JOP. J (Online) 2017 Mar 30; 18(2):97-100.

REVIEW ARTICLE

Pancreas Divisum: On Life Support, But Not Quite Dead

Dennis Kumral, John Baillie

Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, VA, 23298, USA ABSTRACT Pancreas divisum, the failure of fusion of the dorsal and ventral pancreatic ductal systems in utero, is the most common congenital acute or recurrent . With increasing use of magnetic resonance imaging and magnetic resonance cholangiopancreatography abnormality of the pancreas. The clinical significance of pancreas divisum is often considered when it is found in patients with idiopathic pancreatopathyin the past twenty caused years, by thea stenotic detection minor of pancreaspapilla. Developments divisum is increasingly in the study common of the genetics in patients of pancreatitis undergoing have cross-sectional fueled the debate imaging. as Therapeutic interventions for patients with recurrent and pancreas divisum aim to relieve the relative obstructive etiology of recurrent acute pancreatitis should be abandoned. Others have suggested that further study is needed in the understanding of to whether pancreas divisum in itself causes pancreatitis. Some have argued that pancreas divisum is a bystander and that its role as an the association of pancreas divisum with genetic mutations, such as cystic fibrosis transmembrane conductance regulator. Historically, the study of pancreas divisum has been limited to uncontrolled and observational studies with the level of evidence reviewed. This paper will review the , diagnostic and therapeutic modalities, and developments in the genetics of pancreas divisum to revive the discussion on this much-debated topic. INTRODUCTION in Figure 1 Pancreas divisum is the most common congenital anatomic variant findings in pancreas divisum is illustrated anatomic abnormality of the pancreas. During the sixth . Another anatomic variant, incomplete pancreas divisum, is infrequent, and presents as a narrow and often the fusion of the dorsal and ventral pancreatic buds. The inadequate connection between the dorsal and ventral week of gestation, the pancreas normally develops from reportedpancreatic the ducts, incidence with the of majoritypancreas ofdivisum drainage to occurringbe in the bud develops into the uncinate process. In the majority of via the smaller minor papilla [3]. Autopsy series have dorsal bud forms the head, body, and tail while the ventral pancreas divisum is a congenital anomaly present at birth, of their ductal systems such that the main order of 5-10% of the general population [4, 5]. Although servesindividuals, as the the path union for of emptying these structures of pancreatic allows forsecretions a fusion it becomes symptomatic [6, 7]. With increasing use of it is often not diagnosed until the fifth decade of life, when normal variant anatomy is present in approximately 30% into the duodenum via the . A being diagnosed earlier in asymptomatic patients. cross-sectional diagnostic imaging, pancreas divisum is persists as an accessory pancreatic duct and empties via theof individuals, minor duodenal where papilla the proximal [1]. On thedorsal contrary, pancreatic in typical duct Pancreas divisum, the fusion of the dorsal and ventral acuteThe or clinicalrecurrent significance pancreatit of pancreas divisum is often considered when it p isancreas found divisum in patients and withdevelopment idiopathic of the dorsal duct draining the majority of the pancreas via pancreatitis in a retrospectiveis. series Cotton of patients[6] first suggestedundergoing a theductal minor systems papilla fails, and forming the ventral two duct distinct draining conduits only with the correlationendoscopic betweenretrograde cholangiopancreatography (ERCP). inferior portion of the head of the pancreas via the major While the overall incidence of p

ancreas divisum was papilla [2]. The normal anatomy of the pancreas as well as 3.6% in the series, patients with unexplained recurrent

Keywords Gene Expression; Immunotherapy; Pancreatic Neoplasms didpancreatitis not consider had alternative a much higher etiologies incidence for pancreatitis, of 25.6%. AbbreviationsReceived December 2nd, 2016 - Accepted February 08th, 2017 suchAlthough as geneticthis study or wasautoimmune weakened causes, by a referral it did biaslead and to CFTR cystic fibrosis transmembrane conductance further interest in a potential role of pancreas divisum in cholangiopancreatographyregulator; MRI magnetic resonance imaging; RAP recurrent acute the development of acute and recurrent pancreatitis. The Correspondencepancreatitis; s-MRCP John secretin Baillie enhanced magnetic resonance proposed mechanism for pancreatitis in pancreas divisum

TelGateway Building, 4th Floor, 1200 E. Marshall St. papilla bearing the responsibility for draining the majority E-mailRichmond, [email protected] Virginia 23298 is an obstructive pancreatopathy, with the narrow minor +804 828-8508

JOP. Journal of the Pancreas - http://pancreas.imedpub.com/ - Vol. 18 No. 2 –Mar of2017. the [ISSN pancreas 1590-8577] by way of the dorsal pancreatic duct [6, 8].97 JOP. J Pancreas (Online) 2017 Mar 30; 18(2):97-100.

Figure 1. Pancreatic ductal anatomy variants.

et al. [9] performed Therapeutic Interventions andIn an found attempt relatively to quantify increased this, pressuresStaritz in the dorsal duct ERCP with manometry on patients with pancreas divisum relieveTherapeutic the relative interventions obstructive for pancreatopathy patients with causedrecurrent by et al. [10] found no difference in both aacute stenotic pancreatitis minor papilla. (RAP) While and surgical pancreas intervention divisum aim such to asbasal compared and phasic to the manometric ventral duct. pressures However, from the evidence the major is equivocal: Satterfield

as minora less papilla invasive sphincteroplasty treatment modality. has been Endotherapy performed with for etand al. minor [11] usedpapilla magnetic in patients resonance with pancreas imaging divisum (MRI) and pancreassome success divisum [15, 16,may 17], include endoscopic dorsal therapy duct pancreaticis favored magneticacute pancreatitis. resonance Fromcholangiopancreatography an anatomic standpoint, (MRCP) Wang to

stent placement [18] or, more frequently, endoscopic support the dorsal obstructive hypothesis by showing that minor papillotomy [19]. In a randomized controlled trial, isolated dorsal pancreatic involvement was more common either dorsal duct stent placement (in 10 patients) or no patients with pancreas divisum were randomized to in patients with pancreatitis and pancreas divisum, 44.74% as compared to 22.22% in controls, with pancreatitis but up of about 30 months, no patients in the stent group intervention in controls (9 patients). With a mean follow- without pancreas divisum. years, the detection of pancreas divisum is increasingly With increasing use of MRI and MRCP in the past twenty required hospitalization for but five out of stentedthe nine patients patients and in the seven control of the group nine control were readmitted patients [20]. for accuracycommon inin patientsthe diagnosis undergoing of pancreas cross-sectional divisum as imaging. ERCP pain management. RAP was documented in one of the ten MRCP has been shown to have the same diagnostic may enhance detection of pancreas divisum by stimulating In a long-term efficacy study endoscopic therapy, twenty- [12]. Furthermore, secretin-enhanced MRCP (S-MRCP) four patients with RAP and underlying pancreas divisum were treated with sphincterotomy of the minor papilla (8 bicarbonate and fluid secretion into the pancreatic ducts, patients) or dorsal duct stent insertion (16 patients). Acute allowing for improved visualization of anatomic features pancreatitis recurred in two of the eight patients treated [13]. A meta-analysis of 10 studies with 1474 patients with sphincterotomy of the minor papilla and there was showed that secretin-enhanced MRCP had increased no recurrence in patients that received a stent with a diagnostic performance with sensitivity of 86% as median duration of follow-up of 39 months. On the other compared to 52% for standard MRCP, thus strengthening hand, complication rate was less significant in the minor the role of non-invasive imaging for the diagnosis of papillotomy group (25%) as compared to the dorsal duct pancreas divisum [14]. With increased access to radiology stent group (44%) [21]. These endoscopic therapies have diagnosisfacilities of with pancreas MRI/MRCP divisum. capabilities, these imaging shown clinical benefits in patients with RAP associated with modalities will continue to serve as the new standard in pancreas divisum, while patients with JOP. Journal of the Pancreas - http://pancreas.imedpub.com/ - Vol. 18 No. 2 –Mar associated2017. [ISSN 1590-8577] with pancreas divisum, or abdominal pain

98 JOP. J Pancreas (Online) 2017 Mar 30; 18(2):97-100.

Table 1. Level of evidence of cited studies. Genetic Mutations Level of Evidence (based on Pancreas Divisum Studies Oxford Centre for Evidence- (Reference number) Based Medicine) Kleitsch et al IV This argument was further advanced by the observation Langman et al IV that genetic mutations associated with pancreatitis may . 1955 [4] divisum. Pramod et al. [29] found SPINK-1 Cotton et al IV be seen in higher frequencies in patients with pancreas . 1961 [5] Bernard et al. 1990 [7] IV mutations were . 1980 [6] IV more common in patients with pancreas divisum with RAP et al IV Gregg 1977 [8] (41.6%) as compared to healthy controls without pancreas et al IV Staritz . 1986 [9] divisum (2%). The mutation was present in similar Wang et al. 2013 [11] III Statterfield . 1988 [10] frequency in patients without pancreas divisum whoSPINK-1 had Bret et al. 1996 [12] IV mutationidiopathic and chronic not pancreas pancreatitis divisum (43.3%) may andbe a idiopathic common Matos et al. 2001 [13] IV factorRAP (35.7%) leading suggestingto development that inof pancreatitis.this population, Rustagi, et al III Gregg et al IV . 2014 [14] CFTR gene have also been associated Russell et al IV . 1983 [15] Varshney et al. 2002 [17] IV Anomalies of the . 1984 [16] divisum. Dray et al. IV with development of pancreatitis in patients with pancreas et al IV Ertan. 2000 [18] found to have a mildly [30] abnormal reported CFTR two cases of young Lyssa et al IV Gerke . 2004 [20] female patients with pancreas divisum and RAP who were Kanth et al III . 2008 [21] genotypeCFTR protein (IVS8- Mariani et al III . 2014 [22] dysfunction5T-TG12) which and resulting led to RAP impaired with only epithelial mild upper ion transport airway Moffatt et al III . 2014 [23] manifestations. They theorized that the mild et al. 2007 [26] III . 2011 [25] Garg, et al. 2009 [27] IV et al. Spicak results in abnormal pancreatic fluid secretion, leading to Dray et al IV RAP in pancreas divisum. Gerlud [31] showed that Gerlud et al III CFTR . 2007 [28] patients with pancreas divisum and RAP had a decrease in Bertin et al. 2012 [30] III . 2004 [29] function intermediate between patients with cystic Ballard et al III CFTR fibrosis and healthy controls. They hypothesized that in . 2015 [32] titis, may not be ideal candidates for addition to increased viscosity of pancreatic fluid, dysfunction may also causep anancreas excessive divisum, host inflammatorypredisposing without pancrea patientsresponse to that pancreatitis. may further In a recent narrow MRCP the alreadystudy, Bertin smaller et these interventions [22, 23, 24]. Additionally, endotherapy al.pancreatic duct orifice in chronicin patients pancreatitis, with RAP suggesting due to Pancreas that earlier divisum therapy has beenmay and chronic pancreatitis and found that the frequency shown to decrease interval endosonographic findings of of [32]p enrolled consecutive patients with acute recurrentCFTR be warranted in these patients [25]. However, while the ancreas divisum was greater in patients with - ducttypical cannulation rate of post-ERCP and minor pancreatitis sphincter is estimatedpapillotomy at 3.5%[27]. associated pancreatitis (47%), as compared to healthy [26], this risk is increased to as high as 10.6% with dorsal controls (7%) and alcohol-induced pancreatitis (7%). pWith these findings, the investigators suggested CFTR Therefore, the benefits must be weighed against the risks mutations or other polymorphisms in patients with papillotomy.of endotherapy, with particular consideration to the added otherancreas hand, divisum in their might editorial explain for the why Bertin only et a subsetal. study, of risk of post-ERCP pancreatitis with endoscopic minor DiMagnopatients with and DiMagnothis disorder [33] cautiondevelops that pancreatitis. “correlation On does the Is Endotherapy Alone the Answer? not equal causation” and suggest that CFTR mutations and pancreas divisum p susceptibility to pancreatitis. Recently, Ballard et al. ongoingAlthough debate patient abouts the with true RAP cause and of the pancreatitis: is it ancreas divisum may co-exist without influencing genetic theundoubtedly anatomy alone, benefit or are from other minor comorbidities papillotomy, responsible? there is [34] et al. found that in individuals with adult-onset pancreatic of pancreas divisum on the natural course of chronic studydisease, into the the discovery association of of high CFTR risk mutation mutations and p mayancreas be Spicakpancreatitis. [28] They used found MRCP that and p ancreasERCP to studydivisum the did impact not facilitated with using complete gene sequencing. Further modify the age of onset of CP, and, despite the presence needed to settle this debate. of pancreas divisum, a majority of their patients still had divisum, perhaps using complete gene sequencing, will be Summary abnormalities of the ventral duct (75% in patients with, and th 72% in patients without, a history of alcohol abuse), with Although pancreas divisum has been an anatomic a low frequencyp ancreashaving dorsal divisum duct in involvement itself does not (25% modify and finding described in the literature for since the 19 28%,the natural respectively). course of With chronic these pancreatitis. findings, the investigators century, the debate as to whether it causes pancreatitis, or theorized that is simply a bystander, lives on to this day. Historically, the JOP. Journal of the Pancreas - http://pancreas.imedpub.com/ - Vol. 18 No. 2 –Mar 2017. [ISSN 1590-8577] 99 JOP. 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