Timing of cholecystectomy after acute biliary pancreatitis

(1) Department of Surgery, Radboud university medical center, Nijmegen, The Netherlands (2) Department of Surgery, Tweesteden Hospital, Tilburg, The Netherlands (3) Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands (4) Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands

Entry Version: 

Version 1.0, July 8, 2015


Bouwense, Stefan A. van Baal, Mark C. da Costa, David. Besselink, Marc G. (2015). Timing of cholecystectomy after acute biliary pancreatitis.
Pancreapedia: Exocrine Pancreas Knowledge Base, DOI: 10.3998/panc.2015.23

1. Introduction

Acute pancreatitis is a common gastrointestinal disorder and in the majority of patients the etiology is either alcohol-associated or biliary, i.e. caused by gallstones or sludge (37, 40),. The incidence of acute biliary pancreatitis is increasing worldwide, possibly due to an increased risk of gallstone disease due to nutritional and lifestyle factors and obesity (34, 41). The economic burden of acute pancreatitis is high; In the United States alone, the annual costs of acute pancreatitis currently exceed $2.2 billion (10). The majority of patients with acute pancreatitis (80%) have a mild course of their disease, but 20% of patients develop severe pancreatitis, which is associated with high morbidity and mortality (4). Once biliary pancreatitis is resolved, cholecystectomy is indicated to reduce the risk of recurrent gallstone-related complications such as acute pancreatitis, cholecystitis, cholangitis or gallstone colics (32, 38). A much discussed question is when during the course of pancreatitis the gallbladder should be removed.

High complication and mortality rates after early cholecystectomy in patients with severe pancreatitis have prompted guidelines recommending delaying cholecystectomy until all signs of inflammation have resolved (i.e. interval cholecystectomy) (17, 22, 38). After mild biliary pancreatitis early cholecystectomy is advised by current guidelines (11, 38, 39). However, no consensus exists between these guidelines about the exact definition of ‘early’. The British Society of Gastroenterology recommend cholecystectomy within 2 weeks after discharge, whereas the International Association of Pancreatology (IAP) and the American Gastroenterological Association recommend that all patients with mild biliary pancreatitis should undergo cholecystectomy as soon as the patient has recovered from the attack (32, 38, 39). However, in contrast with these guidelines, in daily practice cholecystectomy after mild biliary pancreatitis is often postponed for several weeks after hospital discharge (interval cholecystectomy). Nationwide audits from Europe and the United States have shown that laparoscopic cholecystectomy is usually performed around 6 weeks after discharge from hospital admission for mild biliary pancreatitis (3, 5, 9, 18, 24-26, 29, 33). A perceived danger of perioperative complications in early cholecystectomy after acute pancreatitis is the main reason for this delay in cholecystectomy (21, 24). It is believed that distorted biliary tract anatomy by inflammation and edema may complicate dissection with a higher risk of conversion and surgical complications, such as bile duct injury (16, 17, 31). Another reason is that a delayed approach facilitates surgical scheduling, as emergency theatre capacity is often limited (21).

In patients with mild biliary pancreatitis, the role of endoscopic sphincterotomy is limited when cholangitis is not present (38). However, large nationwide studies from the United Kingdom and United States still show a relatively high percentage of patients with mild biliary pancreatitis undergoing endoscopic sphincterotomy (14, 16, 24). Several retrospective studies have suggested that patients do not need to undergo early cholecystectomy after sphincterotomy (13). However, a recent meta-analysis on prophylactic cholecystectomy after sphincterotomy for gallstone-related complications other than pancreatitis still suggests that a cholecystectomy should be performed even after sphincterotomy to further reduce recurrent biliary events (19).

In severe pancreatitis, some have advocated the use of endoscopic sphincterotomy as a bridge to cholecystectomy (13, 27). This issue has not been addressed in prospective trials and needs further study in patients with severe biliary pancreatitis.

The drawback of the present practice of postponing cholecystectomy until several weeks after discharge is that during this period patients are at risk of developing recurrent biliary events (e.g. recurrent biliary pancreatitis, cholecystitis, symptomatic choledocholithiasis and biliary colics). This risk is substantial and has been reported to occur in up to 60% of patients in observational studies (2, 36). It is thought that the lack of high quality evidence may attribute to the reported low adherence to guidelines (9, 14, 16, 18, 24).

Three main questions will be discussed in this review:

  1. Does early cholecystectomy reduce recurrent biliary events compared to interval cholecystectomy?
  2. Is early cholecystectomy technically more difficult to perform than interval cholecystectomy?
  3. Are patients in whom early cholecystectomy is performed more at risk for complications than patients who undergo interval cholecystectomy?

In the next paragraphs we will discuss available studies on timing of cholecystectomy and try to answer the above mentioned three questions.

2. Studies Addressing the Timing of Cholecystectomy in Mild Biliary Pancreatitis

In 2011, Bakker et al. published a retrospective multicenter study which evaluated recurrent biliary events as a consequence of delayed cholecystectomy following mild biliary pancreatitis (3). Patients with mild biliary pancreatitis who were candidates for cholecystectomy were registered prospectively in 15 Dutch hospitals from 2004 to 2007. Recurrent biliary events requiring admission were evaluated before and after cholecystectomy, as well as for a subgroup of patients who underwent endoscopic sphincterotomy. Of 308 patients with mild biliary pancreatitis, 267 had an indication for cholecystectomy. An early cholecystectomy was performed in 18 patients (7%) and late in 188 patients after a median of 6 weeks (76%). Before cholecystectomy was performed, 34 patients (14%) were readmitted for biliary events, including 24 patients with recurrent biliary pancreatitis. During the initial admission, endoscopic sphincterotomy had been performed in 108 patients. Among these patients, eight patients (7%) suffered from recurrent biliary events after endoscopic sphincterotomy and before cholecystectomy. In the group of patients who did not undergo endoscopic sphincterotomy, 26 of 141 patients (18%) had recurrent biliary events, which was significant compared to the group of patients who did have an endoscopic sphincterotomy (risk ratio 0·51, 95% confidence interval 0·27 to 0·94; P = 0.015). It was concluded that an interval cholecystectomy after mild biliary pancreatitis carries a substantial risk of recurrent biliary events. Endoscopic sphincterotomy reduces the risk of recurrent biliary pancreatitis but not of other biliary events. Shortcomings of this study were: 1) the study was not primarily designed to analyse safety of cholecystectomy, and 2) the study design was not a randomized clinical trial comparing early versus interval cholecystectomy.

In 2012, van Baal et al. published a systematic review on the timing of cholecystectomy after mild biliary pancreatitis (35). The objective was to determine the risk of recurrent biliary events in the period after mild biliary pancreatitis but before interval cholecystectomy and to determine the safety of cholecystectomy during the index admission. A systematic search in PubMed, Embase, and Cochrane for studies published from January 1992 to July 2010 was performed. Cohort studies of patients with mild biliary pancreatitis reporting on the timing of cholecystectomy, number of readmissions for recurrent biliary events before cholecystectomy, operative complications (e.g., bile duct injury, bleeding), and mortality were included. Also study quality and risks of bias were assessed. From 2413 screened studies, 8 cohort studies and 1 randomized trial were included, in total describing 998 patients. An early cholecystectomy was performed in 483 patients (48%) without any reported readmissions (Table 1). An interval cholecystectomy was performed in 515 patients (52%) after a median of 40 days (interquartile range: 19 – 58 days). Before the interval cholecystectomy was performed 95 patients (18%) were readmitted for recurrent biliary events (0% vs. 18%; P < 0.0001).

This table was adapted from the original manuscript of van Baal et al (35). *In one study, 2 different groups of interval cholecystectomy were described.

Forty-three patients (8%) were readmitted due to recurrent biliary pancreatitis, 17 patients (3%) with acute cholecystitis and 35 patients (7%) with biliary colics. Fewer recurrent biliary events were present in patients who had an endoscopic sphincterotomy (10% vs. 24%; P = 0.001), with especially less recurrent biliary pancreatitis (1% vs. 9%). No differences were found in operative complications, conversion rate (7%), and mortality (0%) between early and interval cholecystectomy. Baseline characteristics were often missing and only reported in 26% of patients, so subgroups could not be compared. It was concluded that interval cholecystectomy after mild biliary pancreatitis is associated with a high risk of readmission for recurrent biliary events, especially recurrent biliary pancreatitis. Furthermore, early cholecystectomy for mild biliary pancreatitis appears to be safe. The main shortcomings of this systematic review were: 1) all included studies were of relatively low quality, and 2) selection bias could not be excluded.

In 2010, a randomized clinical trial on the timing of cholecystectomy after mild biliary pancreatitis was published by Aboulian et al (1). The authors hypothesized that a laparoscopic cholecystectomy performed within 48 hours after admission for mild biliary pancreatitis would result in shorter hospital stay. Patients with mild pancreatitis (defined as a Ranson score ≤ 3) were randomized to early laparoscopic cholecystectomy (within 48 hours of admission) or to control laparoscopic cholecystectomy, performed after resolution of abdominal pain and normalizing trend of laboratory enzymes. In this single centre study at interim analyses, 25 patients were randomized to early cholecystectomy and 25 patients to the control group who subsequently would undergo cholecystectomy after resolution of abdominal pain and normalization of laboratory values. Median duration of symptoms was 2 days upon presentation with a median Ranson score of 1. Duration of hospital stay was 1 day shorter in the early cholecystectomy group with a median of 3 days (interquartile range 2 – 4) compared with the control group with a median of 4 days (interquartile range 4 – 6; P = 0.0016). There were no statistically significant differences between both groups for conversions to an open procedure or in perioperative complications. It was concluded that a laparoscopic cholecystectomy performed within 48 hours after admission (very early cholecystectomy) results in shorter hospital stay and appears to be safe and not more technical demanding. Shortcomings of this study were: 1) the study was not powered to detect differences in clinically relevant outcomes such as recurrent biliary events, and 2) cholecystectomy within 48 hours after admission in gallstone pancreatitis is controversial because patients may still develop pancreatic necrosis or organ failure during this phase of the disease, which both are considered contraindications for early surgery.

These three studies all show a benefit of early cholecystectomy in mild biliary pancreatitis, which appears a safe strategy without an increase in difficulty of the cholecystectomy. However, the quality of the evidence in these studies and their study design was not particularly high. It appeared that a well-designed randomized clinical trial was needed to resolve the issue of timing of cholecystectomy in mild biliary pancreatitis.

In 2012, the study protocol for a randomized controlled trial titled: pancreatitis of biliary origin, optimal timing of cholecystectomy (PONCHO trial) was published by Bouwense et al (6). The hypothesis for this trial is: early laparoscopic cholecystectomy minimizes the risk of recurrent biliary events in patients with mild biliary pancreatitis without increasing the difficulty of dissection and the surgical complication rate compared with interval laparoscopic cholecystectomy. PONCHO is a randomized controlled superiority multicenter trial in which patients are randomly allocated to undergo early laparoscopic cholecystectomy, within 72 hours after randomization, or interval laparoscopic cholecystectomy, 25 to 30 days after randomization. Patients are randomized during their index admission when all signs of the disease have been resolved and patients are expected to be discharged within 1 – 2 days. In 18 Dutch hospitals a total of 266 patients were enrolled. The primary endpoint is a composite endpoint of mortality and acute readmissions for biliary events (e.g. recurrent biliary pancreatitis, acute cholecystitis, symptomatic/obstructive choledocholithiasis requiring endoscopic retrograde cholangiopancreaticography including cholangitis (with/without endoscopic sphincterotomy), and uncomplicated biliary colics) occurring within 6 months following randomization. Secondary endpoints include the individual endpoints of the composite endpoint, surgical and other complications, technical difficulty of cholecystectomy and costs. The results of the PONCHO trial are expected to be published at the end of 2015. This trial will provide the high level of evidence needed to finally close the debate on timing of cholecystectomy in mild biliary pancreatitis.

3. Conclusion

In patients with severe biliary pancreatitis, it is generally accepted to perform an interval cholecystectomy. In mild biliary pancreatitis, although advocated by current guidelines, patients frequently do not undergo an early cholecystectomy, resulting in a high percentage of hospital readmissions due to recurrent biliary events. All published studies are of medium to low methodological quality and the results of the first randomized controlled clinical trial comparing early versus interval cholecystectomy in patients with mild biliary pancreatitis is expected at the end of 2015. The role of endoscopic sphincterotomy is still under debate, although it is generally accepted that endoscopic sphincterotomy in patients without cholangitis is not indicated. It is thought that endoscopic sphincterotomy will reduce the number of recurrent biliary events, but will not prevent all events.

4. References

  1. Aboulian A, Chan T, Yaghoubian A, Kaji AH, Putnam B, Neville A, et al. Early cholecystectomy safely decreases hospital stay in patients with mild gallstone pancreatitis: a randomized prospective study. Ann Surg 251(4): 615-619, 2010. PMID: 20101174.
  2. Alimoglu O, Ozkan OV, Sahin M, Akcakaya A, Eryilmaz R and Bas G. Timing of cholecystectomy for acute biliary pancreatitis: outcomes of cholecystectomy on first admission and after recurrent biliary pancreatitis. World J Surg 27(3): 256-259, 2003. PMID: 12607047.
  3. Bakker OJ, Van Santvoort HC, Hagenaars JC, Besselink MG, Bollen TL, Gooszen HG, et al. Timing of cholecystectomy after mild biliary pancreatitis. Br.J.Surg. 98(10): 1446-1454, 2011. PMID: 21710664.
  4. Banks PA and Freeman ML. Practice guidelines in acute pancreatitis. Am.J Gastroenterol. 101(10): 2379-2400, 2006. PMID: 17032204.
  5. Barnard J and Siriwardena AK. Variations in implementation of current national guidelines for the treatment of acute pancreatitis: implications for acute surgical service provision. Ann R Coll Surg Engl 84(2): 79-81, 2002. PMID: 11995768.
  6. Bouwense SA, Besselink MG, van Brunschot S, Bakker OJ, van Santvoort HC, Schepers NJ, et al. Pancreatitis of biliary origin, optimal timing of cholecystectomy (PONCHO trial): study protocol for a randomized controlled trial. Trials 13: 225, 2012. PMID: 23181667.
  7. Cameron DR and Goodman AJ. Delayed cholecystectomy for gallstone pancreatitis: re-admissions and outcomes. Ann.R.Coll.Surg.Engl. 86(5): 358-362, 2004. PMID: 15333174.
  8. Clarke T, Sohn H, Kelso R, Petrosyan M, Towfigh S and Mason R. Planned early discharge-elective surgical readmission pathway for patients with gallstone pancreatitis. Arch Surg 143(9): 901-905; discussion 905-906, 2008. PMID: 18794429.
  9. El-Dhuwaib Y, Deakin M, David GG, Durkin D, Corless DJ and Slavin JP. Definitive management of gallstone pancreatitis in England. Ann R Coll Surg Engl 94(6): 402-406, 2012. PMID: 22943329.
  10. Fagenholz PJ, Fernandez-del Castillo C, Harris NS, Pelletier AJ and Camargo CA. Direct medical costs of acute pancreatitis hospitalizations in the United States. Pancreas 35(4): 302-307, 2007. PMID: 18090234.
  11. Forsmark CE and Baillie J. AGA Institute Technical Review on Acute Pancreatitis. Gastroenterology. 132(5): 2022-2044, 2007. PMID: 17484894.
  12. Griniatsos J, Karvounis E and Isla A. Early versus delayed single-stage laparoscopic eradication for both gallstones and common bile duct stones in mild acute biliary pancreatitis. Am Surg 71(8): 682-686, 2005. PMID: 16217952.
  13. Heider TR, Brown A, Grimm IS and Behrns KE. Endoscopic sphincterotomy permits interval laparoscopic cholecystectomy in patients with moderately severe gallstone pancreatitis. J Gastrointest Surg 10(1): 1-5, 2006. PMID: 16368484.
  14. Hwang SS, Li BH and Haigh PI. Gallstone pancreatitis without cholecystectomy. JAMA Surg 148(9): 867-872, 2013. PMID: 23884515.
  15. Ito K, Ito H and Whang EE. Timing of cholecystectomy for biliary pancreatitis: do the data support current guidelines? J Gastrointest.Surg 12(12): 2164-2170, 2008. PMID: 18636298.
  16. Johnstone M, Marriott P, Royle TJ, Richardson CE, Torrance A, Hepburn E, et al. The impact of timing of cholecystectomy following gallstone pancreatitis. Surgeon 12(3): 134-140, 2014. PMID: 24210949.
  17. Kelly TR and Wagner DS. Gallstone pancreatitis: a prospective randomized trial of the timing of surgery. Surgery 104(4): 600-605, 1988. PMID: 3175860.
  18. Lankisch PG, Weber-Dany B and Lerch MM. Clinical perspectives in pancreatology: compliance with acute pancreatitis guidelines in Germany. Pancreatology 5(6): 591-593, 2005. PMID: 16110257.
  19. McAlister VC, Davenport E and Renouf E. Cholecystectomy deferral in patients with endoscopic sphincterotomy. Cochrane Database Syst Rev(4): CD006233, 2007. PMID: 17943900.
  20. McCullough LK, Sutherland FR, Preshaw R and Kim S. Gallstone pancreatitis: does discharge and readmission for cholecystectomy affect outcome? HPB (Oxford) 5(2): 96-99, 2003. PMID: 18332964.
  21. Monkhouse SJ, Court EL, Dash I and Coombs NJ. Two-week target for laparoscopic cholecystectomy following gallstone pancreatitis is achievable and cost neutral. Br J Surg 96(7): 751-755, 2009. PMID: 19526610.
  22. Nealon WH, Bawduniak J and Walser EM. Appropriate timing of cholecystectomy in patients who present with moderate to severe gallstone-associated acute pancreatitis with peripancreatic fluid collections. Ann Surg 239(6): 741-749, 2004. PMID: 15166953.
  23. Nebiker CA, Frey DM, Hamel CT, Oertli D and Kettelhack C. Early versus delayed cholecystectomy in patients with biliary acute pancreatitis. Surgery. 145(3): 260-264, 2009. PMID: 19231577.
  24. Nguyen GC, Boudreau H and Jagannath SB. Hospital volume as a predictor for undergoing cholecystectomy after admission for acute biliary pancreatitis. Pancreas 39(1): e42-47, 2010. PMID: 19910833.
  25. Pezzilli R, Uomo G, Gabbrielli A, Zerbi A, Frulloni L, De Rai P, et al. A prospective multicentre survey on the treatment of acute pancreatitis in Italy. Dig Liver Dis 39(9): 838-846, 2007. PMID: 17602904.
  26. Sandzen B, Haapamaki MM, Nilsson E, Stenlund HC and Oman M. Cholecystectomy and sphincterotomy in patients with mild acute biliary pancreatitis in Sweden 1988 - 2003: a nationwide register study. BMC Gastroenterol 9: 80, 2009. PMID: 19852782.
  27. Sanjay P, Yeeting S, Whigham C, Judson H, Polignano FM and Tait IS. Endoscopic sphincterotomy and interval cholecystectomy are reasonable alternatives to index cholecystectomy in severe acute gallstone pancreatitis (GSP). Surg Endosc 22(8): 1832-1837, 2008. PMID: 18071797.
  28. Schachter P, Peleg T and Cohen O. Interval laparoscopic cholecystectomy in the management of acute biliary pancreatitis. HPB Surg 11(5): 319-322, 2000. PMID: 10674747.
  29. Senapati PS, Bhattarcharya D, Harinath G and Ammori BJ. A survey of the timing and approach to the surgical management of cholelithiasis in patients with acute biliary pancreatitis and acute cholecystitis in the UK. Ann R Coll Surg Engl 85(5): 306-312, 2003. PMID: 14594533.
  30. Sinha R. Early laparoscopic cholecystectomy in acute biliary pancreatitis: the optimal choice? HPB (Oxford). 10(5): 332-335, 2008. PMID: 18982148.
  31. Tate JJ, Lau WY and Li AK. Laparoscopic cholecystectomy for biliary pancreatitis. Br J Surg 81(5): 720-722, 1994. PMID: 8044561.
  32. Tenner S, Baillie J, Dewitt J and Vege SS. American College of Gastroenterology Guideline: Management of Acute Pancreatitis. Am J Gastroenterol 108(9):1400-1415, 2013. PMID: 23896955.
  33. Toh SK, Phillips S and Johnson CD. A prospective audit against national standards of the presentation and management of acute pancreatitis in the South of England. Gut 46(2): 239-243, 2000. PMID: 10644319.
  34. Torgerson JS, Lindroos AK, Naslund I and Peltonen M. Gallstones, gallbladder disease, and pancreatitis: cross-sectional and 2-year data from the Swedish Obese Subjects (SOS) and SOS reference studies 704. Am J Gastroenterol 98(5): 1032-1041, 2003. PMID: 12809825.
  35. van Baal MC, Besselink MG, Bakker OJ, van Santvoort HC, Schaapherder AF, Nieuwenhuijs VB, et al. Timing of cholecystectomy after mild biliary pancreatitis: a systematic review. Ann Surg 255(5): 860-866, 2012. PMID: 22470079.
  36. van Geenen EJ, van der Peet DL, Mulder CJ, Cuesta MA and Bruno MJ. Recurrent acute biliary pancreatitis: the protective role of cholecystectomy and endoscopic sphincterotomy. Surg Endosc 23(5): 950-956, 2009. PMID: 19266236.
  37. Venneman NG, van Brummelen SE, van Berge-Henegouwen GP and van Erpecum KJ. Microlithiasis: an important cause of "idiopathic" acute pancreatitis? Ann Hepatol 2(1): 30-35, 2003. PMID: 15094703.
  38. Working Group IAPAPAAPG. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology 13(4 Suppl 2): e1-15, 2013. PMID: 24054878.
  39. Working Party of the British Society of Gastroenterology, Association of Surgeons of Great Britain and Ireland, Pancreatic Society of Great Britain and Ireland and Association of Upper GI Surgeons of Great Britain and Ireland. UK guidelines for the management of acute pancreatitis. Gut 54 Suppl 3: iii1-iii9, 2005. PMID: 15831893.
  40. Yadav D and Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology 144(6): 1252-1261, 2013. PMID: 23622135.
  41. Yadav D and Lowenfels AB. Trends in the epidemiology of the first attack of acute pancreatitis: a systematic review. Pancreas 33(4): 323-330, 2006. PMID: 17079934.