphy, the gold standard method for deﬁnitive diagnosis

andtreatmentofpseudoaneurysms.Proximalembolization

withcoilsisthepreferredtechniqueandhasreplaced

sur-gical ligation of the damaged artery as the best method

for treatment.6 _Injection_of _a _haemostatic_gelatin _sponge

(spongostan®), cyanoacrylate, thrombin or placement of

covered stents may also be useful. Published case series

include a relatively low number of cases, but show that

embolizationis a safemethod withhigh success rateand

relativelylowriskofrecurrenceorischemia.7,8_To_the_best

of our knowledge, thereis only oneother case report of

a pseudoaneurysm complicating a probable drug-induced

acutepancreatitis.3

According to Badalov classiﬁcation,9 _cyclosporine _is

a class III drug concerning the risk of inducing acute

casesinmedicalliterature,butwithnoconsistentlatency

timebetweenexposuretothedrugandensuingsymptoms

or evidenceof positiverechallenge. Thosecases occurred

in post-transplant setting.10 Despite the paucity of

clini-calreportsabout cyclosporine-inducedacutepancreatitis,

thereisanexperimentalmodelthatsuggestsadeleterious

roleforthedruginpancreastransplantrecipients,causing

pancreatitismoreoftenthantacrolimus.11_Since_rechallenge

isnotanoptionduetoobviousmedicalandethicalconcerns,

diagnosisofdrug-inducedpancreatitisreliesoncareful

his-torytakingandhighindexofsuspicion.

2. Case

report

We presentthe case ofa 40year-oldfemalepatientwith

a medical history of severe systemic lupus

erythemato-sus(SLE)andsecondaryanti-phospholipidicsyndrome,with

past episodesof venous thrombosis (pulmonary and deep

venous thrombosisin 2008)thatledtoplacementofa

ﬁl-ter in the inferior vena cava and in the right iliac vein.

The patient was anticoagulated with warfarin. She was

alsotakingprednisolone,hydroxychloroquine,ramipril,

ser-traline and alprazolam. Due to lupus reactivation, she

was recently medicated with cyclosporine. There was no

historyof alcoholconsumption,familialhistoryof

pancre-atitis, cholelithiasis or hypertriglyceridemia. There were

also no previous endoscopic or surgical abdominal

inter-ventions. Two weeks after being prescribed with 150mg

ofcyclosporine,shewasadmittedtotheemergencyroom

with acute epigastric abdominal pain with lumbar

irradi-ation, fever, nausea and vomiting that started four days

before admission. Elevated levels of amylase and lipase

(morethanthreetimesabovetheuppernormallimit)

sup-portedthe diagnosisof acutepancreatitis.Therewereno

Ranson criteria at admission, BISAP score (bedside index

forseverityinacutepancreatitis)waszeroandtherewere

no signs of organ failure or SIRS (systemic inﬂammatory

responsesyndrome).Threedaysafteradmission,thepatient

sufferedalipothymiaandabriskfallinherhemoglobin

lev-elswasnoticed(from119g/Lto64g/L).AnabdominalCT

wasconducted revealing a peripancreaticacute ﬂuid

col-lection with active bleeding within (Figs. 1 and 2). The

collectiondeveloped about aweek afterdisease onset.It

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Figure1 Peripancreaticcollectionwithspontaneously hyper-densecontentsuggestiveofhematoma(arrows)(abdominalCT, beforecontrastadministration).

Figure 2 Pseudoaneurysm with active bleeding (triangle)

within the peripancreatic collection (arrows) (abdominal CT, arterialphase,maximumintensityprojectionreformation).

artery into the right gastroepiploic artery and the

ante-riorsuperior pancreaticoduodenalartery. The patientwas

transferredtoourcenterfor an angiographyoftheceliac

trunkandsuperiormesentericartery.Twopseudoaneurysms

inthegastroduodenalandpancreatoduodenalarterieswith

activebleedingwerediagnosedandsuccessfullyembolized

withtwocoils(Figs.3and4).Theprocedurewas

success-fulandtherewerenosignsofiatrogenicregionalischemia,

which could occur due tolimited blood supply caused by

theembolization.Initially,thepatientwasunstable,buther

hemodynamicstatusimprovedwithadequateﬂuid

resusci-tation,freshplasmaandpackedredbloodcellstransfusion.

Aftercontrollingthehemorrhage,itwasdecidedto

imme-diately restart anticoagulation, given the major risk of

thrombosisin apatientwithphospholipidicsyndrome and

aﬁlterin theinferior venacava. The followingweek was

uneventful and the patient was discharged and told to

maintainthesamemedication, includingcyclosporineand

enoxaparin. About one week after being discharged, the

patienthadarecrudescenceoftheabdominalpainandwas

againadmittedtoherlocalhospital.Inthe followingday,

a newsudden fall in hemoglobinlevels occurred (123g/L

Figure 3 Saccular pseudoaneurysm in the gastroduodenal

artery(arrow)beforeembolizationwasperformed(ﬁrst angiog-raphy).

Figure4 Embolizationwithtwocoilsinthegastroduodenal

artery(bluearrow)andinabranchofthesuperiormesenteric artery(redarrow)(ﬁrstangiography).

to48g/L)andasecond angiographywasperformed.Again

there were signs of active bleeding into the

peripancre-aticcollectionandthegastroduodenalarterywasembolized

withathirdcoil(Figs.5and6).Theprocedurewassuccessful

andtherewasafavorableevolutionwithnosignsof

hem-orrhageuntildischarge.Afterconsultingwiththepatient’s

Rheumatologist,it was decidedto stop cyclosporine asit

probablycausedthepancreatitis.Untilthisdate,thepatient

remainswellandwithoutfurthercomplications.

3. Discussion

Several issues regarding this case merit careful analysis.

First,theetiologyofthepancreatitisshouldbediscussed.

Afterathoroughmedicalhistory,mostcausesof

pancreati-tiswereexcluded.Thepatienthadnohistoryofalcoholism

or smoking, recent acute illness, abdominal trauma or

surgery.Therewasnofamilialhistoryof pancreatitis.She

deniedcomplaintsoflong-standingabdominalpain,weight

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Figure 5 Recurrence of bleeding from the gastroduodenal artery(arrow)(secondangiography).

Figure 6 A third coil was inserted in the gastroduodenal

arterywithsuccessfulembolizationofthisvessel(greenarrow) (secondangiography).

Laboratory analysis excluded hypertriglyceridemia and

hypercalcemia aspotential causes aswell. There was no

elevationofhepaticenzymesorbileductdilationsuggestive

ofmicrolithiasis.AbdominalultrasoundandCTscanshowed

nosignsofcholelithiasis,bilio-pancreaticlesionsorchronic

pancreatitis (CP). However, in early stage CP, imaging

methods may show only minimal changes. Endoscopic

ultrasonography(EUS)hasbeenshowntobehighlyaccurate

for the identiﬁcation of gallbladder sludge/microlithiasis,

common bile duct stones, and pancreatic diseases

(pan-creaticneoplasmsandchronicpancreatitis)12_and_would_be

usefultoexcludethesediagnosesinourpatient.Inpatients

considered to have idiopathic acute pancreatitis, after

negativeinitial work-upfor biliaryetiology,EUSis

recom-mendedastheﬁrststeptoassessforoccultmicrolithiasis,

neoplasmsandchronicpancreatitis.13

Concerning medication, only cyclosporinewasrecently

introduced. Prednisolone and ramipril are also potential

agents of drug-induced acute pancreatitis. However, the

patientwastakingthesemedicationsforoverthreeyears.

pancreaticﬂuids(e.g.,corticosteroids)intravascular

throm-bosis(withestrogens)oraccumulationofatoxicmetabolite

(drugssuchasvalproicacidortetracyclines).14_Due_to_this

varietyof causativemechanisms,thetimebetween

expo-sure to the drug and initial symptoms may be as short

as a few days for immunologicreactions or even several

monthsifthereisslowaccumulationoftoxins.Therewas

noeosinophiliaorskin rash,buttheseﬁndingsareseldom

foundinsuchcases.

Anotherpossibleetiology for thisepisodeis lupus

pan-creatitis.Itis aquiterareandill-deﬁned entity.Ithasno

speciﬁc diagnostic criteria and it usually occurs during a

ﬂare of SLE. Usually its treatment is based in high-dose

corticosteroids.15 _The _patient_recently _had_a _ﬂare_of_SLE.

However, her full recovery from it and being medicated

with a potent immunosuppressive agent like cyclosporine

andalowdoseofcorticosteroidsargueagainstthis

diagno-sis.Furthermore,accordingtothepatient’sRheumatologist,

therewerenosignsofanewSLEﬂarewhenthepancreatitis

occurred---absenceofcytopenias,rash,renalor

neurologi-calabnormalities.DuetothequiescentstatusofSLE,itwas

consideredrelativelysafetosuspendcyclosporine.Therisk

ofanewepisodeofpancreatitisandhemorrhagewas

con-sidered moresigniﬁcantandlife-threatening thanthe risk

ofanewﬂareofSLE.

Anotherpertinentclinicalissuewasthedecisionto

rein-stateanticoagulation.Whenperitonealhemorrhagewasﬁrst

suspected,anticoagulationwassuspendedbutaftertheﬁrst

embolization,itwasdecidedtorestartitafewhourslater.

The recurrenceofthehemorrhagewasprobablybolstered

bythisdecision.However,giventheveryhighriskof

throm-bosisduetothephospholipidicsyndromeandtwovascular

ﬁlters, it would be at least equally risky not to restart

anticoagulation.Inthesehigh-riskpatients,thedecisionto

suspendorrestartanticoagulationshouldbemadeina

case-by-casebasis.Inourpatient’scase,theﬁrstangiographywas

successful and there were apparently no technical issues

that could have contributed to the rebleeding episode.

There is probably no advantage in switching to the new

oral anticoagulants(NOACs), astheirrisk of

gastrointesti-nalorabdominalbleedingisatleastsimilartooldervitamin

Kantagonists.16

Bothangiographieswere life-savingprocedures for our

patient. This case highlights the importance of having a

24-hour interventional radiology teamoncall with

exper-tiseintheseprocedures.Whenavailable,angiographywith

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hemostasis.Itssuccessratesarehighbutrebleedingisnot

an uncommonevent(upto19---23%).17 _Surgery _remains_an

importanttreatmentmodalityespeciallyinmassive

bleed-ing,afterembolizationorstentingfailureorfortreatment

of the underlying condition (e.g., bleeding from a

post-operativepseudoaneurysm).

Inconclusion,whenevaluatingapatientadmittedforan

acutepancreatitiswithaseveregastrointestinalbleeding,

hemoperitoneum or hemodynamic instability, hemorrhage

fromapseudoaneurysm shouldbesuspected and

immedi-atelytreatedifpresent.Tothebestofourknowledge,this

is only the second described case of hemorrhage from a

pseudoaneurysmafterdrug-inducedacutepancreatitis.

Ethical

disclosures

Protection of human and animal subjects.The authors

declarethatnoexperimentswereperformedonhumansor

animalsforthisstudy.

Conﬁdentialityofdata.Theauthorsdeclarethattheyhave

followedtheprotocolsoftheirworkcenteronthe

publica-tionofpatientdata.

Righttoprivacyandinformedconsent.The authorshave

obtained the written informedconsent ofthe patients or

subjectsmentionedinthearticle.Thecorrespondingauthor

isinpossessionofthisdocument.

Conﬂicts

of

interest

Theauthorshavenoconﬂictsofinteresttodeclare.

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