Endoscopic Treatment of Recurrent Acute Pancreatitis and Smoldering Acute Pancreatitis




Recurrent acute pancreatitis (RAP) is a challenging condition that can lead to chronic pancreatitis and long-term morbidity. Etiology-based treatment can potentially have an impact on the natural history of RAP and its progression to chronic pancreatitis. In cases of divisum-associated RAP and idiopathic RAP, several studies have been performed to evaluate the efficacy of endoscopic therapy in alleviation of symptoms and frequency of AP events. This review discusses the literature available on these topic as well as touching on the role of endoscopic therapy in smoldering acute pancreatitis.


Key points







  • •

    In pancreas divisum–associated recurrent acute pancreatitis (RAP) data from uncontrolled retrospective studies point toward a benefit from minor papillary endoscopic intervention.


  • •

    The literature around idiopathic RAP (IRAP), although generally prospective, is heterogeneous, with differing cohort compositions and endoscopic interventions. Randomized data do not support the use of endotherapy in IRAP associated with elevated pancreatic sphincter pressures.


  • •

    Smoldering acute pancreatitis (AP) is a poorly defined entity. The role of endotherapy in smoldering AP needs further investigation.






Introduction


RAP is a challenging condition, because it leads to significant patient morbidity, has potential for progression to chronic pancreatitis (CP), and has limited management options in many patients. Endoscopic therapy, in the form of papillary sphincterotomy and/or pancreatic duct stenting, is often used as a treatment modality for patients with RAP in the setting of pancreas divisum or idiopathic etiology, aiming to eliminate recurrent attacks and progression to CP. The goal of this review is to discuss the role of endoscopic therapy in RAP related to pancreas divisum and IRAP, focusing on the methodology, findings, and limitations of available literature. The endoscopic management of smoldering AP, a poorly defined entity related to AP, also is discussed later.




Introduction


RAP is a challenging condition, because it leads to significant patient morbidity, has potential for progression to chronic pancreatitis (CP), and has limited management options in many patients. Endoscopic therapy, in the form of papillary sphincterotomy and/or pancreatic duct stenting, is often used as a treatment modality for patients with RAP in the setting of pancreas divisum or idiopathic etiology, aiming to eliminate recurrent attacks and progression to CP. The goal of this review is to discuss the role of endoscopic therapy in RAP related to pancreas divisum and IRAP, focusing on the methodology, findings, and limitations of available literature. The endoscopic management of smoldering AP, a poorly defined entity related to AP, also is discussed later.




Recurrent acute pancreatitis


RAP is defined as the occurrence of 2 or more episodes of AP in a given patient, without concurrent clinical or imaging evidence supportive of CP. In natural history studies examining the long-term outcomes of patients after an index episode of AP, the incidence of RAP is estimated to be between 3% and 5% per 100 patient-years, with an overall prevalence of 17% to 20%. RAP has a variable etiology, with the most common causes alcohol abuse and gallstone disease. Pancreatobiliary malformation, specifically pancreas divisum, has also been associated with the development of RAP. A significant proportion of patients with RAP, despite thorough work-up, have no etiology identified, and their disease is thus labeled idiopathic.


Irrespective of etiology, RAP is independently associated with the development of CP, although the true incidence and prevalence of this complication, outside of recurrent alcoholic pancreatitis, is unclear. Given the socioeconomic impact of CP, alleviation and/or cessation of RAP with etiology-based treatment may have an impact on health care costs and patient morbidity. As discussed previously, endoscopic therapy has been studied as a management option specifically within the context of divisum-associated RAP and IRAP and is the focus of this article.


Pancreas Divisum–Associated Recurrent Acute Pancreatitis and the Utility of Endoscopic Therapy


During embryologic development of the foregut, the pancreatic parenchyma is formed from the rotation and eventual fusion of the ventral and dorsal anlages. Parenchymal fusion is also associated with ductal fusion in greater than 90% of individuals, and failure of the ventral and dorsal ductal systems to fuse is termed, pancreas divisum . Pancreas divisum is the most common congenital anomaly of the pancreas, with a prevalence of 6% to 8% based on prior autopsy and endoscopic retrograde cholangiopancreatography (ERCP) series. Pancreas divisum has traditionally been diagnosed via ERCP, although secretin-enhanced magnetic resonance cholangiopancreatography (MRCP) has recently allowed for an accurate, noninvasive mode of diagnosis.


It is controversial as to whether pancreas divisum by itself is a causative factor for the development of RAP. Pathophysiologically, this is thought related to impaired pancreatic ductal drainage through the smaller minor papillary orifice. Retrospective studies have supported this hypothesis and found pancreas divisum significantly more common in patients with RAP compared with normal controls or patients with obscure abdominal pain.


In the most recent study investigating this issue, Bertin and colleagues examined the prevalence of pancreas divisum, as diagnosed by MRCP, in patients with RAP and/or CP deemed idiopathic or associated with CFTR, SPINK1 , and/or PRSS1 mutations. The frequency of pancreas divisum in the idiopathic group was 5%, not significantly different from the frequency found in both control groups and patients with SPINK1 or PRSS1 mutations. The frequency of pancreas divisum in patients with concurrent CFTR mutation–associated RAP and/or CP was significantly higher at 47%. This finding suggests that pancreas divisum increases the risk of pancreatitis only in combination with another source of pancreatic injury, specifically CFTR dysfunction.


Characteristics of Available Studies for Endoscopic Therapy in Divisum-Associated Recurrent Acute Pancreatitis


The hypothesis of pancreas divisum as an obstructive cause of recurrent pancreatitis and clinical improvement with minor papillary endoscopic intervention were first described by Cotton in 1980 . This has subsequently led to numerous studies examining the efficacy of endoscopic therapy in symptomatic pancreas divisum ( Table 1 and 2 ).



Table 1

Characteristics of selected studies for endoscopic therapy in symptomatic pancreas divisum
























































































Author, Year Type of Study No. of Patients Patient Population Follow-up in Recurrent Acute Pancreatitis Patients Control Population
Lans et al, 1992 Randomized controlled trial 19 RAP 30 mo Yes—pancreas divisum without RAP
Lehman et al, 1993 Retrospective 52 RAP (17), CP (11), chronic pain (24) 20 mo No
Kozarek et al, 1995 Retrospective 39 RAP (15), CP (19), chronic pain (5) 26 mo No
Wehrmann et al, 1999 Prospective 5 RAP 10 mo No
Ertan, 2000 Prospective 25 RAP 24 mo No
Heyries et al, 2002 Retrospective 24 RAP 39 mo No
Gerke et al, 2004 Retrospective 53 RAP (30), RAP with chronic pain (14), chronic pain alone (9) 29 mo No
Chacko et al, 2008 Retrospective 57 RAP (27), CP (20), abdominal pain (8), other (2) 20 mo No
Kwan et al, 2008 Retrospective 21 RAP 38 mo No
Borak et al, 2009 Retrospective 113 RAP (62), CP (22), abdominal pain (29) 47 mo No
Mariani et al, 2014 Retrospective 33 RAP 54 mo Yes—pancreas divisum without RAP in past year


Table 2

Reported efficacy of endoscopic therapy for pancreas divisum in selected studies












































































Author, Year Minor Papillary Intervention Outcome Studied Results for Recurrent Acute Pancreatitis Group Complications Overall
Lans et al, 1992 Pancreatic duct stent No. of subsequent AP episodes Stent group—1 episode; control group—7 episodes Stent migration (2)
Lehman et al, 1993 NK minor sphincterotomy Hospital days for AP, symptom score 76% Symptom improvement, 92% reduction in hospital days Post-ERCP pancreatitis (13%), Sphincterotomy bleeding (2%), stent occlusion (47%)
Kozarek et al, 1995 NK minor sphincterotomy and/or pancreatic duct stent Reduction in frequency of AP episodes 86% Post-ERCP pancreatitis (20%), papillary restenosis (12%)
Wehrmann et al, 1999 Minor papillary botulinum toxin injection Relapse-free period >3 mo 4/5 Relapse at 1, 7, 9, and 10 mo None
Ertan, 2000 Pancreatic duct stent Hospital days for AP, frequency of AP episodes 83% Reduction in AP episodes, 87% reduction in hospital days Stent migration (4%), stent occlusion (40%)
Heyries et al, 2002 Pull or NK minor sphincterotomy Complete resolution in AP episodes 92% Post-ERCP pancreatitis (13%), sphincterotomy bleeding (4%), stent migration (4%)
Gerke et al, 2004 Pull or NK minor sphincterotomy No recurrence of pain symptoms 43% Post-ERCP pancreatitis (11%)
Chacko et al, 2008 Pull or NK minor sphincterotomy >50% Reduction in annual hospitalizations/emergency department visits for AP 76% Post-ERCP pancreatitis (11%), perforation (1%)
Kwan et al, 2008 Pull or NK minor sphincterotomy Complete resolution in AP episodes 62% Post-ERCP pancreatitis (10%)
Borak et al, 2009 Pull or NK minor sphincterotomy Improvement or cure of condition with lack of narcotic use 71% Post-ERCP pancreatitis (9%), post-sphincterotomy bleeding (2%)
Mariani et al, 2014 Pull minor sphincterotomy Complete resolution in AP episodes 74% Post-ERCP pancreatitis (12%), post-sphincterotomy bleeding (2%)


A majority of studies done thus far have been retrospective in nature and lacking controls— groups of patients who did not receive endotherapy. Prospective studies have been limited, and to date only 1 randomized controlled trial has been performed. In most studies, symptomatic pancreatic divisum has been defined as RAP, with only a minority of studies explicitly mentioning having previous evaluation for alternative etiologies. Other studies have also included patients with divisum-associated CP as well as divisum-associated chronic abdominal pain in the absence of clear biochemical or imaging evidence of pancreatitis.


Efficacy and Complications


In general, endoscopic therapy for symptomatic pancreas divisum refers to minor papilla sphincterotomy. This may be performed via a pull or needle-knife (NK) technique. Pull sphincterotomy is accomplished by deep cannulation of the papillary orifice with a narrow tip catheter or sphincterotome using contrast or a wire-guided technique. A guide wire is then advanced deep in the accessory duct and a 3- to 4-mm incision is performed with the sphincterotome over the guide wire using pure cut. The NK sphincterotomy technique is accomplished by placing a 3F to 5F pancreatic duct stent into the accessory duct first, followed by performing a free-hand NK sphincterotomy over the pancreatic stent, aiming at the 10- to 12-o’clock position. These 2 techniques have been shown equally effective. Two studies have looked at pancreatic duct stenting without performing sphincterotomy, and 1 report assessed botulinum toxin injection at the minor papilla.


A recent systematic review was published as an attempt to summarize the currently available data. Overall, 22 studies with a total of 838 patients were included. The review highlighted the variability in study outcomes, with 45% using an objective measure of pancreatitis, 36% using patient-perception based definitions, and the remaining studies having unclear definitions. Technical success of endotherapy was reported in only 4 studies and ranged between 17% and 86%. The overall estimated response rate ranged between 31% and 92% (median 62%), with the highest response rate seen in those presenting with RAP without CP (median 76%). The rate of post-ERCP pancreatitis was 18%, with the majority of cases (90%) mild and self-limited.


Conclusions Regarding Endoscopic Therapy for Symptomatic Pancreas Divisum


Although the efficacy of endoscopic therapy in divisum-associated RAP is reported at 70% to 80%, this is primarily based on retrospective data, small sample sizes, and a wide variety of outcome definitions. Accordingly, future studies should be prospective, be ideally randomized, and focus on the rate of AP attacks before and after endotherapy so as to garner its true impact on the natural history of divisum-associated RAP.


In the authors’ practice, when pancreas divisum is identified on MRCP during a thorough work-up of RAP, endoscopic therapy in the form of minor papillary sphincterotomy and stenting is offered to the patient ( Figs. 1 ) after a discussion of the limitations of available evidence. An important consideration in the authors’ decision making is the frequency of RAP and its impact on a patient’s quality of life. Given the risk for post-ERCP pancreatitis in such cases, the authors routinely administer 1 to 2 L of lactated Ringer solution and 100 mg of indomethacin (rectally) and place pancreatic duct stents perioperatively.


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Sep 10, 2017 | Posted by in GASTOINESTINAL SURGERY | Comments Off on Endoscopic Treatment of Recurrent Acute Pancreatitis and Smoldering Acute Pancreatitis

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