Ursodeoxycholic acid therapy for primary sclerosing cholangitis: results of a 2-year randomized controlled trial to evaluate single versus multiple daily doses.

BACKGROUND/AIMS: Ursodeoxycholic acid has been reported to be of potential benefit for primary sclerosing cholangitis but little is known about the long-term biochemical, histological and radiological efficacy or the optimum frequency of ursodeoxycholic acid administration. METHODS: A 2-year multicentre randomised controlled trial was initiated to assess the effects of ursodeoxycholic acid (10 mg kg(-1).d(-1), given in either single or multiple daily doses, on symptoms, serum liver tests, cholangiographic and histological findings and the occurrence of treatment failure. Liver biopsies were taken and endoscopic retrograde cholangiography was performed at entry and after 2 years; follow-up examinations were at 3-month intervals. Treatment failure was defined as death, liver transplantation, 4-fold increase in serum bilirubin, variceal bleeding, de novo ascites or cholangitis. Actuarial survival was compared with predicted survival using the revised Mayo natural history model for primary sclerosing cholangitis. RESULTS: Forty-eight patients were enrolled. In one case, ursodeoxycholic acid had to be discontinued because of gastro-intestinal complaints. No other side-effects were observed. After 2 years of follow-up, treatment was not associated with a beneficial effect on either symptoms or liver histology. Serum liver tests (alkaline phosphatase, y-glutamyl transferase, aspartate aminotransferase) improved significantly in both groups, while serum bilirubin (which was near normal at entry) and IgG remained stable. No major changes in radiographic bile duct appearance seemed to be present. After 2 years, actuarial survival was 91% (95 CI 83%-99%), which is comparable to the predicted 97% survival rate. Treatment failure occurred in 15% of cases. No significant differences in any of the study endpoints (symptoms, serum liver tests, cholangiographic findings, histology, disease progression) were found between the two groups. CONCLUSIONS: Ursodeoxycholic acid is well tolerated in primary sclerosing cholangitis. Significant effects on biochemical parameters were found and symptoms, bilirubin and histology did not deteriorate. No advantage of a multiple daily dose over a single dose was observed.

Choledochocele presenting with anaemia.

A 31-year-old man presented with abdominal pain and iron deficiency anaemia due to gastrointestinal blood loss. Endoscopic retrograde cholangiopancreatography (ERCP) revealed a choledochocele, located between the ampullary sphincter and the sphincters of the common bile duct and pancreatic duct. The choledochocele was removed surgically and appeared to be covered with duodenal mucosa. Gastrointestinal blood loss is explained by the extensive erosions found in the duodenal mucosa of the choledochocele. Choledochoceles should be treated by radical resection.

Needle-knife sphincterotomy guided by a biliary endoprosthesis in Billroth II gastrectomy patients.

BACKGROUND AND STUDY AIMS: All available techniques for performing endoscopic sphincterotomy in Billroth II gastrectomy patients have their limitations, and no standard technique has emerged. A new technique, needle-knife sphincterotomy guided by a thin (7 Fr) biliary endoprosthesis, is described here that overcomes some of the limitations of other techniques. PATIENTS AND METHODS: The technique was attempted in 19 nonselected patients during a three-year period. The results were retrospectively assessed. The outcome variables were the achievement of an adequate sphincterotomy and complications. RESULTS: An adequate sphincterotomy could be performed without much technical difficulty in 18 of the 19 patients. There was one complication, a retroperitoneal leakage, that settled with conservative treatment. CONCLUSIONS: In patients with Billroth II anastomoses, endoprosthesis-guided sphincterotomy is a new and relatively easy procedure, which is especially attractive once selective bile duct cannulation has been achieved. This technique allows the performance of sphincterotomy as a well-controlled procedure, and may, therefore, be safer than nonguided techniques. In contrast to previously reported guided techniques using nasobiliary cannulas, the endoprosthesis technique does not necessitate withdrawing and reinserting the endoscope.

Endoscopic sphincterotomy and biliary drainage in patients with cholangitis due to common bile duct stones.

OBJECTIVES: In a prospective study, we analyzed 95 consecutive patients undergoing endoscopic papillotomy (EP) for cholangitis due to common bile duct (CBD) stones; our purpose was to evaluate the risk factors influencing the complication rate due to cholangitis, with special attention to the clinical history. METHODS: Patients with previous gastric surgery or EP were excluded. Complications subsequent to sphincterotomy were recorded over a 3-month period. RESULTS: In patients with persistent cholangitis before EP, the risk for complications due to cholangitis increased with increasing delay between the onset of cholangitis and biliary drainage. In patients with a good response to antibiotics before EP, the delay in biliary drainage did not influence the risk of complications. After complete CBD stone removal, the morbidity (42% vs. 4%, p = 0.001) and the mortality (8% vs. 0%, NS) due to cholangitis were much higher in 12 patients with progressive cholangitis for > 3 days before biliary drainage, compared with 73 cases who had experienced a good response to antibiotics before EP and/or early drainage (< 3 days) after the onset of cholangitis. Two patients with advanced cholangitis and septic shock at the time of EP died < 12 h after completed sphincterotomy with CBD stone removal. Three patients with retained CBD stones and failed biliary drainage after EP experienced disastrous morbidity (100% vs. 9%, p < 0.01) and mortality (67% vs. 1%, p < 0.01) due to cholangitis, compared with 85 patients without retained CBD stone(s). CONCLUSIONS: We recommend emergency biliary drainage in all patients presenting with calculous cholangitis who are severely ill with continuous fever for several days. Emergency nasobiliary drainage without EP or after a limited EP may be a safer treatment in patients with (impending) septic shock. We believe that a more conservative approach is justified in patients presenting with symptoms of mild cholangitis, restricting emergency biliary drainage for those who do not respond rapidly (< 24 h) to antibiotics. Further emergency surgical or percutaneous biliary drainage should be performed immediately on patients in whom CBD stones are retained, after EP and drainage fails, especially if a stone is left impacted distally.

Endoscopic papillotomy for common bile duct stones: factors influencing the complication rate.

In a prospective study, the complications observed in 242 consecutive patients after endoscopic sphincterotomy for common bile duct stones were recorded over a period of up to three months. Patients with previous gastric surgery, papillotomy, or additional pancreato-biliary disease other than gallbladder stones were excluded. The overall complication rate was 14%, 74% of these complications being moderate or severe. The complication rate due to cholangitis was higher in (1) the group with retained stones following complete papillotomy and without biliary drainage, and (2) the group with failed precut papillotomy and drainage after cholangiography, both compared to patients with successful drainage (75% vs. 2.6%: p < 0.001 and 40% vs. 2.6%: p = 0.001 respectively). Both pancreatitis and retroperitoneal air leakage occurred in 1.7% of cases. They were more frequently observed in patients with a smaller diameter (< 10 mm) in the distal common bile duct (5.6% vs. 0%: p = 0.007 for pancreatitis, and 2.8% vs. 1.2%; n.s. for perforation) and especially following precut papillotomy (13.0% for pancreatitis and 8.7% for perforation), which had to be performed more often in these patients. Bleeding following sphincterotomy was relatively frequent when the papilla was located at the lower rim of or inside a diverticulum, compared to patients without a diverticulum (16.2% vs. 2.7%: p = 0.004 and 26.7% vs. 2.7%: p < 0.001 respectively). When the papilla was located inside diverticula, both the rate of perforation and bleeding increased following precut papillotomy, compared with standard papillotomy only (33% vs. 0%, n.s., and 33% vs. 22%, n.s.).(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma of the pancreas and periampullary region: palliation versus cure.

A retrospective study of 310 patients with carcinoma of the head of the pancreas or periampullary region was performed. Preoperative bile drainage by placement of a stent reduced the number of postoperative complications, especially bleeding (P = 0.03). The operative mortality rate was nil in patients with periampullary cancer aged under 70 years and 23 per cent in those over 70 years of age (P < 0.001). In the last 2 years of the study, the mortality rate following resection decreased to 2 per cent. Tumour-containing resection margins did not influence survival after resection (P = 0.48). Tumour dimension of pancreatic and periampullary cancer and the presence of tumour in locoregional lymph nodes (N1a) resected with the primary tumour in cancer of the head of the pancreas were of no prognostic value. Following palliative resection of carcinoma of the pancreatic head, median survival was significantly better than when no resection was performed (10.1 versus 3.9 months, P < 0.001). In conclusion, even palliative resection may benefit some patients. Preoperative bile drainage is indicated in those with jaundice. Resection should be performed, irrespective of tumour size, provided that the unit's operative mortality rate is sufficiently low.

Endoscopic papillotomy in biliary tract pain and fluctuating cholestasis with common bile duct dilatation and small gallbladder stones.

In patients suspected of having functional disorders of the papilla it is often difficult to establish the indications whether or not to perform endoscopic papillotomy (EP). We report on thirty-two consecutive patients referred for endoscopic retrograde cholangiopancreatography who all had longstanding biliary tract pain and episodes of liver enzyme elevation indicating cholestasis. Further features were: 1) a dilated common bile duct (CBD) after cholecystectomy (n = 11) or 2) a dilated CBD without or with larger (greater than cystic duct diameter) gallbladder stones (n = 6) or 3) multiple small gallbladder stones, with a normal or dilated CBD, in patients with signs of acute gallstone pancreatitis or in whom elective cholecystectomy was not indicated (n = 15). No CBD stones, organic obstruction or other disorders were found in these patients. Without further diagnostic procedures, EP was routinely performed. The laboratory (up to 3 months) and clinical findings (2 to 4 years follow up) showed improvement in all patients undergoing EP. We conclude that immediate EP appears justified in these selected patients.

Prognostic implications of the localization of carcinoma in the head of the pancreas.

Between 1974 and 1989, 411 patients with pathologically and anatomically proven carcinoma of the head of the pancreas underwent endoscopic retrograde cholangiopancreatography (ERCP). According to the localization of the tumor, these patients were divided into those with a cranially, centrally (periductally), caudally, or indeterminately localized tumor. In cranially localized tumors, extrahepatic metastases and vessel invasion were absent or resectable in 53% and 46%, respectively. The tumor was resectable in 41% of cases. If a patient with a cranially localized tumor could not be operated curatively for secondary reasons, the prognosis was better than for tumors with another localization. If there was unresectable vessel invasion and the tumor was not resectable, the 0% survival rate was reached at 33 months. Of the curatively operated patients, 26% were alive at 36 months after the start of complaints. Of the centrally or periductally localized tumors, there were no liver metastases in 73%. Extrahepatic metastases and vessel invasion were absent or resectable in 57% and 53%, respectively. The tumor was resectable in 48% of cases. If there was unresectable vessel invasion or the tumor was unresectable, the 0% survival rate was reached after 18 months. These tumors have maximal chances at curative resection. Of the curatively operated patients, 31% were alive at 36 months after the start of complaints. In caudally localized tumors, there were liver metastases in 59%, unresectable other abdominal metastases in 93%, unresectable vessel invasion in 91%, and the tumor was unresectable in 96%. In patients with an unresectable vessel invasion or an unresectable tumor, the 0% survival rate was reached after 33 months; 3% of these patients were operated curatively. Indeterminately localized tumors had liver metastases in 77%, unresectable extrahepatic metastases in 90%, unresectable vessel invasion in 95%, and the tumor was unresectable in 91%. Only one of the 44 patients (2%) could be operated curatively.

Prognostic implications of tumor diameter in carcinoma of the head of the pancreas.

Two hundred twenty patients with a carcinoma in the head of the pancreas were divided into three tumor diameter groups: group 1, 0.5 to 4.4 cm (n = 72); group 2, 4.5 to 6.0 cm (n = 77); and group 3, 6.1 to 15.0 cm (n = 71). For these tumor diameter groups a six-fold eliminatory curability analysis was performed. Of the patients with liver metastases in group 1 the last patient had died at 10 months and in groups 2 and 3 no patients were alive at 18 months after the start of complaints. Patients with extrahepatic metastases did not survive 12 months in group 1, 16 months in group 2, and 25 months in group 3. The 6% actuarial survival rate for inoperable patients was reached in group 1 after 17 months, in group 2 after 36 months, and in group 3 after 27 months after the start of complaints. For groups 1 through 3 in curable, but not curatively operated patients, the respective 0% actuarial survival rate was reached at 24 months, 23 months, and 14 months. The 0% actuarial survival rate in patients with irresectable vessel invasion was reached in group 1 at 33 months, in group 2 at 23 months, and in group 3 at 25 months. The 0% actuarial survival rate in patients with an irresectable tumor was reached at 33 months, 31 months, and 27 months after the start of complaints in groups 1, 2, and 3, respectively. The 0% actuarial survival rate in curatively operated patients was reached in group 3 after 26 months and in group 2 after 29 months. In group 1 25% of the patients were alive at 36 months after the start of complaints. Small tumors were associated with the greatest chance of curative operation and on average had the longest survival. However, small tumors with liver or other metastases carried a worse prognosis than large tumors with liver or other metastases. If tumors were found not to be resectable at the time of operation, the size of the tumor did not appear to affect survival.

Malignant common bile duct obstruction: factors influencing the success rate of endoscopic drainage.

The problems encountered in draining the bile ducts endoscopically in 148 patients with malignant obstruction of the mid or distal common bile duct and/or the papilla were assessed. Endoscopically visible extrinsic invasion of the papilla by a malignancy in the pancreatic head, with or without duodenal stenosis, appeared to be the major reason for the failure to insert a stent. The larger a tumor in the pancreatic head the greater the chance of invasion of the papillary region. This appeared to be evident for tumors restricted to the non-uncinate region of the pancreatic head. We would recommend primary percutaneous biliary drainage or surgery when the size of a proven malignancy restricted to the non-uncinate region of the pancreatic head is 5 cm or more, or when diagnostic duodenoscopy reveals extrinsic invasion of the papilla of Vater, or severe duodenal involvement with stenosis.

ERCP diagnosis of tumors in the region of the head of the pancreas. Analysis of criteria and computer-aided diagnosis.

During the period 1974-1983, 320 patients with pancreas carcinoma, papilla of Vater carcinoma, bile duct bifurcation carcinoma, or duodenal carcinoma were examined by ERCP. Using 30 ERCP criteria, a radiological diagnosis was made. A valid pathological diagnosis was available in 200 patients (62.5%). In 183 of the 200 patients (91.5%), the ERCP diagnosis and the pathological diagnosis were identical. We then performed an analysis using 52 ERCP criteria. In 192 of the 200 patients (96.0%), the ERCP diagnosis based on this reanalysis and the pathological diagnosis were identical. By discriminant analysis, 13 ERCP criteria with a maximal discriminatory value were selected in patients in whom all diagnostic structures (bile ducts, pancreatic duct, and duodenum) were visible. Using these 13 criteria selected by discriminant analysis, the diagnostic score was 98.9%. A computer program based on these 13 ERCP criteria was designed for use in practice. The diagnostic accuracy of this computer program was 98.4%. Finally we tested this computer program on 171 new patients who were seen in the period 1983-1986. In 143 of the 171 patients, a valid pathological diagnosis was available (83.6%). Comparing the ERCP diagnosis in all patients (even if not all structures were visible) with a valid pathological diagnosis, the prospective score of the computer program was 91.6%. Using this program it was possible to evaluate examinations in which not all structures were visible. When the ERCP diagnosis was uncertain, the doubt could be quantified.

Non-surgical palliative treatment of patients with malignant biliary obstruction--the place of endoscopic and percutaneous drainage.

Non-surgical methods to treat patients with inoperable malignant biliary obstruction are endoscopic retrograde biliary drainage and ultrasound guided percutaneous transhepatic biliary drainage. During a 2 year evaluation a total of 144 patients were admitted with malignant biliary obstruction: 93 with a mid- or distal common bile duct stenosis; 51 patients with a perihilar stenosis. Endoscopic biliary drainage was performed in 123 patients and ultrasound guided percutaneous biliary drainage in 57 patients. An effect on jaundice was seen in more patients after percutaneous biliary drainage (91%) than with endoscopic biliary drainage (70%). However with the percutaneous method only 63% of patients were drained internally. The site of the stenosis seemed to be an important factor. In patients with perihilar obstruction early complications after endoscopic biliary drainage occurred in 41% of drained patients compared with 3% procedure-related and 28% catheter-related complications with ultrasound guided drainage. A major complication of the endoscopic method in perihilar disease was cholangitis due to inadequate drainage.

Comparison of endoscopic retrograde pancreatography with functional and histologic changes in chronic pancreatitis.

The findings from endoscopic retrograde pancreatography (ERP) and secretin-CCK test data were compared in 69 patients: 36 with chronic pancreatitis, 9 with possible chronic pancreatitis, and 24 without chronic pancreatic disease. The ERP findings were also compared with the histologic changes in pancreatic tissue in 18 patients who underwent pancreatic surgery for chronic pancreatitis. ERP films were reviewed according to the criteria proposed by Kasugai et coll. with special attention paid to the side branches. Secretin-CCK test data were interpreted using the discriminant analysis. A good correlation between bicarbonate and chymotrypsin output and ductular changes at ERP was found. The results of ERP and the secretin-CCK test were compatible in 86 per cent of the patients. The relationship between ERP findings and histologic changes was not straightforward. It was concluded that ERP and the secretin-CCK test are complementary in the diagnosis of chronic pancreatitis. ERP does not necessarily represent the histology in chronic pancreatitis.

Primary malignant tumours of the duodenum.

The clinical and radiological findings in 19 patients with primary duodenal malignancy are described. Weight loss, abdominal pain, nausea and vomiting were the main symptoms. Diagnosis was made by endoscopy or ERCP (71%) or by barium studies (68%). In retrospect the tumour was visible in 97% of the studies. Tumour growth was longitudinal, circular or spiral, the inner curvature being involved over a greater length than the outer curvature. Exophytic tumour growth, involvement of the papilla of Vater, malignant spikes, transient, non-constant tumour image, skip lesions and ulceration were often seen. Mean survival time was 18 months from start of symptoms in 10 inoperable patients, and 24 months in 9 patients undergoing resection.

Carcinoma of the head of the pancreas. Therapeutic implications of endoscopic retrograde cholangiopancreatography findings.

During a 10-yr period starting January 1973, 123 patients with a carcinoma at the head of the pancreas underwent endoscopic retrograde cholangiopancreatography at our hospital. Analysis of their case histories revealed that the early complaints of pancreatic head carcinoma are rather nonspecific--sudden onset of diabetes mellitus (33.3%), weight loss (80.5%), tiredness and malaise (42.3%), change in bowel habits (41.5%), and upper abdominal discomfort (22.0%)--and that jaundice (88.6%) and classic pain (70.7%) are late symptoms. The diagnostic accuracy of endoscopic retrograde cholangiopancreatography (92.7%) was much higher than that of computed tomography (58.5%) and echography (54.4%). The patients were divided according to the maximal tumor diameter into three groups: group 1, tumor diameter ranging between 2.5 and 4.0 cm; group 2, tumor diameter ranging between 4.5 and 6.0 cm; and group 3, tumor diameter ranging between 7.0 and 15.0 cm. The tumor diameter did not correlate with the degree of differentiation. Extension of the tumor, vascular involvement, and metastases were evaluated for the several tumor diameters. The tumor was, in principle, operable in 77% of group 1 patients; in 24% of group 2 patients; and in 9% of group 3 patients. Tumors less than 3 cm in diameter were always resectable; tumors greater than 8 cm in diameter were seldom (9%) resectable. A curative resection was performed in 22.0% of the patients. The 4-yr survival of these patients was 44% as opposed to no survivors among the patients who had received only palliative or symptomatic treatment. During the decade, there was a tendency toward the diagnosis of smaller tumors (mean tumor diameter decreased from 9.0 +/- 1.7 to 5.4 +/- 2.8 cm) with a higher chance of resectability (from 25% to 44%).

Carcinoma of the ampulla and papilla of Vater.

We reviewed 30 patients with a carcinoma of the ampulla and papilla of Vater. The first symptoms were weight loss, sudden onset of diabetes mellitus, loss of appetite, tiredness, and upper abdominal discomfort or pain. Jaundice and fever were found to be late symptoms. The mean delay between the onset of complaints and diagnosis was 2 1/2 months. The diameter of the tumour varied from 4 to 35 millimetres. Seven patients had a tumour diameter of less than 9 millimetres. Extension of the tumour in the duodenum was never seen with tumours less than 8 millimetres in diameter. Extension of the tumour into the pancreas and metastases in the peripancreatic lymph nodes were only found with tumours with a diameter greater than 15 millimetres. The mean delay between onset of symptoms and operation was 3 months. At 52 months 79% of the patients younger than 64 years were still alive, while the survival rate of the patients of 65 years and older was 11%. Also at 52 months 58% of patients with a tumour size less than 2 centimetres were still alive, while the survival rate of the patients with a tumour larger than 2 centimetres was 31%.

A mathematical approach to the common bile duct.

Changes in the shape of the common bile duct (CBD) can be expressed mathematically by measuring the C.B.D.-diameter at five points and expressing these measurements as a percentage of the mean diameter. Variations in magnification are compensated for by relating the mean diameter to the length of the C.B.D. By comparing the shape of the C.B.D. in patients with various diseases with the shape of the normal common bile duct it was possible to define pathognomonic signs of various diseases of the extrahepatic biliary system. Indirect signs of pathology of the extrahepatic bile ducts are discussed.