Severe acute pancreatitis: pathogenesis， diagnosis and surgical management

Mark Portelli and Christopher David Jones

Ayr， UK

Severe acute pancreatitis: pathogenesis， diagnosis and surgical management

Mark Portelli and Christopher David Jones

Ayr， UK

BACKGROUND: Severe acute pancreatitis is a subtype of acute pancreatitis， associated with multiple organ failure and systemic inflammatory response syndrome. In this qualitative review we looked at the principles of pathogenesis， classification and surgical management of severe acute pancreatitis. We also looked at the current shift in paradigm in the management of severe acute pancreatitis since the guideline developed by the British Society of Gastroenterology.

DATA SOURCES: Studies published between 1st January 1991 and 31st December 2015 were identified with PubMed， MEDLINE， EMBASE and Google Scholar online search engines using the following Medical Subject Headings: “acute pancreatitis， necrosis， mortality， pathogenesis， incidence” and the terms“open necrosectomy and minimally invasive necrosectomy”. The National Institute of Clinical Excellence (NICE) Guidelines were also included in our study. Inclusion criteria for our clinical review included established guidelines， randomized controlled trials and non-randomized controlled trials with a follow-up duration of more than 6 weeks.

RESULTS: The incidence of severe acute pancreatitis within the UK is significantly rising and pathogenetic theories are still controversial. In developed countries， the most common cause is biliary calculi. The British Society of Gastroenterology， acknowledges the Revised Atlanta criteria for prediction of severity. A newer Determinant-based system has been developed. The principle of surgical management of acute necrotizing pancreatitis requires intensive care management， identifying infection and if indicated， debridement of any infected necrotic area. The current procedures opted for include standard surgical open necrosectomy， endoscopic necrosectomy and minimally invasive necrosectomy. The current paradigm is shifting towards a step-up approach.

CONCLUSIONS: Severe acute pancreatitis is still a subject of grey areas in its surgical management even though new studies have been recorded since the origin of the latest UK guidelines for management of severe acute pancreatitis.

(Hepatobiliary Pancreat Dis Int 2017;16:155-159)

severe acute pancreatitis;

acute pancreatitis;

necrosis;

mortality;

pathogenesis;

incidence;

open necrosectomy and minimally invasive necrosectomy

Introduction

Pancreatitis is defined as an inflammatory process where autodigestion occurs due to erratic activation of trypsin with resultant zymogen activation within the pancreas.[1-3]Patients can go on to develop severe acute pancreatitis. The widely understood definition is that of an acute pancreatitis in association with multiple organ failure and systemic inflammatory response syndrome. In most cases necrotic foci are noted within the pancreatic tissue.[4-6]Located within the retroperitoneum， the pancreas is well protected from both environmental and mechanical injury.[2]Severe acute pancreatitis can have several etiologies with gallstones and alcohol being the most prevalent in presentations.[3]In the majority of patients， the condition resolves without complications， however it can cause substantial complications and mortality in up to 25% of those affected with hospitalization periods in an intensive care unit beyond 2 weeks.[7，8]Studies show a decreasing mortality.[9]The incidence of mortality changes between different socioeconomic population groups.[10，11]In this qualitative review we looked at the principles of pathogenesis， classification and surgical management of severe acute pancreatitis. We also looked at the current shift in paradigm in the management of severe acute pancreatitis since theguideline developed by the British Society of Gastroenterology.[12]There is a lot of discussion about whether patients with severe acute pancreatitis should undergo invasive surgical procedures.

Methods

Studies published between 1st January 1991 and 31st December 2015 were identified with PubMed， MEDLINE， EMBASE and Google Scholar online search engines using the following Medical Subject Headings: “acute pancreatitis， necrosis， mortality， pathogenesis， incidence”and the terms “severe acute pancreatitis， open necrosectomy and minimally invasive necrosectomy”. The National Institute of Clinical Excellence (NICE) Guidelines were also included in our study. Inclusion criteria for our clinical review included established guidelines， randomized controlled trials and non-randomized controlled trials with a follow up duration of more than 6 weeks. The literature search was performed independently by both authors. In duplicate and independently， we extracted data on the population， epidemiology， pathogenesis， diagnosis and management of severe acute pancreatitis.

Results and discussion

A total of 39 papers were recorded and analyzed. In our study we reviewed 6 retrospective studies， 14 prospective studies， 14 systematic reviews， 2 meta-analyses and 3 guidelines. Each study was individually reviewed and similarities and differences between studies were observed and documented.

Epidemiology and pathogenesis

The British Society of Gastroenterology reports that the incidence of acute pancreatitis in the UK ranges between 150 and 420 cases per million population， with the incidence significantly rising over the past decade.[12]About 20% of affected patients develop severe acute pancreatitis.[4]

Many causes of severe acute pancreatitis have been recorded in the literature but the pathogenetic theories are still controversial. The risk of severe acute pancreatitis increases due to several factors including genetic， environmental and metabolic factors.[2]In developed countries， the most common causes include choledocholithiasis and alcohol excess， accounting for 75%-85% of cases.[7，13]Alcohol lowers the threshold for trypsin activation within the pancreatitis， causing cellular necrosis.[14]Interestingly numerous factors including age， gender， obesity， number of attempts to cannulate papilla and poor emptying of pancreatic duct， increase the likelihood of the condition.[7]

Multiple adaptive and protective mechanisms have been reported which prevent the onset of pancreatitis. Disruption of such mechanisms can amplify the susceptibility of the patient towards developing severe acute pancreatitis.[2]Studies have recorded gene variants which result in such a loss of adaptive mechanisms including human cationic trypsinogen [PRSS1]， cymtripsin C [CTRC]， carboxypeptidase A1 [CPA1] and serine protease inhibitor， Kazal type 1 [SPINK1] mutations.[15]The duct cells can express sensors within the luminal surface such as protease-activated receptors 1 and 2 [PAR1， PAR2] which detect trypsin and its activity. These provide protective mechanisms. Other molecules such as P2Y purinoreceptor 2 [P2Y2]， P2X， ligand-gated ion channel 4 [P2X4] and P2X ligand-gated ion channel 7 [P2X7] recognize calcium concentration. When these are activated， secretion of fluid flushes the damaging fluid into the duodenum. Defect in these receptors can result in an inadequate protective mechanisms， thereby increasing the risk of developing severe acute pancreatitis.[15]A study by Papachristou et al suggests that a single nucleotide pleomorphism in the gene producing monocyte chemotatctic protein-1， predicted a systemic inflammatory response causing severe acute pancreatitis associated with a high mortality.[16]

Cystic fibrosis transmembrane conductance regulator [CFTR] gene mutations noted predominantly in patients with cystic fibrosis significantly increase the susceptibility to pancreatitis. In a study by Pezzilli et al， 12.2% of patients diagnosed with acute pancreatitis had CFTR variants.[17]

Outlining severity

Two severity scoring systems have been identified in the literature which include the Revised Atlanta criteria and the Determinant-based Classification. They are both based on local and systemic factors.[18]The British Society of Gastroenterology， acknowledges the Revised Atlanta criteria for prediction of severity.[12]

The Revised Atlanta criteria are based on a multifactorial scoring system and predictive factors of severity.[17]According to these criteria， within the first 24 hours， indicators of severity include: clinical suspicion， a raised BMI， pleural effusions and a raised Acute Physiology and Chronic Health Evaluation II [APACHEII] Score.[12，19]After the first 24 hours， other indicators include: persisting organ failure and/or an Imrie score of >3. A worse severity score is also predicted if the C-reactive protein is >150 mg/L or if biomarkers such as interleukin (IL)-8， IL-6， procalcitonin， IL-10 and IL-1 beta-receptor antago-nist are raised.[12，19]

Further scores for estimation of severity have been developed， the most popular of which include the Ranson and Imrie scores. These have a sensitivity of 80% at 48 hours.[18]Such scores identify whether the patient would require further management in an intensive care setting.

A newer system for scoring severity is the Determinant-based system and is a measure of actual severity. This system was developed due to the newer imaging modalities and a better understanding of the high risk of organ failure in patients with pancreatitis. This scoring system is based on identification of sterile or infected pancreatic necrosis and signs of organ failure.[20]

Serum biomarkers such as urinary trypsin activation peptide and serum amyloid A have been looked at as potential early markers for prediction of severity of severe acute pancreatitis.[19]

Surgical management of necrotizing pancreatitis

The principle of surgical management of acute necrotizing pancreatitis requires intensive care management， identifying infection and if indicated， debridement of any infected necrotic areas.[21]

Invasive procedures for severe acute pancreatitis can be indicated in biliary pancreatitis， infected pancreatic necrosis， massive hemorrhage， sterile pancreatic necrosis， drainage of pancreatic abscess and symptomatic organized necrosis.[22-24]The current consensus is that a diagnosis of biliary pancreatitis requires a laparoscopic cholecystectomy at the point of diagnosis or within 2 weeks of diagnosis. This may relieve the obstruction and therefore improves the chance of successful resolution of severe acute pancreatitis without resorting to procedures with higher risk of complications.[12]

Initial management of severe acute pancreatitis requires continuous monitoring because of the risk of superadded bacterial infections in a necrosed pancreas. Bacterial infection occurs in 3%-7% of all cases of pancreatitis.[25]About 10%-50% of patients with pancreatic necrosis develop a superadded bacterial infection.[11，12，26]In these cases infection typically presents after 2-3 weeks from the point of presentation.[25]In view of this， some randomized controlled studies have explored the role of prophylactic antibiotics with results being inconclusive.[12，27，28]

Definitive diagnosis of infective pancreatitis requires the use of CT imaging with or without a positive fine needle aspiration for bacteriology.[11，12]Patients with persistent pain or features suspicious of underlying sepsis with greater than 30% necrosis confirmed radiologically should undergo fine needle aspiration.[12]Without treatment， mortality in such group of patients has been reported as high as 80%.[29]Prior to the guideline by the British Society of Gastroenterology， the general consensus was that infected necrosis is an indication for surgical treatment or interventional drainage.[12]If less than 30% of pancreatic tissue is necrotic with fluid collections， this can be managed by minimally invasive necrosectomy.[21]Recent data showed that surgical procedures can be avoided. A meta-analysis by Mouli et al showed that 64% of patients who were diagnosed with infected pancreatic necrosis had successful resolution with conservative management with a mortality rate of 12%. The current paradigm is shifting towards a conservative approach.[30]

Surgery in pancreatic necrosectomy must usually be delayed for 14 days in order to allow demarcation of the necrosum， unless the condition can be resolved by elimination of the cause， such as in the case of cholecystectomy for gallstone induced pancreatitis.[23]

Early surgery is only opted for proven infected necrotizing pancreatitis. In fact mortality rates of up to 65% have been noted with early surgery in severe acute pancreatitis.[11，31]Patients with severe necrotizing pancreatitis would therefore eventually undergo surgical debridement with the ideal time being set at the third or fourth week from the onset of disease.

The choice of surgical procedure is at present very arguable and is mainly based on the facilities and surgical ability of the surgeon performing the procedure.[11]The current procedures opted for include the standard surgical open necrosectomy， endoscopic necrosectomy and minimally invasive necrosectomy.

This approach to remove the infected necrotic tissue was associated with a high rate of complications with studies noting between 34%-95% of procedures with complications. Mortality results in several studies are between 6% and 50%.[11，20，21，32，33]Considering these findings one could explain why the interest in open necrosectomy is losing favor. It is noted in the literature that preference is shifting towards the safer procedure of minimally invasive necrosectomy.[11]In a study by Bakker et al， endoscopic necrosectomy showed better results in terms of pro-inflammatory response and clinical end point identified by recording IL-6 levels which were noted to decrease after endoscopic procedures when compared to open surgery with significant values on correlation.[33]

Castellanos et al[34]states that all patients undergoing translumbar retroperitoneal endoscopy showed good results with the procedure. They were noted to avoid subsequent surgical operations for debridement. Similar studies have showed high success rates.[35]

The NICE guidelines list two types of endoscopicnecrosectomies， namely the percutaneous retroperitoneal endoscopic necrosectomy and the endoscopic transluminal necrosectomy.[36，37]

In an interview done to Baron， despite the risk of complications， with proper expertise 90% of patients can have complete resolution of the necrotizing pancreatitis with endoscopic necrosectomy. However， such a procedure needs to be performed in specialised centers.[38]

Sileikis et al[21]noted that minimally invasive necrosectomy is recorded as being the best option in treating necrotising pancreatitis. Such patients have less risks of complications including reduced incidence of bacteremia， multiple organ failure and post-operative complications. They also have a reduced operating table to discharge time.[32]Unfortunately as with the endoscopic approach， the procedure requires multiple sittings in order to resect the whole necrosum.[20]

The current paradigm is shifting towards a step-up approach， where catheterization for drainage is followed by videoscopic assisted retroperitoneal debridement.[11，25，39]van Stantvoort et al[40]noted that when compared to primary open necrosectomy， the step-up approach provided less complications. Removal of pressure and infected fluid from around the pancreas together with intravenous antibiotics can avoid further invasive management and any remaining necrotic tissue would be removed by the patient’s own immune system.[39]videoscopic assisted retroperitoneal debridement tends to follow the initial drainage if the symptomatology persists.

Conclusion

Severe acute pancreatitis causes sig nificant mortality rates. This study is a qualitative review of the literature. Unfortunately it is difficult to encompass the whole wealth of knowledge on the topic of severe acute pancreatitis in the literature. We have included the relatively more influential studies in our review based on our inclusion criteria. Severe acute pancreatitis is still a subject of grey areas in its surgical management albeit new studies have been recorded since the origin of the latest UK guidelines for management of acute pancreatitis and severe acute pancreatitis. We do encourage further studies in this surgical topic with an aim to further reduce the associated mortality with severe acute pancreatitis.

Contributors: PM proposed the study， performed the research and wrote the first draft. JCD reviewed and analyzed the data. Both authors contributed to the design and interpretation of the study and to further drafts. PM is the guarantor.

Funding: None.

Ethical approval: Not needed. Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received February 14， 2016

Accepted after revision July 29， 2016

Author Affiliations: Department of General Surgery， University Hospital Ayr， Ayr， KA6 6DX， UK (Portelli M and Jones CD)

Mark Portelli， MD， Department of General Surgery， University Hospital Ayr， Dalmellington Road， Ayr， KA6 6DX， UK (Email: markportellicaruana@gmail.com)

? 2017， Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(16)60163-7

Published online December 28， 2016.