Restoration Of Bile Flow Research Articles

Portal vein hypoplasia is present in patients with biliary atresia at the time of diagnosis.

In patients with biliary atresia (BA), severe portal hypertension (HTN) develops even with successful bile flow restoration, suggesting an intrinsic factor driving portal HTN independent from bile obstruction. We hypothesize that patients with BA have abnormal portal vein (PV) development, leading to PV hypoplasia. In this observational cohort study, we enrolled patients who were referred to a tertiary center from 2017 to 2021 to rule out BA. Newborns who underwent computed tomography angiogram as a clinical routine before intraoperative cholangiogram, and laparoscopic Kasai hepatoportoenterostomy. The diameter of the PV and hepatic artery (HA) were compared to the degree of liver fibrosis in the wedge biopsies. The jaundice clearance, native liver survival, and clinical portal hypertensive events, including ascites development and intestinal bleeding, were assessed. 47 newborns with cholestasis were included in the cohort; 35 were diagnosed with BA. The patients with BA had a smaller median PV diameter (4.3 vs. 5.1 mm; p < 0.001) and larger median HA diameter (1.4 vs. 1.2 mm; p < 0.05) compared to the patients with other forms of cholestasis. The median PV and HA diameter did not correlate with the degree of liver fibrosis. Among 35 patients with BA, 29 patients (82.9%) achieved jaundice clearance, and 23 patients (65.7%) were alive with their native liver at two years of age. Seven patients (20%) developed intestinal bleeding, and seven patients (20%) developed ascites, with one overlapping patient. PV hypoplasia is present in patients with BA independent of liver fibrosis at the time of diagnosis.

Management of biliar injuries during colecystectomies and remotecomplications after restoration of bile flow in a territorial emergency

Management of biliar injuries during colecystectomies and remotecomplications after restoration of bile flow in a territorial emergency

Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy.

X-linked myotubular myopathy (XLMTM) is a fatal congenital disorder caused by mutations in the MTM1 gene. Currently, there are no approved treatments, although AAV8-mediated gene transfer therapy has shown promise in animal models and preliminarily in patients. However, 4 patients with XLMTM treated with gene therapy have died from progressive liver failure, and hepatobiliary disease has now been recognized more broadly in association with XLMTM. In an attempt to understand whether loss of MTM1 itself is associated with liver pathology, we have characterized what we believe to be a novel liver phenotype in a zebrafish model of this disease. Specifically, we found that loss-of-function mutations in mtm1 led to severe liver abnormalities including impaired bile flux, structural abnormalities of the bile canaliculus, and improper endosome-mediated trafficking of canalicular transporters. Using a reporter-tagged Mtm1 zebrafish line, we established localization of Mtm1 in the liver in association with Rab11, a marker of recycling endosomes, and canalicular transport proteins and demonstrated that hepatocyte-specific reexpression of Mtm1 could rescue the cholestatic phenotype. Last, we completed a targeted chemical screen and found that Dynasore, a dynamin-2 inhibitor, was able to partially restore bile flow and transporter localization to the canalicular membrane. In summary, we demonstrate, for the first time to our knowledge, liver abnormalities that were directly caused by MTM1 mutation in a preclinical model, thus establishing the critical framework for better understanding and comprehensive treatment of the human disease.

Development of liver inflammatory injury in biliary atresia: from basic to clinical research.

Biliary atresia (BA) is a severe cholangiopathy in infants. It is characterized by inflammatory fibro-obliteration of the intra- and extrahepatic bile ducts. Although the restoration of bile flow can be successful after Kasai operation, the rapid progression of liver fibrosis can continue, leading to cirrhosis. It is believed that the progression of liver fibrosis in BA is exacerbated by complicated mechanisms other than the consequence of bile duct obstruction. The fibrogenic cascade in BA liver can be divided into three stages, including liver inflammatory injury, myofibroblast activation, and fibrous scar formation. Recent studies have revealed that the activation of an immune response following bile duct injury plays an important role in promoting the inflammatory process, the releasing of inflammatory cytokines, and the development of fibrogenesis in BA liver. In this article, we summarized the evidence regarding liver inflammatory injury and the possible mechanisms that explain the rapid progression of liver fibrosis in BA.

Odevixibat: an investigational inhibitor of the ileal bile acid transporter (IBAT) for the treatment of biliary atresia

ABSTRACT Introduction Biliary atresia (BA) is a rare, non-curable cholestasis-causing disease in infancy, due to progressive ascending bile duct sclerosis. Even after restoration of bile flow following Kasai portoenterostomy, about half of these children need a liver transplant by their 2nd birthday, due to progressive fibrosis. Toxicity of bile acids may play a central role in disease progression, but drug therapies are not yet available. With ileal bile acid transporter (IBAT) inhibitors, there is a potential novel drug option that inhibits the absorption of bile acids in the small intestine. As a result of reduced bile acid accumulation in the cholestatic liver, it may be possible to delay hepatic remodeling. Areas covered This review summarizes the dataset on bile acids and the potential effects of odevixibat, an IBAT inhibitor, in children with BA. Expert opinion Systemic reduction of bile acids with the aim of preventing inflammation, and thus liver remodeling, is a novel, promising, therapeutic concept. In principle, however, the time until diagnosis and surgical treatment of BA should still be kept as short as possible in order to minimize liver remodeling before medical intervention can be initiated. IBAT inhibitors may add to the medical options in limiting disease progression in BA.

Pneumoperitoneum: A rare life threatening complication post ERCP!

Respected Editor, Endoscopic Retrograde Cholangiopancreatography (ERCP) is an invasive medical procedure commonly used to identify and treat biliary system and pancreatic disorders. It is the combination of both endoscopic and radiologic imaging techniques that, although widely used, and usually a safe procedure, it can rarely lead to life threatening complications including but not limited to pancreatitis, cholangitis, hemorrhage and perforation leading to pneumoperitoneum. The occurrence of free air in the peritoneal cavity post-ERCP is a rare event (&lt; 1%), which is usually the result of duodenal or ductal perforation related to therapeutic ERCP with sphincterotomy.[1] Our discussion is based on the incidence of pneumoperitoneum occurring in patients post ERCP. According to a case report, a 29- year- old female was diagnosed with postpartum jaundice and biliary stones. Consequently, she was investigated using ERCP and treated with biliary stenting and bile flow restoration. Post ERCP, the patient developed severe epigastric pain radiating to the right shoulder and x-ray revealed air under the diaphragm, i.e. pneumoperitoneum.[2] In another report, a 72 year old woman who underwent ERCP to treat biliary stricture and provide stenting was found to have pneumobilia and pneumoperitoneum due to rupture of intrahepatic bile ducts during ERCP.[3] Another case has been reported with the same issue in which an 84 year old known case of pancreatic carcinoma with hepatic and lung metastasis underwent multiple ERCPs due to obstructive jaundice, performed an urgent CT scan, the very next day, which showed the presence of free air in the peritoneal cavity.[4] Therefore, in light of the cases mentioned above-, physicians should be mindful of this rare, life- threatening complication of ERCP and take great care and warn the patient before performing the procedure. A useful strategy to combat this complication, a nasogastric tube for bowel decompression immediately after ERCP can greatly reduce the chances of developing a pneumoperitoneum.

Pre-operative Non-Invasive Imaging for Neonatal Cholestasis in a Child with Extrahepatic Biliary Atresia

Hepatobiliary iminodiacetic acid (HIDA) scintigraphy is a non-invasive, functional imaging of the hepatobiliary system that serves as an adjunct imaging modality for neonatal cholestasis work-up. In view of the urgency to diagnose biliary atresia and restore bile flow through surgery, HIDA scintigraphy could help to distinguish between neonatal cholestasis due to biliary atresia and neonatal hepatitis of various causes. We describe a full-term male infant with jaundice beyond the physiological period in which HIDA scintigraphy showed absent tracer excretion from the biliary system into the intestines up to 5 hours on follow-up imaging. The intraoperative diagnosis confirmed the diagnosis of biliary atresia. The prognosis of the patient with biliary atresia depends on early surgical planning and intervention. Therefore, non-invasive diagnostic tools play an important role in the evaluation of a child with neonatal cholestasis.

Characteristics of Gut Microbiota in Children With Biliary Atresia After Liver Transplantation.

Background and AimsBiliary atresia (BA) is an idiopathic neonatal cholestasis and is the most common indication in pediatric liver transplantation (LT). Previous studies have suggested that the gut microbiota (GM) in BA is disordered. However, the effect of LT on gut dysbiosis in patients with BA has not yet been elucidated.MethodsPatients with BA (n = 16) and healthy controls (n = 10) were recruited. In the early life of children with BA, Kasai surgery is a typical procedure for restoring bile flow. According to whether BA patients had previously undergone Kasai surgery, we divided the post-LT patients into the with-Kasai group (n = 8) and non-Kasai group (n = 8). Fecal samples were collected in both the BA and the control group; among BA patients, samples were obtained again 6 months after LT. A total of 40 fecal samples were collected, of which 16 were pre-LT, 14 were post-LT (8 were with-Kasai, 6 were non-Kasai), and 10 were from the control group. Metagenomic sequencing was performed to evaluate the GM.ResultsThe Kruskal-Wallis test showed a statistically significant difference in the number of genes between the pre-LT and the control group, the pre-LT and the post-LT group (P < 0.05), but no statistical difference between the post-LT and the control group. Principal coordinate analysis also showed that the microbiome structure was similar between the post-LT and control group (P > 0.05). Analysis of the GM composition showed a significant decrease in Serratia, Enterobacter, Morganella, Skunalikevirus, and Phifllikevirus while short chain fatty acid (SCFA)-producing bacteria such as Roseburia, Blautia, Clostridium, Akkermansia, and Ruminococcus were increased after LT (linear discriminant analysis > 2, P < 0.05). However, they still did not reach the normal control level. Concerning functional profiles, lipopolysaccharide metabolism, multidrug resistance, polyamine biosynthesis, GABA biosynthesis, and EHEC/EPEC pathogenicity signature were more enriched in the post-LT group compared with the control group. Prior Kasai surgery had a specific influence on the postoperative GM.ConclusionLT partly improved the GM in patients with BA, which provided new insight into understanding the role of LT in BA.

Secretin Treatment Promotes Hepatic Progenitor Cell Activation, Ductal‐Canalicular Junction Formation and Amelioration of Liver Damage in a Model of Late‐Stage Primary Biliary Cholangitis

Introduction PBC is a cholestatic disease characterized by bile duct loss, ductular reaction and liver fibrosis. The canals of Hering (CoH) are the site of ductulo-canalicular junction (DCJ) that maintain proper bile drainage from the liver, and contain the hepatic progenitor cell (HPC) population. CoH loss is noted in PBC and correlates with scoring. Secretin binds to its receptor (SR, expressed by large cholangiocytes) to promote biliary proliferation during cholestasis; however, during large duct damage, small cholangiocytes acquire large cholangiocyte phenotypes including SR expression. Secretin/SR expression is downregulated in late-stage PBC; therefore, we aimed to understand the role of the secretin/SR axis during PBC. We hypothesized that secretin treatment restores DCJ through HPC activation and ameliorates liver phenotypes associated with late-stage PBC. Methods Female 34 wk old wild-type (WT) and dominant-negative transforming growth factor-β receptor II (dnTGFβRII, model of late-stage PBC) mice were treated with control or secretin (2.5 nmol/kg BW) for 8 wk by IP implanted minipumps. Cholangitis activity, hepatitis activity and bile duct loss were determined by the Nakanuma scoring system. Ductular reaction was measured by semi-quantitative CK-19 immunostaining. Liver fibrosis was evaluated by Sirius Red staining, collagen-1a immunostaining and qPCR for α-SMA. Hepatic stellate cell (HSC) presence was determined by desmin immunostaining. Cholestasis was indicated by hepatic total bile acid (TBA) levels using EIA. DCJ presence was evaluated by co-immunostaining for ABC transporter bile salt export pump (BSEP)/CK-19 and semi-quantification. HPC activation was assessed by Sox9 staining and semi-quantification. Results dnTGFβRII mice had an increase in cholangitis and hepatitis activity; however, 8 wks of secretin treatment significantly reduces cholangitis, but not hepatitis, activity. dnTGFβRII mice present with ductular reaction and significant bile duct loss, which was reversed with 8 wks secretin treatment. Hepatic TBA levels, liver fibrosis and HSC presence are increased in dnTGFβRII mice, but significantly reduced following 8 wks of secretin treatment. In line with human studies, dnTGFβRII mice have significant loss of DCJ and reduced HPC number; however, 8 wks of secretin treatment restores these parameters. Conclusion Long-term secretin treatment (i) reduces ductular reaction, (ii) reverses bile duct loss, (iii) decreases liver fibrosis, (iv) promotes HPC activity and (v) restores DCJ presence in a model of late-stage PBC. Secretin maintenance of the DCJ may be due to (i) the restoration of bile flow and release of toxic bile acids or (ii) secretin binding to SR acquired on small cholangiocytes/HPCs. Treatment with secretin may be a therapeutic option for late-stage PBC patients.

Unaltered Liver Regeneration in Post-Cholestatic Rats Treated with the FXR Agonist Obeticholic Acid.

In a previous study, obeticholic acid (OCA) increased liver growth before partial hepatectomy (PHx) in rats through the bile acid receptor farnesoid X-receptor (FXR). In that model, OCA was administered during obstructive cholestasis. However, patients normally undergo PHx several days after biliary drainage. The effects of OCA on liver regeneration were therefore studied in post-cholestatic Wistar rats. Rats underwent sham surgery or reversible bile duct ligation (rBDL), which was relieved after 7 days. PHx was performed one day after restoration of bile flow. Rats received 10 mg/kg OCA per day or were fed vehicle from restoration of bile flow until sacrifice 5 days after PHx. Liver regeneration was comparable between cholestatic and non-cholestatic livers in PHx-subjected rats, which paralleled liver regeneration a human validation cohort. OCA treatment induced ileal Fgf15 mRNA expression but did not enhance post-PHx hepatocyte proliferation through FXR/SHP signaling. OCA treatment neither increased mitosis rates nor recovery of liver weight after PHx but accelerated liver regrowth in rats that had not been subjected to rBDL. OCA did not increase biliary injury. Conclusively, OCA does not induce liver regeneration in post-cholestatic rats and does not exacerbate biliary damage that results from cholestasis. This study challenges the previously reported beneficial effects of OCA in liver regeneration in cholestatic rats.

Gut Microbiome: A Potential Modifiable Risk Factor in Biliary Atresia.

Biliary atresia (BA) is a fibro-obliterative condition of the biliary tree, presenting in infancy. The bilioenteric conduit formed at Kasai portoenterostomy (KPE), achieves restoration of bile flow in approximately 60% of infants. Even if the operation is successful, cirrhosis and its associated complications are, however, common. BA remains the leading cause for liver transplantation (LT) in children. Antibiotic, choleretic, and steroid therapy post-KPE have not convincingly reduced LT rates. Advances in molecular technology have enabled characterisation of the encoded genes of the gut microbiota (gut microbiome). The gut microbiome plays an important role in host metabolism, nutrition, and immune function, with alterations in its diversity and/or composition, known as dysbiosis, being described in disease states, including liver disease. Liver-gut microbiome exploration in adulthood largely focuses on nonalcoholic liver disease, cirrhosis (mainly alcohol- or viral-based aetiology) and cholestatic liver diseases (eg, primary sclerosing cholangitis), with microbial signatures correlating to disease severity. Investigation of the gut microbiota in BA had been limited to culture-based methodology, but molecular studies are emerging, and although in their infancy, highlight a potential pathogenic role for Enterobacteriaceae and Streptococcus, and a potential beneficial role for Bifidobacteria. Bacterial translocation, and the production of gut microbiome-derived metabolites, are key host-microbiome-mechanistic pathways in liver disease pathogenesis. Microbiome-targeted therapeutics for liver disease are in development, with faecal microbiota transplantation showing promise in cirrhosis. Could the gut microbiome be a novel modifiable risk factor in BA, reducing the need for LT?

Current Concepts of Biliary Atresia and Matrix Metalloproteinase-7: A Review of Literature.

Biliary atresia (BA) is a rare cholangiopathy of infancy in which the bile ducts obliterate, leading to profound cholestasis and liver fibrosis. BA is hypothesized to be caused by a viral insult that leads to over-activation of the immune system. Patients with BA are surgically treated with a Kasai portoenterostomy (KPE), which aims to restore bile flow from the liver to the intestines. After KPE, progressive liver fibrosis is often observed in BA patients, even despite surgical success and clearance of their jaundice. The innate immune response is involved during the initial damage to the cholangiocytes and further differentiation of the adaptive immune response into a T-helper 1 cell (Th1) response. Multiple studies have shown that there is continuing elevation of involved cytokines that can lead to the progressive liver fibrosis. However, the mechanism by which the progressive injury occurs is not fully elucidated. Recently, matrix metalloproteinase-7 (MMP-7) has been investigated to be used as a biomarker to diagnose BA. MMPs are involved in extracellular matrix (ECM) turnover, but also have non-ECM related functions. The role of MMP-7 and other MMPs in liver fibrosis is just starting to be elucidated. Multiple studies have shown that serum MMP-7 measurements are able to accurately diagnose BA in a cohort of cholestatic patients while hepatic MMP-7 expression correlated with BA-related liver fibrosis. While the mechanism by which MMP-7 can be involved in the pathophysiology of BA is unclear, MMP-7 has been investigated in other fibrotic pathologies such as renal and idiopathic pulmonary fibrosis. MMP-7 is involved in Wnt/β-catenin signaling, reducing cell-to-cell contact by shedding of E-cadherin, amplifying inflammation and fibrosis via osteopontin (OPN) and TNF-α while it also appears to play a role in induction of angiogenesis This review aims to describe the current understandings of the pathophysiology of BA. Subsequently, we describe how MMP-7 is involved in other pathologies, such as renal and pulmonary fibrosis. Then, we propose how MMP-7 can potentially be involved in BA. By doing this, we aim to describe the putative role of MMP-7 as a prognostic biomarker in BA and to provide possible new therapeutic and research targets that can be investigated in the future.

Percutaneous Transhepatic Intervention for Malignant Biliary Obstruction

Biliary obstruction is a serious clinical condition resulting from either benign or malignant etiologies. For malignant obstruction, curative resection is rarely performed due to disease progression, thus decompression drainage is the management of choice. Percutaneous transhepatic drainage and stenting are effective alternative treatments to surgical bypass and endoscopic biliary drainage when these two modalities are contraindicated. Percutaneous biliary intervention is safe and effective in both drainage and restoration of bile flow with high successful rate and acceptable risk of complication. Multidisciplinary approach, proper patient selection, careful image review and comprehensive knowledge of available techniques, success rates and complications are utmost importance for a successful procedure.

Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders.

Biliary atresia is a rare cholestatic liver disease that presents in infants and rapidly advances to death in the absence of intervention. As a result of blockage or destruction of the biliary tract, bile acids accumulate and drive inflammation, fibrosis, and disease progression. The standard of care, Kasai portoenterostomy (KPE), is typically performed shortly after diagnosis (currently at ~ 2months of age) and aims to restore bile flow and relieve cholestasis. Nevertheless, most patients continue to experience liver injury from accumulation of bile acids after KPE, since there are no known effective therapeutics that may enhance survival after KPE. Improving cholestasis via interruption of the enterohepatic circulation of bile acids may directly attenuate hepatic bile acid retention and reduce the risk of early organ failure. Directly addressing intrahepatic accretion of bile acids to avoid inherent bile acid toxicities provides an attractive and plausible therapeutic target for biliary atresia. This review explores the novel therapeutic concept of inhibiting the sole ileal bile acid transporter (IBAT), also known as ASBT (apical sodium-bile acid transporter, encoded by SLC10A2), as a means to reduce hepatic bile acid concentration after KPE. By reducing return of bile acids to the cholestatic liver, IBAT inhibitors may potentially lessen or delay liver damage associated with the hepatotoxicity and cholangiopathy of bile acid accumulation. The clinical programs of 2 IBAT inhibitors in development for the treatment of pediatric cholestatic liver diseases, maralixibat and odevixibat, are highlighted.

Anatomical and histological characteristics of the hepatobiliary system in adult Sox17 heterozygote mice.

Biliary atresia (BA) is a rare neonatal disease characterized by inflammation and obstruction of the extrahepatic bile ducts (EHBDs). The Sox17-haploinsufficient (Sox17+/- ) mouse is an animal model of BA that encompasses bile duct injury and subsequent BA-like inflammation by the neonatal stage. Most Sox17+/- neonates die soon after birth, but some Sox17+/- pups reach adulthood and have a normal life span, unlike human BA. However, the phenotype and BA-derived scars in the hepatobiliary organs of surviving Sox17+/- mice are unknown. Here, we examined the phenotypes of the hepatobiliary organs in post-weaning and young adult Sox17+/- mice. The results confirmed the significant reduction in liver weight, together with peripheral calcinosis and aberrant vasculature in the hepatic lobule, in surviving Sox17+/- mice as compared with their wild-type (WT) littermates. Such hepatic phenotypes may be sequelae of hepatobiliary damage at the fetal and neonatal stages, a notion supported by the slight, but significant, increases in the levels of serum markers of liver damage in adult Sox17+/- mice. The surviving Sox17+/- mice had a shorter gallbladder in which ectopic hepatic ducts were more frequent compared to WT mice. Also, the surviving Sox17+/- mice showed neither obstruction of the EHBDs nor atrophy or inflammation of hepatocytes or the intrahepatic ducts. These data suggest that some Sox17+/- pups with BA naturally escape lethality and recover from fetal hepatobiliary damages during the perinatal period, highlighting the usefulness of the in vivo model in understanding the hepatobiliary healing processes after surgical restoration of bile flow in human BA.

Hemobilia as a Complication of Transhepatic Percutaneous Biliary Drainage: a Rare Indication for Laparoscopic Common Bile Duct Exploration

BackgroundHemobilia is the presence of blood in the biliary tree and is a frequent complication after percutaneous transhepatic biliary drainage (PTBD).1 Most of these episodes are self-limited; nevertheless, in less than 5% of cases, hemobilia is clinically significant, requiring an intervention (hepatic artery embolization, stenting, or percutaneous thrombin injection).2,3 Adequate treatment requires control of hemorrhage and restoration of bile flow. Surgery is the last resort and is indicated when the other modalities fail. MethodsA 65-year-old man with multiple comorbidities was admitted with cholangitis. The patient underwent PTBD (Figure 1) but had persistent cholestasis. Thus, he underwent endoscopic cholangiopancreatography (ERCP), in which a plastic stent was misplaced within the common bile duct (CBD) and could not be removed (Figure 2). Afterwards, as the patient had persistently high bilirubin levels and the previously placed stent was malpositioned, the decision was made to proceed with laparoscopic cholecystectomy and CBD exploration. ResultsThe operation was performed with choledocoscope guidance, and the CBD was closed over a T-tube. The operative time was 280 min. Postoperative course was uneventful; the T-tube was clamped 1 week after discharge. Four weeks postoperatively, the T-tube cholangiogram showed a patent extrahepatic biliary tree with no filling defects (Figure 3). The T-tube was then removed. ConclusionsBiliary obstruction secondary to hemobilia is a rare occurrence after PTBD. Surgical CBD exploration is required when conservative management and endoscopic treatment fail and can be done successfully through a minimally invasive approach.

Adjuvant treatments for biliary atresia.

The treatment of biliary atresia (BA) is predominantly surgical with firstly an attempt at restoration of bile flow from the native liver by wide excision of the obstructed, obliterated extrahepatic biliary tree to the level of the porta hepatis and a portoenterostomy using a long Roux loop—Kasai portoenterostomy (KPE). Liver transplantation is reserved for those that fail this and for those where surgery is considered futile for reasons of age or stage of disease. As the aetiology of BA remains ill-defined, so adjuvant treatment has been largely based on pragmatism, trial and error. Systematic analysis of the few randomized placebo-controlled trial data and less well-controlled cohort studies have suggested benefit from post-operative high-dose steroids and ursodeoxycholic acid (UDCA) while the benefit of long-term prophylactic antibiotics, bile acid sequestrants (e.g., colestyramine) or probiotics remains unproven. Newer modalities such as antiviral therapy (AVT), immunoglobulin, FXR agonists (e.g., obeticholic acid), ileal bile acid transporter (IBAT) antagonists (e.g., maralixibat) remain unproven. This article reviews the current evidence for the efficacy of adjuvant medical therapy in BA.

Mo1994 ROLE OF ERCP IN THE DIAGNOSIS OF BILIARY ATRESIA: A RETROSPECTIVE SERIES FROM A LARGE HPB CENTRE

Cholestatic jaundice affects up to 1 in 2500 newborns. Possible causes include bacterial sepsis, galactosemia, tyrosinemia, panhypo-pituitarism, bile acid synthetic defects, obstructive gallstones and Biliary atresia (BA). BA is a destructive cholangiopathy of neonates, which can lead to portal hypertension and liver failure if not identified early and a Kasai hepatoportoenterostomy performed timely to restore bile flow. Diagnostic algorithms vary substantially between different centres, with some units advocating ERCP be performed in every case. We report outcomes from our large HPB centre where ERCP is performed on a selective basis for suspected biliary atresia. Patients were included in the study who were referred for ERCP with a conjugated hyperbilirubinamia and suspected biliary atresia between January 2008 and December 2018. Patient demographics, laboratory results, imaging, endoscopy and surgical findings were recorded in each case. Of the 374 children undergoing an ERCP during this period, 15% (56) had it performed for conjugated hyperbillirubinaemia with suspected BA. Median age at the time of ERCP was 2 months (0 – 9 months). 82% (46) patients were male. ERCP confirmed diagnosis of BA in 25% (14) cases of which 64% (9) were type 3 BA, 36% (5) type 2 BA and 0% type 1 BA. The majority of patients confirmed with BA were <3 months of age (86% (12)). No endoscopic or anaesthetic adverse events occurred. All patients with BA were surgically managed at a median time of 6 days (1 – 146 days) post ERCP. 93% (13) were managed with Kasai hepatoportoenterotomy, and 1 with orthotopic liver transplantation. ERCP had a diagnostic sensitivity for BA of 74%, with 5 (9%) patients being misdiagnosed with BA on initial assessment, later disproved on liver biopsy; and diagnostic specificity of 71%. Of the 42 (75%) who did not have BA, 36% (15) were diagnosed as conjugated hyperbillirubinaemia of infancy, 36% (35) had Alagille syndrome or alpha1 anti-trypsin, 12% (5) had either choledocholithiasis or biliary sludge, 7% (3) had choledochomalformations, 5% (2) were diagnosed with neonatal hepatitis and 5% (2) with neonatal sclerosing cholangitis. Selective use of ERCP is a sensitive method of diagnosing BA in infants, enabling timely surgery to improve biliary drainage. It is a clinically safe procedure with no endoscopic or anaesthetic adverse events.

A novel murine model of reversible bile duct obstruction demonstrates rapid improvement of cholestatic liver injury.

There are limited murine models of cholestatic liver diseases characterized by chronic biliary obstruction and resumption of bile flow. While murine bile duct ligation (BDL) is a well‐established model of obstructive cholestasis, current models of BDL reversal (BDLR) alter biliary anatomy. We aimed to develop a more physiologic model of BDLR to evaluate the time course and mechanism for resolution of hepatic injury after biliary obstruction. In the present study, we restored bile flow into the duodenum without disruption of the gall bladder after murine BDL using biocompatible PE‐50 tubing. After establishing the technique, overall survival for BDLR at 7 or 14 days after BDL was 88%. Sham laparotomy was performed in control mice. Laboratory data, liver histology, and hepatic gene expression were compared among BDL, BDLR, and controls. Laboratory evidence of cholestatic liver injury was observed at day 7 after BDL and rapid improvement occurred within 48 hr of BDLR. After BDLR there was also enhanced gene expression for the bile acid transporter Abcb11, however, bile duct proliferation persisted. Assessment of the immune response showed increased gene and protein expression for the general immune cell marker Cd45 in BDLR versus BDL mice suggesting a reparative immune response after BDLR. In summary, we have established a novel murine model of BDLR that allows for the investigation into bile acid and immune pathways responsible for hepatic repair following obstructive cholestasis. Future studies with our model may identify targets for new therapies to improve outcome in pediatric and adult cholestatic liver disease.

If It Looks Like a Duct and Acts Like a Duct: On the Role of Reprogrammed Hepatocytes in Cholangiopathies.

Cholangiopathies are chronic, progressive diseases of the biliary tree, and can be either acquired or genetic. The primary target is the cholangiocyte (CC), the cell type lining the bile duct that is responsible for bile modification and transport. Despite advances in our understanding and diagnosis of these diseases in recent years, there are no proven therapeutic treatments for the majority of the cholangiopathies, and liver transplantation is the only life-extending treatment option for patients with end-stage cholestatic liver disease. One potential therapeutic strategy is to facilitate endogenous repair of the biliary system, which may alleviate intrahepatic cholestasis caused by these diseases. During biliary injury, hepatocytes (HC) are known to alter their phenotype and acquire CC-like features, a process known as cellular reprogramming. This brief review discusses the potential ways in which reprogrammed HC may contribute to biliary repair, thereby restoring bile flow and reducing the severity of cholangiopathies. Some of these include modifying bile to reduce toxicity, serving as a source of de novo CC to repair the biliary epithelium, or creating new channels to facilitate bile flow.