The theory of 'persisting' common bile duct

Transcription

1 Annals of the Royal College of Surgeons of England (1989) vol. 71 The theory of 'persisting' common bile duct stones in severe gallstone pancreatitis JOHN P NEOPTOLEMOS MD FRCS Senior Registrar Department ofsurgery, Leicester Royal Infirmary, Leicester Key words: CHOLEDOCHOLITHIASIS; CHOLECYSTOLITHIASIS; ACUTE PANCREATITIS; ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY; ENDOSCOPIC SPHINCTEROTOMY Summary There have been uncertainties as to the role of common bile duct (CBD) stones in severe gallstone pancreatitis. In order to resolve this, ERCPfindings in 131 patients with acute pancreatitis were compared with predicted severity, clinical course andfinal outcome. Significant associations were found between 'persisting' CBD stones, coincidental acute cholangitis, predicted severity and actual outcome. There was evidence for acute obstruction of both the CBD and the pancreatic duct by CBD stones. The theory was therefore proposed that small migrating stones tend to initiate the attack, whereas larger 'persisting' stones tend to convert a mild attack into a severe attack. This hypothesis resolves previously irreconcilable theories and lends support to the use of urgent endoscopic sphincterotomy for treatment, but only in cases predicted to be severe. Introduction In 1901, Eugene Opie (1) proposed that stone impaction at the ampulla of Vater resulted in reflux of bile along a common channel into the pancreatic duct causing acute pancreatitis. Although this has prompted attempts at urgent (<72 h) surgical biliary decompression (2,3), this has failed to gain general acceptance for several reasons: 1 Anatomical studies have shown apparent deficiencies in the common channel theory (4,5); 2 Common bile duct (CBD) stones are passed through the ampulla of Vater into the duodenum by virtually all patients with gallstone pancreatitis (6,7); 3 With adequate supportive care, the majority of patients recover from the attack (8,9); 4 The general experience is that urgent biliary decompression is associated with an unacceptably high mortality (9-12). Based on a Hunterian Lecture delivered at the Royal College of Surgeons of England, Lincoln's Inn Fields, London, on 18 March 1988 Present appointment and correspondence to: MrJohn P Neoptolemos MD FRCS, Senior Lecturer, University Department of Surgery, Dudley Road Hospital, Birmingham B18 7QH This has resulted in alternative theories to explain the initiation of acute pancreatitis. Bile may reflux into the pancreatic duct because of transient obstruction at the ampulla of Vater (6) or, alternatively, due to obstruction caused by oedema of the migrating stone (3). Others have proposed that duodenal contents reflux into the pancreatic duct through a gaping papilla (13,14). These different theories have been considered mutually exclusive (13,15). This theoretical conflict has been at the root of contradictory methods of management which seem to be irreconcilable. Two innovations which have made it possible to provide some elucidation of the problem are the application of prognostic criteria of severity and endoscopic retrograde cholangiopancreatography (ERCP). These methods have been applied in the present study in order to establish the relationship between CBD stones, predicted severity, and actual outcome. Patients and methods One-hundred patients- with acute pancreatitis due to gallstones, were studied by ERCP during the same hospital admission over a 10-year period. The diagnosis of acute pancreatitis was based on serum amylase >1000 U/l (Phadebas) in the presence of a compatible clinical picture (normal upper limit of amylase is 300 U/l). The diagnosis of gallstones was based on unequivocal radiological findings and/or the findings at operation or post-mortem. Another 31 patients without gallstones, who also underwent ERCP during acute pancreatitis, were studied for comparison. In this group, gallstones were excluded by at least three separate ultrasound examinations (including one 6 months after the attack) and at least one ERCP. The serum bilirubin was also measured within 48 h of admission using the SMAC autoanalyser (Technicon; normal range of bilirubin 3-17 [tmol/l). The predicted severity of the attack was determined using modified Glasgow criteria (16); three or more of the following eight criteria predicted a severe attack, while two or less predicted a mild attack: age >55 years, white cell count >15 X 109/1, blood glucose >10 mmol/l (in

2 non-diabetic patients), urea >16 mmol/l, Pao2 <8.0 kpa, serum albumin <32 g/l, serum calcium <2.0 mmol/l and serum lactate dehydrogenase >600 IU/l. ERCP was performed using a standard technique involving pharyngeal local anaesthesia 1% lignocaine spray, mild intravenous sedation using either diazepam (5-10 mg) or midazolam (2.5-5 mg) and duodenal relaxation with hyoscine butylbromide. If stones were identified in the main biliary tree, an endoscopic sphincterotomy was performed and stones extracted as previously described (17). All patients received intravenous fluids, oxygen support as required and intravenous antibiotics for at least 3 days. All patients had abdominal examination with at least one ultrasound examination, and in the latter half of the study most patients underwent serial examination by computed tomography. A severe outcome was defined as one in which the patient died or sustained a significant complication. Included were pseudocysts, ascites, pancreatic necrosis or abscess, respiratory failure, multisystem failure, pseudo-obstruction, cerebrovascular accident and disseminated intravascular coagulation (DIC). A pseudocyst was defined as a circumscribed pancreatic or peripancreatic collection of fluid present on serial scanning. Pancreatic necrosis was defined as extensive non-viable pancreatic tissue requiring surgical removal or apparent at post-mortem. Pancreatic or peripancreatic abscess was defined as a localised collection of pus. Cardiovascular failure was defined as the need to use inotropic agents for at least 24 h in order to maintain a systolic blood pressure >100 mmhg. Renal failure was defined as oliguria of <500 ml/24 h in the presence of adequate hydration and cardiovascular support. Respiratory failure was defined as the use of 02 until death or at least 5 days if surviving in order to maintain the Pao2 >9 kpa. Multisystem failure was described as failure of the cardiovascular, renal and respiratory systems despite adequate fluid replacement and oxygen support. The presence or absence of CBD stones was noted at urgent (<72 h after admission) ERCP or early (3-30 days after admission) ERCP. The maximum CBD diameter and pancreatic duct diameter was recorded at the time of ERCP, and corrected for radiological magnification by comparison with the known diameter of the duodenoscope with the patient lying in the prone position. Statistical analysis of discrete variables was undertaken using the X2 test; Yate's correction was used for expected small numbers. Continuous variables were analysed using the two-tailed Mann-Whitney U test. Simple correlations were determined using the Minitab computer package. Partial correlation coefficients were determined as previously described (18). Statistical significance was assumed as P<0.05. Results The median age of the 100 patients was 69 years (range 2-86 years), of whom 60 were women. Fifty-five patients had an urgent ERCP. Overall, 38 patients had a predicted severe attack; 19 had an actual severe outcome (Table I). Two deaths occurred in patients who had clear bile ducts and did not have an endoscopic sphinc- 'Persisting' common bile duct stones 327 TABLE I Complications in all 100 patients with gallstone associated pancreatitis undergoing ERCP+endoscopic sphincterotomy during the same admission Complications Total Pseudocysts 14 Pancreatic necrosis 4 (2t) Pancreatic abscess 4 (It) Peripancreatic abscess 3 (It) Liver abscess 1 Pseudo-obstruction 1 Respiratory failure 5 (It) Multisystem failure 1(I ) DIC 1 Lumbar osteitis I Empyema of gallbladder I Number of patients with complications 19* Number of deaths 2* DIC=Disseminated intravascular coagulation * In patients undergoing endoscopic sphincterotomy alone (n=37) there were 12 complications and no deaths t Complications associated with death terotomy. The incidence of actual complications was significantly greater in those with predicted severe attacks (11 out of 38 cases (29%), compared to those with predicted mild attacks (8 out of 62 cases (13%); X2=5.86, df=l, P<0.02). Thirty-seven of the patients were found to have CBD stones. Significantly, more patients with predicted severe attacks had CBD stones compared with those predicted mild (57% vs 29%, respectively). This distinction was more marked in comparing those undergoing an ERCP within 72 h with those having a subsequent ERCP (Fig. 1). All 37 patients with CBD stones underwent sphincterotomy without mortality. The incidence of actual complications was significantly greater in those with CBD stones (12 out of 37 cases, or 32%), compared with those predicted mild (7 out of 63 cases, or 11%; X2=6.89, df=l, P<0.01). Although Percent 70 -I _ O - <72 hours PI,M I days I--. All cases PS PM PS PM PS PM X2=&8.43 X2= 7.39 df = 3 df = 1 p <0.05 p = FIG. 1 This shows the incidence of common bile duct stones in relation to predicted severity (PS=severe; PM=mild) and timing of ERCP.

3 328 J P Neoptolemos Percent n =20 PS n =17 _-I CBD stones x2= 9.09, df=3, n =18 PS n =45 ~~~~~- I PM No CBD stones p<0.05 FIG. 2 This shows the incidence of actual complications in relation to the presence or absence of common bile duct (CBD) stones and predicted severity (PS=severe; PM=mild). interconnected, the presence of CBD stones seemed to have a more important effect than predicted severity on actual outcome (Fig. 2). There were 23 patients who presented with coexisting acute cholangitis, the relative incidence of which was greater in those predicted severe (13 out of 38 cases, or 34%), than in those predicted mild (10 out of 62 cases or 16%; x2=4.35, df=i, P<0.05). Eight (35%) of these patients had an adverse outcome, compared with only 11 out of 77 (14%) cases without coincident cholangitis (X2=4.83, df=l, P<0.05). Moreover, a higher proportion of patients with cholangitis had CBD stones (15 out of 23 cases, or 65%) than those without (22 out of 77 cases, or 29%; X2= 10.20) df=l, P<0.002). Cholangiograms were obtained in 94 patients and pancreatograms in 75 patients. Whereas there was no significant difference in the incidence of cholangiograms when comparing predicted outcome, the incidence of pancreatograms was much lower in those predicted severe (50%) compared to those predicted mild (82%; x2=7.10, df= 1, P<0.01). The mean±sd CBD diameters (9.2±4.5 mm) were significantly greater in this group of gallstone patients compared with the 31 patients with non-gallstone pancreatitis (5.0±1.9 mm; P<0.0001). Similarly, the pancreatic duct diameters were also greater in the gallstone versus the non-gallstone cases (3.63±1.21 mm vs 3.10±1.57; P=0.0592). Patients with CBD stones had greater CBD diameters (12.5±4.9 mm) than those with gallbladder stones only (7.1±2.7 mm; P<0.0001). Although no such difference was observed with respect to pancreatic duct diameters, only 50% of patients with CBD stones had pancreatic duct filling compared to 95% in those with a clear biliary tree (X2=7.47,df=l, P<0.01). The mean serum bilirubin was significantly higher in patients with choledocholithiasis (83±53 [tmol/l) than in those without (37±46 [tmol/l; P<0.0001). Significant correlations were observed between the admission serum bilirubin and both the CBD diameters (r=0.396, n=94; P<0.001) and pancreatic duct diameters (r=0.291, n=75; P<0.01). Similarly, a significant correlation was observed between the CBD and pancreatic duct diameters (r=0.317, n=71; P<0.01). All these correlations maintained statistical significance when correcting for age (which was also correlated with these variables) using partial correlation analysis (all P<0.05 to P<0.001). Discussion The important findings in this study can be summarised as follows: 1 The presence of CBD stones was significantly related to both predicted severity and actual outcome, including pancreatic complications. 2 Acute cholangitis coincidental with acute panreatitis was more frequent in those with predicted severe attacks and with CBD stones. 3 The diameters of the CBD and pancreatic duct were significantly greater in patients with gallstone pancreatitis compared with those without. Whereas CBD diameters were greater in gallstone patients who also had CBD stones, pancreatic duct filling was significantly less on ERCP in the presence of choledocholithiasis. 4 There was a significant three-way correlation between the admission serum bilirubin (an accurate indicator of CBD stones in acute pancreatitis) (19), CBD diameters and pancreatic duct diameters. These original observations can be used to reconcile what seems to be a fundamental paradox in the pathogenesis of acute gallstone pancreatitis. On the one hand, virtually all patients will pass stones into the faeces during an acute attack (6,7). On the other hand, up to 60% of patients who die from acute gallstone pancreatitis are found to have choledocholithiasis, although only in about 5% will these be impacted in the ampulla of Vater (8,20-22). Along with the current data, these observations can be incorporated into a unifying concept-the theory of 'persisting' CBD stones in severe gallstone pancreatitis. It is proposed that there are two phases in this process (Fig. 3). In the first phase small migrating stones will lead to the initiation of the attack. In the vast majority of cases, the outcome will be a mild attack. Any one of three proposed mechanisms may be involved, although the pathobiochemical link between any of these processes and the initiation of acute pancreatitis remains speculative (14,23). The bulk of the evidence favours the bile reflux theory. Pancreatic duct reflux is frequently observed with antegrade cholangiography (24). Certain anatomical features of the choledochal-pancreatic duct junction favouring such reflux in patients with acute pancreatitis have been described (25). The idea that

4 e41 GALLSTONE - PANCREATITIS O1A-A i -SD MIGRATION *EMOu AlrYACK (a) GALLSTONE - PANCREATIT1N NHASE 1II PERSIBTINQ CD S8l ascending cholongitis 'Persisting' common bile duct stonef 329 (28). In particular, patients with acute pancreatitis who have undergone endoscopic sphincterotomy will not sustain further attacks despite gallbladders with stones ATTACK being left intact (29). In the second phase of the newly advanced theory, it is proposed that it is the presence of 'persisting' larger CBD stones which predispose to the development of a severe attack (Fig. 3b). It is envisaged that these stones block the egress of pancreatic juice which now contains activated enzymes. Histological studies have indicated that the pancreatic necrosis stems primarily from intraductal and periductal inflammation (30,31). A stone blocking the ampulla of Vater may lead to a severe attack, but will not necessarily have initiated the attack. The concept of 'persisting' CBD stones is a broad one. Situations in which stones will block the pancreatic duct will include not only those cases in which they impact in the ampulla, but also in which they lodge in the lower CBD at a site where the pancreatic duct lies in close proximity to it. #-ES These stones may well cause intermittent pancreatic duct obstruction by repeated impaction at these sites, followed by disimpaction back into the common bile duct. Similarly, the repeated passage of stones through the ampulla of Vater during the early stages of the attac'k will have a similar effect. $19VEPkE ATTACK (b) FIG. 3 (a) In Phase I, small migrating common bile duct (CBD) stones initiate the attack. In the vast majority only a mild attack results. (b) In Phase II, persisting CBD stones, either because they are larger, or if smnall because they are numerous, not only obstruct the CBD but block the egress of activated enzymes from the pancreatic duct. This results in an increased incidence of coincident ascending cholangitis and a predisposition to a severe attack of pancreatitis. oedema of ampulla rather than an impacted stone predisposes to bile reflux means that the previous rigid arithmetical restrictions on Opie's theory need no longer apply. Although the duodenal reflux theory cannot be entirely dismissed as a causative mechanism, particularly in patients with a 'closed' duodenal loop (13,14), the evidence is against this being of major importance in gallstone pancreatitis. Unless the gallbladder is removed and the bile ducts cleared, recurrent attacks of acute pancreatitis are frequent (9,11). Dysfunction of the sphincter of Oddi is likely to be due to stone passage rather than a primary phenomenon (26). McCutcheon (27), a great proponent of this theory, wrote in 1964 that "if the theory of duodenal reflux is correct, there are... important implications for treatment... sphincterotomy is contraindicated". Since then, more than sphincterotomies have been performed, with acute pancreatitis (other than as a procedural event) being exceedingly rare FIG. 4 This typical collection of gallstones came from one patient with an attack of acute pancreatitis. Note the wide variation in gallstone size: the smaller ones are considered to initiate the attack, the larger ones are considered to predispose to a severe attack.

5 330 J P Neoptolemos TABLE II Combined results of endoscopic sphinterotomy for common bile duct stones in acute pancreatitis in eight different series Series Complications Number related to of endoscopic patients sphincterotomy All deaths Classen et al. (1978) (36) Van der Spuy (1981) (37) Safrany (1982) (38) Schott et al. (1982) (39) Kautz et al. (1982) (40) Reiman and Lux (1984) (41) Rosseland and Salhaug (1984) (42) 29* 2 1 Present series 37 3 (12t) 0 Total (21t) 4 (2.1%) * 15 Patients had sphincterotomy <48 h and 14 at 7-8 weeks. t All complications McMahon and Shefta (32) have previously described the size and shape of gallstones typically found in acute pancreatitis. What is striking is the wide variation in size (Fig. 4). This observation is not only consistent but necessary for the present hypothesis. The smaller stones initiate the attack; the larger stones are not only likely to lead to a severe attack of pancreatitis, but also to acute cholangitis. Although poorly recognised, coexisting acute cholangitis is well described in acute pancreatitis and is associated with an increased adverse outcome from pancreatic complications (33-35). These observations have important implications for treatment. Preliminary results of endoscopic sphincterotomy have suggested a good outcome for patients with acute pancreatitis and 'persisting' CBD stones (36-42) (Table II). The results of a prospective randomised trial (which included some of the patients in this study), have shown that ERCP performed within 72 h of the attack resulted in a marked improvement in those with predicted severe attacks, by enabling removal of CBD stones following sphincterotomy (43). It is essential that this approach forms only one part of the overall management of the patient which must include adequate supportive care and timely surgical intervention where indicated. The best results will only be achieved where a team approach is used, requiring in particular a skilled endoscopist. Conclusions Important evidence has been presented showing that obstruction of both the CBD and pancreatic duct occurs in acute gallstone pancreatitis. These changes are directly linked to 'persisting' CBD stones, which are related to outcome. The theory of 'persisting' common bile duct stones in acute pancreatitis is proposed which reconciles previously conflicting observations. The way ahead lies in refining techniques of demonstrating 'persisting' CBD stones and the wider application of ERCP and endoscopic sphinterotomy. The results of such an approach will ultimately test this new hypothesis. This study would not have been possible without the cooperation of all the consultant surgeons and physicians in the Leicester hospitals, nor without the assistance of the Departments of Radiology, Biochemistry and Haematology, junior surgical and medical staff, ward sisters and endoscopy units. My special appreciation is extended to David Carr-Locke, David Fossard, Peter Bell, Kenneth Wood, John Bolton- Carter, David Watkin, Nick London, Ian Bailey, Nick Slater and Derek James. This work is a tribute to the Pancreatic Society of Great Britain and Ireland, and in particular to Clem Imrie, which has provided the vital background stimulus. I acknowledge the superb art and secretarial skills of Dilys Thomas. References I Opie EL. The etiology of acute hemorrhagic pancreatitis. Johns Hopkins Hosp Bull 1901; 121: Acosta JM, Rossi R, Galli OMR, Pellegrini LA, Skinner DB. Early surgery for acute gallstone pancreatitis: Evaluation of a systematic approach. 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6 24 Cuschieri A, Hughes JH. Pancreatic reflux during operative choledochography. Br J Surg 1973;60: Armstrong CP, Taylor TV, JeacockJ, Lucas S. The biliary tract in patients with acute gallstone pancreatitis. BrJ Surg 1985;72: Cuschieri A, Cumming JGR, Wood RAB, Baker PR. Evidence for sphincter dysfunction in patients with gallstone associated pancreatitis: effect of ceruletide in patients undergoing cholecystectomy for gallbladder disease and gallstone associated pancreatitis. BrJ Surg 1983;71: McCutcheon AD. Reflux of duodenal contents in the pathogenesis of pancreatitis. Gut 1964;5: Cotton PB. Endoscopic management of bile duct stones (apples and oranges). Gut 1984;25: Davidson BR, Neoptolemos JP, Carr-Locke DL. Endoscopic sphinterotomy for common bile duct calculi in patients with gallbladder in situ considered unfit for surgery. Gut 1988;29: Foulis AK. Histological evidence of initiating factors in acute necrotising pancreatitis in man. 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Endoscopy 1978;10: Van Spuy DS. Endoscopic sphincterotomy in the management of gallstone pancreatitis. Endoscopy 1981; 13: Safrany L. Controversies in acute pancreatitis. In: Hollender LF. ed. Controversies in Acute Pancreatitis. New York: Springer-Verlag, 1982; Schott B, Neuhaus B, Portacarrero G, Krause S, Safrany L. Endoskopische papillotomie bei akuter bilaren pankreatitis. Klinikarzt 1982;1 1: Kautz G, Kohaus H, Keferstein R-D, Bunte H. Zur pathogenese und endoskopishen therapic der okuten bilaren pankreatitis. Klinikarzt 1982; 11: Riemann JF von, Lux G. Therapeutische strategie bei der akuten pankreatitis (I). Fortschr Med 1984; 102: Rosseland AR, Solhaug JH. Early or delayed endoscopic papillotomy (EPT) in gallstone pancreatitis. Ann Surg 1984; 199: Neoptolemos JP, Carr-Locke DL, London NJ, Bailey IA, James D, Fossard DP. Results of a controlled trial of urgent ERCP and endoscopic sphincterotomy in patients with acute pancreatitis due to gallstones. Lancet 1988;ii: Received 11 January 1989 Notes on books Oxygen Radicals in the Pathophysiology of Heart Disease edited by Pawan K Singal. 348 pages, illustrated. Kluwer Academic Publishers, Boston Many of the chapters in this book are papers given at a Symposium on Oxygen Radicals in Heart Pathophysiology held in Winnipeg in The aim of the volume is to offer an integrated view of the pathophysiological aspects of oxygen toxicity in the heart and blood vessels. Of interest to cardiac surgeons and anaesthetists. Liver Tumors: Multidisciplinary Management edited by W John B Hodgson. 323 pages, illustrated. Warren H Green International, St Loulis. $ There has recently been a very much more aggressive approach to the management of liver tumours, particularly metastases from colorectal carcinoma. In the United States alone there are estimated to be thirty thousand cases of hepatic colorectal metastases a year and it is therefore opportune that this book should be published. 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No results are given and so it is not possible for the reader to assess whether the laser confers any advantage over the scalpel. An Illustrated Guide to Gastrointestinal Motility edited by D Kumar and S Gustavsson. 470 pages, illustrated. John Wiley & Sons, Chichester An international team of contributors cover all aspects of gastrointestinal motility. Section 1 is on physiology, Section 2 on methodology and subsequent sections on normal and abnormal motility of individual parts of the gastrointestinal tract. Numerous illustrations, clear layout, comprehensive referencing make this book invaluable to research workers in the field and to gastroenterologists who wish to improve their understanding and management of patients with gastrointestinal motility disorders.