Pathogenesis of Gallstone Pancreatitis Olin G. Thurston, MD, FRCS(C), FACS, Edmonton, Alberta, Canada
Gallstones appear to be the precipitating factor in approximately one half of all patients with acute pancreatitis [I]. The sequence of events leading to pancreatitis in patients with gallstones is unclear, and attempts to piece together the pathogenesis from experimental and clinical data are hampered by the tendency to combine all varieties of pancreatitis, in both human and animal subjects, in the search for common factors. In this study, patients with gallstone pancreatitis were separated from patients with other forms of pancreatitis so that differences between gallstone pancreatitis and other forms would be apparent and the sequence of initiating events in gallstone pancreatitis could be postulated. Material and Methods The patients selected for study were a personal series of six consecutive patients with gallstone pancreatitis seen between 1966 and 1972. The diagnosis of acute pancreatitis, suspected on clinical grounds, was made on the basis of laboratory and operative findings. (Table I.) All six patients had cholecystectomy and operative cholangiography. Two patients also had choledochostomy. The operative procedure was performed during the same hospital admission as that when the diagnosis of acute pancreatitis was made, and was usually carried out when the acute episode of pancreatitis was subsiding clinically. All six patients were available for follow-up study seventeen to eighty-five months after surgery. Two control groups of patients were selected and studied. The first group was a personal series of eightyfour consecutive patients who had cholecystectomy and From the Dewtment of Surgery, I I-104D Clinical Sciences Building, University of Alberta, Edmonton, Alberta, Canada. Reprint requests should be addressed to Olln G. Thurston, MD, Department of Surgery, 1 I-1040 Clinical Sciences Building, University of Alberta, Edmonton, Alberta, Canada T6G 2G3.
vohnne 129. March 1975
operative cholangiography for gallstones without evidence of pancreatitis; the second control group consisted of eleven patients with alcoholic, idiopathic, and familial pancreatitis seen at the University of Alberta Hospital during the five year period from 1968 to 1972. These eleven patients included all patients with nongallstone pancreatitis who underwent an abdominal procedure including operative cholangiography during this time period. The diagnosis of pancreatitis in these eleven patients was made on the same basis as that used in patients with gallstone pancreatitis. The patients with nongallstone pancreatitis were operated on because of uncertainty about the diagnosis of pancreatitis or because of a deterioration in the patient’s condition. Cholangiography was performed in these patients because of difficulty in assessing the status of the gallbladder and common bile duct by palpation alone. The patients undergoing cholecystectomy had operative cholangiography carried out via a cannula in the cystic duct stump using 25 or 50 per cent diatrizoate sodium (Hypaquee) [2]. Cholangiography in patients with nongallstone pancreatitis was performed by direct injection of contrast material into thegallbladder or common bile duct. Resutts Ampullary Anatomy. Pancreatic duct reflux of cholangiographic contrast material occurred in four of the six patients with gallstone pancreatitis. An additional patient had a periampullary duodenal diverticulum. Thus, five of the six patients (83 per cent) had an anatomic factor which, through pancreatic duct reflux of bile or obstruction, could predispose them to pancreatitis [3,4]. In contrast, only three of eleven patients with nongallstone pancreatitis (27 per cent) and twentyfour of eighty-four patients with cholelithiasis uncomplicated by pancreatitis (29 per cent) had similar findings. (Table II.)
301
Thurston
I
TABLE
Diagnosis of Gallstone A@ (y0 and Sex
Patient
Pancreatitis
Diagnosis of Pancreatitis
AA
62,M
Shock (clinical); >800 units*; pancreas
BB SC
21,M 65,M
AH JK LW
47,M 24, F 51,F
Serum amylase >500 units Serum amylase >400 umts; elevated urine amylase; fat necrosis and edema of pancreas Elevated urine amylase Serum amylase >300 units Fat necrosis of pancreas
* Normal,
TABLE
serum amylase edematous
4 to 54 units.
II
Results of Operative
Condition Gallstone pancreatitis Gallstones only Other pancreatitis
Cholangiography
Pancreatic Duct Reflux
Duodenal Diverticulum
Total
416 24184 3/11
l/6 l/84 0
5/6 (83%) 24/34 (23%) 3/11(27%)
Pathologic Study of Gallbladder and Bile Ducts. Pathologic examination of the gallbladder
in the six patients with gallstone pancreatitis showed chronic cholecystitis in four, acute cholecystitis in one, and a normal gallbladder (containing stones) in one. Only one patient with gallstone pancreatitis had a common duct stone discovered at cholecystectomy, although four patients had small stones in the gallbladder judged capable of traversing the cystic duct. The patient with the duodenal diverticulum and gallstone pancreatitis (Table II) had a solitary stone in the gallbladder. Follow-Up Data. The six patients with gallstone pancreatitis have remained well from the standpoint of biliary tract and pancreatic disease seventeen to eighty-five months after biliary tract surgery. Comments
The constant finding in patients with gallstone pancreatitis is an excellent prognosis after definitive biliary tract surgery. The six patients in this study have followed this pattern. In a much larger series, Howard and Jordan [5] noted a 3 per cent incidence of recurrence in patients with gallstone pancreatitis after definitive biliary tract surgery as opposed to a 77 per cent recurrence rate after cholecystectomy for pancreatitis in the absence of gallstones. These findings indicate that we should study the biliary tract for the underlying mecha-
302
nisms in the pathogenesis of gallstone pancreatitis. Specifically, we should study the gallbladder, the bile and stones therein, and the anatomic relations between the common bile and major pancreatic ducts. The present study indicates that patients with gallstone pancreatitis have a high incidence of anatomic factors predisposing them to pancreatic duct reflux and compression when compared with that of patients with other forms of pancreatitis. In addition, patients with gallstone pancreatitis frequently, but not invariably, have small stones capable of traversing the cystic duct. The frequent finding of small gallstones in the stool of patients with gallstone pancreatitis is of considerable interest in this regard [6]. Bile reflux in the pathogenesis of gallstone pancreatitis has been discredited because bile normally refluxes into the pancreatic duct [7], and sterile bile infused into the pancreatic duct at physiologic pressures does not cause pancreatitis [S]. It must be recalled, however, that patients with gallstones do not have a normal bile; it is frequently infected with enteric bacteria [9] and is abnormal in its chemical composition [IO]. In this regard, experimental studies have shown that unconjugated bile acids formed by the action of anaerobic bacteroides cause pancreatitis when introduced into the pancreatic duct at physiologic pressures [7,11]. Other studies indicate that lysolecithin formed by the action of pancreatic phospholipase A on biliary lecithin causes pancreatitis in animals and is present in large quantities in the necrotic pancreas of patients who die of acute pancreatitis [12]. These studies have refocused our attention on bile reflux and indicate the need for bacteriologic and biochemical investigation of bile in patients with gallstone pancreatitis.
Summary
Patients with gallstone pancreatitis have a high incidence of factors predisposing them to bile reflux and they do well after cholecystectomy. These findings are not evident in other forms of pancreatitis. It is concluded that bile from a stone-filled gallbladder and an anatomic predisposition are important initiating factors in gallstone pancreatitis. Acknowledgment: I wish to thank Doctor L. B. Costopoulos, Department of Radiology, University of Alberta Hospital, for valuable assistance in reading and interpreting the operative cholangiograms.
The American Journal d Surgery
Gallstone Pancreatitis
References 1. Disco JF, Miller LD, Copeland EM: The role of early diignostic laparotomy in acute pancreatiis. Sufg Gyneco/ &stet 129: 283, 1989. 2. Thurston DG: Results of non-routine operattve cholangiography. Arch Surg 108: 512, 1974. 3. Willox GL, Costopoulos LB: Entry of common bile and pancreatic ducts into a duodenal diverticulum. Arch Surg 98: 447, 1989. 4. Costopoulos LB, Miller JDR: Insertion of common bile duct and pancreatic duct into duodenal diverticula. Rediobgy 89: 258, 1987. 5. Howard JM, Jordan GL: Surgical Diseases of the Pancreas. Philadelphia, Lippincott, 1980, p 95. 8. Acosta JM, Ledesma CL: Gallstone migration as a cause of
veknns 129. March 1975
acute pancreatitis. N Engl J Med 290: 484. 1974. 7. Hansson K: Experimental and clinical studies in aetiologic role of bile reflux in acute pancreatitis. Acta Chk Scend (iSuppl) 375: 1, 1987. 8. Konok GP, Thompson AG: Pancreatic ductal mucosa as a protective barrier in the pathogenesis of pancreatii. Am JSurg 117: 18, 1989. 9. Fukunaga FH: Gallbladder bacteriology, histology, and gallstones. Arch Surg 108: 189, 1973. 10. Admirand WH, Small DM: The physicochemical basis of cho lesterol gallstone formation in man. J C/in best 47: 1043, 1988. 11. Gorbach SL, Tabaqchali S: Bacteria. bile and the small bowel. Gut 10: 983, 1989. 12. Schmidt H, Creutzfeldt W: The possible role of phospholipase A in the pathogenesis of acute pancreatitis. Scend J Gestroenterol4: 39, 1989.
303
Gallstones appear to be the precipitating factor in approximately one half of all patients with acute pancreatitis [I]. The sequence of events leading to pancreatitis in patients with gallstones is unclear, and attempts to piece together the pathogenesis from experimental and clinical data are hampered by the tendency to combine all varieties of pancreatitis, in both human and animal subjects, in the search for common factors. In this study, patients with gallstone pancreatitis were separated from patients with other forms of pancreatitis so that differences between gallstone pancreatitis and other forms would be apparent and the sequence of initiating events in gallstone pancreatitis could be postulated. Material and Methods The patients selected for study were a personal series of six consecutive patients with gallstone pancreatitis seen between 1966 and 1972. The diagnosis of acute pancreatitis, suspected on clinical grounds, was made on the basis of laboratory and operative findings. (Table I.) All six patients had cholecystectomy and operative cholangiography. Two patients also had choledochostomy. The operative procedure was performed during the same hospital admission as that when the diagnosis of acute pancreatitis was made, and was usually carried out when the acute episode of pancreatitis was subsiding clinically. All six patients were available for follow-up study seventeen to eighty-five months after surgery. Two control groups of patients were selected and studied. The first group was a personal series of eightyfour consecutive patients who had cholecystectomy and From the Dewtment of Surgery, I I-104D Clinical Sciences Building, University of Alberta, Edmonton, Alberta, Canada. Reprint requests should be addressed to Olln G. Thurston, MD, Department of Surgery, 1 I-1040 Clinical Sciences Building, University of Alberta, Edmonton, Alberta, Canada T6G 2G3.
vohnne 129. March 1975
operative cholangiography for gallstones without evidence of pancreatitis; the second control group consisted of eleven patients with alcoholic, idiopathic, and familial pancreatitis seen at the University of Alberta Hospital during the five year period from 1968 to 1972. These eleven patients included all patients with nongallstone pancreatitis who underwent an abdominal procedure including operative cholangiography during this time period. The diagnosis of pancreatitis in these eleven patients was made on the same basis as that used in patients with gallstone pancreatitis. The patients with nongallstone pancreatitis were operated on because of uncertainty about the diagnosis of pancreatitis or because of a deterioration in the patient’s condition. Cholangiography was performed in these patients because of difficulty in assessing the status of the gallbladder and common bile duct by palpation alone. The patients undergoing cholecystectomy had operative cholangiography carried out via a cannula in the cystic duct stump using 25 or 50 per cent diatrizoate sodium (Hypaquee) [2]. Cholangiography in patients with nongallstone pancreatitis was performed by direct injection of contrast material into thegallbladder or common bile duct. Resutts Ampullary Anatomy. Pancreatic duct reflux of cholangiographic contrast material occurred in four of the six patients with gallstone pancreatitis. An additional patient had a periampullary duodenal diverticulum. Thus, five of the six patients (83 per cent) had an anatomic factor which, through pancreatic duct reflux of bile or obstruction, could predispose them to pancreatitis [3,4]. In contrast, only three of eleven patients with nongallstone pancreatitis (27 per cent) and twentyfour of eighty-four patients with cholelithiasis uncomplicated by pancreatitis (29 per cent) had similar findings. (Table II.)
301
Thurston
I
TABLE
Diagnosis of Gallstone A@ (y0 and Sex
Patient
Pancreatitis
Diagnosis of Pancreatitis
AA
62,M
Shock (clinical); >800 units*; pancreas
BB SC
21,M 65,M
AH JK LW
47,M 24, F 51,F
Serum amylase >500 units Serum amylase >400 umts; elevated urine amylase; fat necrosis and edema of pancreas Elevated urine amylase Serum amylase >300 units Fat necrosis of pancreas
* Normal,
TABLE
serum amylase edematous
4 to 54 units.
II
Results of Operative
Condition Gallstone pancreatitis Gallstones only Other pancreatitis
Cholangiography
Pancreatic Duct Reflux
Duodenal Diverticulum
Total
416 24184 3/11
l/6 l/84 0
5/6 (83%) 24/34 (23%) 3/11(27%)
Pathologic Study of Gallbladder and Bile Ducts. Pathologic examination of the gallbladder
in the six patients with gallstone pancreatitis showed chronic cholecystitis in four, acute cholecystitis in one, and a normal gallbladder (containing stones) in one. Only one patient with gallstone pancreatitis had a common duct stone discovered at cholecystectomy, although four patients had small stones in the gallbladder judged capable of traversing the cystic duct. The patient with the duodenal diverticulum and gallstone pancreatitis (Table II) had a solitary stone in the gallbladder. Follow-Up Data. The six patients with gallstone pancreatitis have remained well from the standpoint of biliary tract and pancreatic disease seventeen to eighty-five months after biliary tract surgery. Comments
The constant finding in patients with gallstone pancreatitis is an excellent prognosis after definitive biliary tract surgery. The six patients in this study have followed this pattern. In a much larger series, Howard and Jordan [5] noted a 3 per cent incidence of recurrence in patients with gallstone pancreatitis after definitive biliary tract surgery as opposed to a 77 per cent recurrence rate after cholecystectomy for pancreatitis in the absence of gallstones. These findings indicate that we should study the biliary tract for the underlying mecha-
302
nisms in the pathogenesis of gallstone pancreatitis. Specifically, we should study the gallbladder, the bile and stones therein, and the anatomic relations between the common bile and major pancreatic ducts. The present study indicates that patients with gallstone pancreatitis have a high incidence of anatomic factors predisposing them to pancreatic duct reflux and compression when compared with that of patients with other forms of pancreatitis. In addition, patients with gallstone pancreatitis frequently, but not invariably, have small stones capable of traversing the cystic duct. The frequent finding of small gallstones in the stool of patients with gallstone pancreatitis is of considerable interest in this regard [6]. Bile reflux in the pathogenesis of gallstone pancreatitis has been discredited because bile normally refluxes into the pancreatic duct [7], and sterile bile infused into the pancreatic duct at physiologic pressures does not cause pancreatitis [S]. It must be recalled, however, that patients with gallstones do not have a normal bile; it is frequently infected with enteric bacteria [9] and is abnormal in its chemical composition [IO]. In this regard, experimental studies have shown that unconjugated bile acids formed by the action of anaerobic bacteroides cause pancreatitis when introduced into the pancreatic duct at physiologic pressures [7,11]. Other studies indicate that lysolecithin formed by the action of pancreatic phospholipase A on biliary lecithin causes pancreatitis in animals and is present in large quantities in the necrotic pancreas of patients who die of acute pancreatitis [12]. These studies have refocused our attention on bile reflux and indicate the need for bacteriologic and biochemical investigation of bile in patients with gallstone pancreatitis.
Summary
Patients with gallstone pancreatitis have a high incidence of factors predisposing them to bile reflux and they do well after cholecystectomy. These findings are not evident in other forms of pancreatitis. It is concluded that bile from a stone-filled gallbladder and an anatomic predisposition are important initiating factors in gallstone pancreatitis. Acknowledgment: I wish to thank Doctor L. B. Costopoulos, Department of Radiology, University of Alberta Hospital, for valuable assistance in reading and interpreting the operative cholangiograms.
The American Journal d Surgery
Gallstone Pancreatitis
References 1. Disco JF, Miller LD, Copeland EM: The role of early diignostic laparotomy in acute pancreatiis. Sufg Gyneco/ &stet 129: 283, 1989. 2. Thurston DG: Results of non-routine operattve cholangiography. Arch Surg 108: 512, 1974. 3. Willox GL, Costopoulos LB: Entry of common bile and pancreatic ducts into a duodenal diverticulum. Arch Surg 98: 447, 1989. 4. Costopoulos LB, Miller JDR: Insertion of common bile duct and pancreatic duct into duodenal diverticula. Rediobgy 89: 258, 1987. 5. Howard JM, Jordan GL: Surgical Diseases of the Pancreas. Philadelphia, Lippincott, 1980, p 95. 8. Acosta JM, Ledesma CL: Gallstone migration as a cause of
veknns 129. March 1975
acute pancreatitis. N Engl J Med 290: 484. 1974. 7. Hansson K: Experimental and clinical studies in aetiologic role of bile reflux in acute pancreatitis. Acta Chk Scend (iSuppl) 375: 1, 1987. 8. Konok GP, Thompson AG: Pancreatic ductal mucosa as a protective barrier in the pathogenesis of pancreatii. Am JSurg 117: 18, 1989. 9. Fukunaga FH: Gallbladder bacteriology, histology, and gallstones. Arch Surg 108: 189, 1973. 10. Admirand WH, Small DM: The physicochemical basis of cho lesterol gallstone formation in man. J C/in best 47: 1043, 1988. 11. Gorbach SL, Tabaqchali S: Bacteria. bile and the small bowel. Gut 10: 983, 1989. 12. Schmidt H, Creutzfeldt W: The possible role of phospholipase A in the pathogenesis of acute pancreatitis. Scend J Gestroenterol4: 39, 1989.
303
