Terminal Bile Duct Research Articles

Pancreaticobiliary maljunction: pathophysiological and clinical aspects and the impact on biliary carcinogenesis.

Pancreaticobiliary maljunction (PBM) is frequently associated with congenital choledochal cyst (CCBD), but differs in embryonic cause and clinical features. It is thought to develop as a misarrangement of the embryonic connections in the pancreaticobiliary ductal system, with the terminal bile duct joined to one of the ducts of the ventral pancreas. Clinical aspects are intermittent abdominal pain, relapsing acute pancreatitis, jaundice, cholangitis, and gallbladder cancer. In patients with PBM and CCBD, primary bile duct stones, acute cholangitis, and bile duct cancer are considered to result from cholestasis, regurgitation of pancreatic juice, and reciprocal reflux of bile and pancreatic juice. The mixture of bile and pancreatic juice due to recipocal reflex very likely plays an important role in biliary carcinogenesis. We reviewed the pathophysiological and clinical aspects and biliary carcinogenesis in 250 PBM patients (169 with benign hepatobiliary and pancreatic disease, 81 with malignancy). PBM patients show elevated cellular proliferation activity in the gallbladder epithelia. A number of oncogenes and tumor suppressor genes have been identified and implicated in carcinogenesis, particularly the K- ras oncogene and the p53 suppressor gene. Some K- ras mutations do not appear essential for hyperplasia but may be an early event in carcinogenesis. The p53 mutations are involved in carcinogenesis in the biliary epithelium in PBM patients.

Recent advances in pancreaticobiliary maljunction.

The purpose of this review is to evaluate our current knowledge of the embryologic etiology of pancreaticobiliary maljunction (PBM), its diagnosis, clinical aspects, and treatment, and to clarify the mechanisms of PBM involvement in carcinogenesis. Although the embryologic etiology of PBM still awaits clarification, an arrest of the migration of the common duct of the biliary and pancreatic ducts inwards in the duodenal wall has hitherto been speculated to result in a long common channel in PBM. However, we propose the hypothesis that the etiology of PBM is caused by a disturbance in the embryonic connections (misarrangement) of the choledochopancreatic duct system in the extremely early embryo. That is, PBM is an anomaly caused by a misarrangement whereby the terminal bile duct joins with a branch of the ventral pancreatic duct system, including the main pancreatic duct. PBM is frequently associated with congenital bile duct cyst (CCBD). However, these two anomalies are thought to have different embryonic etiologies. The diagnostic criteria for PBM are the radiological and anatomical detection of the extramural location of the junction of the pancreatic and biliary ducts in the duodenal wall. However, in PBM patients with a short common duct (less than 1 cm in length), detection of the extramural location is difficult. The clinical features of PBM are intermittent abdominal pain, with or without elevation of pancreatic enzyme levels; and obstructive jaundice, with or without acute pancreatitis, while the clinical features of PBM patients with CCBD are primary bile duct stone and acute cholangitis. The optimum approach for the treatment of PBM is the prevention of the reciprocal reflux of bile and pancreatic juice in the pancreas and the bile duct system. To achieve these aims, the surgical approach is most effective, and complete biliary diversion procedures with bile duct resection (for example, choledochoduodenostomy or choledochojejunostomy of the Roux-en-Y type) are most useful. Recently, it has been recognized that the development of biliary ductal carcinoma is associated with PBM. That is, the development of gallbladder cancer occurs frequently in PBM patients without CCBD, and bile duct cancer originating from the cyst wall also occurs in PBM patients with CCBD. It is speculated that the pathogenesis of the bile duct or gallbladder cancer in PBM patients involves the reciprocal reflux of bile and pancreatic juice. Investigations of epithelial cell proliferation in the gallbladder of PBM patients, and of K- ras mutations and p53 suppressor gene mutations, loss of heterozygosity of p53, and overexpression of the p53 gene product in gallbladder cancer and noncancerous lesions in PBM patients have been carried out in various laboratories around the world. The results support the conclusion that PBM is a high risk factor for the development of bile duct carcinoma.

Development of the intrahepatic biliary tree.

The liver develops from two anlages: the hepatic diverticulum, which buds off the ventral side of the foregut, and the septum transversum, which is the mesenchymal plate that partially separates the embryonic thoracic and abdominal cavities. The endodermal cells of the hepatic diverticulum invade the septum transversum, forming sheets and cords of hepatoblasts arrayed along the sinusoidal vascular channels derived from the vitelline veins emanating from the yolk sac. The vitelline veins fuse to form the portal vein, which ramifies as tributaries within the liver along mesenchymal channels termed portal tracts. Those hepatoblasts immediately adjacent to the mesenchyme of the portal tracts differentiate into a ductal plate, a single circumferential layer of biliary epithelial cells. Mesenchymal cells interpose between the ductal plate and the remaining parenchymal hepatoblasts, which differentiate into hepatocytes. By week 7 the ductal plate begins to reduplicate, forming a double layer of cells around the portal tract. Lumena form between the two cell layers of the ductal plate, forming peripheral biliary tubular structures. These peripheral tubules remodel and, with continued proliferation of the mesenchyme, by the 11th week begin to become more centrally located within portal tracts as terminal bile ducts with a circular cross-section. The remaining ductal plate resorbs, leaving behind only tethers of bile ductules connecting the terminal bile ducts to the parenchyma. Abutting and within the parenchyma are the canals of Hering, ductular structures half-lined by hepatocytes and half-lined by biliary epithelial cells. Maturation of the intrahepatic biliary tree to the mature tubular treelike architecture occurs from the hilum of the liver outward, beginning around the 11th week of gestation and continuing past birth for several months. The architecture of maturation is the same regardless of gestational age or radial location in the liver. Importantly, the immature intrahepatic biliary system maintains patency and continuity with the extrahepatic biliary tree throughout gestation, with no evidence of a solid phase of development. Thus, from the earliest time of hepatocellular bile formation beginning around the 12th week, there is a patent passage to the alimentary canal.

Functional innervation of the biliary sphincter of the guinea-pig revealed by anti-autonomic drugs.

1. The roles of excitatory and inhibitory intrinsic motor nerves on contractions reflexly evoked by wall distension were investigated in the isolated sphincter of Oddi of the guinea-pig (SO-GP). 2. Distension of the terminal bile duct for 30-60 s time periods increased the frequency of contractions from about 2 to 12 min(-1) (n = 16). 3. Hexamethonium (HEX; 300 microM) largely prevented the distension-evoked increase in contraction frequency (4.5 min(-1), n = 8) as did atropine (ATR; 1 microM) (0.8 min(-1), n = 6), while tetrodotoxin (TTX; 1 microM) blocked the contractions triggered during distension. 4. L-nitroarginine (L-NA; 100 microM) significantly increased the frequency of contractions during and in the absence distension while apamin (APAM; 0.5 microM) significantly increased their frequency and doubled their mean amplitude during distension. 5. These results suggest that distension activates excitatory cholinergic motor nerves to increase the frequency of contractions in the SO-GP. These actions are modulated by the concomitant activation of intrinsic nitrergic and non-nitrergic inhibitory motor nerves.

Laparoscopic Findings in Primary Sclerosing Cholangitis

Abstract: The laparoscopic appearance of the liver surface in patients with primary sclerosing cholangitis (PSC) has not been fully delineated. We examined 5 patients with PSC and reviewed 35 previously reported cases. Intense white markings in a mesh‐like pattern were characteristic of PSC. The findings varied depending on the histologic stage and affected site. Red patches which have also been seen in primary biliary cirrhosis (PBC), green patches indicating cholestasis, and dilatation of the terminal bile ducts were also observed. The red patches were wider than those in PBC. The white markings were less well defined in the red patches than in other areas. The severity of the fibrosis and histologic damage was judged to be mild at the red sites. The green patches were caused by localized cholestasis. This indicated that PSC unevenly affects the liver. Severe obstruction may be present between the interlobular bile ducts and the septal bile ducts in anicteric stages. (Dig Endosc 1999; 10: 37–41)

Fusion variations of pancreatic ducts in patients with anomalous arrangement of pancreaticobiliary ductal system.

Fusion variations of the pancreatic ducts were studied to elucidate the significance of such variations. We classified structural fusion anomalies of the main and accessory pancreatic ducts on endoscopic retrograde cholangio-pancreatography (ERCP) in 37 patients with anomalous arrangement of the pancreaticobiliary ductal system (AAPB). The fusion variations of the pancreatic ducts were classified into five types: common, ansa pancreatica, branch fusion, looped, and separated. These fusion variations, except for common type, were found in 68% of the 37 patients with AAPB on ERCP. Fusion variations of the pancreatic ducts were very frequent (93%) in the 30 patients with congenital cystic dilatation of the common bile duct (CCD). The branch confluence fashion, in which the terminal bile duct communicated with a pancreatic duct branch, was found only in patients with cystic dilatation cyst of the CCD, and it appeared that cystic dilatation cyst of CCD might differ from spindle or cylindrical cyst originating from embryonic formation of an anomalous confluence. It was also suggested that in patients with fusion variations of the pancreatic ducts, the flow of pancreatic juice might be disordered, leading to the development of acute pancreatitis or pancreatic dysfunction. Consequently, it appears to be necessary to carefully examine patients with AAPB for the presence or absence of any fusion variations of the pancreatic ducts and to observe such patients with long-term monitoring by ERCP, and computed temography, and with pancreatic function tests.

Malignant change in the biliary tract after excision of choledochal cyst

Choledochal cyst is a rare congenital condition with a high risk of malignant change if untreated. The risk of malignancy after surgical excision of choledochal cyst is not known. Forty-eight patients with choledochal cysts managed over a 21-year period were reviewed, to determine the risk of malignant change after cyst excision. Thirty-nine of 48 patients had no carcinoma at first admission; their mean(s.d.) age was 20(18) years. Thirty-seven of 39 patients underwent cyst excision and cholecystectomy followed by hepaticoenterostomy. Cyst excision was incomplete in 28 of the 37 patients because dilated portions of the biliary ducts remained proximally and/or distally. In these 37 patients, no carcinoma has developed in the remnant proximal hepatic duct or the terminal bile duct after mean(s.d.) follow-up of 9.1(6.4) years. In the remaining nine patients, biliary carcinoma was diagnosed at the first visit. Six patients died from recurrence with a mean(s.d.) survival time of 13(11) months, while three patients were alive and free from recurrence 2 months, 1 year and 7 years after operation. Malignant change has not been observed after total or subtotal excision of choledochal cysts in this series.

Laparoscopic Common Duct Exploration in a Child with Recurrent Pancreatitis due to a Primary Fungus Ball in the Terminal Common Bile Duct

We report on a case of a fungus ball obstructing the distal common bile duct and causing recurrent pancreatitis in an otherwise healthy 3-year-old boy. Laparoscopic exploration of the common bile duct was performed using a 10 french rigid fiberoptic cystoscope and a Dormia basket. This is the first example of a primary fungus ball in common bile duct presenting as a pancreatitis and treated laparoscopically.

Clinical aspects of congenital cystic dilatation of the common bile duct in adults

We reviewed the data for 155 patients with congenital cystic dilatation of the common bile duct (CCDB; Alonso-Lej Type I) treated at our institute in the past 12 years. Our definition of CCDB was segmental enlargement of the common bile duct or enlargement involving the proximal bile duct, visualized on cholangiograms. CCDB was subclassified as infant or adult type cyst, based on the extent of the enlargement and the clinicopathologic findings. The former is typically an enlargement of the common bile duct or an enlargement involving the common hepatic duct, while the latter is an enlargement of the entirety of the extrahepatic ducts or involves the intrahepatic bile ducts. Of the 155 patients, 5 (including 1 child) had infant type cysts and 150 (including 1 child) had adult type cysts; 125 patients had benign CCDB (3 with infant type cyst) and 30 exhibited CCDB biliary malignancy (2 with infant type). Anomalous arrangement of the pancreaticobiliary ductal system (AAPB) and congenital biliary stricture were frequently associated with CCDB and these features played an important role in the presenting symptoms of CCDB: AAPB was detected in 100 of the 155 patients, and stricture in 51. AAPB caused disturbance of the passage of bile from the terminal bile duct to the duodenum and cholestasis in the enlargement, with reciprocal regurgitation of bile into the pancreas and pancreatic juice into the bile duct, and the AAPB appeared to precede obstructive jaundice, acute pancreatitis, or biliary malignancies. Stricture was observed at one to all of six sites in the hepatic hilum. Intrahepatic stones were seen in 30 patients, and intrahepatic bile duct cancer was seen in 8 patients; in all these 8 patients, the cancer was associated with primary intrahepatic stones.

Antineutrophil cytoplasmic antibody positive autoimmune hepatitis: [formula omitted]. University of Iowa Dept. Internal Medicine and Pathology, Iowa City, IA

Cholangiographic changes of the biliary system in 16 patients with proven hepatic clonorchiasis, diagnosed by positive stool or bile ova isolates, were studied. All patients presented with epigastric pain. Other symptoms included jaundice in 31% (5 of 16) and fever in 12.5% (2 of 16). Praziquantel given at 25 mg/kg for three doses in 1 day were administered. Three consecutive stool tests were performed 3 months after treatment and were negative in 87.5% (14 of 16). ERCP studies were repeated at a mean interval of 31.6 months (range, 8 to 69 months). Measurements of the bile ducts on retrograde cholangiograms before and after treatment were compared using the paired Student’s t test. Filling defects and blunting of the terminal bile ducts seen on the initial cholangiogram, interpreted as the presence of adult worms, disappeared after treatment. However, there was no significant change between pre- and post-treatment measurement of bile duct caliber. Bile duct dilation, irregularities, and ductal proliferation persisted despite eradication of the parasite.

Undifferentiated carcinoma of the duodenal ampulla

This report demonstrates a case of undifferentiated carcinoma of the duodenal ampulla. A 74-year male experienced jaundice lasting for 3 weeks. An upper gastrointestinal series demonstrated a polypoid, ovoid filling defect in the second portion of the duodenum, and duodenoscopy disclosed a protruding mass involving the orifice of the papilla of Vater. Cholangiography demonstrated obstruction due to compression in the terminal common bile duct. Pylorus-preserving pancreatoduodenectomy was performed on the diagnosis of ampullary carcinoma. The gross specimen showed a polypoid mass, measuring 3.5 cm in diameter, in the ampulla, located mainly in the duodenal submucosal layer and invading the terminal common bile duct. Histologically, the tumor was small cell type, undifferentiated carcinoma, arising from the duodenal epithelium adjacent to the ampulla.

Complications of Primary Upper Gastrointestinal Lymphoma

This study reports the gastrointestinal complications of primary upper gastrointestinal lymphoma (PUGIL). of thirty-three patients with PUGIL, twenty-one (64%) had complications. These included upper gastrointestinal bleeding, narrowing of the lumen, malabsorption and obstructive jaundice in 11, 9, 5 and 4 patients, respectively. Perforation and fistula formation were encountered in one patient each. THe patients with complications were treated with chemotherapy alone (13), in combination with surgery (6), or combination with surgery and radiotherapy (2). Only in one of four patients was the mortality due to gastrointestinal complication in the form of severe upper gastrointestinal hemorrhage. The remaining three patients died of refractory septicemia. In conclusion, there was a high rate of gastrointestinal complications in patients with PUGIL in our population. Mortality was commonly unrelated to these gastrointestinal complications.

Bile flow analysis by hepatobiliary scintigraphy in the terminal bile duct in patients with congenital malformations of the pancreatico-biliary ductal system

The authors employed hepatobiliary scintigraphy (HBS), to study a dynamic state of bile stasis in the common bile duct and bile flow through the papilla of Vater in patients with congenital malformations of the pancreatico-biliary ductal system, such as congenital cystic dilatation of the common bile duct (CCDB) and anomalous arrangement of the pancreatico-biliary ductal system (AAPB). The HBS data were evaluated by a cholestatic index (CI), as an indicator of bile stasis in the common bile duct, and passage time (PT), as an indicator of bile flow through the papilla of Vater. CI was significantly higher in CCDB (3.67 +/- 0.92), in AAPB (2.87 +/- 0.28) and in both CCDB and AAPB with symptoms (2.86 +/- 0.59), compared with patients without CCDB or AAPB (0.96 +/- 0.41). PT was prolonged only in patients with AAPB with/without CCDB (greater than 30 minutes) compared to patients without AAPB (less than 12 minutes). This result suggested that bile stasis in the common bile duct was caused by a pooling of bile in the dilated common bile duct in CCDB, and by a disturbance of bile flow through the papilla of Vater in AAPB.

Endoscopic cholangiopancreatography in hepatic clonorchiasis—a follow-up study

Cholangiographic changes of the biliary system in 16 patients with proven hepatic clonorchiasis, diagnosed by positive stool or bile ova isolates, were studied. All patients presented with epigastric pain. Other symptoms included jaundice in 31% (5 of 16) and fever in 12.5% (2 of 16). Praziquantel given at 25 mg/kg for three doses in 1 day were administered. Three consecutive stool tests were performed 3 months after treatment and were negative in 87.5% (14 of 16). ERCP studies were repeated at a mean interval of 31.6 months (range, 8 to 69 months). Measurements of the bile ducts on retrograde cholangiograms before and after treatment were compared using the paired Student's t test. Filling defects and blunting of the terminal bile ducts seen on the initial cholangiogram, interpreted as the presence of adult worms, disappeared after treatment. However, there was no significant change between pre- and post-treatment measurement of bile duct caliber. Bile duct dilation, irregularities, and ductal proliferation persisted despite eradication of the parasite.

Endoscopic Placement of Biliary Endoprostheses in Patients with Endoscopically Unextractable Common Bile Duct Stones

Endoscopic sphincterotomy for removal of stones from the common bile duct, in particular in high-risk patients is an established procedure. However, the size of the stones and the appearance of the terminal bile duct prior to sphincterotomy have an influence on the outcome. In the period 1984-1987, thirty-four patients considered to be at high risk for surgery were treated endoscopically by insertion of a biliary endoprosthesis (15 cm long, 3.2 mm diameter) after unsuccessful attempts to remove common bile duct (CBD) stones following endoscopic sphincterotomy. These patients were admitted to the hospital with biliary colic, obstructive jaundice and/or cholangitis. Eight patients were lost to follow-up. The remaining patients comprised 20 females and 6 males, with a mean age of 81 years (range: 60-96). Five patients underwent surgical treatment for perforation (one patient, 11 months after insertion), persistent jaundice (one patient) or recurrent obstructive jaundice (endoprosthesis clogging in one, endoprosthesis dislodgement in two patients) 2 to 40 months after insertion. In one patient, recurrent obstructive jaundice was successfully treated by replacing the clogged endoprosthesis 4 months after the initial treatment. Ten patients died of unrelated causes (myocardial infarction, accident, etc.) 2 to 28 months after insertion. The remaining ten patients were still alive without symptoms after a median follow-up of 26 months. On the basis of these findings we therefore conclude that endoscopic insertion of a biliary endoprosthesis is a safe and effective treatment for huge CBD stones in high-risk patients in whom endoscopic sphincterotomy and attempts to remove the stones are not successful.

Fehlbildungen des Ductus choledochus und der Papilla Vateri bei den verschiedenen Formen der Duodenalatresie

Associated anomalies are often found in newborn with duodenal obstruction. Anomalies of the biliary tract are of special interest. Malformations of the terminal common bile duct and the papilla of Vater are the most common ones. The recognition of the possible anatomical variations is most important to avoid inadvertent injuries in the correction of duodenal obstruction.

Immunochemical evidence for interaction between cholecystokinin C-terminal peptides and the protein inhibitor of adenosine 3',5'-cyclic monophosphate dependent protein kinase in hog terminal bile ducts.

The interaction of cholecystokinin (CCK) C-terminal peptides with the protein inhibitor (PK-I) of adenosine 3',5'-cyclic monophosphate-dependent protein kinase (A-PK) was studied by immunoprecipitation using anti-PK-I antibody. The binding of CCK-4 peptide to PK-I was shown to be specific; while CCK-4 enhanced precipitation of PK-I with antibody, it did not enhance precipitation of bovine serum albumin (BSA) by anti-BSA. The interaction of CCK-4 with PK-I is reversible and similar to that of urea but different from that of alkali. These results support the conclusion that CCK-C terminal peptides interact specifically with PK-I.

Caerulein in the treatment of biliary and renal colic

A randomized controlled study has been carried out in order to check the activity of caerulein in the treatment of biliary and renal colic. In 88% out of 107 patients caerulein, 1 ng/kg IV, relieved biliary colic and had no side effects. To elucidate the mechanism of action of the peptide, 22 cholecystectomized patients, showing a dilatation of the common bile duct (CBD), were submitted to caerulein treatment under echo-control. Reduction of CBD caliber was noticed when the dilatation was due to functional obstruction, whereas an organic obstruction of the terminal tract of CBD was found in the non-responding patients. Caerulein appears to be an effective agent in relieving biliary colic through a relaxation of Oddi's sphincter, and may be used in ultrasound differential diagnostics of terminal bile duct obstruction. Caerulein, 75 ng/kg intramuscularly, relieved renal colic in 75% of the examined patients; it is suggested that the effect of caerulein in this syndrome is due to central analgesic action.

Extrahepatic biliary obstruction associated with pancreatitis.

A total of 40 patients with pancreatitis had associated extrahepatic biliary obstruction. Eighteen had biliary-induced pancreatitis. Comprehensive correction of the biliary tract disease, including cholecystectomy, common duct exploration and, when indicated, transduodenal sphincteroplasty, resulted in a high recovery rate (83%) with no recurrence of pancreatitis. Twenty-two patients had chronic pancreatitis with involvement of the terminal biliary tract by a long tapering stenosis. Nineteen of these patients had chronic fibrocalcific pancreatitis secondary to chronic alcohol abuse. In five patients, the stenosis produced a high grade obstruction which required biliary bypass with choledochoduodenostomy (four) or cholecystoduodenostomy (one). The remaining 14 patients maintained patency of the biliary tract following correction of the underlying pancreatic pathology. The latter consisted of drainage (nine) or resection (five) of 14 associated pseudocysts (present in 64% of the 22 patients), combined with side-to-side pancreaticojejunostomy to decompress an obstruction of the major pancreatic duct. In assessing the degree of terminal bile duct stenosis, calibration of the duct with Bakes dilators or rubber catheters was a useful aid. Two of the 22 patients ultimately proved to have carcinomas, producing obstruction of the pancreatic duct in the head of the gland. Both were treated initially with choledochoduodenostomy. This possibility must be considered in the management of these patients.

Endogenous opioid peptide effects on the guinea-pig biliary tract

The effects of the endogenous opioid peptides, dynorphin (1–13), Met-enkephalin and β-endorphin, on contraction induced by transmural stimulation of terminal bile duct preparations (terminal cavity and ampulla) and gallbladder were investigated in vitro. These peptides inhibited ampulla contraction, dose dependently. The potency order, indicated by ID 50, was the same as in the guinea-pig ileum, but the absolute ID 50 values in the ampulla were lower than in the ileum. In the terminal cavity, the dynorphin (1–13) ID 50 was still less than in the ampulla, and β-endorphin and Met-enkephalin did not reduce contraction by as much as 50%. In the gallbladder, the effects of these opioid peptides on contraction induced by transmural stimulation were not significant. The results suggest differences in the receptor populations of the ampulla and terminal cavity, and lack of opiate receptors (at least μ and κ receptors) in the gallbladder.