Hemosuccus pancreaticus:a rare cause of gastrointestinal bleeding

Harbin,China

Introduction

An upper gastrointestinal (GI) hemorrhage which is discharged from the papilla of Vater via the pancreatic duct is referred to as hemosuccus pancreaticus (HP).Although this condition was first reported in 1931,[1]the formal name was first coined by Sandblom in his report on three patients who had ruptured pseudoaneurysms in the pancreatic duct and were experiencing GI bleeding.[2]HP is a rare cause of acute alimentary tract bleeding that is predominantly observed in men (male-to-female ratio of 7:1) and is highly correlated with chronic alcohol ingestion.The mean age of onset is 50 to 60 years old.[3]Other terms have been used to describe this syndrome,including Wirsungorrhage,[4]equivalent hemowirsungia,[3]Santorinirrhage,[5]pseudohemobilia[6]and hemoductal pancreatitis.[7,8]In the medical literature,HP is mostly limited to case reports.Because of its rarity,only approximately 100 cases have been reported in the literature.[9]Its relatively nonspecific presentation makes HP challenging to diagnose and treat.

We searched the relevant literature that was published from January 1967 to September 2011 in the PubMed database using the following search terms:"hemosuccus pancreaticus", "wirsungorrhage", "santorinirrhage","pseudohemobilia","hemoductal pancreatitis" or any other alias name describing this condition.Additional search terms including "pancreatitis-related pseudoaneurysm/aneurysm","hemorrhagic pseudocyst" or "pancreatic gastrointestinal hemorrhage/hemorrhage/bleeding" were used to prevent omission.Furthermore,we manually searched the reference lists of identified articles tofind relevant articles.Then,we systematically reviewed the etiology,pathophysiology,clinical presentation,diagnosis and treatment of HP in these articles.

Etiology

There are many potential causes of HP,including acute or chronic pancreatitis,tumors or vessel malformation.We summarize all the causes in the Table and introduce them in detail in the text.

Acute and chronic pancreatitis

HP usually occurs as a complication of acute or chronic pancreatitis.[10]During an episode of acute pancreatitis,HP occurs after necrosis of arterial walls (e.g.,splenic artery,gastroduodenal artery and duodenopancreatic arcade) or rupture of pseudoaneurysms originating from the enzymatic destruction of these arterial walls.[3]When the involved artery or pseudoaneurysm is opened to the pancreatic duct,blood may enter the duct and empty from the papilla into the duodenum.

The most common cause of HP is pseudoaneurysm formation secondary to chronic pancreatitis.It has been reported that arterial pseudoaneurysms and aneurysms are common in patients with chronic pancreatitis (10%).[11,12]The two relatively independent diseases are often associated,but no causal relationship has been established.[3]Local chronic in flammation is usually combined with the local release of elastase,which leads to either auto-digestion of peripancreatic vessels or erosion of a concomitant pseudocyst into the artery.[13]In this way the pseudocyst is converted into a pseudoaneurysm.[14,15]Then the pseudoaneurysm communicates with the pancreatic duct[16]through a pancreatic pseudocyst or afistula secondary to the destruction of its walls by enzymatic injury and compression.When a pseudoaneurysm ruptures,HP occurs.Finally,vascular ulceration by a dilated and cystic main pancreatic duct is another mechanism of pseudoaneurysm formation.[3]

The splenic artery is the most commonly involved vessel (60%-65%),most likely because the majority of its route is adjacent to the pancreas.A pseudoaneurysm of any other peripancreatic or intrapancreatic vessels,such as the hepatic (5%-10%),gastroduodenal (20%-25%),pancreaticoduodenal (10%-15%),left gastric (2%-5%)arteries,[17-21]superior mesenteric arteries[22]or splenic veins,[23]has also been reported as a source of bleeding.

Another major cause of HP is pancreatolithiasis secondary to chronic pancreatitis.Ductal calculi compress the pancreatic tissue to cause pancreatic duct wall necrosis and subsequent vascular ulceration,thus leading to pseudoaneurysm formation[8,24,25]and ultimately hemorrhage.

Unlike the situation described above,Shah and Barkin[26]introduced a new mechanism of HP,in which upper GI bleeding originated from a pseudoaneurysm via erosion into the duodenum and creates afistula.

Mizutamari et al[27]reported a case of hereditary pancreatitis complicated by HP.Hereditary pancreatitis,a rare type of pancreatic in flammatory disorder,is caused by R122H mutation in the cationic trypsinogen gene.This mutation leads to pancreatitis by altering a trypsin recognition site associated with the inactivation of trypsin within the pancreas and prolonged the activityof the mutated trypsin enzyme.

Table.All possible causes of HP

Tumors

Although the major cause of HP is pancreatitis,pancreatic tumors can also lead to HP.[28]Either primary or metastatic benign or malignant tumors can result in HP.At present,there are onlyfive reported cases in the English literature and four cases in the Japanese literature.

Pancreatic carcinoma,serous cystic neoplasm,microcystic adenoma,primary pancreatic lymphoma and neuroendocrine tumors[9,29-33]are all associated with HP.[34]Metastatic cancer,especially renal cell carcinoma(RCC),can also lead to HP.Tongio et al[35]found that intestinal bleeding was the presenting symptom in 60%of patients who suffered from metastatic RCC to the pancreas.Kassabian et al[36]and Kurland et al[37]also reported several cases of metastatic RCC to the pancreas,which were manifested by HP.

Vascular diseases

Approximately 20% of HP cases correspond to vascular anomalies.[9]There are several causes for the anomalies,including atheroma,hereditary dystrophy of elastic tissue (Marfan disease and Ehlers-Danlos syndrome),fibromuscular dysplasia of the arterial wall,portal hypertension,syphilis,vasculitis (particularly periarteritis nodosa) and α-1 anti-trypsin deficiency.[38]

Most patients with arterial anomalies have aneurysms of digestive arteries.The splenic artery is the third most common site for intra-abdominal aneurysms,after the abdominal aorta and iliac arteries,and is the most common site for splanchnic arterial aneurysms.[39]True splenic artery aneurysms account for approximately 60% of splanchnic artery aneurysms and occur mostly in women (male-to-female ratio of 1:4).[40]They are generally located in the middle and distal segments of the artery,and they may be solitary or occur in different times.Their characteristic feature is a diffuse enlargement of the vessel.These aneurysms are usually asymptomatic,but in some cases a primary splenic artery aneurysm ruptures into the pancreatic duct via a pseudocyst[41-43]or pancreatic tumor,[6]thereby leading to HP.

Fazel et al[44]reported a rare case of HP associated with a celiac trunk true aneurysm.Wang et al[45]reported a case caused by a spontaneous celiac trunk dissection.

Naitoh et al[46]and Obara et al[47]reported two cases of HP caused by a primary splenic artery aneurysm associated with segmental arterial mediolysis (SAM).SAM is a rare,non-atherosclerotic,non-in flammatory vascular disease of unknown cause that is characterized by vacuolization and lysis of cells of the arterial smooth muscle.SAM lesions are most commonly observed in the branches of the superior mesenteric artery and the celiac artery,where they exhibit a "skip" pattern.[46,47]The most common presentation of patients with SAM is intraabdominal hemorrhage caused by the rupture of the aneurysm.[46,47]

According to the literature,atherosclerotic aneurysms and intrapancreatic arteriovenous malformations that are secondary to hereditary telangiectasia can also lead to HP.[30]

Iatrogenic disease

The development of endoscopic techniques has led to additional complications.Some cases of HP caused by medical procedures involving the pancreas have been reported.

Intracystic hemorrhage occurs in up to 6% of endoscopic ultrasound-guidedfine needle aspiration (EUSFNA) procedures used to treat pancreatic cysts; however,only two cases have resulted in HP.[48,49]Seicean et al[50]reported a case secondary to a splenic arterialfistula that was caused by the penetration of a pancreatic stent after the drainage of pancreatic collection.Endoscopic ultrasonography (EUS) performed after a digestive hemorrhage revealed a plastic pancreatic stent in the pancreatic duct with the distal end penetrating the splenic artery.HP may also occur as a complication of endoscopic retrograde cholangiopancreatography (ERCP).[3]

Congenital abnormalities

HP may be caused by several congenital abnormalities.[5]Heterotopic pancreas is a rare congenital anomaly defined as pancreatic tissue that is located outside of its normal anatomical site and lacks both anatomic and vascular connections.Ninety percent of heterotopic pancreas tissue is located in the upper GI tract.[51]Symptoms include abdominal pain,nausea,vomiting and bleeding.[51]However,ectopic pancreas is not often diagnosed because many patients are asymptomatic.[51]Meneu et al[51]reported a 29-year-old man with severe and acute GI hemorrhage through the duct of a heterotopic pancreas that was located in the upper jejunum with no definitive histological or clinical evidence of pancreatic in flammation.In the literature,HP may also occur in the setting of pancreas divisum.[32]Suttor et al[52]described a case of HP associated with the pancreas divisum in a patient with multiple endocrine neoplasia type 1 (MEN-1) syndrome.

Rare causes

Some causes of HP are relatively rare.One of these rare causes is infection.Belo et al[53]reported that a 75-year-old male dairy farmer with a pancreatic mass was diagnosed with HP secondary to chronic pancreatic brucellosis.Hisfinal episode of bleeding was due to the rupture of a mycotic pseudoaneurysm originating from the splenic artery inside of the pancreatic duct in the setting of a chronic Brucella infection and in flammation.In the literature,mycotic and syphilitic aneurysms have also induced hemorrhage via the pancreatic duct.[54]

Blunt or penetrating abdominal trauma can also lead to HP.However,the essence is the formation of a post-traumatic pseudoaneurysm.Kim et al[55]described a case of massive HP induced by the rupture of a posttraumatic pseudoaneurysm arising from an anomalous right hepatic artery originating from the superior mesenteric artery that was caused by a gunshot to the upper abdomen.

Although it was not directly related to the primary condition,Izadyar et al[56]reported a 33-year-old man with Glanzmann thrombasthenia who was diagnosed with HP.

Pathophysiology

Bleeding induced by the various causes described above flows into the pancreatic duct or pseudocyst.As the blood coagulates and obstructs the drainage passage,[2]the pressure within these structures increases to temporarily tamponade the hemorrhage.Meanwhile,this increased pressure not only causes the abdominal pain experienced by the patient but also may lead to hyperamylasemia due to the pancreatic enzymes entering blood stream.[12,13,16,23,25,30,31,57-59]Hemorrhage then recurs days or even weeks later after the intraductal or intracystic clot dissolves.Thus,HP is characterized by intermittent and repetitive bleeding.

Clinical presentation

Patients with HP usually present with the triad of abdominal pain (epigastralgia),GI hemorrhage and hyperamylasemia,[1]just as the triad of abdominal pain,GI hemorrhage,and jaundice is the typical presentation of hemobilia.[2]

This typical presentation is associated with intermittent abdominal pain and digestive bleeding.The epigastric pain,which usually radiates posteriorly,[60]is caused by increased intraductal pressure due to acute distention of the main bile duct with blood.[61,62]Digestive bleeding,which is generally melena or hematemesis but could more rarely be hematochezia,occurs 48 hours later,relieving the pain.These types of pain and time sequence are pathognomonic signs of HP.Additionally,the intermittent and repetitive nature of the bleeding,which is caused by the formation and dissolution of a clot in the main pancreatic duct or pseudocyst,[38]is very specific.[9,55]Although the hemorrhage is often due to arterial bleeding,it is typically not severe enough to induce hemodynamic instability.[55]However,on rare occasions,the bleeding is so acute and massive to induce hemorrhagic shock.[38,63]Because of the repeated GI bleeding (including occult bleeding),patients may present with the signs and symptoms of anemia.[1]

An elevated serum amylase level is common in HP[1,46]and may be due to increased intraductal/intracystic pressure.Other clinical signs are more dramatic,including vomiting,weight loss,jaundice secondary to pancreatobiliary re flux due to clot obstruction[64]or palpable pulsating epigastric mass with a systolic thrill in the setting of an aneurysm.[38]Iron deficiency is common,but liver function tests are generally normal apart from increased serum bilirubin in the event of pancreatobiliary re flux.[3]

Diagnosis

The diagnosis of this condition is extremely difficult because it is rare and its symptoms are intermittent.When encountering such patients,we must differentiate them carefully.Abdominal pain,GI hemorrhage,and hyperamylasemia usually suggest HP,especially in patients with a history of pancreatic disease,such as tumors,vascular disease and chronic pancreatitis.Specifically,the typical recurrent episodes of spontaneously resolving acute epigastric pain radiating to the back are always followed by melena,and they are almost pathognomonic signs for HP.

In addition,a variety of diagnostic techniques (i.e.,endoscopy,CT,angiography) can be used to make an accurate diagnosis.Despite the availability of these techniques,it is still difficult to correctly diagnose HP during the first episode of GI bleeding.We designed a brief diagnostic and therapeutic flow chart,shown in Fig.

Endoscopy

Fig.A brief diagnostic and therapeutic flow sheet.

Endoscopy,including gastroscopy,duodenoscopy,colonoscopy and small intestinal endoscopy,is a most useful and indispensable tool for detecting lesions that may cause hemorrhage of the upper and lower digestive tracts.Endoscopy is also used to distinguish HP from other common causes of GI bleeding,such as peptic ulcers,esophageal and gastric fundus varices and erosive gastritis.[1,3,38]At time of endoscopy,when bloody pancreatic juice exuding from the papilla of Vater is observed,a diagnosis of either HP or hemobilia is reliable.[1]Furthermore,HP should be considered when blood with no obvious source is found in the descending part of the duodenum.[1]Upper GI endoscopy can detect active bleeding via the papilla in 30% of patients.[9]Because the characteristics of HP occur intermittently,endoscopy is rarely sufficient to make an initial precise diagnosis.It is sometimes necessary to examine the patient on several occasions to identify the problem,but negative endoscopy outcome can not exclude the possibility of HP.If this examination is not relevant,other diagnostic procedures (i.e.,radiology or other imaging techniques) are required.

ERCP may either arouse suspicion or confirm a diagnosis of HP.An intraductalfilling defect suggests that blood clots are present or that,more rarely,a pseudoaneurysm is compressing the pancreatic duct lumen.Imaging findings of chronic pancreatitis and the pseudocyst communicating with afilling defect further suggest HP.[62]Often ERCP can detect a lesion under direct visualization,and some therapeutic measures,such as papilla sphincterectomy,can be addressed immediately to assist the total treatment.[65]

EUS is an extraordinary procedure that can guide the diagnosis of GI bleeding and direct therapy to a specific anatomical location.EUS imaging provides many important details that re flect local pathological changes,such as the appearance,size,and precise location of the lesion,as well as information about the surrounding vascular anatomy.Therefore,EUS can be used to guide therapy precisely to the location of the lesion based on intraluminal endoscopic visualization,which is not possible with any other hemostatic techniques.[66]

Angiography

Angiography,especially selective arteriography of the celiac trunk and superior mesenteric artery,represents the optimal imaging tool for detecting HP.In patients with an undetermined source of upper GI bleeding,especially those with a history of pancreatic disorders,this approach can precisely localize the presence of a pseudoaneurysm or aneurysm originating from the splenic,common hepatic or gastroduodenal artery.[61]The sensitivity of angiography is 96%,[55]which can help to establish a definitive diagnosis.However,this technique may fail to localize the bleeding source because the hemorrhage is usually intermittent.However,if the hemorrhage is localized,angiography is useful for not only locating the source but also arresting the bleeding with transcatheter embolization (TAE).

Ultrasonography

Ultrasonography can be used to visualize pancreatic pseudocysts or aneurysms of the peripancreatic arteries and other features of acute or chronic pancreatitis,such as peripancreatic fluid collections,pancreatic calcification and atrophy of the pancreas.Doppler ultrasound and dynamic ultrasound are reported to be diagnostic of HP,[11,67]especially when assisted by contrast substances.[68]

Abdominal CT and MRI

As a supplementary approach for diagnosing HP,abdominal CT may visualize a pseudoaneurysm adjacent to or within a pseudocyst and can even visualize the typical findings of clotted blood in the pancreatic duct known as the sentinel clot.[69]Contrast-enhanced CT is an outstanding technique for illustrating pancreatic pathology,including the traits of chronic pancreatitis,pseudoaneurysms and pseudocysts,[70]and it can sometimes directly diagnose HP.[71,72]

Contrast-enhanced CT and angiography generally require an intravenous injection with a large amount of iodinated contrast medium.If a patient is allergic to iodine,this procedure is contraindicated to apply these procedures.Miki et al[73]reported one case of HP secondary to chronic pancreatitis which was diagnosed by gadolinium-enhanced magnetic resonance imaging(MRI) using carbon dioxide as the contrast medium as well as successful treatment by TAE of the splenic artery with metallic coils.

Radionuclide tests

As a conventional diagnostic tool for hemorrhage,radionuclide tests such as the 99mTc-tagged red blood cell scintiscan are thought to be of little use for diagnosing HP because its symptoms are intermittent.[1]However,Izadyar et al[56]recently reported a case of HP for which red blood cell scintigraphy was used to diagnose this condition using 740 MBq 99mTc-tagged red blood cells.

Treatment

There are two main therapeutic options for this condition:angiographic embolotherapy and surgery.Supportive treatment alone is not recommended because that will lead to a mortality rate of more than 90%.[74]

Once the patient's hemodynamic situation is relatively stable,interventional radiographic methods are the first choice for initial treatment,with immediate good results in 79%-100% of cases and an overall success rate of 67%,including re-embolization for recurrent bleeding.[75-78]Two main techniques can be used:balloon obstruction and the placement of prosthetic material.Inserting a balloon to obstruct the involved artery before open surgery can limit bleeding and shorten the operative time,particularly in the event of portal hypertension secondary to thrombosis of the splenic vein or massive hemorrhage.[9]The balloon can be de flated and left in place for a secondary use if needed.Coil embolization techniques stimulate thrombus formation in the aneurysm but also occlude the entire artery.[79]Ischemia can develop in the tissue that is supplied by the artery if the collateral circulation is insufficient.Embolization of the celiac trunk,superior mesenteric or common hepatic artery is contraindicated.[79]In addition,aneurysm infection and splenic infarction are other possible complications.[1]As reported previously,patients were usually free from recurrent hemorrhage after exclusive endovascular treatment,but they had a recurrence rate of 30% and mortality rates ranging from 6% to 33%.[70,76,77,80]

Surgical treatment is indicated for uncontrolled hemorrhage, persistent shock, rebleeding after initial embolization and when embolization is not feasible or successful.[3,77]Ligature of the pancreatic ducts can be used as a conservative surgery,but the results are unsatisfactory because the original lesion remains present.Exclusion of the pseudoaneurysm with proximal and distal arterial ligation is not recommended for pseudoaneurysms originating from the pancreaticoduodenal and gastroduodenal arteries because there is a high recurrence rate due to the abundant collateral supply.However,exclusion using a shunt to the proper hepatic artery may be acceptable for lesions in the common hepatic artery.[42,58]More aggressive surgery,such as pancreatic resection,simultaneously solves pancreatic and arterial diseases but increases the difficulty of the operation.In patients with indications for surgery,such as severe and incapacitating pain due to chronic pancreatitis,compression of the bile duct or duodenum by in flammatory mass and suspicion of malignancy,pancreaticoduodenectomy or splenopancreatoectomy are preferred.[3]In some cases,high morbidity and mortality rates,severe local in flammatory response,and abdominal adhesion are contraindicated for pancreatic resection.In these cases,drainage of the pancreatic pseudocyst associated with arterial ligation is uniquely effective when a pseudocyst is present,but there is a high rate of complications including infection,necrosis and recurrence.[81,82]In the absence of a pseudocyst and when pancreatic resection is not an option,excluding pseudoaneurysm may be the safest treatment of choice.[1]Selective embolization can be performed before surgery to stabilize the hemodynamic situation.[9,13]Most of these surgical procedures have shown the success rates of 70%-85% and rebleeding rates of 0%-5%.[10,21,22,83]Operative mortality rates of 10%-50% have been reported in the literature with the initial hemodynamic state,transfusion requirement and category of pancreatitis affecting survival.[77,84]

During a non-bleeding episode,if HP is suspected,an endoscopic or radiologic diagnosis and successful transcatheter embolization should be performed regardless of whether the patient shows signs of active bleeding.[85]

Recently,new HP treatments have gradually emerged,but their therapeutic effectiveness and safety must be confirmed.Will et al[86]presented the first report on the successful cessation of recurrent hemorrhage into a pseudocyst by repeated ultrasoundguided transcutaneousfibrin glue and histoacryl/lipiodol applications into the bleeding artery.This procedure should be performed with angiographic backup to respond appropriately in cases of possible complications.However,this approach is far less invasive than angiographic therapy and surgery,which are necessary if the new approach fails.Levy et al[66]reported their experience in performing EUS-guided angiotherapy during the management offive cases of severe refractory bleeding,including four cases of HP.This new procedure offers an effective therapeutic option for managing severe and refractory GI bleeding such as HP in selected patients.The intraluminal endoscopic visualization of EUS provides a unique advantage over the usual hemostatic techniques and can be used to guide therapeutic tools precisely to vascular lesions.

Conclusions

HP,which is defined as upper GI hemorrhage from the papilla of Vater via the pancreatic duct,is rare and difficult to diagnose.There is a broad spectrum of causes of HP,with the most common cause being chronic pancreatitis.Although an accurate diagnosis is difficult to make,appropriate endoscopic or radiological procedures that are performed on patients who present with abdominal pain,GI hemorrhage,and hyperamylasemia,and especially those patients with known pancreatic disorders,are helpful in establishing a correct diagnosis.Angiographic embolization and surgery are therapeutic options for this condition,but transcatheter intervention is the treatment of choice for hemodynamically stable patients.Additional innovative treatments have emerged,but their therapeutic effectiveness and safety must be confirmed in future studies.

Contributors:SB proposed the review.HB and SZF performed the research and wrote the draft.HB and SZF contributed equally to this paper.All authors contributed to the design and interpretation of the study and further drafts.SB is the guarantor.

Funding:This study was supported by grants from the National Natural Scientific Foundation of China (30901437,81170431,81100314 and 81101799) and the Fund for Scientific and Technological Projects in the Heilongjiang Province,China (GC09C407-2).

Ethical approval:Not needed.

Competing interest:No benefits of any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

1 Sakorafas GH,Sarr MG,Farley DR,Que FG,Andrews JC,Farnell MB.Hemosuccus pancreaticus complicating chronic pancreatitis:an obscure cause of upper gastrointestinal bleeding.Langenbecks Arch Surg 2000;385:124-128.

2 Sandblom P.Gastrointestinal hemorrhage through the pancreatic duct.Ann Surg 1970;171:61-66.

3 Lermite E,Regenet N,Tuech JJ,Pessaux P,Meurette G,Bridoux V,et al.Diagnosis and treatment of hemosuccus pancreaticus:development of endovascular management.Pancreas 2007;34:229-232.

4 Frayssinet R,Sahel J,Sarles H.Wirsungorrhagia.Report of a case and review of the literature (author's transl).Gastroenterol Clin Biol 1978;2:993-1000.

5 Vázquez-Iglesias JL,Durana JA,Ya?ez J,Rodriguez H,Garcia-Vallejo L,Arnal F.Santorinirrhage:hemosuccus pancreaticus in pancreas divisum.Am J Gastroenterol 1988;83:876-878.

6 Pinarba?i B,Poturo?lu S,Yanar H,Güven K,Akyüz F,Dizdaro?lu F,et al.A rare cause of hemosuccus pancreaticus:primary splenic artery aneurysm ruptured into pancreatic serous cystadenoma.Turk J Gastroenterol 2008;19:57-63.

7 Longmire WP Jr,Rose AS 3rd.Hemoductal pancreatitis.Surg Gynecol Obstet 1973;136:246-250.

8 Yokoyama I,Hashmi MA,Srinivas D,Shaikh KA,Levine SM,Sorokin JJ,et al.Wirsungorrhagia or hemoductal pancreatitis:report of a case and review of the literature.Am J Gastroenterol 1984;79:764-768.

9 Péroux JL,Arput JP,Saint-Paul MC,Dumas R,Hastier P,Caroli FX,et al.Wirsungorrhagia complicating chronic pancreatitis associated with a neuroendocrine tumor of the pancreas.Gastroenterol Clin Biol 1994;18:1142-1145.

10 Kapoor S,Rao P,Pal S,Chattopadhyay TK.Hemosuccus pancreaticus:an uncommon cause of gastrointestinal hemorrhage.A case report.JOP 2004;5:373-376.

11 Risti B,Marincek B,Jost R,Decurtins M,Ammann R.Hemosuccus pancreaticus as a source of obscure upper gastrointestinal bleeding:three cases and literature review.Am J Gastroenterol 1995;90:1878-1880.

12 El Hamel A,Parc R,Adda G,Bouteloup PY,Huguet C,Malafosse M.Bleeding pseudocysts and pseudoaneurysms in chronic pancreatitis.Br J Surg 1991;78:1059-1063.

13 Arnaud JP,Bergamaschi R,Serra-Maudet V,Casa C.Pancreatoduodenectomy for hemosuccus pancreaticus in silent chronic pancreatitis.Arch Surg 1994;129:333-334.

14 Maus TP.Pseudoaneurysm hemorrhage as a complication of pancreatitis.Mayo Clin Proc 1993;68:895-896.

15 Stanley JC,Frey CF,Miller TA,Lindenauer SM,Child CG 3rd.Major arterial hemorrhage:a complication of pancreatic pseudocysts and chronic pancreatitis.Arch Surg 1976;111:435-440.

16 Camishion RC,Pello MJ,Spence RK,Alexander JB,Atabek UM,Kuroda K.Hemoductal pancreatitis.Surgery 1992;111:86-89.

17 Marescaux J,Evrard S,Aprahamian M,Stock-Damge C,Coumaros D,Sibilly A.Pancreatic lithiasis:a rare cause of gastrointestinal hemorrhage.Surgery 1989;105:682-685.

18 Eckhauser FE,Stanley JC,Zelenock GB,Borlaza GS,Freier DT,Lindenauer SM.Gastroduodenal and pancreaticoduodenal artery aneurysms:a complication of pancreatitis causing spontaneous gastrointestinal hemorrhage.Surgery 1980;88:335-344.

19 Steckman ML,Dooley MC,Jaques PF,Powell DW.Major gastrointestinal hemorrhage from peripancreatic blood vessels in pancreatitis.Treatment by embolotherapy.Dig Dis Sci 1984;29:486-497.

20 Pungpapong S,Raimondo M.Hepatic and splenic arteries'pseudoaneurysms causing hemosuccus pancreaticus.JOP 2004;5:395-396.

21 Bender JS,Bouwman DL,Levison MA,Weaver DW.Pseudocysts and pseudoaneurysms:surgical strategy.Pancreas 1995;10:143-147.

22 Heath DI,Reid AW,Murray WR.Bleeding pseudocysts and pseudoaneurysms in chronic pancreatitis.Br J Surg 1992;79:281.

23 Smith RE,Fontanez-Garcia D,Plavsic BM.Gastrointestinal case of the day.Pseudoaneurysm of the left gastric artery as a complication of acute pancreatitis.Radiographics 1999;19:1390-1392.

24 Jin S,Dong X,Ping C.Image of the month.Pancreaticoduodenal artery and superior mesenteric artery pseudoaneurysm associated with hemosuccus pancreaticus.Clin Gastroenterol Hepatol 2010;8:e11-12.

25 Glaser K,Bodner E,Wetscher G,Weger A,Tschmelitsch J,Klingler P,et al.Hemorrhage from the pancreatic duct caused by a splenic veinfistula.Endoscopy 1994;26:268-269.

26 Shah S,Barkin JS.Hemosuccus pancreaticus:a new mechanism.Pancreas 2011;40:317-318.

27 Mizutamari H,Masamune A,Asakura T,Nagasaki Y,Satoh A,Sakai Y,et al.A case of hemosuccus pancreaticus associated with hereditary pancreatitis.Tohoku J Exp Med 2001;195:191-195.

28 Dinu F,Devière J,Van Gossum A,Golzarian J,Dussaussois L,Delhaye M,et al.The wirsungorrhagies:causes and management in 14 patients.Endoscopy 1998;30:595-600.

29 Kanno A,Satoh K,Hamada S,Hirota M,Masamune A,Motoi F,et al.Serous cystic neoplasms of the whole pancreas in a patient with von Hippel-Lindau disease.Intern Med 2011;50:1293-1298.

30 Williams DM,Shetzline MA,Guarisco SA,Branch MS.Presumed arteriovenous malformation mimicking hemosuccus pancreaticus of Santorini's duct with normal pancreatic anatomy.Gastrointest Endosc 1996;44:348-350.

31 Mizukami Y,Arisato S,Satou K,Nakano Y,Ohta T,Ohta H,et al.A case of anaplastic carcinoma of the pancreas,disclosed a hemosuccus pancreaticus.Nihon Shokakibyo Gakkai Zasshi 1997;94:706-711.

32 Shan YS,Sy ED,Tsai HM,Lin PW.Chronic hemosuccus pancreaticus:a rare complication of pancreatic microcystic adenoma successfully treated with Whipple's procedure.Pancreas 2000;20:416-418.

33 Dupre MP,Dixon E,Heitman SJ.Primary pancreatic lymphoma:a rare cause of massive upper gastrointestinal hemorrhage.Can J Gastroenterol 2011;25:532-533.

34 Shinzeki M,Hori Y,Fujino Y,Matsumoto I,Toyama H,Tsujimura T,et al.Mucinous cystic neoplasm of the pancreas presenting with hemosuccus pancreaticus:report of a case.Surg Today 2010;40:470-473.

35 Tongio J,Peruta O,Wenger JJ,Warter P.Duodenal and pancreatic metastases of nephro-epithelioma (author's transl).Ann Radiol (Paris) 1977;20:641-647.

36 Kassabian A,Stein J,Jabbour N,Parsa K,Skinner D,Parekh D,et al.Renal cell carcinoma metastatic to the pancreas:a single-institution series and review of the literature.Urology 2000;56:211-215.

37 Kurland J,Matthews T,Hoff E,Gentry A,Cash B.Hemosuccus pancreaticus caused by metastatic renal cell carcinoma.Gastrointest Endosc 2007;66:1241-1242.

38 Etienne S,Pessaux P,Tuech JJ,Lada P,Lermite E,Brehant O,et al.Hemosuccus pancreaticus:a rare cause of gastrointestinal bleeding.Gastroenterol Clin Biol 2005;29:237-242.

39 de Perrot M,Bühler L,Deléaval J,Borisch B,Mentha G,Morel P.Management of true aneurysms of the splenic artery.Am J Surg 1998;175:466-468.

40 Jakobs R,Riemann JF.Hemosuccus pancreaticus due to a pressure ulcer in pancreatolithiasis.Dtsch Med Wochenschr 1992;117:1956-1961.

41 Shahani RB,Bijlani RS,Dalvi AN,Shah HK,Samsi AB.Massive upper gastrointestinal haemorrhage due to direct visceral erosion of splenic artery aneurysm.J Postgrad Med 1994;40:220-222.

42 Wagner WH,Cossman DV,Treiman RL,Foran RF,Levin PM,Cohen JL.Hemosuccus pancreaticus from intraductal rupture of a primary splenic artery aneurysm.J Vasc Surg 1994;19:158-164.

43 Massani M,Bridda A,Caratozzolo E,Bonariol L,Antoniutti M,Bassi N.Hemosuccus pancreaticus due to primary splenic artery aneurysm:a diagnostic and therapeutic challenge.JOP 2009;10:48-52.

44 Fazel I,Asle Soleimani H,Fallah S,Babaei M,Sedighi N,Marashi A,et al.Hemosuccus pancreaticus in a patient with celiac trunk aneurysm.Arch Iran Med 2008;11:658-661.

45 Wang WL,Lee JY,Lin JT,Liu KL,Wang HP.A rare cause of obscure gastrointestinal bleeding.Gut 2008;57:878,886.

46 Naitoh I,Ando T,Shimohira M,Nakazawa T,Hayashi K,Okumura F,et al.Hemosuccus pancreaticus associated with segmental arterial mediolysis successfully treated by transarterial embolization.JOP 2010;11:625-629.

47 Obara H,Matsubara K,Inoue M,Nakatsuka S,Kuribayashi S,Kitagawa Y.Successful endovascular treatment of hemosuccus pancreaticus due to splenic artery aneurysm associated with segmental arterial mediolysis.J Vasc Surg 2011;54:1488-1491.

48 Singh P,Gelrud A,Schmulewitz N,Chauhan S.Hemosuccus pancreaticus after EUS-FNA of pancreatic cyst (with video).Gastrointest Endosc 2008;67:543.

49 Keswani RN.Hemosuccus pancreaticus after endoscopic ultrasound-guidedfine needle aspiration of a pancreatic cyst.Endoscopy 2010;42:E79.

50 Seicean A,Stan-Iuga R,Munteanu D.An unusual cause of hemosuccus pancreaticus diagnosed by endoscopic ultrasonography:splenic arterialfistula due to a pancreatic stent (with video).Endoscopy 2010;42:E239-240.

51 Meneu JA,Fernandez-Cebrian JM,Alvarez-Baleriola I,Barrasa A,Morales V,Carda P.Hemosuccus pancreaticus in a heterotopic jejunal pancreas.Hepatogastroenterology 1999;46:177-179.

52 Suttor VP,Biankin AV,Chin WK,Chow C,Biankin SA,Merrett ND,et al.Pancreatic anomaly with multiple endocrine neoplasia type 1:a case of pancreas divisum and hemosuccus pancreaticus (santorinirrhage).Pancreas 2008;36:314-315.

53 Belo AC,Grabowski EW,Zhang C,Longworth DL,Desilets DJ.Case of chronic pancreatic brucellosis presenting as hemosuccus pancreaticus.JOP 2007;8:429-432.

54 Pasha SF,Blair JE,Garvey PB,Gray RJ,Mulligan DC,Collins JM,et al.Hemosuccus pancreaticus in the era of capsule endoscopy and double balloon enteroscopy complicated by multifocal mycobacterium chelonae/abscessus infection.Case Rep Gastroenterol 2007;1:38-47.

55 Kim SS,Roberts RR,Nagy KK,Joseph K,Bokhari F,An G,et al.Hemosuccus pancreaticus after penetrating trauma to the abdomen.J Trauma 2000;49:948-950.

56 Izadyar S,Toogeh G,Eftekhari M,Gholamrezanezhad A.Hemosuccus pancreaticus in Glanzmann thrombasthenia:implication of scintigraphy in gastrointestinal bleeding (GIB)of unknown origin.Clin Nucl Med 2011;36:597-598.

57 Harper PC,Gamelli RL,Kaye MD.Recurrent hemorrhage into the pancreatic duct from a splenic artery aneurysm.Gastroenterology 1984;87:417-420.

58 Werner C,Bonnevie B.Gastrointestinal bleeding from afistula between an aneurysm of the hepatic artery and the pancreatic duct.Eur J Vasc Surg 1993;7:95-97.

59 van Rooyen W,van Blankenstein M,Eeftinck Schattenkerk M,de Vries JE,Obertop H,Bruining HA,et al.Haemorrhage from the pancreatic duct:a rare form of upper gastrointestinal bleeding.Br J Surg 1984;71:137-140.

60 Rohner A.Severe digestive hemorrhage caused by rupture of an aneurysm of the splenic artery into the pancreatic ducts.Gastroenterologia 1967;108:31-43.

61 Suter M,Doenz F,Chapuis G,Gillet M,Sandblom P.Haemorrhage into the pancreatic duct (Hemosuccus pancreaticus):recognition and management.Eur J Surg 1995;161:887-892.

62 Clay RP,Farnell MB,Lancaster JR,Weiland LH,Gostout CJ.Hemosuccus pancreaticus.An unusual cause of upper gastrointestinal bleeding.Ann Surg 1985;202:75-79.

63 Castillo-Sang M,Higgins JA,Tsang AW,Cason F,Sferra J,Mancho S.Hemosuccus pancreaticus.Am Surg 2009;75:865-867.

64 Bohl JL,Dossett LA,Grau AM.Gastroduodenal artery pseudoaneurysm associated with hemosuccus pancreaticus and obstructive jaundice.J Gastrointest Surg 2007;11:1752-1754.

65 Lacey SR,Chak A.Hemosuccus pancreaticus:dorsal pancreatic duct stone and gastroduodenal artery pseudoaneurysm.Gastrointest Endosc 2001;54:363.

66 Levy MJ,Wong Kee Song LM,Farnell MB,Misra S,Sarr MG,Gostout CJ.Endoscopic ultrasound (EUS)-guided angiotherapy of refractory gastrointestinal bleeding.Am J Gastroenterol 2008;103:352-359.

67 Benz CA,Jakob P,Jakobs R,Riemann JF.Hemosuccus pancreaticus--a rare cause of gastrointestinal bleeding:diagnosis and interventional radiological therapy.Endoscopy 2000;32:428-431.

68 Badea R,Seicean A,Procopet B,Dina L,Osian G.Pseudoaneurysm of splenic artery ruptured in pancreatic pseudocyst and complicated by wirsungorrhagia:the role of the ultrasound techniques and contrast substances.Ultraschall Med 2011;32:205-207.

69 Koizumi J,Inoue S,Yonekawa H,Kunieda T.Hemosuccus pancreaticus:diagnosis with CT and MRI and treatment with transcatheter embolization.Abdom Imaging 2002;27:77-81.

70 de Perrot M,Berney T,Bühler L,Delgadillo X,Mentha G,Morel P.Management of bleeding pseudoaneurysms in patients with pancreatitis.Br J Surg 1999;86:29-32.

71 Contro A,Carbognin G,Genovese G,Mansueto G.Haemosuccus pancreaticus in chronic pancreatitis:direct diagnosis by CT.Dig Liver Dis 2011;43:e11.

72 Ray S,Das K,Ray S,Khamrui S,Ahammed M,Deka U.Hemosuccus pancreaticus associated with severe acute pancreatitis and pseudoaneurysms:a report of two cases.JOP 2011;12:469-472.

73 Miki S,Mori K,Masanari S,Furuta T,Saida T,Hiratsuka M,et al.Hemosuccus pancreaticus in a patient with iodine allergy:successful diagnosis with magnetic resonance imaging and treatment with transarterial embolization using carbon dioxide as the contrast medium.Cardiovasc Intervent Radiol 2009;32:1296-1299.

74 Tabrizian P,Newell P,Reiter BP,Heimann TM.Successful multimodality treatment for hemosuccus pancreaticus.Am J Gastroenterol 2009;104:1060.

75 Stabile BE,Wilson SE,Debas HT.Reduced mortality from bleeding pseudocysts and pseudoaneurysms caused by pancreatitis.Arch Surg 1983;118:45-51.

76 Gambiez LP,Ernst OJ,Merlier OA,Porte HL,Chambon JP,Quandalle PA.Arterial embolization for bleeding pseudocysts complicating chronic pancreatitis.Arch Surg 1997;132:1016-1021.

77 Sethi H,Peddu P,Prachalias A,Kane P,Karani J,Rela M,et al.Selective embolization for bleeding visceral artery pseudoaneurysms in patients with pancreatitis.Hepatobiliary Pancreat Dis Int 2010;9:634-638.

78 Zyromski NJ,Vieira C,Stecker M,Nakeeb A,Pitt HA,Lillemoe KD,et al.Improved outcomes in postoperative and pancreatitis-related visceral pseudoaneurysms.J Gastrointest Surg 2007;11:50-55.

79 Akpinar H,Dicle O,Ellidokuz E,Okan A,G?ktay Y,Tankurt E,et al.Hemosuccus pancreaticus treated by transvascular selective arterial embolization.Endoscopy 1999;31:213-214.

80 Huizinga WK,Kalideen JM,Bryer JV,Bell PS,Baker LW.Control of major haemorrhage associated with pancreatic pseudocysts by transcatheter arterial embolization.Br J Surg1984;71:133-136.

81 Knight RW,Kadir S,White RI Jr.Embolization of bleeding transverse pancreatic artery aneurysms.Cardiovasc Intervent Radiol 1982;5:37-39.

82 Morse JM,Reddy KR,Thomas E.Hemosuccus pancreaticus:a cause for obscure gastrointestinal bleeding--diagnosis by endoscopy and successful management by total parenteral nutrition.Am J Gastroenterol 1983;78:572-574.

83 Waltman AC,Luers PR,Athanasoulis CA,Warshaw AL.Massive arterial hemorrhage in patients with pancreatitis.Complementary roles of surgery and transcatheter occlusive techniques.Arch Surg 1986;121:439-443.

84 Sand JA,Sepp?nen SK,Nordback IH.Intracystic hemorrhage in pancreatic pseudocysts:initial experiences of a treatment protocol.Pancreas 1997;14:187-191.

85 Str?mmer L,Albiin N,Calissendorff B,Granlund H,Permert J.Diagnosis and treatment of hemosuccus pancreaticus during a nonbleeding episode:A case report of a patient with obscure intermittent gastrointestinal bleeding and silent chronic pancreatitis.Pancreatology 2004;4:7-11.

86 Will U,Mueller AK,Grote R,Meyer F."Hemosuccus pancreaticus"--primarily ultrasound-guided successful intervention using transcutaneousfibrin glue application and histoacryl injection.Ultraschall Med 2008;29:260-263.