Pancreaticobiliary Maljunctions in European Patients with Bile Duct Cysts: Results of the Multicenter Study of the French Surgical Association (AFC).

BACKGROUND: Pancreaticobiliary maljunctions (PBMs) are congenital anomalies of the junction between pancreatic and bile ducts, frequently associated with bile duct cyst (BDC). BDC is congenital biliary tree diseases that are characterized by distinctive dilatation types of the extra- and/or intrahepatic bile ducts. Todani's types I and IVa, in which dilatation involves principally the main bile duct, are the most frequent. PBM induces pancreatic juice reflux into the biliary tract that is supposed to be one of the main factors of biliary cancer degeneration, although the diagnostic criteria of PBM that can be either morphological and/or functional are not well defined especially in Western series. OBJECTIVE: The aim of this study was to assess the relative prevalence of PBM in BDC in a large European multicenter study, to analyze the characteristics of PBM and try to propose diagnostic criteria of PBMs based on morphological and/or functional criteria and define the positive, negative predictive values, sensibility and specificity of either criteria. RESULTS: From 1975 to 2012, 263 patients with BDC were analyzed. Among them, 190 (72.2 %) were considered to present PBM. Types I and IVa had a similar rate of PBM association. According to the "AFC classification," 57.2 % had a C-P type, 34.5 % a P-C type and 8.3 % a complex type ("anse-de-seau"). The median length of the common channel in patients with PBM was 15.8 ± 6.8 mm (range 5-40 mm). The median intrabiliary amylase and lipase levels were 65,249 and 172,104 UI/L, respectively. For the diagnostic of PBM, a common channel length of more than 8 mm and an intrabiliary amylase level superior to 8000 UI/L were associated with a predictive positive value and a specificity of more than 90 %. Synchronous biliary cancer had an incidence of 8.7 % in all patients with BDC and PBM 11.1 % in adults. Compared to type IV, the type I BDC was associated with statistically more cancer patients in the presence of PBM. CONCLUSIONS: Characteristics of PBM associated with BDC in Western population are quite close to reported Eastern series. The results suggest considering both the intrabiliary value of amylase >8000 UI/L and a length of a common channel >8 mm as appropriate values for positive diagnosis of PBM.

High drain amylase and lipase values predict post-operative pancreatitis for choledochal cyst.

BACKGROUND: Post-operative pancreatitis is a severe complication after cyst excision with hepaticoenterostomy (CEHE) for choledochal cysts. The aim of this study was to examine the dynamic post-operative changes in drain amylase and lipase values after CEHE for choledochal cysts, and then compare these values with the clinical outcomes in order to identify risk factors for post-operative pancreatitis after CEHE. PATIENTS AND METHODS: A total of 19 patients with choledochal cysts were retrospectively examined in the period between 2005 and 2012. The amylase and lipase values in the drainage and the serum, and the output of the effluent were measured post-operatively. The associations between their values and the clinical outcomes were evaluated. RESULTS: Six were found to have a pancreatic leak according to an international study group definition. In two of them, who developed post-operative pancreatitis, both amylase and lipase values in drainage were markedly elevated at 1 post-operative day (1 POD). The drain amylase value seemed to elevate rather specifically dependent on the occurrence of post-operative pancreatitis, whereas the drain lipase value tended to elevate regardless of the presence/absence of post-operative pancreatitis. CONCLUSION: It was indicated that amylase and lipase values in drainage at 1 POD could be effective predictors of post-operative pancreatitis after CEHE.

Carcinogenic Potential of Biliary Epithelium of Congenital Choledochal Cyst Model in Rats: A Special Reference to HDAC Expression.

BACKGROUND/AIMS: Pancreaticobiliary maljunction (PBM) is well known to have carcinogenic potential. The goal of this study was to clarify the carcinogenic potential of the epithelium of choledochal cyst particularly by paying attention of HDAC1 and COX-2 expressions. METHODOLOGY: Six-week male Lewis rats were divided into two groups; 1) single dose of dibutyltin dichloride (8 mg/kg) was administered intravenously (DBTC group), 2) saline administration was done with the same manner (control group). Morphological changes of biliary tract and expressions of carcinogenesis-related genes, Ki67, HDAC1 and cyclooxygenase-2 (COX-2) were examined immunohistochemically after administration. RESULTS: In the DBTC group, the bile duct had been gradually dilated on day 3 after administration and the biliary epithelium of dilated bile duct was papillary proliferated on day 7. Ki67 and COX-2 expressions gradually increased and reached the highest value of 6.0% and 3.6% on day 14, respectively. HDAC1 expression increased at the early postoperative period prior to other oncogene, and reached the highest level of 15% on day 7. CONCLUSIONS: These findings suggested that HDAC1 played an important role in carcinogenesis of PBM through the regulation of COX-2.

Monoamine oxidase A expression is suppressed in human cholangiocarcinoma via coordinated epigenetic and IL-6-driven events.

The secretion of dopamine and serotonin is increased in cholangiocarcinoma, which has growth-promoting effects. Monoamine oxidase A (MAOA), the degradation enzyme of serotonin and dopamine, is suppressed in cholangiocarcinoma via an unknown mechanism. The aims of this study were to (i) correlate MAOA immunoreactivity with pathophysiological parameters of cholangiocarcinoma, (ii) determine the mechanism by which MAOA expression is suppressed and (iii) evaluate the consequences of restored MAOA expression in cholangiocarcinoma. MAOA expression was assessed in cholangiocarcinoma and nonmalignant controls. The control of MAOA expression by promoter hypermethylation was evaluated and the contribution of interleukin-6 (IL-6) signaling to the suppression of MAOA expression was determined. The effects of MAOA overexpression on cholangiocarcinoma growth and invasion were also assessed. MAOA expression is correlated with differentiation, invasion and survival in cholangiocarcinoma. The MAOA promoter was hypermethylated immediately upstream of the start codon in cholangiocarcinoma samples and cell lines but not in nonmalignant counterparts. IL-6 signaling also decreased MAOA expression via a mechanism independent of hypermethylation, involving the regulation of the balance between SP-1 transcriptional activity and its inhibitor, R1 repressor. Inhibition of both IL-6 signaling and DNA methylation restored MAOA levels to those observed in cholangiocytes. Forced MAOA overexpression inhibited cholangiocarcinoma growth and invasion. MAOA expression is suppressed by the coordinated control of promoter hypermethylation and IL-6 signaling. MAOA may be a useful prognostic marker in the management of cholangiocarcinoma, and therapies designed to increase MAOA expression might prove beneficial in the treatment of cholangiocarcinoma.

Intrahepatic duct dilatation in type 4 choledochal malformation: pressure-related, postoperative resolution.

BACKGROUND: Type 4 choledochal malformations (CMs) may be defined as those with both intrahepatic and extrahepatic bile duct dilatation. The aims of this study were to investigate possible causes of intrahepatic duct (IHD) dilatation in CM and to define the effect of surgery over time. METHODS: This study was a single-center retrospective review of a database of all children with CM undergoing surgery (excision of extrahepatic bile duct dilatation and hepaticojejunostomy) and identified as type 4 (on imaging and at surgery). Data included intraoperative choledochal pressure measurements and biliary amylase content and were expressed as median (interquartile range [IQR]). All comparisons used nonparametric statistical tests. P ≤.05 was regarded as significant. RESULTS: Twenty children were identified as type 4 CM (age, 4.3 years; range, 2.7-10.4 years) with preoperative IHD dilatation (right duct: diameter [range], 8.5 [4.5-14] mm; left: 8 [4-14.5] mm). Median intraoperative choledochal pressure was 17 (8-27) mm Hg (normal, <5 mm Hg), and intraoperative bile amylase was 3647 (range, 500-58,000) IU/L (normal, <100 IU/L). Preoperative IHD diameter correlated with choledochal pressure (right: r(s)=0.46, P = .03; left: r(s)=0.34, P = .07) but not with biliary amylase (P = .28 and P = .39, respectively). At 1 year postsurgery, median (range) IHD diameter had decreased to 1 (1-2.5) mm for right duct (P = .0002) and 1.5 (1-3) mm for left duct (P = .0006) and remained stable for up to a 10-year follow-up. CONCLUSION: Our data suggest that IHD dilatation is related to sustained increased intrabiliary pressure rather than any intrinsic intrahepatic CM. Effective surgery invariably reduces measured IHD toward normal values.

Choledochal cysts in infants and children: experiences over a 20-year period at a single institution.

This analysis was undertaken to compare the clinicopathological features of infants with choledochal cysts to those of older children with these entities and to evaluate the surgical outcomes for both subject groups. The medical records of all children admitted to the Cathay General Hospital with choledochal cysts over a 20-year period were retrospectively reviewed. Twenty-five subjects were included and divided into the infant (<1 year at presentation; 8 subjects) and classical pediatric (1-18 years at presentation; 17 subjects) groups. Anatomical subtypes were: IA (16), IC (6), and IVA (3). The median biliary amylase value was markedly elevated for the pediatric group but not for the infant group. Most (82.4%) patients in the pediatric group, but none in the infant group, presented with abdominal pain. Jaundice and clay-colored stool were present in all patients in the infant group but only 35% of those in the pediatric group. All patients underwent choledochocystectomy and Roux-en-Y hepaticojejunostomy with good outcomes. Neonates/infants with choledochal cysts present differently from older children with these entities. Amylase measurements may serve to distinguish biliary atresia with cystic dilatation from choledochal cyst in neonates/infants. Prognosis following radical cyst excision and reconstruction with Roux-en-Y hepaticojejunostomy is excellent.

Expression of matrix metalloproteinase 1 and 2 in congenital choledochal cyst and its clinical significance.

BACKGROUND: The pathogenesis of congenital choledochal cyst (CCC) is still not well elucidated. This study was conducted to detect the expression of matrix metalloproteinase-1 and 2 (MMP-1 and MMP-2) in CCC. The roles of MMP-1 and MMP-2 in CCC formation were also discussed. METHODS: Specimens of CCC and gallbladders were taken from 53 patients with CCC, including 21 boys and 32 girls aged from 4 months to 17 years (mean: 6.5 years old). Twenty-eight normal gallbladders served as controls. Immunohistochemical method was used to detect the expressions of MMP-1 and MMP-2. Image analysis was made to quantitatively analyze the protein expression. RESULTS: The expressions of MMP-1 and MMP-2 were located in epithelial cells, matrix cells, and inflammatory cells of the CCC wall. Various expressions were also found in the mucosa membrane cells of the CCC gallbladder. The expressions of MMP-1 and MMP-2 were low in the control group. Quantitatively, the expressions of MMP-1 and MMP-2 in the CCC wall were markedly higher than in the CCC gallbladder and the control group (P<0.01). There was no significant difference between the CCC gallbladder and the control group (P>0.05). CONCLUSIONS: The expression of MMP-1 and MMP -2 in the CCC wall is higher than in the CCC gallbladder and controls. The over-expression of MMP-1 and MMP-2 may be involved in the pathogenesis of CCC.

Fecal elastase 1, serum amylase and lipase levels in children with cholestasis.

BACKGROUND/AIM: The pancreatic functions of children with cholestatic liver diseases were unclear. Due to anatomic vicinity and common ontogenic origin, hepatobiliary disorders of infancy may also affect pancreatic function. The aim of the study was to evaluate the exocrine pancreatic function and common pancreatic function tests in children with cholestatic disorders. METHODS: In 40 children with cholestasis, fecal elastase 1 (FE1) concentrations were measured. Serum amylase and lipase values were tested. The diagnoses included 32 patients with extrahepatic cholestasis (biliary atresia (BA) and choledochal cyst), and 8 patients with intrahepatic cholestasis (progressive familial intrahepatic cholestasis and Alagille syndrome). None had renal insufficiency or clinical symptoms/signs of acute pancreatitis. RESULTS: All the patients had normal FE1 (>200 microg/g). Nineteen percent (7/37) had elevated serum amylase levels (>100 U/l). Thirty-two percent (12/37) had elevated serum lipase levels above the normal (>120 U/l). Seventy-three percent (8/11) of BA patients with bilirubin >2 mg/dl had elevated serum lipase levels compared to 18% (3/17) with bilirubin < or = 2 mg/dl (p = 0.0036). None had detectable pancreatic abnormality on ultrasonography and magnetic resonance images. CONCLUSIONS: None of the cholestatic children in this study had exocrine pancreatic insufficiency as detected by FE1. Hyperamylasemia and/or hyperlipasemia were frequently found. In children with BA, those with impaired biliary excretion tended to have elevated serum pancreatic enzymes as compared with those who had no jaundice. A decreased hepatic metabolism may be the cause.

Potential diagnostic value of pancreatic isoamylases for pancreaticobiliary maljunction with mild biliary dilatation in patients and a porcine model.

PURPOSE: The aim of this study was to evaluate the diagnostic value of serum pancreatic isoamylases for pancreaticobiliary maljunction (PBM) with mild biliary dilatation. METHODS: Serum and bile from 8 children with PBM and mild biliary dilatation (6 to 11 mm in diameter) and 4 young pigs with an anastomosis constructed between an isolated pancreas-duodenal segment and the gallbladder were studied for pancreatic isoamylases. Using an electrophoretic technique, the assay of pancreatic isoamylases was expressed by peak appearance rate (PAR). Serum from 20 healthy children served as normal controls. RESULTS: In the serum of the patients, preoperatively there were 5 pancreatic peaks with PAR as follows: P1, 100%; P2, 100%; P3, 100%; P4, 100%; and P5, 66.7%. These abnormal pancreatic isoamylases disappeared 2 weeks after operative treatment. In normal controls, there were only P1 (PAR, 40%) and P2 (PAR, 100%). Mild cylindrical dilatation (6 to 8 mm in diameter) of the common bile duct developed in the porcine PBM model. There were P1 (PAR, 100%) and P2 (PAR, 100%) in the porcine serum preoperatively. Thirty days and 60 days after establishing the model, there appeared in the serum 6 pancreatic peaks with PAR as follows: P1, 100%; P2, 100%; P3, 75%; P4, 100%; P5, 100%, and P6; 75%. The bile patterns of pancreatic isoenzymes in the patients and pigs were similar to those in serum. CONCLUSIONS: Abnormal pancreatic isoamylases are characteristically present in the serum from both children and a porcine model of PBM and mild biliary dilatation. Assay for these abnormalities is promising to recognize this subset of patients in whom diagnosis remains a challenge.

Different expression of cyclooxygenase-2 in biliary epithelia of bile duct cancer with or without pancreaticobiliary maljunction.

BACKGROUND: Cyclooxygenase-2 (COX-2) has been reported to play an important role in the pathogenesis of a variety of cancers. Little is known about the relationship between bile duct cancer associated with pancreaticobiliary maljunction (PBM) and COX-2. MATERIALS AND METHODS: We compared the expression of COX-2 in bile duct epithelium in bile duct cancer with or without PBM. RESULTS: Immunohistochemical analysis showed that the rate of positive COX-2 expression was 42.9% for cancerous lesions and 7.1% for noncancerous lesions in cases of bile duct cancer without PBM. On the other hand, no positive expression of COX-2 was observed in cancerous lesion of bile duct cancer with PBM. Twenty % of the noncancerous bile duct mucosa with PBM was positive for COX-2. CONCLUSION: COX-2 is expressed in bile duct cancer while it is not expressed in bile duct cancer accompanied by PBM.

Abnormal pancreatic isoamylases in the serum of children with choledochal cyst.

PURPOSE: To investigate the changes of pancreatic isoamylases in the serum of children with choledochal cyst. METHODS: Serum and bile from 20 children with choledochal cyst were studied for total amylase activity and isoamylases. Using electrophoresis, the assay of pancreatic isoamylases was expressed by peak appearance rate (PAR) and ratio of isoenzyme activity (RIA). Serum from 20 healthy children and 12 adults with acute pancreatitis served as a comparison. RESULTS: The total amylase activity in the serum of children with choledochal cyst was slightly higher than that of healthy controls, but dramatically lower than that of acute pancreatitis. The serum of children with choledochal cyst showed 5 pancreatic peaks (PAR: P1, 100 %; P2, 100 %; P3, 100 %; P4, 75 %; P5, 45 %) without any major peak. In healthy controls, only P1 and P2 were present (PAR: P1, 40 %; P2, 100 %) with the latter being a major peak (RIA: 81.8 +/- 25.3 %). These results in children with choledochal cyst differed from those of patients with acute pancreatitis who presented with the less common P4 and no P5 (PAR: P1, 100 %; P2, 100 %; P3, 91.6 %; P4, 8.3 %). The pattern of pancreatic isoenzymes in bile was similar to that in the serum from patients with choledochal cyst. These abnormal pancreatic isoamylases gradually disappeared after operation. CONCLUSIONS: Abnormal pancreatic isoamylases, especially P4 and P5, are found in the serum of patients with choledochal cyst, which would point to a reflux of pancreatic juice into the biliary tract.

Carcinoma arising in choledochocele.

BACKGROUND AND STUDY AIMS: Choledochocele has a potential for carcinogenesis, but no report has described malignant changes of the choledochocele in relation to pancreaticobiliary reflux because its anatomic form does not fit the criteria of pancreaticobiliary malunion (PBM). The aims of this study were to analyze the amylase level in bile in patients with choledochocele and to clarify whether the presence of a choledochocele predisposed to carcinoma. PATIENTS AND METHODS: Records of 2826 patients who had undergone endoscopic retrograde cholangiopancreatography between 1995 and 1999 were reviewed for the presence of choledochocele and/or periampullary carcinoma. As an evidence of pancreaticobiliary reflux, amylase activity was examined in common duct bile obtained at surgery or by endoscopy. The prevalence of periampullary carcinoma was compared between patients with and without choledochocele. RESULTS: A total of 11 patients were diagnosed as having a choledochocele. The amylase level in bile was higher in patients with choledochocele (120,922 +/- 62,269 IU/l; n = 4) than in previously examined patients with functioning gallbladders (15 +/- 24 IU/l; n = 10, P = 0.005). The prevalence of periampullary carcinoma in patients with choledochocele (27%, 3/11) was significantly higher than that in those without choledochocele (0.9%, 26/2815; P<0.0002). CONCLUSION: The bile analysis of the present study presents one possible explanation for the predisposition to carcinoma in choledochocele as bile containing amylase may stagnate in the choledochocele and then carcinoma may develop in the inner epithelium of the choledochocele by the same mechanism as that leading to carcinogenesis in patients with PBM.

Does hyperamylasemia in choledochal cyst indicate true pancreatitis? An experimental study.

Patients with choledochal cyst often have repeated attacks of abdominal pain accompanied by hyperamylasemia, and they may be diagnosed as having acute pancreatitis. However, the attacks generally tend to subside in a short period by conservative treatment, and evidence of pancreatitis is rarely observed at the time of surgery. Choledochal cyst is commonly associated with pancreatobiliary maljunction, and high concentrations of pancreatic enzymes in bile are usually observed. When the bile duct pressure increases due to obstructive cholangitis, pancreatic enzymes in bile may regurgitate into the blood stream. Cholangiovenous reflux of amylase might cause hyperamylasemia. In order to investigate the mechanism of hyperamylasemia by cholangiovenous reflux, canine pancreatic juice or bile from a patient with choledochal cyst was injected into the obstructed common bile duct in dogs. The pancreatic enzymes in bile could readily enter into the blood stream at the pressure level of 15 mmHg or more in the bile duct. The peak amylase level in the thoracic lymph was observed to be more than 4 times higher than that in the blood serum, and the lymph flow during 30 minutes increased significantly from 8.1 to 20.4 ml at the bile duct pressure level of 20 mmHg. The reflux of amylase in bile into the blood stream via both the hepatic vein and thoracic duct might result in hyperamylasemia in the patients with choledochal cyst.

Characteristics of choledochal cysts in neonates and early infants.

Thirty-six infants with choledochal cyst consisting of 28 babies less than 12 months of age and 8 between 13 and 24 months of age, were analyzed. Characteristics of cases were as follows: (1) they were usually of the cystic type, (2) a huge abdominal mass and jaundice with alcoholic stool were typically found, (3) no symptom suggesting acute pancreatitis was observed, (4) amylase levels in bile were usually low, despite the presence of pancreatobiliary malunion, while other pancreatic enzymes in bile commonly showed a high concentration, and (5) primary cyst excision and biliary reconstruction was the treatment of choice, and could be safely performed with favorable outcomes even in babies less than 1 year of age.

How great is the incidence of truly congenital common bile duct dilatation?

In an attempt to investigate the causes of common bile duct dilatation (CBDD), activity of the pancreatic enzymes in bile aspirated from the dilated duct during laparotomy was measured in 24 children with CBDD. The reasoning behind this is the fact that the existence of activated pancreatic enzymes, namely raised activity of all enzymes accompanied by trypsin activation, can be regarded as an acquired result of an anomalous choledochopancreaticoductal junction (ACP-DJ). All of the pancreatic enzymes measured were activated in 14 cases (58.3%) but no evidence of activation of enzymes, such as trypsin or others except for amylase and lipase, was observed in the remaining 10 cases (41.7%), whether an ACPDJ was present or absent. Eight of the 10 patients with no enzyme activation (33.3% of the total) were less than 2 months old. The findings in these eight infants, which included cystic dilation or hypoplasia of the intrahepatic duct, provide strong suggestive evidence of the congenital nature of these cases. These results suggest that at least one third of CBDD cases are congenital and the remaining cases are either acquired or a combination of congenital and acquired, or both.

Pseudopancreatitis in choledochal cyst in children: intraoperative study of amylase levels in the serum.

A case of acute necrotizing pancreatitis in association with choledochal cyst is presented. Pancreatitis associated with choledochal cyst is probably caused by a biliary reflux into the pancreatic duct via a pancreatobiliary malunion, as the intraductal pressure of the cyst exceeds that of the pancreatic duct. Ampullar stenosis due to gallstones or inflammatory changes may increase the intraductal pressure. Bile with activated pancreatic enzymes refluxes into the pancreatic duct, and possibly results in acute pancreatitis. However, patients with choledochal cyst presenting with recurrent bouts of abdominal pain, vomiting, and fever have often been diagnosed as having acute pancreatitis because of hyperamylasemia, despite no evidence of pancreatitis at the time of surgery. At the time of bouts, they also show a slight elevation of serum bilirubin, and an increase in the degree of the choledochal dilatation that are possibly caused by biliary obstruction, not ampullar obstruction, due to suppurative cholangitis. The term "fictitious pancreatitis" or "pseudopancreatitis" in choledochal cyst appears to be appropriate. This clinical study shows that amylase in the biliary tract has ready access to the blood stream, probably through a sinusoidal pathway by cholangiovenous reflux, and a lymphatic pathway, via the Disse's space and denuded cyst wall, provided the biliary ductal pressure is increased.

[Analysis of pancreatic enzymes in the bile of congenital choledochal cyst with anomalous pancreaticobiliary ductal union].

Pancreatic enzymes in the bile of congenital choledochal cyst with anomalous pancreaticobiliary ductal union were analyzed. Almost all pancreatic proteases were already activated in the bile aspirated immediately after insertion of PTCD tube. However, inactive proteases gradually increased after continuation of drainage by PTCD. Pancreatic protease activities appeared again after clamping the PTCD tube. In vitro study of trypsin activities in the bile containing no initial trypsin activity, active type of trypsin did not appear throughout the experimental period. It is suggested that continuous reflux of pancreatic juice into the bile and certain incubation time are necessary for activation of pancreatic protease in bile of congenital choledochal cyst.