Real-time segmentation of biliary structure in pure laparoscopic donor hepatectomy.

Pure laparoscopic donor hepatectomy (PLDH) has become a standard practice for living donor liver transplantation in expert centers. Accurate understanding of biliary structures is crucial during PLDH to minimize the risk of complications. This study aims to develop a deep learning-based segmentation model for real-time identification of biliary structures, assisting surgeons in determining the optimal transection site during PLDH. A single-institution retrospective feasibility analysis was conducted on 30 intraoperative videos of PLDH. All videos were selected for their use of the indocyanine green near-infrared fluorescence technique to identify biliary structure. From the analysis, 10 representative frames were extracted from each video specifically during the bile duct division phase, resulting in 300 frames. These frames underwent pixel-wise annotation to identify biliary structures and the transection site. A segmentation task was then performed using a DeepLabV3+ algorithm, equipped with a ResNet50 encoder, focusing on the bile duct (BD) and anterior wall (AW) for transection. The model's performance was evaluated using the dice similarity coefficient (DSC). The model predicted biliary structures with a mean DSC of 0.728 ± 0.01 for BD and 0.429 ± 0.06 for AW. Inference was performed at a speed of 15.3 frames per second, demonstrating the feasibility of real-time recognition of anatomical structures during surgery. The deep learning-based semantic segmentation model exhibited promising performance in identifying biliary structures during PLDH. Future studies should focus on validating the clinical utility and generalizability of the model and comparing its efficacy with current gold standard practices to better evaluate its potential clinical applications.

Altered biliary microbial and metabolic profile reveals the crosstalk between NAFLD and cholelithiasis.

BACKGROUND: The relationship between non-alcoholic fatty liver disease (NAFLD) and cholelithiasis is intricate, with alterations in the microenvironment potentially mediating this interplay. Thus, this study aimed to explore the biliary microbiota and metabolites of patients with cholelithiasis and detect changes induced by comorbid NAFLD. METHODS: In this study, 16S rRNA gene sequencing and metabolome analysis were performed on biliary samples collected from 35 subjects. Then, patients were stratified into two groups: the comorbidity group (n = 18), consisting of cholelithiasis patients with NAFLD, and the non-comorbidity group (n = 17), comprising cholelithiasis patients without NAFLD. RESULTS: Comorbid NAFLD did not significantly increase α-diversity but affected ß-diversity. A statistically significant difference was observed in the abundance of biliary metabolites between the two groups. Specifically, differences in the abundance of 4 phyla, 19 genera, and 28 metabolites were significant between the two groups. Correlation analysis demonstrated positive associations among 12α-hydroxylated bile acid levels, Pyramidobacter and Fusobacterium abundance, AST levels, and the fibrosis-4 index (p < 0.05, r > 0.3), all of which were increased in patients with cholelithiasis and comorbid NAFLD. CONCLUSIONS: The relationship between cholelithiasis and NAFLD influences the biliary microbial and metabolic profile, creating a detrimental microenvironment that promotes the disease progression.

Management of iatrogenic perforations during endoscopic interventions in the hepato-pancreatico-biliary tract.

Endoscopic retrograde cholangiopancreaticography (ERCP) and endoscopic ultrasound (EUS) guided interventions are among the most challenging procedures performed by interventional endoscopists and are associated with a significant risk of complications. Early recognition and classification of perforations allows immediate therapy which improves clinical outcomes. In this article we review the different aspects of iatrogenic perforations associated with pancreatico-biliary interventions, elucidating risk factors, diagnostic challenges and the latest therapeutic interventions.

Human Hepatobiliary Organoids: Recent Advances in Drug Toxicity Verification and Drug Screening.

Many drug and therapeutic modalities have emerged over the past few years. However, successful commercialization is dependent on their safety and efficacy evaluations. Several preclinical models are available for drug-screening and safety evaluations, including cellular- and molecular-level models, tissue and organoid models, and animal models. Organoids are three-dimensional cell cultures derived from primary tissues or stem cells that are structurally and functionally similar to the original organs and can self-renew, and they are used to establish various disease models. Human hepatobiliary organoids have been used to study the pathogenesis of diseases, such as hepatitis, liver fibrosis, hepatocellular carcinoma, primary sclerosing cholangitis and biliary tract cancer, as they retain the physiological and histological characteristics of the liver and bile ducts. Here, we review recent research progress in validating drug toxicity, drug screening and personalized therapy for hepatobiliary-related diseases using human hepatobiliary organoid models, discuss the challenges encountered in current research and evaluate the possible solutions.

Epidemiology of biliary tract-associated bloodstream infections and adequacy of empiric therapy: an Australian population-based study.

PURPOSE: Although the biliary tract is a common source of invasive infections, the epidemiology of cholangitis- and cholecystitis-associated bloodstream infection (BSI) is not well defined. The objective of this study was to determine the incidence, clinical determinants, microbiology of biliary tract-associated BSI, and predicted adequacy of common empiric therapy regimens. METHODS: All biliary tract-associated BSI in Queensland during 2000-2019 were identified using state-wide data sources. Predicted adequacy of empiric antimicrobial therapy was determined according to microbiological susceptibility data. RESULTS: There were 3,698 episodes of biliary tract-associated BSI occurred in 3,433 patients of which 2,147 (58.1%) episodes were due to cholangitis and 1,551 (41.9%) cholecystitis, for age- and sex-standardized incidence rates of 2.7, and 2.0 per 100,000 population, respectively. An increasing incidence of biliary tract-associated BSI was observed over the study that was attributable to an increase in cholangitis cases. There was a significant increased risk for biliary tract-associated BSI observed with advancing age and male sex. Patients with cholangitis were older, more likely to have healthcare associated infection, and have more comorbidities most notably liver disease and malignancies as compared to patients with cholecystitis. The distribution of infecting pathogens was significantly different with polymicrobial aetiologies more commonly observed with cholangitis (18.4% vs. 10.5%; p < 0.001). The combination of ampicillin/gentamicin/metronidazole was predicted to have the overall highest adequacy (96.1%), whereas amoxicillin/clavulanate had the lowest (77.0%). Amoxicillin/clavulanate (75.2% vs. 79.4%, p:0.03) and ceftriaxone/metronidazole (83.4% vs. 89.6%; p < 0.001) showed significantly inferior predicted adequacy for cholangitis as compared to cholecystitis. CONCLUSIONS: Bloodstream infections related to cholecystitis and cholangitis exhibit different epidemiology, microbiology, and requirements for empiric therapy.

Imaging of Biliary Tree Abnormalities.

Pathologic conditions of the biliary system, although common, can be difficult to diagnose clinically. Challenges in biliary imaging include anatomic variants and the dynamic nature of the biliary tract, which can change with age and intervention, blurring the boundaries of normal and abnormal. Choledochal cysts can have numerous appearances and are important to diagnose given the risk of cholangiocarcinoma potentially requiring surgical resection. Choledocholithiasis, the most common cause of biliary dilatation, can be difficult to detect at US and CT, with MRI having the highest sensitivity. However, knowledge of the imaging pitfalls of MRI and MR cholangiopancreatography is crucial to avoid misinterpretation. Newer concepts in biliary tract malignancy include intraductal papillary biliary neoplasms that may develop into cholangiocarcinoma. New paradigms in the classification of cholangiocarcinoma correspond to the wide range of imaging appearances of the disease and have implications for prognosis. Accurately staging cholangiocarcinoma is imperative, given expanding curative options including transplant and more aggressive surgical options. Infections of the biliary tree include acute cholangitis or recurrent pyogenic cholangitis, characterized by obstruction, strictures, and central biliary dilatation. Inflammatory conditions include primary sclerosing cholangitis, which features strictures and fibrosis but can be difficult to differentiate from secondary causes of sclerosing cholangitis, including more recently described entities such as immunoglobulin G4-related sclerosing cholangitis and COVID-19 secondary sclerosing cholangitis. The authors describe a wide variety of benign and malignant biliary tract abnormalities, highlight differentiating features of the cholangitides, provide an approach to interpretation based on the pattern of imaging findings, and discuss pearls and pitfalls of imaging to facilitate accurate diagnosis. ©RSNA, 2024 Supplemental material is available for this article.

Booster administration of Tc-99m PMT for delayed static imaging in patients with biliary atresia.

OBJECTIVE: Tc-99m N-pyridoxyl-5-methyl-tryptophan (PMT) hepatobiliary scintigraphy has high diagnostic performance for biliary atresia. Our hospital implements standard Tc-99m PMT administration followed by a 6 h static imaging review; booster doses are given in cases requiring 24 h delayed scans. This study aimed to evaluate the diagnostic performance of this method. METHODS: A total of 37 pediatric patients who underwent Tc-99m PMT biliary scintigraphy were classified into the surgically-diagnosed biliary atresia or non-biliary atresia groups. The absence of tracer accumulation in the small bowel was considered a hepatobiliary scintigraphic diagnosis of biliary atresia. The Clopper-Pearson method was used to calculate the 95% confidence intervals (CIs) for determining the diagnostic accuracy, negative predictive value, positive predictive value, sensitivity, and specificity of Tc-99m PMT biliary scintigraphy. RESULTS: Among the 37 patients, 12 were classified into the diagnosis of biliary atresia group. Regarding biliary scintigraphy findings, 16 of 37 patients demonstrated tracer accumulation in the small bowel within 6 h of testing. These cases were diagnosed as non-biliary atresia, requiring no further testing or booster administration. In contrast, 21 patients underwent delayed testing requiring booster administration, which revealed 13 without tracer excretion and 11 who were diagnosed with biliary atresia. Among the eight patients with tracer accumulation, only one was diagnosed with biliary atresia. Furthermore, two cases without tracer excretion and seven cases with tracer excretion were clinically diagnosed as non-biliary atresia. The diagnostic performance of our examination was as follows: a diagnostic accuracy of 91.9% (34/37; 95% CIs 78.0-98.3%), sensitivity of 91.6% (11/12; 95% CIs 61.5-99.8%), specificity of 92.0% (23/25; 95% CIs 74.0-99.0%), a positive predictive value of 84.6% (11/13; 95% CIs 54.6-98.0%), and a negative predictive value of 95.8% (23/24; 95% CIs 78.9-99.9%). CONCLUSIONS: Our protocol for Tc-99m PMT biliary scintigraphy using tracer booster administration demonstrated reliable diagnostic performance for biliary atresia. Notably, 43% of cases did not require booster administration, indicating that lesser radiation exposure may still yield comparable diagnostic accuracy.

Determining the patency of biliary tracts in dogs with gallbladder mucocele using near-infrared cholangiography with indocyanine green.

Cholecystectomy is indicated for gallbladder mucoceles (GBM). Evaluating the patency of the biliary duct and precise biliary tree visualization is crucial for reducing the risk of compromised bile flow after surgery. Therefore, intraoperative cholangiography (IOC) is recommended during cholecystectomy to prevent biliary tract injury. Although indocyanine green (ICG) cholangiography has been extensively reported in human medicine, only one study has been conducted in veterinary medicine. Therefore, this study aimed to demonstrate the use of ICG for IOC to identify fluorescent biliary tract images and determine the patency of the common bile duct during cholecystectomy in dogs. This study comprised 27 dogs, consisting of 17 with gallbladder mucoceles (GBM) and 10 controls, specifically including dogs that had undergone elective cholecystectomy for GBM. ICG injection (0.25 mg/kg) was administered intravenously at least 45 minutes before surgery. During the operation, fluorescent images from cholangiography were displayed on the monitor and obtained in black-and-white mode for the comparison of fluorescence intensity (FI). The FI values of the gallbladders (GBs) and common bile duct (CBD) were measured using FI analyzing software (MGViewer V1.1.1, MetapleBio Inc.). The results demonstrated successful CBD patency identification in all cases. Mobile GBM showed partial gallbladder visibility, whereas immobile GBM showed limited visibility. Additionally, insights into the adequate visualization of the remaining extrahepatic biliary tree anatomy were provided, extending beyond the assessment of CBD patency and gallbladder intensity. Our study demonstrates the potential of fluorescent IOC using intravenous injection of ICG for assessing the patency of the cystic duct and common bile duct during cholecystectomy in patients with GBM, eliminating the need for surgical catheterization and flushing of the biliary ducts. Further research is warranted to investigate and validate the broader applicability of ICG cholangiography in veterinary medicine.

Forward genetics combined with unsupervised classifications identified zebrafish mutants affecting biliary system formation.

Impaired formation of the biliary network can lead to congenital cholestatic liver diseases; however, the genes responsible for proper biliary system formation and maintenance have not been fully identified. Combining computational network structure analysis algorithms with a zebrafish forward genetic screen, we identified 24 new zebrafish mutants that display impaired intrahepatic biliary network formation. Complementation tests suggested these 24 mutations affect 24 different genes. We applied unsupervised clustering algorithms to unbiasedly classify the recovered mutants into three classes. Further computational analysis revealed that each of the recovered mutations in these three classes has a unique phenotype on node-subtype composition and distribution within the intrahepatic biliary network. In addition, we found most of the recovered mutations are viable. In those mutant fish, which are already good animal models to study chronic cholestatic liver diseases, the biliary network phenotypes persist into adulthood. Altogether, this study provides unique genetic and computational toolsets that advance our understanding of the molecular pathways leading to biliary system malformation and cholestatic liver diseases.

Acquisition of epithelial plasticity in human chronic liver disease.

For many adult human organs, tissue regeneration during chronic disease remains a controversial subject. Regenerative processes are easily observed in animal models, and their underlying mechanisms are becoming well characterized1-4, but technical challenges and ethical aspects are limiting the validation of these results in humans. We decided to address this difficulty with respect to the liver. This organ displays the remarkable ability to regenerate after acute injury, although liver regeneration in the context of recurring injury remains to be fully demonstrated. Here we performed single-nucleus RNA sequencing (snRNA-seq) on 47 liver biopsies from patients with different stages of metabolic dysfunction-associated steatotic liver disease to establish a cellular map of the liver during disease progression. We then combined these single-cell-level data with advanced 3D imaging to reveal profound changes in the liver architecture. Hepatocytes lose their zonation and considerable reorganization of the biliary tree takes place. More importantly, our study uncovers transdifferentiation events that occur between hepatocytes and cholangiocytes without the presence of adult stem cells or developmental progenitor activation. Detailed analyses and functional validations using cholangiocyte organoids confirm the importance of the PI3K-AKT-mTOR pathway in this process, thereby connecting this acquisition of plasticity to insulin signalling. Together, our data indicate that chronic injury creates an environment that induces cellular plasticity in human organs, and understanding the underlying mechanisms of this process could open new therapeutic avenues in the management of chronic diseases.

Normal morphometry of the biliary tree in pediatric and adult populations: A systematic review and meta-analysis.

PURPOSE: This study aimed to characterise the normal morphometry of the biliary tree in pediatric and adult populations, through a systematic review and meta-analysis. METHODS: This study, conducted using the PRISMA guidelines and registered with PROSPERO, searched MEDLINE, EMBASE, SCOPUS and Web of Science databases up to October 2022, and updated to August 2023. Studies that reported extractable data on diameter and length of the right, left and common hepatic ducts (LHD, RHD and CHD), and common bile duct (CBD) were included. Quality of the included studies were assessed using the Anatomical Quality Assessment (AQUA) tool. Statistical analysis included subgroup analyses according to sex, age, geographical location, and imaging modality. RESULTS: In total, 60 studies were included, of which 44 studies reported adequate data for meta-analysis on 23,796 subjects. Overall, the pooled mean diameter of the CBD was 4.69 mm (95 % CI: 4.28-5.11). Significant differences were found between pediatric (1.32 mm, 95 % CI: 1.03-1.61) and adult (4.97 mm, 95 % CI: 4.67-5.27) subjects, as well as US (3.82 mm, 95 % CI: 3.15-4.49) and other imaging modalities, including MRI (6.21 mm, 95 % CI: 4.85-7.57) and ERCP (7.24 mm, 95 % CI: 6.08-8.40). The CBD diameter measured significantly larger distally (5.20 mm, 95 % CI: 4.60-5.80) than proximally (4.01 mm, 95 % CI: 3.51-4.51). CONCLUSIONS: The results obtained from this evidence-based study may guide the establishment of standardised reference values and ranges of the normal biliary tree in pediatric and adult populations and aid clinical understanding.

BiliQML: a supervised machine-learning model to quantify biliary forms from digitized whole slide liver histopathological images.

The progress of research focused on cholangiocytes and the biliary tree during development and following injury is hindered by limited available quantitative methodologies. Current techniques include two-dimensional standard histological cell-counting approaches, which are rapidly performed, error prone, and lack architectural context or three-dimensional analysis of the biliary tree in opacified livers, which introduce technical issues along with minimal quantitation. The present study aims to fill these quantitative gaps with a supervised machine-learning model (BiliQML) able to quantify biliary forms in the liver of anti-keratin 19 antibody-stained whole slide images. Training utilized 5,019 researcher-labeled biliary forms, which following feature selection, and algorithm optimization, generated an F score of 0.87. Application of BiliQML on seven separate cholangiopathy models [genetic (Afp-CRE;Pkd1l1null/Fl, Alb-CRE;Rbp-jkfl/fl, and Albumin-CRE;ROSANICD), surgical (bile duct ligation), toxicological (3,5-diethoxycarbonyl-1,4-dihydrocollidine), and therapeutic (Cyp2c70-/- with ileal bile acid transporter inhibition)] allowed for a means to validate the capabilities and utility of this platform. The results from BiliQML quantification revealed biological and pathological differences across these seven diverse models, indicating a highly sensitive, robust, and scalable methodology for the quantification of distinct biliary forms. BiliQML is the first comprehensive machine-learning platform for biliary form analysis, adding much-needed morphologic context to standard immunofluorescence-based histology, and provides clinical and basic science researchers with a novel tool for the characterization of cholangiopathies.NEW & NOTEWORTHY BiliQML is the first comprehensive machine-learning platform for biliary form analysis in whole slide histopathological images. This platform provides clinical and basic science researchers with a novel tool for the improved quantification and characterization of biliary tract disorders.

Three-dimensional magnetic resonance cholangiography is superior to two-dimensional single-shot magnetic resonance cholangiography for visualization and image quality of the feline and canine biliary tract: A postmortem study.

Magnetic resonance cholangiography (MRC) is an established diagnostic tool for noninvasive assessment of the biliary tract in humans. It has also been found to be feasible in companion animals, but no published studies have compared MRC sequences in veterinary medicine. The present study is part of a prospective, observational, analytical investigation on MR cholangiopancreatography performed on the donated bodies of 12 cats and eight dogs. The main aim of this study was to compare the images of 2D-SSh-TSE-MRC and 3D-TSE-MRC sequences for visualization and image quality of the feline and canine biliary tract. Both sequences are T2-weighted and noncontrast. Three independent readers scored the visibility of four segments of the biliary tract, namely the gallbladder (GB), cystic duct, common bile duct (CBD), and extrahepatic ducts, and the image quality of the two MRC sequences using five-point Likert scales. Wilcoxon signed-rank test was used to compare the scores between the MRC sequences separately for cats and dogs. Inter- and intraobserver agreements were measured using Gwet's AC2 with linear weighting. The 3D-TSE-MRC images were scored significantly higher than the 2D-SSh-TSE-MRC for both visibility and image quality (P < .001-.016 for cats, P = .008-.031 for dogs); the only exception was GB in dogs. In both cats and dogs, interobserver agreement for segment visibility and image quality ranged from slight to substantial in 2D-SSh-TSE-MRC and from poor to almost perfect in 3D-TSE-MRC. Most of the assessments (73% for segment visibility and 66% for image quality) had substantial to almost perfect intraobserver agreement. Findings from the current study support the use of 3D-TSE-MRC over 2D-SSh-TSE-MRC for evaluation of the feline and canine biliary tract, but further studies on live animals are warranted.

Intestinal microbiota and biliary system diseases.

Introduction: The incidence of biliary system diseases has been continuously increasing in the past decade. Biliary system diseases bring a heavy burden to humanity and society. However, the specific etiology and pathogenesis are still unknown. The biliary system, as a bridge between the liver and intestine, plays an indispensable role in maintaining the physiological metabolism of the body. Therefore, prevention and treatment of biliary diseases are crucial. It is worth noting that the microorganisms participate in the lipid metabolism of the bile duct, especially the largest proportion of intestinal bacteria. Methods: We systematically reviewed the intestinal microbiota in patients with gallstones (GS), non-calculous biliary inflammatory, and biliary tract cancer (BTC). And searched Pubmed, Embase and Web of science for research studies published up to November 2023. Results: We found that the abundance of Faecalibacterium genus is decreased in GS, primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and BTC. Veillonella, Lactobacillus, Streptococcus and Enterococcus genus were significantly increased in PSC, PBC and BTC. Interestingly, we found that the relative abundance of Clostridium was generally reduced in GS, PBC and BTC. However, Clostridium was generally increased in PSC. Discussion: The existing research mostly focuses on exploring the mechanisms of bacteria targeting a single disease. Lacking comparison of multiple diseases and changes in bacteria during the disease process. We hope to provide biomarkers forearly diagnosis of biliary system diseases and provide new directions for the mechanism of intestinal microbiota in biliary diseases.

The dysregulation of biliary tract microflora is closely related to primary choledocholithiasis: a multicenter study.

Bile microecology changes play an important role in the occurrence and development of choledocholithiasis. At present, there is no clear report on the difference of bile microecology between asymptomatic patients with gallbladder polyps and choledocholithiasis. This study compared bile microecology between gallbladder polyp patients and patients with choledocholithiasis to identify risk factors for primary choledocholithiasis. This study was conducted in 3 hospitals in different regions of China. Bile samples from 26 patients with gallbladder polyps and 31 patients with choledocholithiasis were collected by laparoscopic cholecystectomy and endoscopic retrograde choledocholithiasis cholangiography (ERCP), respectively. The collected samples were used for 16S ribosomal RNA sequencing and liquid chromatography mass spectrometry analysis. The α-diversity of bile microecological colonies was similar between gallbladder polyp and choledocholithiasis, but the ß-diversity was different. Firmicutes, Proteobacteri, Bacteroidota and Actinobacteriota are the most common phyla in the gallbladder polyp group and choledocholithiasis group. However, compared with the gallbladder polyp patients, the abundance of Actinobacteriota has significantly lower in the choledocholithiasis group. At the genera level, the abundance of a variety of bacteria varies between the two groups, and Enterococcus was significantly elevated in choledocholithiasis group. In addition, bile biofilm formation-Pseudomonas aeruginosa was more metabolically active in the choledocholithiasis group, which was closely related to stone formation. The analysis of metabolites showed that a variety of metabolites decreased in the choledocholithiasis group, and the concentration of beta-muricholic acid decreased most significantly. For the first time, our study compared the bile of gallbladder polyp patients with patients with choledocholithiasis, and suggested that the change in the abundance of Actinobacteriota and Enterococcus were closely related to choledocholithiasis. The role of Pseudomonas aeruginosa biofilm in the formation of choledocholithiasis was discovered for the first time, and some prevention schemes for choledocholithiasis were discussed, which has important biological and medical significance.

Van Gogh-like 2 is essential for the architectural patterning of the mammalian biliary tree.

BACKGROUND & AIMS: In the developing liver, bipotent epithelial progenitor cells undergo lineage segregation to form hepatocytes, which constitute the bulk of the liver parenchyma, and biliary epithelial cells (cholangiocytes), which comprise the bile duct (a complex tubular network that is critical for normal liver function). Notch and TGFß signalling promote the formation of a sheet of biliary epithelial cells, the ductal plate, that organises into discontinuous tubular structures. How these structures elongate and connect to form a continuous duct remains undefined. We aimed to define the mechanisms by which the ductal plate transitions from a simple sheet of epithelial cells into a complex and connected bile duct. METHODS: By combining single-cell RNA sequencing of embryonic mouse livers with genetic tools and organoid models we functionally dissected the role of planar cell polarity in duct patterning. RESULTS: We show that the planar cell polarity protein VANGL2 is expressed late in intrahepatic bile duct development and patterns the formation of cell-cell contacts between biliary cells. The patterning of these cell contacts regulates the normal polarisation of the actin cytoskeleton within biliary cells and loss of Vangl2 function results in the abnormal distribution of cortical actin remodelling, leading to the failure of bile duct formation. CONCLUSIONS: Planar cell polarity is a critical step in the post-specification sculpture of the bile duct and is essential for establishing normal tissue architecture. IMPACT AND IMPLICATIONS: Like other branched tissues, such as the lung and kidney, the bile ducts use planar cell polarity signalling to coordinate cell movements; however, how these biochemical signals are linked to ductular patterning remains unclear. Here we show that the core planar cell polarity protein VANGL2 patterns how cell-cell contacts form in the mammalian bile duct and how ductular cells transmit confluent mechanical changes along the length of a duct. This work sheds light on how biological tubes are patterned across mammalian tissues (including within the liver) and will be important in how we promote ductular growth in patients where the duct is mis-patterned or poorly formed.