Biliary atresia-specific deciduous pulp stem cells feature biliary deficiency

Background Biliary atresia (BA) is a severe hepatobiliary disease in infants that ultimately results in hepatic failure; however, its pathological mechanism is poorly elucidated. Current surgical options, including Kasai hepatoportoenterostomy and orthotopic liver organ transplantations, are palliative; thus, innovation in BA therapy is urgent. Methods To examine whether BA-specific post-natal stem cells are feasible for autologous cell source for BA treatment, we isolated from human exfoliated deciduous teeth, namely BA-SHED, using a standard colony-forming unit fibroblast (CFU-F) method and compared characteristics as mesenchymal stem cells (MSCs) to healthy donor-derived control SHED, Cont-SHED. BA-SHED and Cont-SHED were intrasplenically transplanted into chronic carbon tetrachloride (CCl4)-induced liver fibrosis model mice, followed by the analysis of bile drainage function and donor integration in vivo. Immunohistochemical assay was examined for the regeneration of intrahepatic bile ducts in the recipient’s liver using anti-human specific keratin 19 (KRT19) antibody. Results BA-SHED formed CFU-F, expressed MSC surface markers, and exhibited in vitro mesenchymal multipotency similar to Cont-SHED. BA-SHED showed less in vitro hepatogenic potency than Cont-SHED. Cont-SHED represented in vivo bile drainage function and KRT19-positive biliary regeneration in chronic carbon tetrachloride-induced liver fibrosis model mice. BA-SHED failed to show in vivo biliary potency and bile drainage function compared to Cont-SHED. Conclusion These findings indicate that BA-SHED are not feasible source for BA treatment, because BA-SHED may epigenetically modify the underlying prenatal and perinatal BA environments. In conclusion, these findings suggest that BA-SHED-based studies may provide a platform for understanding the underlying molecular mechanisms of BA development and innovative novel modalities in BA research and treatment.

MODERN ASPECTS OF RESTORATION OF BILE FLOW IN CHOLELITHIASIS COMPLICATED BY OBSTRUCTIVE JAUNDICE

Patients with surgical diseases of the liver and extrahepatic bile ducts, the obstruction of which is accompanied by obstructive jaundice, constitute the most severe group of patients in surgical hospitals. The main cause of obstruction of the biliary tract is choledocholithiasis, which accounts for 30-70%. In the era of dominance of endoscopic surgery in the treatment of patients with obstructive jaundice, the benefits of transpapillary interventions are undeniable. At the same time, there are opinions that traditional surgical interventions for this type of pathology are desperate operations. In this regard, the role and place of laparoscopic interventions in the treatment of patients with cholelithiasis complicated by obstructive jaundice at the present stage requires detailed investigation. The aim of this study is to improve the results of treatment of patients with cholelithiasis complicated with obstructive jaundice by optimizing strategic approaches to performing bile drainage interventions. For this purpose, we conducted a study including 54 patients divided into two groups. The study has demonstrated that cholelithiasis complicated by obstructive jaundice, is more likely in women, 94.4% of all cases, than in men, 5.6%. The restoration of the total bilirubin level occurs faster in the patients who had laparoscopic surgery. The duration of the postoperative pain syndrome was twice as less in the patients of the second group due to less extent of surgical trauma. Our data confirm the concept according to which preference should be given to minimally invasive methods of surgical intervention in patients with cholelithiasis complicated by obstructive jaundice.

Generation of functional liver organoids on combining hepatocytes and cholangiocytes with hepatobiliary connections ex vivo

In the liver, the bile canaliculi of hepatocytes are connected to intrahepatic bile ducts lined with cholangiocytes, which remove cytotoxic bile from the liver tissue. Although liver organoids have been reported, it is not clear whether the functional connection between hepatocytes and cholangiocytes is recapitulated in those organoids. Here, we report the generation of a hepatobiliary tubular organoid (HBTO) using mouse hepatocyte progenitors and cholangiocytes. Hepatocytes form the bile canalicular network and secrete metabolites into the canaliculi, which are then transported into the biliary tubular structure. Hepatocytes in HBTO acquire and maintain metabolic functions including albumin secretion and cytochrome P450 activities, over the long term. In this study, we establish functional liver tissue incorporating a bile drainage system ex vivo. HBTO enable us to reproduce the transport of hepatocyte metabolites in liver tissue, and to investigate the way in which the two types of epithelial cells establish functional connections.

Choledochal cyst with secondary cholangitis, choledochitis, duodenal papillitis, and pancreatitis in a young domestic shorthair cat

Choledochal cysts, congenital segmental dilations of the common bile duct, have been reported in few cats, and histologic characterization is lacking. A 20-mo-old spayed female domestic shorthair cat was presented because of vomiting and weight loss. There was progressive elevation of liver enzyme activity (ALT > ALP, GGT) and hyperbilirubinemia. Diagnostic imaging identified focal cystic dilation of the common bile duct, dilation and tortuosity of adjacent hepatic ducts, and a prominent duodenal papilla. A choledochal cyst was suspected, and the animal was euthanized. On postmortem examination, there was a 2-cm, firm, thickened, cystic dilation of the common bile duct, patent with adjacent ducts. Histologically, the cyst wall was expanded by fibroblasts, collagen, and lymphoplasmacytic inflammation. Adjacent bile ducts were markedly dilated and tortuous, with lymphoplasmacytic inflammation and papillary mucosal hyperplasia that extended to the major duodenal papilla. There was chronic neutrophilic cholangitis, suggesting bacterial infection and/or disturbed bile drainage, extrahepatic obstruction, and lymphoplasmacytic pancreatitis with ductular metaplasia. Prominent lymphoid follicles within biliary ducts and duodenum suggested chronic antigenic stimulation. Choledochal cysts can be associated with chronic neutrophilic cholangitis, extrahepatic obstruction, choledochitis, duodenal papillitis, and pancreatitis, and should be a differential for increased hepatic enzymes and hyperbilirubinemia in young cats.

Endoscopic ultrasound-guided hepaticogastrostomy vs. ERCP for preoperative biliary drainage in patients undergoing pancreatic resection

Objective Preoperative bile drainage in patients with obstructive jaundice due to pancreatic head malignancy is needed, if pancreatic head resection cannot be performed in a timely fashion. The safety and efficacy of ultrasound-guided hepaticogastrostomy (HGS) as an alternative to the established endoscopic retrograde cholangio-pancreatography (ERCP) with stent placement needs further investigation. Methods Clinicopathological data of patients who underwent partial or total pancreaticoduodenectomy between January 2017 and December 2019 in a major swiss hepatopancreatobiliary center were assessed. We compared the HGS with ERCP/stent regarding the kinetics of bilirubin decrease, the procedure-related morbidity, and the postoperative surgical outcomes. Results During the study period, 102 patients underwent pancreaticoduodenectomy or total pancreatectomy for pancreatic malignancy. Preoperative bile drainage was performed in 65 patients (20 HGS, 45 ERCP). HGS was associated with a faster (6 vs. 10 days, P = 0.042) and more effective (133 µmol/L vs. 101 µmol/L, P = 0.037) reduction of the serum bilirubin levels. HGS was safe and did not differ from ERCP with stent placement concerning post-interventional complications (P = 0.565), postoperative mortality (P = 0.996) and postoperative morbidity (P = 0.896), including infectious complications (wound infection, P = 0.662/ intra-abdominal abscess, P = 0.587), severe pancreatic fistula (P = 0.587), bile leak (P = 0.131), and postoperative hemorrhage (P = 0.886). Conclusion HGS performed in a specialized multidisciplinary hepatopancreatobiliary center is feasible and safe and may result in more accelerated and effective bile drainage compared to the established ERCP. In patients with obstructive jaundice related to pancreatic malignancy unable to undergo adequate bile drainage by ERCP, HGS may be an effective alternative method enabling surgery in a timely manner.

Don’t Forget about the Sump! An Uncommon Complication Many Years after a Choledochoduodenostomy

Bilioenteric anastomoses were common interventions before the rise of minimal invasion procedures, specifically, before endoscopic retrograde cholangiopancreatography. During a choledochoduodenostomy (CDS) the distal part of the common bile duct is excluded from the bile drainage and behaves as a “sump,” a poorly drained part that works as a reservoir which is responsible of the development of complications of the bilio-pancreatic tract. The consequent sump syndrome is a rare medical complication that presents a diversity of symptoms, for which there is no well-defined diagnostic algorithm. We present the case of a 72-year-old male patient with multiple comorbidities. He presented to the ER because of recurrent episodes of cholangitis; after having obtained the patient’s medical records, lab and image studies, the latter showed pneumobilia. After considering all the results plus the pneumobilia we suspect the presence of this uncommon complication of CDS. The patient was subjected to an unsuccessful endoscopic treatment followed by surgery, after which he showed signs of improvement and adequate evolution till hospital discharge.

Medium-term outcomes after laparoscopic revision of laparoscopic Kasai portoenterostomy in patients with biliary atresia

Objective: To determine whether revision laparoscopic Kasai portoenterostomy (RLKPE) is a viable treatment option for patients with biliary atresia (BA) who underwent initially successful laparoscopic Kasai portoenterostomy (ILKPE).Methods: The medical records of 312 patients with nonsyndromic BA who underwent ILKPE between May 2009 and May 2017 were retrospectively reviewed. The patients were divided into three groups according to their outcomes after ILKPE: group A: 25 patients who underwent RLKPE; group B: 203 patients who underwent ILKPE and required no further surgical intervention; and group C: 84 patients with failed ILKPE who either died or required liver transplantation for survival. The 3-year and 5-year survival with native liver (SNL) rates were compared between groups A and B C. Among the 25 patients in group A, the perioperative data of RLKPE were compared with those of ILKPE.Results: Of the 312 patients who underwent ILKPE, 228 reached the normal bilirubin concentration range within 6 months postoperatively. Among them, 25 patients with a sudden cessation of bile flow underwent RLKPE. Adequate biliary drainage evidenced by normalized conjugated bilirubin levels was achieved in 80% of the patients who underwent RLKPE. The perioperative variables, including operative time, blood loss, rate of conversion to open surgery and complications of RLKPE, were not significantly different between RLKPE and ILKPE. The 3-year and 5-year SNL rates in patients after RLKPE were 64.0% and 52.0%, respectively, which were not significantly different from the corresponding 86.2% and 73.9% in patients after unrevised ILKPE (P>0.05).Conclusion: Our data demonstrated that RPLKE can be a viable and effective treatment opinion in patients who experience sudden cessation of bile drainage after ILKPE. RPLKE can delay the need for liver transplantation, yielding encouraging medium-term patient outcomes.

Generation of functional liver tissue by establishing hepatobiliary connections ex vivo

In the liver, the bile canaliculi of hepatocytes are connected to intrahepatic bile ducts lined with cholangiocytes, which remove cytotoxic bile from the liver tissue. We have developed a hepatobiliary organoid using mouse hepatocyte progenitors and cholangiocytes. Hepatocyte metabolites were secreted into the bile canaliculi, and then transported into the biliary structure. Hepatocytes in the organoid acquired and maintained metabolic functions including albumin secretion and cytochrome P450 activities, over the long term. In this study, we established functional liver tissue incorporating a bile drainage system ex vivo. This hepatobiliary organoid enabled us to reproduce the transport of hepatocyte metabolites in liver tissue, and to investigate the way in which the two types of epithelial cells establish functional connections.

Medium-term outcomes after laparoscopic revision of laparoscopic Kasai portoenterostomy in patients with biliary atresia

Objective To determine whether revision laparoscopic Kasai portoenterostomy (RLKPE) is a viable treatment option for patients with biliary atresia (BA) who underwent initially successful laparoscopic Kasai portoenterostomy (ILKPE). Methods The medical records of 312 patients with nonsyndromic BA who underwent ILKPE between May 2009 and May 2017 were retrospectively reviewed. The patients were divided into three groups according to their outcomes after ILKPE: group A: 25 patients who underwent RLKPE; group B: 203 patients who underwent ILKPE and required no further surgical intervention; and group C: 84 patients with failed ILKPE who either died or required liver transplantation for survival. The 3-year and 5-year survival with native liver (SNL) rates were compared between groups A and B and between groups A and C. Among the 25 patients in group A, the perioperative data of RLKPE were compared with those of ILKPE. Results Of the 312 patients who underwent ILKPE, 228 reached the normal bilirubin concentration range within 6 months postoperatively. Among them, 25 patients with a sudden cessation of bile flow underwent RLKPE. Adequate biliary drainage evidenced by normalized conjugated bilirubin levels was achieved in 80% of the patients who underwent RLKPE. The perioperative variables, including operative time, blood loss, rate of conversion to open surgery and complications of RLKPE, were not significantly different between RLKPE and ILKPE. The 3-year and 5-year SNL rates in patients after RLKPE were 64.0% and 52.0%, respectively, which were not significantly different from the corresponding 86.2% and 73.9% in patients after unrevised ILKPE (P > 0.05) but were significantly better than the corresponding values of group C (P < 0.01). Conclusion Our data demonstrated that with appropriate patient selection, RPLKE can be a viable and effective treatment opinion in patients who experience sudden cessation of bile drainage after ILKPE. RPLKE can delay the need for liver transplantation, yielding encouraging medium-term patient outcomes.