Choledocholithiasis and gallstone pancreatitis

3 Choledocholithiasis

and gallstone pancreatitis

MICHAEL

MB, BS, PRCS

G. T. RARATY

Research Fellow

IAN M. POPE

BA, BM, BCh, FRCS(Ed)

Research Fellow

MARGARET FINCH

BA, MD

Lecturer in Surgery

JOHN P. NEOPTOLEMOS”

MA, MB, MD, FXCS, BCh

Professor of Surgery Department of Surgery, University Hospital, Daulby Street, Liverpool,

of Liverpool, 5th Floor L69 3GA, UK

UCD Building,

Royal

Liverpool

(lniversity

Gallstones are commonly found within the main bile duct (MBD) of patients undergoing cholecystectomy. Retained MBD stones are a common cause of obstructive symptoms and complications. Endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy (ES) is the recommended modality for both the detection of such stones and their extraction. Recent trials of ERCP in conjunction with laparoscopic cholecystectomy suggest that it should be reserved for use post-operatively. Gallstones within the MBD are the most common single cause of acute pancreatitis. Initial treatment is supportive, although new agents designed to suppress the systemic inflammatory response are under development and have proved beneficial in clinical trials. Severe cases should be treated with systemic antibiotics and early removal of the obstructing stones by ERCP and ES. Prophylactic cholecystectomy is recommended to prevent further attacks of gallstone pancreatitis. Key words: common pancreatitis aetiology.

bile duct calculi:

cholangiopancreatography,

sphincterotomy,

Stones are found in the main bile duct (MBD) in 7-20% of patients undergoing cholecystectomy (Faris et al, 1975; Hermann, 1989). In addition, autopsy studies have shown that many patients with asymptomatic gallbladder stones also have stones in the main bile duct (Crump, 1931). Up to * Corresponding author Baillihe

k Clinical

Gastroenterology-

Vol. II, No. 4, December 1997 ISBN &7020-2383-3 0950-3528/97/040663 + 18 $12.00/00

Copyright 0 1997, by Bail&e All rights

of reproduction

in any form

663 Tindall reserved

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the age of 60 years, the incidence of bile duct stones increases gradually. In older patients, however, the increase is dramatic, and the reported incidence is as high as 31% between the ages of 61 and 70 years and 52% between 71 and 90 years (Hermann, 1989). The incidence of bile duct stones also rises with the duration of symptoms related to gallbladder stones (Heyd, 1941; Wenckert and Robertson, 1966). For patients known to have retained MBD stones following cholecystectomy, the cumulative rate of symptoms and complications is up to 94%, with a mortality rate of 3.3% (Hicken and McAllister, 1964). Patients with MBD stones may present with obstructive jaundice, cholangitis or acute pancreatitis. These symptoms may present singly or in combination, and all three usually result from the passage of a stone through the ampulla of Vater. CHOLEDOCHOLITHIASIS Detection of bile duct stones The initial investigation of patients presenting with obstructive jaundice generally includes ultrasonography, which confirms the presence of intrahepatic and extrahepatic biliary dilatation in the majority of patients. Ultrasonography can diagnose gallbladder stones with an accuracy of 95-98%; however, stones in the MBD are often overlooked, reported sensitivities ranging from 19 to 55% for these stones (Gross et al, 1983; Laing and Jeffrey 1983; O’Conner et al, 1986). Computed tomography (CT) has a reported sensitivity of up to 90% for the diagnosis of bile duct stones (Thomas et al, 1982). Other authors, however, have suggested that the accuracy of CT is lower, with reported sensitivities of 76% and 67%, respectively (Baron 1987; Wyatt and Fishman, 1997). Confirmation that obstruction is caused by biliary stones requires cholangiography. This may be achieved by percutaneous transhepatic cholangiography (PTC) or endoscopic retrogade cholangiopancreatography (ERCP), or by per-operative cholangiography. The performance of PTC requires the presence of dilated intrahepatic bile ducts but may be more successful in providing biliary decompression for high biliary obstruction (Nelson et al, 1996). In patients without dilated ducts, ERCP is more successful and is more accurate in assessing disease of the lower duct and ampulla (Matzen et al, 1981; Thomas et al, 1982). This statement is particularly true of obstruction from gallstones where the ampulla may be gaping, suggesting the recent passage of a stone, or a stone may be seen to be impacted at the ampulla, causing bulging of the infundibulum. In addition, ERCP is less hazardous than PTC in the presence of a bleeding diathesis or ascites. Operative cholangiography has played a major part in reducing unnecessary bile duct exploration and in reducing the incidence of bile duct stones. The frequency of false-positive results in recent studies ranges from 0.7 to 5% (Mofti et al, 1986; Pemthaler et al, 1990; Shivel et al, 1990). In contrast, stones are missed using operative cholangiography in about 2% of

CHOLEDOCHOLITHIASIS

665

patients with choledocholithiasis. Arguments suggest some additional benefit in terms of avoiding iatrogenic bile duct injury at laparoscopic cholecystectomy (Berci et al, 1991), but no published evidence supports this, and the bile duct injury rate has fallen rapidly into the range previously reported for open cholecystectomy (Macintyre and Wilson, 1993). Treatment

of bile duct stones

Dissolution

therapy

Dissolution therapy of cholesterol bile duct stones may be achieved by desaturation therapy with a variety of oral agents. The success rate in 91 patients from several series was 42%, continuous treatment being required for between 3 months and 4 years (Neoptolemos et al, 1986). Direct dissolution therapy is possible via a T-tube tract, percutaneous catheter or endoscopically placed nasobiliary catheter using either mono-octanoin or methyl tertiary butyl ether (MTBE). A clinically useful effect is produced in 58% of patients treated with mono-octanoin, with a complication rate of 9% (Palmer and Hofmann, 1986). In a UK study, MTBE therapy was clinically useful in 36% of patients but was associated with a high complication rate of 79% (Neoptolemos et al, 1990). A further small study from Spain has confirmed the effectiveness of this technique but again demonstrated a high complication rate (Vilaseca et al, 1994). Percutaneous extraction The biliary tree may be accessed by percutaneous transhepatic puncture and tract dilatation for stone removal, fragmentation, transpapillary expulsion or chemolysis (Geisinger et al, 1989; Gunther and Vorwerk, 1994; Silver et al, 1996). The sphincter of Oddi may be dilated to allow stones to pass into the duodenum, and stents can be deployed across strictures. Transhepatic techniques are best applied to patients with high bile duct strictures and hepatolithiasis. Transhepatic manipulation is more difficult and potentially more dangerous than manipulation via a T-tube (Gunther and Vorwerk, 1994). Percutaneous extraction via a T-tube has an established role in the treatment of retained bile duct stones and is as effective as endoscopic extraction but avoids the need for sphincterotomy. Success rates vary from 78% to 97% with a 4-5% complication rate and a low mortality rate of about 0.1% (Burhenne, 1980; Nussinson et al, 1991). Some studies, however, have shown a high rate of gallstone recurrence of up to 40% after percutaneous removal (Courtois et al, 1996). Surgical choledocholithotomy Bile duct exploration during cholecystectomy increases morbidity, and increasing age is associated with an increased mortality rate. The mortality rate for bile duct exploration is below 1% in patients less than 70 years old but 10% or more in patients over the age of 70. Overall mortality rates from

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bile duct exploration vary from 0% to 7.4% (Winslet and Neoptolemos, 1991); however, mortality is substantially higher for patients with acute cholangitis (Leese et al, 1986; Lai et al, 1992) or for those undergoing surgery for acute pancreatitis (Stone et al, 1981; Kelly and Wagner, 1988). The introduction of operative choledochoscopy has considerably reduced the incidence of retained stones following choledocholithotomy. Recent series show an incidence of retained stones of l-5% compared with earlier series, which had a reported incidence of 4-16% (Winslet and Neoptolemos, 1991). Endoscopic sphincterotomy If, at the time of ERCP, stones are identified within the main bile duct (MBD) endoscopic sphincterotomy (ES) may be performed. Stone extraction may then be facilitated by the use of a balloon catheter or dormia basket. ERCP/ES has been shown to result in duct clearance in more than 90% of cases (Cotton, 1984). Success rates may be further improved by the use of needle-knife sphincterotomy (Dowsett et al, 1990) or a combined percutaneous/endoscopic technique (Dowsett et al, 1989). Sphincterotomy, however, carries risks of bleeding, duodenal perforation and pancreatitis (Freeman et al, 1996). The published series demonstrate complication rates of 5-10% and mortality rates of O&1.4% (Winslet and Neoptolemos, 1991), which compares favourably with the morbidity and mortality following operative choledochotomy. A recently introduced technique is endoscopic balloon dilatation, which in a recent randomized trial has been shown to be as effective as sphincterotomy in extracting gallstones from the MBD but carries less risk of bleeding and does not permanently compromise the sphincter of Oddi (Bergman et al, 1997). Endoscopic gallstone extraction is the treatment of choice in patients with acute cholangitis (Leese et al, 1986; Lai et al, 1992) or severe gallstone pancreatitis (Neoptolemos et al, 1988; Fan et al, 1993). For patients with symptomatic common duct stones and intact gallbladders who are suitable candidates for surgery, it has been suggested that pre-operative ERCP with or without sphincterotomy prior to cholecystectomy may reduce morbidity and mortality in addition to hospital time and cost. Neoptolomos et al (1987a) have performed a prospective randomized trial of sphincterotomy followed by cholecystectomy versus surgery alone. In a series of 120 patients, the overall major complication rate for endoscopic sphincterotomy and cholecystectomy was 16.4%, compared with 8.4% in the surgery-alone group. The only significant advantage of preoperative endoscopic sphincterotomy was a reduction in hospital time, although this trial was restricted to patients of low or moderate surgical risk. In elderly, high-risk patients, endoscopic sphincterotomy is superior to operative choledochotomy. In a multivariate analysis of pre-operative risk factors for patients with bile duct stones, Neoptolemos et al (1989) have shown that the presence of medical risk factors was an independent, significant variable with relation to outcome in patients undergoing surgery, whereas it was not so in patients treated by ERCP. It was therefore

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concluded that patients at high risk should be treated by endoscopic sphincterotomy alone in the first instance, avoiding cholecystectomy if possible. A number of studies have examined the risk of further problems from gallstones if the gallbladder remains following endoscopic sphincterotomy (Davidson et al, 1988a; Hansel1 et al, 1989; Ingolby et al, 1989; Hill et al, 1991). Many patients will have no further symptoms in the short term, and cholecystectomy may therefore be safely avoided. Failure to achieve bile duct clearance at the time of ERCP results in a considerable increase in the incidence of major complications (Neoptolemos et al, 1987b; Boender et al, 1994). A wide variety of adjuvant techniques is therefore now available to facilitate duct clearance or to deal with large biliary stones. These techniques include mechanical lithotripsy, electrohydrolytic lithotripsy, laser lithotripsy and extracorporeal lithotripsy (Winslet and Neoptolemos, 1991; Hagenmuller and Schwacha, 1992; Moody, 1993). Alternative approaches for the management of unextractable stones include endoscopic placement of a biliary stent in order to maintain biliary drainage (Kiil et al, 1989) or chemical dissolution via an endoscopically placed nasobiliary catheter as described above (Neoptolemos et al, 1990). A mortality rate of 3% may be anticipated in patients in whom mechanical means of stone extraction initially fail (Cairns et al, 1989). This rate would be acceptable in elderly, high-risk patients, but surgery would probably be appropriate at an earlier stage in younger patients. Choledocholithiasis

and laparoscopic

cholecystectomy

Laparoscopic cholecystectomy is now considered the treatment of choice for patients requiring cholecystectomy. However, the management of common bile duct stones in patients subjected to laparoscopic cholecystectomy remains a subject of considerable debate (Perissat et al, 1994). The incidence of bile duct stones is lower in patients undergoing laparoscopic cholecystectomy than in other series. In a collected series (Macintyre and Wilson, 1993) of 3057 patients who underwent laparoscopic cholecystectomy, 363 (11.9%) were selected to have ERCP and only 135 of these (37.2%; 4.4% of the total) were found to have bile duct stones. This rate compares with an anticipated incidence of between 7% and 20% from published surgical series (Faris et al, 1975; Hermann, 1989). This observation may be explained by the lower average age of patients undergoing laparoscopic cholecystectomy. In contrast to previous surgery versus ERCP/ES studies, most laparoscopic cholecystectomy studies include patients with a mean age of 40-50 years, compared with 50-60 years in surgical series. In up to one third of cases, patients undergoing laparoscopic cholecystectomy are found to have asymptomatic ductal stones that were unsuspected pre-operatively (Schwesinger, 1997). The indications for intervention in the presence of asymptomatic ductal stones are not clearly defined. Two randomized trials have shown a detection rate of 3-12% for bile duct stones in an operative cholangiography arm but no symptoms in the control arm

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after 1-8 years of follow-up (Hauer-Jensen et al, 1986; Murison et al, 1989). Presumably, a similar prevalence of ductal stones exists in the control arm but that these remain asymptomatic. It is not clear whether such stones pass spontaneously into the duodenum or remain in the MBD without causing symptoms, although they may present with significant complications at a later date. This situation provides a dilemma regarding the treatment of unsuspected stones found at laparoscopic cholecystectomy. Three altematives are available: to remove the stones laparoscopically, to convert to an open bile duct exploration or to leave the stones in situ and proceed to endoscopic removal at a later date. In the latter case, an option is to remove endoscopically all stones or only those which ultimately cause symptoms. In practice, the preferred option is likely to depend on the expertise of local endoscopic and surgical units. All three approaches have been shown to have similar success rates in retrieval of stones from the MBD (Table 1). Table

1. Retrieval

rates of stones from the main bile duct Stone retrieval

Laparoscopic exploration Open choledochotomy Endoscopic sphincterotomy

rate (70)

90-99 96-98 SO-95

Mortality

rate (%)

0.4-2.0 0.5-2.5 0.5-1.0

Laparoscopic MBD exploration may be performed via the cystic duct or by direct choledochotomy. Both methods have been shown to be highly successful in skilled hands (Table 2). Transcystic stone retrieval is most successful in patients with small stones less than 8 mm in diameter. It is quite possible that stones of this size will pass spontaneously, but stones greater than 8 mm in diameter are much less likely to pass. If the bile duct is greater than 10 mm in diameter, laparoscopic direct choledochotomy is an option. Failure to retrieve stones laparoscopically necessitates postoperative ERCP or open choledocholithotomy. At present, the availability of laparoscopic bile duct exploration is limited by the relatively small number of appropriately trained surgeons. It has been suggested that pre-operative ERCP would be advantageous in identifying all MBD stones prior to surgery. Chan et al (1996) performed a prospective study of 609 patients undergoing laparoscopic cholecystectomy and selective pre-operative ERCP ERCP was performed in patients with a history of cholangitis, acute pancreatitis, jaundice, abnormal liver function tests or an ultrasound (US) scan showing a dilated MBD or ductal Table 2. Different Author Berci and Morganstem De Paula et al (1994) Phillips et al (1994) Rhodes et al (1995) Franklin and Dorman Robinson et al (1995)

approaches

used for laparoscopic

Approach (1994)

( 1995)

Transcystic Transcystic Transcystic Transcystic Choledochotomy Choledochotomy

bile duct exploration.

No. of patients 226 114 120 129 15 50

Success 97 95 93 92 99 94

(%)

Mortality 0.4 0.9 0.8 0.0 1.3 2.0

(%)

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stones. Of 139 patients, however, only acute cholangitis and the presence of MBD stones on US were shown to be independent significant risk factors for the presence of MBD stones. Rijna et al (1995) performed a prospective study of 699 patients with symptomatic gallstones at risk of MBD stones. One hundred and nineteen patients underwent ERCP with or without endoscopic sphincterotomy. Patients with acute cholangitis or persistent obstructive jaundice, or in the acute phase of gallstone pancreatitis, had a high positive predictive value (greater than 85%) for the presence of MBD stones. In contrast, for patients with increased liver enzyme levels or a wide MBD, or after the resolution of jaundice or pancreatitis, the positive predictive value was less than 25%. ERCP and ES had a complication rate of 14% and a mortality rate of 2%. Therefore, although pre-operative ERCP allows the demonstration and removal of MBD stones before laparoscopic cholecystectomy, it does carry significant risks. It is therefore more appropriate for patients thought to be at risk of having MBD stones to undergo operative cholangiography and either laparoscopic bile duct exploration or post-operative ERCP, as facilities and expertise allow.

GALLSTONE

PANCREATITIS

Background The first person to clearly establish the link between gallstones and acute pancreatitis was Opie (1901), although such a link had previously been described (Prince, 1882). Many studies since then have demonstrated the presence of stones in 20 to 76% of patients with acute pancreatitis. In an analysis of 5842 patients with pancreatitis from 26 studies, 2771 (47%) were found to have gallstones as the cause (Howard, 1987). More recently, advances in ultrasound and the wider use of ERCP for diagnosis have demonstrated that, in cases which would previously have been classified as ‘idiopathic’, small microcalculi are, indeed, present in up to 75% of patients (Farinon et al, 1987; Ros et al, 1991; Lee et al, 1992; Marota et al, 1996). Although some geographical variation exists, gallstones probably account for more than half of all cases of acute pancreatitis. Clinical features Like gallstones in general, gallstone pancreatitis is more common in women than in men and tends to occur in an older age group than pancreatitis due to alcohol ingestion (Clemens and Cameron, 1989). Acute pancreatitis occurs in 3-8% of all patients with symptomatic gallstones (Armstrong et al, 1985). The precise incidence varies with the population prevalence of gallstones (Winslet et al, 1992) but is approximately 360 per million population in the West Midlands of England (Neoptolemos, unpublished data).

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Gallstone pancreatitis tends to follow an acute intermittent disease pattern, individual attacks being clinically very similar to those arising from other aetiologies (Winslet et al, 1992). However, bacteraemia and ascending cholangitis are more common in association with gallstones than with other, non-obstructive causes (Neoptolemos et al, 1987~; Chang et al, 1995). As well as increased susceptibility to infection, some studies have shown a higher mortality rate among patients with gallstones when compared with other causes of pancreatitis (Kaufmann et al, 1996). This study showed a mortality rate of 13% among patients with gallstones compared with 3% for alcohol-induced cases. This finding may partly be explained by the higher average age of the patients in the gallstone group as 75% of the fatalities were in patients aged over 60. This study also revealed a generally more severe disease course among patients with gallstones. A separate study (Uhl et al, 1996) showed mortality rates of 5.3% for alcohol-induced pancreatitis, 10% for biliary pancreatitis and 5.5% for other aetiologies. These differences were not, however, statistically significant. Without treatment of the gallstones, the risk of recurrent attacks following a single attack of biliary pancreatitis is in the region of 30% (Neoptolemos et al, 1997), and the average delay before the second attack in one series was 108 days (Paloyan et al, 1975). Diagnosis The standard investigation for gallstones remains ultrasound (US), although during an attack of acute pancreatitis its sensitivity is only about 60-70% as a result of the frequent presence of an ileus and overlying gasfilled bowel loops (Neoptolemos et al, 1984). It is also common for biliary pancreatitis to result from small stones, which are less easily detected by US. Computed tomography (CT) is even less sensitive to the presence of gallstones (London et al, 1989). The most accurate investigation for detecting CBD stones is ERCP, with a sensitivity of greater than 95%, but it carries an associated morbidity (Freeman et al, 1996) and should only be performed if therapeutic intervention is envisaged (Neoptolemos et al, 1988). A number of biochemical parameters have been investigated to differentiate biliary pancreatitis from other aetiologies. Studies have suggested that serum amylase levels on admission to hospital are higher with gallstones (Davidson et al, 1988b) but then tend to decline rapidly (Dougherty et al, 1988). Others have shown a high amylase : lipase ratio to be predictive of gallstones (Gumaste et al, 1991), although this finding is not consistent. A recent study used retrospective multivariate analysis to identify predictive factors differentiating between alcohol and gallstones as the cause of acute pancreatitis (Stimac et al, 1996). Serum amylase, ALT, AST and alkaline phosphatase, together with urinary amylase, were all shown to be higher in patients with gallstone pancreatitis. A number of other serum markers have been studied, including phospholipase A2, trypsinogen activation peptide (TAP), interleukins IL-2, IL-6 and

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IL-8, and tumour necrosis factor. None of these, however, has yet been shown to have any predictive value in gallstone pancreatitis, although serum TAP has been shown experimentally to be useful and may yet prove clinically valuable in that its serum level appears to correlate with disease severity (Gudgeon et al, 1990). Pathogenesis It is now widely accepted that gallstone-associated pancreatitis results from the passage of stones through the sphincter of Oddi into the duodenum. Acosta and Ledesma (1974) analysed the faeces of patients with gallstones and pancreatitis. They identified stones in the faeces of 94% of patients with gallstone-associated pancreatitis but only 8% of patients with uncomplicated biliary colic without pancreatitis. Opie described the discovery of a stone impacted at the ampulla of Vater in a common biliary/pancreatic channel of a patient who had died of acute pancreatitis. He therefore suggested that reflux of bile into the pancreatic duct may have been the precipitating cause of the acute pancreatitis. Experimentally, Opie was able to demonstrate that forcible injection of bile into the pancreatic ducts of dogs did, indeed, induce inflammation of the pancreas, a finding that has been confirmed by other investigators (Steer, 1988). However, only about two-thirds of the population have such a common ductal channel (Trapnell, 1968; Jones et al, 1987; Misra et al, 1989), and in many cases this is so short that a stone obstructing the common bile duct would also obstruct the pancreatic duct. It is possible, however, that passage of a stone may cause a functional common channel in some patients by causing a stenosis of the ampulla of Vater (Hemandez and Lerch, 1988). This assumes that bile reflux is the trigger for pancreatitis, but at normal pressures bile is not injurious to the pancreas (Robinson and Dunphy, 1963). The pressure in the pancreatic duct is, in fact, normally two to three times higher than that in the bile duct and would therefore tend to favour reflux of pancreatic secretions into the biliary tract rather than vice versa (Menguy et al, 1958; Csendes et al, 1979). Lerch et al (1993) evaluated the effect of obstruction at different sites in the pancreatic/biliary ductal tree on the development of pancreatitis in opossums. They showed that obstruction to the main pancreatic duct alone is sufficient to induce pancreatitis in this animal model and that separate ligation of the common bile duct or ligation of the common biliary/ pancreatic channel did not affect the severity of disease. Other studies have shown that continued stimulation to secretion in the presence of an obstructed duct is important in the development of more severe damage (Steer, 1993) but that relief of the obstruction ameliorates the severity of pancreatitis (Runzi et al, 1993). The pathway by which ductal obstruction leads to pancreatitis is, however, still unclear. The first signs of pancreatic damage appear in the acinar cells themselves, and evidence is accumulating that there is intracellular activation of secretory enzymes combined with a block to their normal secretion (Foitzik et al, 1994; Simpson et al, 1995). It has been suggested

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that the pathogenetic mechanism involves co-localization of zymogen granules with lysosomal hydrolases (Saluja et al, 1989), possibly owing to an abnormality in protein sorting in the Golgi apparatus. A mechanism by which ductal hypertension could lead to such mis-sorting of enzymes has not, however, been demonstrated, and enzyme co-localization has been described in normal cells (Willemer et al, 1990). An alternative hypothesis is that enzyme activation results from disruption to the normal intracellular signalling cascades between acinar cell stimulation and the secretion of zymogens. Co-localization of enzymes therefore occurs as a protective mechanism to eliminate the active enzymes. This signalling pathway relies on intracellular calcium ions acting as a second messenger, and this process has been shown to be abnormal in acute pancreatitis (Ward et al, 1996; Zhou et al, 1996). It has been suggested that ductal hypertension impairs the normal extrusion of calcium from the apical pole of the acinar cell, thereby creating an abnormally high cytosolic calcium concentration that triggers enzyme activation and cellular damage (Ward et al, 1995). Much research effort is currently concentrated in this field. Treatment General measures

Initial management is the same as for pancreatitis of any cause. An attempt should be made to ascertain the aetiology of the pancreatitis. General supportive measures should be instituted, including intravenous fluids, parenteral analgesia and often a nasogastric tube because of nausea and vomiting. All patients should have a full blood count, liver function tests, serum urea and electrolytes, calcium and glucose, and these should be repeated daily as the clinical condition warrants. The oxygen saturation should be measured either by arterial sampling or by percutaneous probe. Plain abdominal and chest X-rays are required to exclude other causes of hyperamylasaemia, such as a perforated abdominal viscus. An assessment of the severity of the attack should be made on admission to hospital, and this should be reviewed regularly and frequently. A number of different scoring systems have been suggested, but the modified Glasgow score (Table 3) has repeatedly been shown to be both accurate and simple to use, although it can only be applied 48 hours after admission (Leese and Shaw 1988). This score has also been shown to be equally valid in pancreatitis of gallstone and non-gallstone origin. The APACHE II scoring system can be applied at any time and has been shown to be equally accurate (Larvin and McMahan, 1989) but it is much more complicated and therefore less easy to apply clinically. The benefit of both systems is the ability to predict which patients are likely to follow a severe disease course, to develop systemic complications and to benefit from more aggressive interventional therapies. Good clinical evidence now exists that systemic antibiotics reduce septic complications and mortality in severe cases (Sainio et al, 1995). Early trials of the platelet activating factor antagonist Lexipafant have been

673

CHOLEDOCHOLITHIASIS Table 3. The modified Glasgow scoring system for predicting severity in acute pancreatitis (Blarney et al, 1984). O-2 factors = mild, 3-8 factors = severe. Prognostic factors Levels

> 55 years Age White cell count >15x109perlitre Blood glucose >l0mmolperlitre Serum urea > 16 mmol per litre PaO, ~7.5 kPa (60mmHg) Serum calcium C2.0 mm01 per litre Serum albumin < 32 g per litre > 600 IU per litre Serum lactate dehydrogenase Reproduced from Blarney et al (1984, Gut 25: 1340-1346) with permission from BMJ Publishing Group.

encouraging (Kingsnorth et al, 1995). This compound is effective in reducing the systemic inflammatory response to pancreatic injury and thereby reducing the incidence of organ failure in severe disease. The results of a double-blind, placebo-controlled study in the use of Lexipafant in patients with prognostically severe pancreatitis have recently been reported. Two hundred and ninety patients with an APACHE II score 26 were entered into the trial. Treatment with Lexipafant was associated with fewer local complications, more rapid resolution of systemic complications and a significantly reduced mortality if treatment was initiated within 48 hours of disease onset (P= 0.04) (Kingsnorth, 1997). No other specific medical therapy has been shown to be of any benefit in acute pancreatitis of any cause. Surgical treatment Most early attempts at open surgery in biliary acute pancreatitis were associated with very high morbidity and mortality rates. However, a recent study employing transduodenal sphincteroplasty suggested the value of early stone extraction and decompression of the biliary tree (Stone et al, 1981). Early reports of benefit from endoscopic decompression (Safrany and Cotton, 198 1) led to randomized clinical trials. It has now become clear that bile duct decompression by early ERCP and sphincterotomy is beneficial, especially in patients with predicted severe pancreatitis (23 Glasgow score) or with concurrent obstructive jaundice. To date, four randomized clinical trials of ERCP/ES have been published; these are summarized in Table 4. The first study (Neoptolemos et al, 1988) was from Leicester. In this study, 121 patients with acute pancreatitis and US evidence of gallstones were randomized to receive either conventional management or urgent ERCPf ES within 72 hours of admission. They were stratified prospectively into severe and mild cases according to the modified Glasgow score (see Table 3 above). This study showed a non-significant reduction in overall mortality but a significant reduction in the complication rate, which

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Table 4. The results of four prospective, randomized clinical trials comparing early endoscopic retrograde cholangiopancreatography and endoscopic sphincterotomy (ERCP/ES) with conventional conservative management in the treatment of acute gallstone pancreatitis. Number Conservative treatment

of patients ERCP/ES

Morbidity Conservative treatment

(%)

Mortality

ERCP/ES

Conservative treatment

ERCP/ES

Leicester Mild Severe

34 28

34 25

12 61

12 24’

18

0 4b

Total

62

59

34

17’

8

2d

Katowice

102

178

36

17b

13

2b

35 28

34 30

17 54

18 13

0

0

22

12

63

64

33

16’

8

24

112

126

51

46d

9

16’

339

427

40

25

9

5

Hong Kong* Mild Severe Total

Overall

*The Hong Kong study included a large number of patients whose origin; therefore only the data for those with stones are included. ‘PcO.01, b P
0

pancreatitis

was not of gallstone

was especially marked in the group predicted to have a severe attack. The outcome was unaffected by treatment in the group predicted to have a mild attack. Intervention also reduced the length of hospital stay for those patients with a severe attack, from a median of 17 days in those on conservative treatment to a median of 9.5 days for those who underwent ERCP/ES (P
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CHOLEDOCHOLITHIASIS

have gallstones as the cause of their pancreatitis. The patients were not prospectively graded for disease severity. Overall, there was a reduction in biliary sepsis in the urgent ERCP/ES group compared with the conservative group (0% versus 12%, P=O.OOl) but no significant reduction in other systemic or local complications. If, however, only the patients who actually proved to have gallstones are analysed, the results show a significant reduction in the complication rate and a non-significant reduction in mortality. The figures from this group of patients are very similar to those of the Leicester study. The most recently published study was a multicentre study from Germany (Folsch et al, 1997). In all, 238 patients from 22 centres were randomized, but patients with jaundice were excluded from the study as they all received ERCP/ES. No prospective severity stratification was employed, and prophylactic antibiotics were not routinely used. The study showed no benefit from early ES in pancreatitis, but the study was terminated early owing to a high incidence of cholangitis and a higher mortality rate in the ERCP group than in the conservative group (much higher than in any of the other published studies). The recruitment rate from individual centres was very poor, and it is likely that individual operators had relatively little experience of performing ERCP in patients with acute pancreatitis. Interpretation of the results of this trial is difficult in the light of its shortcomings. Overall, these studies indicate the value of early intervention to decompress an obstructed biliary/pancreatic duct system, especially in cases in which prognostic scoring has predicted a severe attack of acute pancreatitis and in any case in which there is evidence of biliary obstruction (elevated serum bilirubin or transaminase levels). They also suggest the necessity for adequate experience in the performance of such a procedure, which should preferably be performed in a specialist unit. The use of prophylactic antibiotics in urgent ERCP/ES is mandatory. Prevention offurther

attacks

In the presence of stones within the gallbladder, a likelihood of further attacks of pancreatitis always exists, and cholecystectomy is therefore indicated for any patient who has had an attack of gallstone pancreatitis unless a sphincterotomy has already been performed. This recommendation was first made by Opie in 1903, and its necessity has since been confirmed. Because a second attack may occur within weeks of the first, it is advisable for cholecystectomy to be performed during the same hospital admission. Laparoscopic cholecystectomy has been shown to be safe in patients with resolving pancreatitis and is the treatment of choice (Soper et al, 1994). However, radiological visualization of the biliary tree at the time of surgery in order to exclude the presence of further stones within the common bile duct is important whichever means of cholecystectomy is chosen. If the patient is unfit for surgery, ES is an important alternative means of preventing recurrent attacks. Some studies have shown a high incidence of gallbladder-related complications after ES if the gallbladder is left in situ, and

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cholecystectomy is therefore to be preferred for all fit patients (Hansel1 et al, 1989; Escourrou et al, 1992). Summary Gallstones are a common cause of acute pancreatitis. General clinical management is the same as for pancreatitis of any other cause, but in severe cases and in those in which there is any evidence of biliary obstruction, the use of prophylactic antibiotics and the early application of ERCP+ sphincterotomy reduces both morbidity and mortality. REFERENCES *Acosta

JM & Ledesma CL (1974) Gallstone migration as a cause of acute pancreatitis. New England Journal of Medicine 190: 484-487. Armstrong CP, Taylor TV, Jeacock J & Lucas S (1985) The biliary tract in patients with acute gallstone pancreatitis. Eri?ish Journal of Surgery 72: 551-555. Baron RI (1987) Common bile duct stones: reassessment of criteria for CT diagnosis. Radiology 162: 419-424. Berci G & Morganstern L (1994) Laparoscopic management of common bile duct stones. A multiinstitutional SAGES study. Surgical Endoscopy 8: 1168-1175. Berci G, Sackier JM & Paz-Partlow M (1991) Routine or selected intraoperative cholangiography during laparoscopic cholecystectomy? American Journal of Surgery 161: 355-360. Bergman JJGHM, Rauws EAJ, Fockens P et al (1997) Randomised trial of endoscopic balloon dilatation versus endoscopic sphincterotomy for removal of bile duct stones. Lancer 349: 1124-1129. Blarney SL, Imrie CW, O’Neill J et al (1984) Prognostic factors in acute pancrcatitis. Gut 25: 1340-1346. Boender J, Nix GAJJ, de Ridder MA et al (1994) Endoscopic papillotomy for common bile duct stones-factors influencing the complication rate. Endoscopy 26: 209-216. Burhenne HJ (1980) Percutaneous extraction of retained biliary stones: 661 patients. American Journal of Roenfgenology 134: 888-898. Cairns SR, Dias L, Cotton PB et al (1989) Additional endoscopic procedures instead of urgent surgery for retained common bile duct stones. Gut 30: 535-540. Chan ACW, Chung SCS, Wyman A et al (1996) Selective use of preoperative retrograde cholangiopancreatography in laparoscopic cholecystectomy. Gastrointesrinal Endoscopy 3: 212-215. Chang KK, Lin X2, Chen CY et al (1995) Bacteraemia in acute pancreatitis of different aetiologies. Journal of the Formosan Medical Association 94: 7 13-718. Clemens JA & Cameron JL (1989) The pathogenesis of acute pancreatitis. In Carter DC & Warshaw AL (eds) Clinical Surgery Inrernarional, Vol. 16, Pancreatitis, pp l-30. Edinburgh: Churchill Livingstone. Cotton PB (1984) Endoscopic management of bile duct stones. Gut 25: 587-597. Courtois CS, Picus DD, Hicks ME et al (1996) Percutaneous gallstone removal-long-term followup. Journal of Vascular and Interventional Radiology 7: 229-234. Crump C (1931) The incidence of gallstones and gallbladder disease. Surgery Gynecology and Obstetrics 53: 447-455. Csendes A, Kruse A, Funch-Jensen Pet al (1979) Pressure measurements in the biliary and pancreatic duct systems in controls, and in patients with gallstones, previous cholecystectomy, or common bile duct stones. Gastroenrerology 77: 1203-1210. Davidson BR, Neoptolemos JP & Cam-Locke DL (1988a) Endoscopic sphincterotomy for common bile duct calculi in patients with gallbladder in situ considered unfit for surgery. Gut 29: 114-120. Davidson BR, Neoptolemos JP, Leese T & Cam-Locke DL (1988b) Biochemical prediction of gallstones in acute pancreatitis: a prospective study of three systems. British Journal of Surgery 75: 213-215.

CHOLEDOCHOLITHIASIS

677

Dougherty SH, Saltstein EC, Peacock JB et al (1988) Rapid resolution of high level hyperamylasaemia as a guide to clinical diagnosis and timing of surgical treatment in patients with gallstones. Surgery, Gynecology and Obstetrics 166: 491496. Dowsett JF, Vaira D, Hatfield ARW et al (1989) Endoscopic biliary therapy using the combined percutaneous and endoscopic technique. Gastroenterology 96: 1180-1186. Dowsett JF, Polydotou AA, Vaira D et al (1990) Needle knife papillotomy: how safe and how effective. Cur 31: 905-908. Escourrou J, Delvaux M, Ruscail Let al (1992) Is acute cholecystitis more frequent after endoscopic sphincterotomy for biliary acute pancreatitis? Gastrointestinal Endoscopy 38: A249 (abstract). *Fan S-T, Lai ECS, Mok FPT et al (1993) Early treatment of acute biliary pancreatitis by endoscopic papillotomy. New England Journal of Medicine 328: 228-232. Farinon AM, Ricci GL, Sianesi M et al (1987) Physiopathological role of microlithiasis in gallstone pancreatitis. Surgery, Gynecology and Obstetrics 164: 252-256. Faris I, Thompson JPS, Gmndy DJ et al (1975) Operative cholangiography: a reappraisal based on a review of 400 cholangiograms. British Journal of Surgery 62: 966-972. Foitzik T, Lewandrowski KB, Femandez-de1 Castillo C et al (1994) Evidence for extraluminal trypsinogen activation in three different models of acute pancreatitis. Surgery 115: 698-702. Folsch UR, Nitsche R, Ltidtke R et al (1997) Early ERCP and papillotomy compared with conservative treatment for acute biliary pancreatitis. New England Journal of Medicine 336: 237-242. Franklin M Jr & Dorman J (1995) Laparoscopic common bile duct exploration. Surgical Technology International 2: 47-50. Freeman ML, Nelson DB, Sherman S et al (1996) Complications of endoscopic biliary sphincterotomy. New England Journal of Medicine 335: 909-918. Geisinger MA, Owens DB & Meany TF (1989) Radiological methods of bile duct stone extraction. American Journal of Surgery 158: 222-227. Gross BH, Harter LP, Gore RM et al (1983) Ultrasonic evaluation of common bile duct stones: prospective comparison with ERCP. Radiology 146: 471-474. Gudgeon AM, Heath DI, Hurley P et al (1990) Trypsinogen activation peptides assay in the early prediction of severity of acute pancreatitis. Lmcet 335: 4-8. Gumaste VV, Dave PB, Weissman D & Messer J (1991) Lipase/amylase ratio. A new index that distinguishes acute episodes of alcoholic from non-alcoholic acute pancreatitis. Gastroenterology 101: 1361-1366. Gunther VW & Vorwerk D (1994) Percutaneous therapy of gallstones. Chirurgia 65: 430-436. Hagenmuller F & Schwacha H (1992) Diagnostic procedures and endoscopic measures for bile duct stones. Clinical Gastroenterology 6: 785-798. Hansel1 DT, Millar MA, Murray WR et al (1989) Endoscopic sphincterotomy for bile duct stones in patients with intact gallbladders. British Journal of Surgery 76: 856858. Hauer-Jensen M, Karesen R, Nygaard K et al (1986). Consequences of routine periopcrative cholangiograpy during cholecystectomy for gallstone disease-a prospective randomised study. World Journal of Surgery 10: 996-1002. Hermann RE (1989) The spectrum of biliary stone disease. American Journal of Surgery 158: 171-173. Hemandez CA & Lerch MM (1993) Sphincter stenosis and gallstone migration through the biliary tract. Lancer 341: 1371-1373. Heyd CG (1941) Gallbladder disease; a consideration of mortality. New York State Journal of Medicine 41: 1183-l 186. Hicken NF & McAllister AJ (1964) Operative cholangiography as an aid in reducing the incidence of _ ‘overlooked’ common bile duct stones. A study of 1293 cholecystectomies. Sur& 55: 753-758. Hill J, Martin DF & Tweedle DEF (1991) Risks of leaving: the gallbladder in situ after endoscouic sphincterotomy for bile duct stones. British Journal orSurg& 78: 554-557. Howard JM (1987) Gallstone pancreatitis. In Howard JM, Jordan GL Jr & Reber HA (eds) Surgical Diseases of the Pancreas, pp 265-283. Philadelphia: Lea & Febiger. Ingolby CJH, El Saadi J, Hall RI et al (1989) Late results of endoscopic sphincterotomy for bile duct stones in elderly patients with gallbladders in situ. Gut 30: 1129-1131. Jones BA, Salsberg BB, Bohnen JMA & Mehta MH (1987) Common pancreaticobiliary channels and their relationship to gallstone size in gallstone pancreatitis. Annals of Surgery 205: 123-125. Kaufmann P, Hofmann G, Smolle KH et al (1996) Intensive care management of acute pancreatitisrecognition of patients at high risk of developing severe or fatal complications. Wiener Klinische Wochenschr# 108: 9-15.

678

M.

G. T. RARATY

ET AL

Kelly TR & Wagner DS (1988) Gallstone pancmatitis: a prospective randomised trial of the timing of surgery. Surgery 104: 600-605. Kiil J, Kruse A & Rokjaer M (1989) Large bile duct stones treated by endoscopic bihary drainage. Surgery 105: 5 l-56. Kingsnorth AN (1997) Early treatment with Lexipafant, a platelet activating factor antagonist reduces mortality in acute pancreatitis: a double blind, randomised, placebo controlled study. Gastroenterology 112: A453 (abstract). Kingsnorth AN, Galloway SW & Formela LJ (1995) Randomised, double-blind phase II trial of Lexipafant, a platelet-activating factor antagonist, in human pancreatitis. British Journal of Surgery 82: 1414-1420. Lai ECS, Mok FPT, Tan ESY et al (1992) Endoscopic biliary drainage for severe acute cholangitis. New England Journal of Medicine 326: 1582-1586. Laing FC & Jeffrey RB Jr (1983) Choledocholithiasis and cystic duct obstruction: difficult ultrasonographic diagnosis. Radiology 146: 475479. Larvin M & McMahon MJ (1989) APACHE I1 score for assessment and monitoring of acute pancreatitis. Lancet ii: 201-204. Lee SP, Nicholls JF & Park HZ (1992) Bilirny sludge as a cause of acute pancreatitis. New England Journal of Medicine 326: 589-593. Leese T & Shaw D (1988) Comparison of three Glasgow multifactor prognostic scoring systems in acute pancreatitis. British Journal of Surgery 75: 46&462. Leese T, Neoptolemos JP, Baker AR & Carr-Locke DL (1986) The management of acute cholangitis and the impact of endoscopic sphincterotomy. British Journal of Surgery 73: 988-992. Lerch MM, Saluja AK, Runzi M et al (1993) Pancreatic duct obstruction triggers acute necrotizing pancreatitis in the opossum. Gastroenterology 104: 853-861. London NJM, Neoptolemos JP, Lavelle J et al (1989) Serial computed tomography in acute pancreatitis: a prospective study. Gut 30: 397-403. Macintyre IMC & Wilson RG (1993) Laparoscopic cholecystectomy. British Journal of Surgery 80: 552-559. Marota PJ, Gregor JC & Taves DH (1996) Biliary sludge-a risk factor for idiopathic pancreatitis. Canadian Journal of Gastroenterology 10: 385-388. Matzen P, Haubeck A, HoIstChristensen J et al (1981) Accuracy of direct cholangiography by endoscopic or transhepatic route in jaundice: a prospective study. Gastroenterology 81: 237241. Menguy RB, Hallenbeck GA, Bollman JL & Grindlay JH (1958) Intraductal pressures and sphincteric resistance in canine pancreatic and biliary ducts after various stimuli. Surgery Gynecology and Obstetrics 106: 306-320. Misra SP, Gulati P, Thorat VK & Anand BS (1989) Pancreaticobiliary ductal union in biliary diseases. Gastroenterology 96: 907-912. Mofti AB, Ahmed I, Tandon RC et al (1986) Routine or selective preoperative cholangiography. British Journal of Surgery 73: 548-550. Moody FG (1993) Lithotripsy in the treatment of biliary stones. American Journal of Surgery 165: 479-482. Murison MSC, Gartell PC & McGinn FP (1989) Does selective peroperative cholangiography result in missed common bile duct stones, British Journal of Surgery 76: 1343 (abstract). Nelson KM, Kastan DJ, Shetty PC et al (1996) Utihsation pattern and efficacy of non surgical techniques to establish drainage for high biliary obstruction. Journal of Vascular and Interventional Radiology 7: 751-756. Neoptolemos JP, Hofmann AF & Moosa AR (1986) Chemical treatment of stones in the biliary tree. British Journal of Surgery 73: 515-525. Neoptolemos JP, &r-Locke DL & Fossard DP (1987a) Prospective randomised study of preoperative endoscopic sphincterotomy versus surgery alone for common bile duct stones. British Medical Journal 294: 470-474. Neoptolemos JP, Davidson BR & Shaw DE (1987b) Study of common bile duct exploration and endoscopic sphincterotomy in a consecutive series of 438 patients. British Journal of Surgery 74: 916-921. Neoptolemos JP, &r-Locke DL, Leese T & James D (1987~) Acute cholangitis in association with acute pancreatitis: incidence, clinical features and outcome in relation to ERCP and endoscopic sphincterotomy. British Journal &Surgery 74: 1103-l 106. Neoptolemos JP, Shaw DE, Davidson BR & Carr-Locke DL (1989) Multivariate analysis of pre-

CHOLEDOCHOLITHIASIS

679

operative risk factors in patients with common bile duct stones: implications for treatment. Annals of Surgety 209: 157-16 1. *Neoptolemos JP, Ogunbiyi G, Wilson P & Carr-Locke DL (1997) Aetiology, pathogenesis, natural history and treatment of biliary acute pancreatitis. In Beger H, Warshaw A, Biichler M et al The Pancreas: A Clinical Textbook (in press). Neoptolemos JP, Hall AW, Finlay DF et al (1984) The urgent diagnosis of gallstones in acute pancreatitis: a prospective study of three methods. British Journal of Surgery 71: 230-233. *Neoptolemos JP, Cur-Locke DL, London NJ et al (1988) Controlled trial of urgent endoscopic retrograde cholangiopancreatography and endoscopic sphincterotomy versus conservative treatment for acute pancreatitis due to gallstones. Lancer ii: 979-983. Neoptolemos JP, Hall C, O’Conner HJ et al (1990) Methyl Tert-Butyl-Ether for treating bile duct stones: the British experience. British Journal of Surgery 77: 32-35. *Nowak A, Nowakowska-Dulawa E, Marek TA & Rybicka J (1995) Final results of the prospective, randomized, controlled study on endoscopic sphincterotomy versus conventional management in acute biliary pancreatitis. Gastroenterology 108: A380 (abstract). Nussinson E, Cairns SR, Vaira D et al (1991) A 10 year single centre experience of percutaneous and endoscopic extraction of bile duct stones with T tube in situ. Cur 32: 104@1043. O’Conner HJ, Hamilton I, Ellis WR et al (1986) Ultrasound detection of choledocholithiasis: prospective comparison with ERCP in the post cholecystectomy patient. Gastrointestinal Radiology 11: 161-164. *Opie EL (1901) The etiology of acute haemorrhagic pancreatitis. Johns Hopkins Hospital Bulletin 12: 182-192. Palmer KR & Hofmann AF (1988) Intraductal mono-octanoin for the direct dissolution of bile duct stones: experience in 343 patients. Gut 27: 196-202. Paloyan D, Simonowitz D & Skinner DB (1975) The timing of billary tract operations in patients with pancreatitis associated with gallstones. Surgery, Gynecology and Obstetrics 141: 737-739. De Paula A, Hashiba K & Bafutto M (1994) Laparoscopic management of choledocholithiasis. Surgical Endoscopy 8: 1399-1403. Perissat J, Huibregtse K, Keane FBV et al (1994) Management of bile duct stones in the era of laparoscopic cholecystectomy. British Journal ef Surgery 81: 799-810. Pemthaler H, Sandbichler P, Schmid TH & Margreiter R (1990) Operative cholangiography in elective cholecystectomy. British Journal qf Surgery 77: 399-400. Phillips EH, Rosenthal RJ, Carroll BJ et al (1994) Laparoscopic transcystic duct common bile duct exploration. Surgical Endoscopy 8: 1389-1394. Prince M (1882) Pancreatic apoplexy with a report of two cases. Boston Medical and Surgical Journal 107: 28, 55. Rhodes M, Nathanson L, O’Rourke N & Fielding G (1995) Laparoscopic exploration of the common bile duct: lessons learned from 129 consecutive cases. British Journal of Surgery 82: 666 668. Rijna H, Borgstein PJ, Meuwissan SGM et al (1995) Selective preoperative endoscopic retrograde cholangiopancreatography in laparoscopic biliary surgery. British Journal of Surgery 82: 1130-1133. Robinson TM & Dunphy JE (1983) Continuous infusion of bile protease activators through the pancreas. Journal of the American Medical Association 183: 530-533. Robinson G, Hollinshead J, Falk G & Moulton J (1995) Technique and results of laparoscopic choledochotomy for the management of bile duct calculi. Australian and New Zealand Journal of Surgery 65: 347-349. Ros E, Navarro S, Bru C et al (1991) Occult microlithiasis in ‘idiopathic’ acute pancreatitis: prevention of relapses by cholecystectomy or ursodeoxycholic acid therapy. Gastroenterology 101: 1701-1709. Runzi M, Saluja A, Lerch MM et al (1993) Early ductal decompression prevents the progression of biliary pancreatitis: an experimental study in the opossum. Gastroenterology 105: 157-164. Safrany L & Cotton PB (198 1) A preliminary report: urgent duodenoscopic sphincterotomy for acute gallstone pancreatitis. Surgery 89: 424-428. *Sainio V, Kempainnen E, Puolakkainen P et al (1995) Early antibiotic treatment in acute necrotizing pancreatitis. Lancer 346: 663-667. Saluja A, Saluja M, Villa A et al (1989) Pancreatic duct obstruction in rabbits causes digestive zymogen and lysosomal enzyme co-localization. Journal of Clinical fnvestigution 84: 1260-1266.

680

M.

G. T. RARATY

ET AL

Schwesinger WH (1997) The unsuspected ductal stone. In Berci G & Cuschieri A (eds) Bile Ducrs and Bile Duct Stones, pp 78-82, Philadelphia: WB Saunders. Shivel EH, Weiman TJ, Adams AL et al (1990) Operative cholangiography. American Journal of Surgery 159: 380-384. Silver RI, Daniels MA, Rollins NK et al (1996) Percutaneous transhepatic endoscopic electrohydraulic lithotripsy of biliary tract calculi after orthotopic liver transplantation. Journal of Laparoendoscopic Surgery 6: 357-364. Simpson KW, Beechey-Newman N, Lamb CR et al (1995) Cholecystokinin-8 induces oedematous pancreatitis in dogs associated with short burst of trypsinogen activation. Digestive Diseases and Sciences 40: 2152-2161. Soper NJ, Brunt LM, Cahery MP et al (1994) Role of laparoscopic cholecystectomy in the management of acute gallstone pancreatitis. American Journal of Surgery 167: 42-51. Steer ML (1988) Experimental models of pancreatitis. In Glazer G & Ransin JHC (eds) Acufe Pancreatitis, pp 207-226. London: WB Saunders. *Steer ML (1993) Etiology and pathophysiology of acute pancreatitis. In Go VLW, DiMagno EP, Gardner JD et al (eds) The Pancreas: Biology, Parhobiology and Disease, 2nd edn pp 581-591. New York: Raven Press. Stimac D, Rubinic M, Lenac T et al (1996) Biochemical parameters in the early differentiation of the aetiology of acute pancreatitis. American Journal of Gastroenterology 91: 2355-2359. Stone HH, Fabian TC & Dunlop WE (1981) Gallstone pancrcatitis: bihary tract pathology in relation to time of operation. Annals of Surgery 194: 305-310. Thomas MJ, Pellegrini CA & Way LW (1982) Usefulness of diagnostic tests for bihary obstruction. American Journal of Surgery 144: 102-108. Trapnell J (1968) The pathogenesis of gallstone pancreatitis. Posrgraduare Medical Journal 44: 497-500. Uhl W, lsenmann R, Curb G et al (1996) Influence of aetiology on the course and outcome of acute pancreatitis. Pancreas 13: 335-343. Vilaseca J, Molero X, Ruis JM et al (1994) Percutaneous dissolution therapy of gallstones with Methyl tert-butyl ester-initial experience. Revista Espanola de Enfermedades Digesrivas 85: 445-451. Ward JB, Petersen OH, Jenkins SA & Sutton R (1995) Is an elevated concentration of acinar cytosolic free ionised calcium the trigger for acute pancreatitis? Lancer 346: 1016-1019. Ward JB, Sutton R, Jenkins SA & Peterson OH (1996) Progressive disruption of acinar cell calcium signalling is an early feature of cerulein-induced pancreatitis in mice. Gasrroenrerology 111: 481-491. Wenckert A & Robertson B (1966) The natural course of gallstone disease: 11 year review of 781 non operated cases. Gastroenterology 50: 376-387. Willemer S, Bialek R & Adler G (1990) Localization of lysosomal and digestive enzymes in cytoplasmic vacuoles in caerulein-pancreatitis. Hisrochemisrry 94: 161-170. *Winslet MC & Neoptolemos JP (1991) The place of endoscopy in the management of gallstones. BailliPre’s Clinical Gasrroenterology 5: 99-129. Winslet MC, Hall C, London NJM & Neoptolemos JP (1992) Relationship of diagnostic serum amylase levels to aetiology and severity of acute pancreatitis. Gur 33: 982-986. Wyatt SH & Fishman EK (1997) Biliary tract obstruction-the role of spiral CT in detection and definition of disease. Clinical Imaging 21: 27-34. Zhou W, Shen F, Miller JE et al (1996) Evidence for altered cellular calcium in the pathogenetic mechanism of acute pancreatitis in rats. Journal @Surgical Research 60: 147-55.