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Clinical case
Drug-Induced Acute Pancreatitis and Pseudoaneurysms: An Ominous Combination
Pancreatite Aguda Medicamentosa e Pseudoaneurismas: Uma Combinação Tenebrosa
Diogo Branquinho
Corresponding author
diogofbranquinho@yahoo.com

Corresponding author.
, Daniel Ramos-Andrade, Luís Elvas, Pedro Amaro, Manuela Ferreira, Carlos Sofia
Gastroenterology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">1</span><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Most cases of pancreatitis are mild and have a favorable prognosis&#46; However they can also be present with a severe form and have ominous complications&#46; Vascular events range from asymptomatic venous thrombosis to severe life-threatening arterial bleeding&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">1</span></a> Hemorrhage from pseudoaneurysms is considered a quite rare complication of acute or more commonly chronic pancreatitis&#44; which is thought to be caused by leakage of pancreatic enzymes that erode the wall of adjacent visceral arteries&#46; The vessel wall may also be damaged by ischemia and compression by inflammatory or necrotic collections&#46; A pseudoaneurysm may also occur after biliopancreatic surgery&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">2</span></a> The most frequently involved vessels are the splenic artery in about 30&#8211;60&#37;&#44; the gastroduodenal artery in 20&#8211;25&#37; and the pancreatoduodenal artery in 10&#8211;15&#37; of the cases&#46; Involvement of the hepatic or left gastric arteries is even less common&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">3</span></a> Bleeding may occur into the gastrointestinal tract and present as melena or hematochezia through the main pancreatic duct &#40;<span class="elsevierStyleItalic">hemosuccus pancreaticus</span>&#41;&#44; into a pseudocyst&#47;peripancreatic collection or into the peritoneal cavity&#46; Pseudoaneurysm hemorrhage may occur from a few days to several years after the onset of pancreatitis&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">When this diagnosis is suspected&#44; contrast-enhanced CT angiography is an excellent modality for identifying and locating the pseudoaneurysm as well as it can demonstrate features of chronic pancreatitis&#46; It may show simultaneous opacification of an aneurysmal artery and pseudocyst or penetration of contrast within a pseudocyst after the arterial phase&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">5</span></a> This is necessary for subsequent selective angiography&#44; the gold standard method for definitive diagnosis and treatment of pseudoaneurysms&#46; Proximal embolization with coils is the preferred technique and has replaced surgical ligation of the damaged artery as the best method for treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">6</span></a> Injection of a haemostatic gelatin sponge &#40;spongostan&#174;&#41;&#44; cyanoacrylate&#44; thrombin or placement of covered stents may also be useful&#46; Published case series include a relatively low number of cases&#44; but show that embolization is a safe method with high success rate and relatively low risk of recurrence or ischemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">7&#44;8</span></a> To the best of our knowledge&#44; there is only one other case report of a pseudoaneurysm complicating a probable drug-induced acute pancreatitis&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">According to Badalov classification&#44;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">9</span></a> cyclosporine is a class III drug concerning the risk of inducing acute pancreatitis&#44; which means that there are at least two known cases in medical literature&#44; but with no consistent latency time between exposure to the drug and ensuing symptoms or evidence of positive rechallenge&#46; Those cases occurred in post-transplant setting<span class="elsevierStyleInf">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">10</span></a> Despite the paucity of clinical reports about cyclosporine-induced acute pancreatitis&#44; there is an experimental model that suggests a deleterious role for the drug in pancreas transplant recipients&#44; causing pancreatitis more often than tacrolimus&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">11</span></a> Since rechallenge is not an option due to obvious medical and ethical concerns&#44; diagnosis of drug-induced pancreatitis relies on careful history taking and high index of suspicion&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle" id="sect0030">Case report</span><p id="par0020" class="elsevierStylePara elsevierViewall">We present the case of a 40 year-old female patient with a medical history of severe systemic lupus erythematosus &#40;SLE&#41; and secondary anti-phospholipidic syndrome&#44; with past episodes of venous thrombosis &#40;pulmonary and deep venous thrombosis in 2008&#41; that led to placement of a filter in the inferior vena cava and in the right iliac vein&#46; The patient was anticoagulated with warfarin&#46; She was also taking prednisolone&#44; hydroxychloroquine&#44; ramipril&#44; sertraline and alprazolam&#46; Due to lupus reactivation&#44; she was recently medicated with cyclosporine&#46; There was no history of alcohol consumption&#44; familial history of pancreatitis&#44; cholelithiasis or hypertriglyceridemia&#46; There were also no previous endoscopic or surgical abdominal interventions&#46; Two weeks after being prescribed with 150<span class="elsevierStyleHsp" style=""></span>mg of cyclosporine&#44; she was admitted to the emergency room with acute epigastric abdominal pain with lumbar irradiation&#44; fever&#44; nausea and vomiting that started four days before admission&#46; Elevated levels of amylase and lipase &#40;more than three times above the upper normal limit&#41; supported the diagnosis of acute pancreatitis&#46; There were no Ranson criteria at admission&#44; BISAP score &#40;bedside index for severity in acute pancreatitis&#41; was zero and there were no signs of organ failure or SIRS &#40;systemic inflammatory response syndrome&#41;&#46; Three days after admission&#44; the patient suffered a lipothymia and a brisk fall in her hemoglobin levels was noticed &#40;from 119<span class="elsevierStyleHsp" style=""></span>g&#47;L to 64<span class="elsevierStyleHsp" style=""></span>g&#47;L&#41;&#46; An abdominal CT was conducted revealing a peripancreatic acute fluid collection with active bleeding within &#40;<a class="elsevierStyleCrossRefs" href="#fig0005">Figs&#46; 1 and 2</a>&#41;&#46; The collection developed about a week after disease onset&#46; It was located close to the bifurcation of the gastroduodenal artery into the right gastroepiploic artery and the anterior superior pancreaticoduodenal artery&#46; The patient was transferred to our center for an angiography of the celiac trunk and superior mesenteric artery&#46; Two pseudoaneurysms in the gastroduodenal and pancreatoduodenal arteries with active bleeding were diagnosed and successfully embolized with two coils &#40;<a class="elsevierStyleCrossRefs" href="#fig0015">Figs&#46; 3 and 4</a>&#41;&#46; The procedure was successful and there were no signs of iatrogenic regional ischemia&#44; which could occur due to limited blood supply caused by the embolization&#46; Initially&#44; the patient was unstable&#44; but her hemodynamic status improved with adequate fluid resuscitation&#44; fresh plasma and packed red blood cells transfusion&#46; After controlling the hemorrhage&#44; it was decided to immediately restart anticoagulation&#44; given the major risk of thrombosis in a patient with phospholipidic syndrome and a filter in the inferior vena cava&#46; The following week was uneventful and the patient was discharged and told to maintain the same medication&#44; including cyclosporine and enoxaparin&#46; About one week after being discharged&#44; the patient had a recrudescence of the abdominal pain and was again admitted to her local hospital&#46; In the following day&#44; a new sudden fall in hemoglobin levels occurred &#40;123<span class="elsevierStyleHsp" style=""></span>g&#47;L to 48<span class="elsevierStyleHsp" style=""></span>g&#47;L&#41; and a second angiography was performed&#46; Again there were signs of active bleeding into the peripancreatic collection and the gastroduodenal artery was embolized with a third coil &#40;<a class="elsevierStyleCrossRefs" href="#fig0025">Figs&#46; 5 and 6</a>&#41;&#46; The procedure was successful and there was a favorable evolution with no signs of hemorrhage until discharge&#46; After consulting with the patient&#39;s Rheumatologist&#44; it was decided to stop cyclosporine as it probably caused the pancreatitis&#46; Until this date&#44; the patient remains well and without further complications&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle" id="sect0035">Discussion</span><p id="par0025" class="elsevierStylePara elsevierViewall">Several issues regarding this case merit careful analysis&#46; First&#44; the etiology of the pancreatitis should be discussed&#46; After a thorough medical history&#44; most causes of pancreatitis were excluded&#46; The patient had no history of alcoholism or smoking&#44; recent acute illness&#44; abdominal trauma or surgery&#46; There was no familial history of pancreatitis&#46; She denied complaints of long-standing abdominal pain&#44; weight loss or steatorrhea that could suggest chronic pancreatitis&#46; Laboratory analysis excluded hypertriglyceridemia and hypercalcemia as potential causes as well&#46; There was no elevation of hepatic enzymes or bile duct dilation suggestive of microlithiasis&#46; Abdominal ultrasound and CT scan showed no signs of cholelithiasis&#44; bilio-pancreatic lesions or chronic pancreatitis &#40;CP&#41;&#46; However&#44; in early stage CP&#44; imaging methods may show only minimal changes&#46; Endoscopic ultrasonography &#40;EUS&#41; has been shown to be highly accurate for the identification of gallbladder sludge&#47;microlithiasis&#44; common bile duct stones&#44; and pancreatic diseases &#40;pancreatic neoplasms and chronic pancreatitis&#41;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">12</span></a> and would be useful to exclude these diagnoses in our patient&#46; In patients considered to have idiopathic acute pancreatitis&#44; after negative initial work-up for biliary etiology&#44; EUS is recommended as the first step to assess for occult microlithiasis&#44; neoplasms and chronic pancreatitis&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">13</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Concerning medication&#44; only cyclosporine was recently introduced&#46; Prednisolone and ramipril are also potential agents of drug-induced acute pancreatitis&#46; However&#44; the patient was taking these medications for over three years&#46; The remaining medication &#40;warfarin&#44; hydroxochloroquine&#44; sertraline and alprazolam&#41; were also prescribed a few years before this episode&#46; It seems more likely that cyclosporine was the culprit due to the short lapse of time between starting this medication and the beginning of clinical manifestations&#46; This is consistent to what is described in one of the case reports of cyclosporine-induced pancreatitis&#46; This supports our hypothesis as consistent latency time among cases is one of the criteria suggested in Badalov classification&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">9</span></a> Drug-induced acute pancreatitis is a rare entity&#44; difficult to diagnose since it has no distinguishing clinical features&#46; Several distinct mechanisms were suggested and include direct toxic effect &#40;such as furosemide&#41;&#44; immunologic reaction &#40;with 6-mercaptopurine or aminosalicylates&#41;&#44; ischemia &#40;for azathioprine&#41;&#44; increased viscosity of pancreatic fluids &#40;e&#46;g&#46;&#44; corticosteroids&#41; intravascular thrombosis &#40;with estrogens&#41; or accumulation of a toxic metabolite &#40;drugs such as valproic acid or tetracyclines&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">14</span></a> Due to this variety of causative mechanisms&#44; the time between exposure to the drug and initial symptoms may be as short as a few days for immunologic reactions or even several months if there is slow accumulation of toxins&#46; There was no eosinophilia or skin rash&#44; but these findings are seldom found in such cases&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Another possible etiology for this episode is lupus pancreatitis&#46; It is a quite rare and ill-defined entity&#46; It has no specific diagnostic criteria and it usually occurs during a flare of SLE&#46; Usually its treatment is based in high-dose corticosteroids&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">15</span></a> The patient recently had a flare of SLE&#46; However&#44; her full recovery from it and being medicated with a potent immunosuppressive agent like cyclosporine and a low dose of corticosteroids argue against this diagnosis&#46; Furthermore&#44; according to the patient&#39;s Rheumatologist&#44; there were no signs of a new SLE flare when the pancreatitis occurred &#8211; absence of cytopenias&#44; rash&#44; renal or neurological abnormalities&#46; Due to the quiescent status of SLE&#44; it was considered relatively safe to suspend cyclosporine&#46; The risk of a new episode of pancreatitis and hemorrhage was considered more significant and life-threatening than the risk of a new flare of SLE&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Another pertinent clinical issue was the decision to reinstate anticoagulation&#46; When peritoneal hemorrhage was first suspected&#44; anticoagulation was suspended but after the first embolization&#44; it was decided to restart it a few hours later&#46; The recurrence of the hemorrhage was probably bolstered by this decision&#46; However&#44; given the very high risk of thrombosis due to the phospholipidic syndrome and two vascular filters&#44; it would be at least equally risky not to restart anticoagulation&#46; In these high-risk patients&#44; the decision to suspend or restart anticoagulation should be made in a case-by-case basis&#46; In our patient&#39;s case&#44; the first angiography was successful and there were apparently no technical issues that could have contributed to the rebleeding episode&#46; There is probably no advantage in switching to the new oral anticoagulants &#40;NOACs&#41;&#44; as their risk of gastrointestinal or abdominal bleeding is at least similar to older vitamin K antagonists&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">16</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Both angiographies were life-saving procedures for our patient&#46; This case highlights the importance of having a 24-hour interventional radiology team on call with expertise in these procedures&#46; When available&#44; angiography with embolization is usually the preferred method to perform hemostasis&#46; Its success rates are high but rebleeding is not an uncommon event &#40;up to 19&#8211;23&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">17</span></a> Surgery remains an important treatment modality especially in massive bleeding&#44; after embolization or stenting failure or for treatment of the underlying condition &#40;e&#46;g&#46;&#44; bleeding from a post-operative pseudoaneurysm&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">In conclusion&#44; when evaluating a patient admitted for an acute pancreatitis with a severe gastrointestinal bleeding&#44; hemoperitoneum or hemodynamic instability&#44; hemorrhage from a pseudoaneurysm should be suspected and immediately treated if present&#46; To the best of our knowledge&#44; this is only the second described case of hemorrhage from a pseudoaneurysm after drug-induced acute pancreatitis&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Ethical disclosures</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Protection of human and animal subjects</span><p id="par0055" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Confidentiality of data</span><p id="par0060" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work center on the publication of patient data&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Right to privacy and informed consent</span><p id="par0065" class="elsevierStylePara elsevierViewall">The authors have obtained the written informed consent of the patients or subjects mentioned in the article&#46; The corresponding author is in possession of this document&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflicts of interest</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Rupture of pseudoaneurysms is rare but can be life-threatening complications of acute or chronic pancreatitis&#44; usually due to enzymatic digestion of vessel walls crossing peripancreatic fluid collections&#46; We report the case of a 40 year-old female&#44; with multisystemic lupus and anticoagulated for prior thrombotic events&#44; admitted for probable cyclosporine-induced acute pancreatitis&#46; Hemodynamic instability occurred due to abdominal hemorrhage from two pseudoaneurysms inside an acute peri-pancreatic collection&#46; Selective angiography successfully embolized the gastroduodenal and pancreatoduodenal arteries&#46; The hemorrhage recurred two weeks later and another successful embolization was performed and the patient remains well to date&#46; The decision to restart anticoagulants and to suspend cyclosporine was challenging and required a multidisciplinary approach&#46; Despite rare&#44; bleeding from a pseudoaneurysm should be considered when facing a patient with pancreatitis and sudden signs of hemodynamic instability&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Os pseudoaneurismas s&#227;o complica&#231;&#245;es raras mas graves da pancreatite aguda ou cr&#243;nica&#46; S&#227;o causados pela digest&#227;o enzim&#225;tica de art&#233;rias que atravessam colec&#231;&#245;es inflamat&#243;rias&#46; Descreve-se o caso de uma doente do sexo feminino&#44; de 40 anos&#44; com l&#250;pus sist&#233;mico e anticoagulada por trombose venosa profunda&#44; admitida por pancreatite aguda associada &#224; ciclosporina&#46; Apresentou sinais de hemorragia abdominal causada por dois pseudoaneurismas dentro de uma colec&#231;&#227;o peri-pancre&#225;tica&#46; Foi ent&#227;o realizada angiografia com emboliza&#231;&#227;o da art&#233;ria gastroduodenal e pancreatoduodenal&#46; Houve recidiva duas semanas depois&#44; com necessidade de nova emboliza&#231;&#227;o bem-sucedida&#46; A decis&#227;o de suspender a ciclosporina e reintroduzir anticoagulantes nesta doente de alto-risco &#233; controversa&#46; Apesar de raros&#44; os pseudoaneurismas devem ser considerados perante um doente com pancreatite e sinais de hemorragia&#46;</p></span>"
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ISSN: 23414545
Original language: English
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

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Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos