Nasser‐Ghodsi, Navine

Cholangiocytes are specialized epithelial cells that line the intrahepatic and extrahepatic biliary tree and play a critical role in bile modification, liver homeostasis, and response to injury. Cholangiocytes exhibit notable heterogeneity and plasticity, and their dysfunction is central to a spectrum of diseases targeting the bile ducts, collectively called cholangiopathies. These disorders include genetic, infectious, immune-mediated, and malignant diseases, with primary sclerosing cholangitis (PSC) representing one of the most complex and enigmatic of these disorders. PSC is a progressive, fibro-inflammatory disease of the bile ducts that is closely linked to inflammatory bowel disease, carries a heightened risk of cancer, and lacks any approved therapies. This review explores the biology of cholangiocytes, including their development, functional plasticity, and roles in secretion, absorption, and cellular signaling. We provide a detailed examination of cholangiopathies, particularly PSC, a complex cholangiopathy characterized by a paradoxical state of cholangiocyte senescence and hyperproliferation. We describe how immune cell dysfunction, the gut microbiome, genetic predispositions, and environmental factors converge to mediate PSC pathogenesis. We revisit the foundational technologies that empowered early discoveries and shaped the field as we know it today. We also explore how newer techniques such as organoid cultures, single-cell transcriptomics, epigenomics, and spatialomics have transformed our modern understanding of biliary pathophysiology. Finally, we provide an overview of existing rodent models of cholangiopathies and discuss their relevance to human disease. PSC remains therapeutically unaddressed, and thus ongoing multidisciplinary efforts are essential to developing targeted interventions. This review serves as a comprehensive resource for researchers and clinicians navigating the rapidly evolving landscape of cholangiocyte-centered liver disease research.

ABSTRACT Background Sampling techniques have poor accuracy for classifying biliary strictures as benign or malignant. Previously, a cholangioscopy artificial intelligence (AI) outperfromed sampling techniques based solely on analysis of previously recorded cholangioscopy footage. The aim of this trial was to compare the performance of a real-time cholangioscopy AI to both sampling techniques and human observers for the task of biliary stricture classification. Methods A cholangioscopy AI computer connected directly to a cholangioscope console. The computer analyzed the cholangioscopy video stream during procedures for suspected biliary strictures. The primary outcome of the study was comparison of the performance of cholangioscopy AI to sampling techniques – brush cytology and transpapillary forceps biopsy – for biliary stricture classification. Secondary outcomes included comparison of the AI classification performance to that of human observers (separated into junior-level and experienced-level cohorts) who reviewed the cholangioscopy footage. Results A total of 41 patients were enrolled in the trial and had biliary strictures analyzed by cholangioscopy AI. For the classification of strictures, the AI had greater classification accuracy than standard sampling techniques (87.8% versus 67.4%; p = 0.043). Additionally, the cholangioscopy AI was significantly more accurate for biliary stricture classification than both junior-level (87.8% versus 61.5%; p = 0.001) and experienced endoscopists (87.8% versus 63.15%; p = 0.011). Conclusions This trial demonstrates that sampling techniques and human assessment of biliary strictures are flawed and there may be a benefit to the use of a cholangioscopy AI system to aid in biliary stricture classification.

Abstract Clinicians struggle to accurately classify biliary strictures as benign or malignant. Current endoscopic retrograde cholangiopancreatography (ERCP)-based sampling modalities including brush cytology and forceps biopsy have poor sensitivity for pathologic confirmation of malignancy. Cholangioscopy allows for direct visualization and sampling of biliary pathology; however, this technology is also associated with inaccurate classification of biliary disease. Previously, an artificial intelligence (AI) system that analyzes cholangioscopy footage was found to be more accurate in diagnosing biliary malignancy than ERCP sampling techniques. The aim of this study was to validate this AI system on a new series of examinations. Three academic centers collected all available unedited cholangioscopy recordings. The videos were processed by the cholangioscopy AI system. After analyzing videos, the AI system provided predictions as to whether malignancy was present. AI performance in classifying strictures was compared with the performance of brush cytology and forceps biopsy. 112 cholangioscopy examinations (containing 4 817 081 images) were generated from 99 patients. Of those examinations, 61 (54.5%) were for investigation of biliary strictures (31 [50.8%] benign, 30 [49.2%] malignant). For the correct classification of strictures, the AI system was 80.0% sensitive and 90.3% specific. It was also significantly more accurate for stricture classification (85.2%) than brush cytology (52.5%; P<0.001), forceps biopsy (68.2%; P=0.04), and the combination of brush cytology and forceps biopsy (66.7%; P=0.02). A previously developed cholangioscopy AI system was found to continually outperform standard ERCP sampling modalities for accurate identification of malignancy, without additional retraining, in a multicenter validation cohort.

Abstract Cholecystectomy (CCY) is the standard treatment for acute cholecystitis. For non-surgical patients, percutaneous cholecystostomy tube (PT-GBD) is recommended but is associated with high readmission rates and poor quality of life. Endoscopic gallbladder decompression techniques, including endoscopic transpapillary gallbladder drainage (ET-GBD) and endoscopic ultrasound-guided gallbladder drainage (EUS-GBD), are alternatives. Studies comparing ET-GBD and EUS-GBD have shown EUS-GBD to have superior outcomes. However, these studies assessed ET-GBD mostly via single transcystic stent placement (SSET-GBD). This study aimed to compare outcomes of dual transcystic stents (DSET-GBD) and EUS-GBD in non-surgical candidates with acute cholecystitis. A multicenter analysis was conducted on patients who underwent ET-GBD or EUS-GBD between January 2019 and January 2023. Data were extracted from electronic medical records and outcomes including technical success, success, adverse events (AEs), and recurrence rates of cholecystitis were measured. Of 129 procedures (56 EUS-GBD; 73 ET-GBD), technical success was achieved in 87.5% of EUS-GBD and 86.3% of ET-GBD attempts. Immediate clinical success was achieved in 98.1% for EUS-GBD and 100% for DSET-GBD. AE rates were similar between the groups. Recurrent cholecystitis rates were 5.3% for EUS-GBD and 8.2% for DSET-GBD (P = 0.692). This study demonstrates that DSET-GBD has similarly low rates of recurrent acute cholecystitis compared with EUS-GBD. DSET-GBD should be considered as an alternative management strategy for management of acute cholecystitis in patients who are unable to undergo CCY.

Objectives: Determine whether the timing of transplantation affects patient mortality. Background: Neoadjuvant therapy and liver transplantation have emerged as an excellent treatment option for select patients with perihilar cholangiocarcinoma (pCCA). However, the optimal timing of transplantation is not known. Methods: We reviewed all patients registered for a standardized pCCA protocol between 1996 and 2020 at our center. After adjusting for confounders, we examined the association of waiting time with patient mortality in an intention-to-treat cohort (n=392) and those who received a liver transplant (n=256). Results: The median (interquartile range) time from registration to transplant or dropout was 5.74 (3.25–7.06) months. Compared with a short wait time (0–3 mo), longer waiting times did not affect all-cause mortality: (3–6 mo) hazard ratio (HR) 0.98; 95% CI: 0.52–1.84; (6–9 mo) HR: 0.80; 95% CI: 0.39–1.65; (9–12 mo) HR: 0.56; 95% CI: 0.26–1.22. Subgroups with a shorter waiting time had similar survival to those with long waiting times: living donor available HR: 0.97; 95% CI: 0.67–1.42; AB or B blood group HR: 0.93; 95% CI: 0.62–1.39. Longer waiting times were associated with decreased all-cause mortality after transplantation (HR: 0.92; 95% CI: 0.87–0.97). This benefit began after a 6-month waiting time minimum (HR: 0.53; 95% CI: 0.26–1.10) and increased further after 9 months (HR: 0.43 95% CI: 0.20–0.93). Waiting time was not associated with residual adenocarcinoma in the explant (odds ratio 0.99; 95% CI: 0.98–1.00). Conclusions: A waiting time of at least 6 months will optimize results with transplantation without affecting overall (intention-to-treat) patient survival.

AbstractBackground and aimsNonalcoholic steatohepatitis (NASH) is associated with metabolic conditions that increase the risk of de novo malignancy following transplant. Patients often have more than one underlying liver disease, which could change the risk of de novo malignancy. This study assessed the incidence of NASH overlap and its effect on de novo malignancy in liver transplant recipients.MethodsData was analyzed from the United Network for Organ Sharing database for all liver transplant recipients from 1997 to 2017 for NASH alone or in combination with another liver disease.ResultsThere is an increasing prevalence of NASH overlap. Of the 98,679 patients included in the analysis, 1238 had a de novo malignancy identified (7.4% by 5 years post‐transplant). The cumulative incidence of de novo malignancy increases in primary sclerosing cholangitis (PSC)/NASH overlap after 5 years and was increased in alcohol‐related liver disease (ALD)/NASH through 10 years compared to ether disease alone. NASH overlaps with “other” diseases experience a cumulative incidence similar to NASH and not the “other” disease. An increased risk of de novo solid organ malignancy was associated with older age, male gender, previous malignancy, and multiorgan transplant.ConclusionThe prevalence of liver transplant recipients with NASH overlap is increasing. These patients may experience different long‐term outcomes than patients with either diagnosis alone. De novo malignancy risk can be influenced by multiple factors and metabolic comorbidities. Further study of patients with overlap diagnoses is important moving forward to guide individualized care and cancer screening programs.

Background and Aims Gastrointestinal (GI) malignancies are common after liver transplantation. The aim of this study was to identify the risk and timing of the more common GI malignancies, colorectal and pancreatic cancer, to aid in optimizing potential posttransplant screening practices. Approach and Results Data from the United Network for Organ Sharing database of all adult liver‐transplant recipients from 1997 to 2017 were analyzed and a comparison made with cancer incidence from general population data using Surveillance, Epidemiology, and End Results data. Of 866 de novo GI malignancies, 405 colorectal and 216 pancreas were identified. The highest cumulative incidence for colorectal cancer occurred in recipients with primary sclerosing cholangitis (PSC), recipients over the age of 50 with non‐alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC)/cholangiocarcinoma (CCA), and females >50 years with alcohol‐associated liver disease and HCC/CCA, with risk increasing above the general population within 5 years of transplant. Patients with PSC and HCC/CCA or NASH and HCC/CCA have the highest cumulative incidence of pancreatic cancer also rising within 5 years following transplant, with those patients >50 years old conferring the highest risk. Conclusions These data identify a high‐risk cohort that warrants consideration for intensified individualized screening practices for colorectal cancer after liver transplantation. In addition to recipients with PSC, further study of recipients with NASH and HCC/CCA and females with alcohol‐associated liver disease and HCC/CCA may be better tailored to colorectal cancer screening ideals. Higher‐risk patient populations for pancreatic cancer (PSC and NASH with HCC/CCA) would benefit from further study to determine potential screening practices. GI malignancies occur at higher rates in liver‐transplant patients compared with the general population. In the era of individualized medicine, this study identifies the highest‐risk transplant recipients (PSC and NASH cirrhosis with coexisting HCC/CCA) who may benefit from altered screening practices for these malignancies.

Primary sclerosing cholangitis (PSC) is a risk factor for cholangiocarcinoma (CCA) and gallbladder carcinoma (GBCa). Surveillance for GBCa is recommended, but the clinical utility of surveillance for other hepatobiliary cancers (HBCa) in PSC, namely CCA and hepatocellular carcinoma (HCC), remains unclear. We aimed to determine whether surveillance is associated with better survival after diagnosis of HBCa in patients with PSC. Medical records of PSC patients seen at the Mayo Clinic Rochester from 1995 to 2015 were reviewed. Patients were included if they had ≥1 year of follow‐up and developed HBCa. Patients were categorized according to their surveillance status (abdominal imaging, carbohydrate antigen 19‐9, and alpha‐fetoprotein). The primary endpoints were HBCa recurrence, HBCa‐related death, and all‐cause mortality. Overall survival was assessed by the Kaplan‐Meier survival method; HBCa‐related survival was assessed using competing risk regression. Tests of significance were two‐tailed, and a P value <0.05 was considered statistically significant. From 1995 to 2015, a total of 79 of 830 PSC patients were diagnosed with HBCa. Cumulative follow‐up was 712 and 283 person‐years pre‐ and post‐HBCa diagnosis, respectively. Seventy‐eight percent of patients (54/79) developed CCA, 21% (17/79) HCC, 6% (5/79) GBCa, 3% (2/79) both CCA and HCC, and 1% (1/79) both HCC and GBCa. Fifty‐one percent (40/79) were under HBCa surveillance, and 49% (39/79) were not. Patients in the surveillance group had significantly higher 5‐year overall survival (68% versus 20%, respectively; P < 0.001) and significantly lower 5‐year probability of experiencing an HBCa‐related adverse event (32% versus 75%, respectively; P < 0.001) compared with the no‐surveillance group. Conclusion: This study demonstrates that HBCa surveillance significantly improves outcomes, including survival, in patients with PSC. (Hepatology 2018;67:2338‐2351).