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Abstract Cholangiocytes are epithelial cells that line the intra‐ and extrahepatic ducts of the biliary tree. The main physiologic function of cholangiocytes is modification of hepatocyte‐derived bile, an intricate process regulated by hormones, peptides, nucleotides, neurotransmitters, and other molecules through intracellular signaling pathways and cascades. The mechanisms and regulation of bile modification are reviewed herein. © 2013 American Physiological Society. Compr Physiol 3:541‐565, 2013.

Background: Primary sclerosing cholangitis (PSC) is an immune-mediated, chronic cholestatic liver disease. Currently, liver transplantation is the only established life-saving treatment. Several studies have evaluated the effect of different biologic therapies on PSC with inconclusive findings. We conducted a systematic review and meta-analysis to assess the effects of biologics in PSC and associated inflammatory bowel disease (IBD). Methods: MEDLINE, Scopus, and Embase were searched up to July 31, 2023, for studies reporting the effects of biologics in patients with PSC-IBD. Effects of biologic therapy on alkaline phosphatase, total bilirubin, ulcerative colitis response score, and adverse events were calculated and expressed as standardized difference of means (SMD), proportions, and 95% CI using a random-effects model. Results: Six studies, including 411 PSC-IBD patients who received biologics, were included. Biologic treatment was associated with no change in alkaline phosphatase (SMD: 0.1, 95% CI: −0.07 −0.17, p=0.43), but a small and statistically significant increase in total bilirubin (SMD: 0.2, 95% CI: 0.05–0.35, p<0.01). 31.2% (95% CI: 23.8–39.7) of patients with IBD achieved endoscopic response, and there was a significant improvement in ulcerative colitis response score (SMD: −0.6,95% CI: −0.88 to 0.36, p<0.01). Furthermore, 17.6% (95% CI: 13.0–23.5) of patients experienced adverse events severe enough to discontinue therapy, and 29.9% (95% CI: 25.2–34.8) had a loss of response to biologics. Conclusions: Treatment of patients with PSC-IBD with biologics (vedolizumab, infliximab, and adalimumab) was not associated with improvement of biochemical markers of cholestasis. Biologics are effective in treating the colitis associated with PSC. Vedolizumab was associated with worsening liver enzymes in contrast to other biologics, a finding that warrants further study.

INTRODUCTION: Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) has been recognized worldwide. However, its natural history and long-term outcomes are not well known. METHODS: In this retrospective, single center, cohort study, we identified patients who received a diagnosis of IgG4-SC at Mayo Clinic Rochester from 1999 to 2018. The diagnosis of IgG4-SC was rigorously ascertained by review of medical records and using the validated HISORt criteria. Comprehensive clinical data was extracted from patients' charts. Long-term outcomes of interest included cirrhosis, cholangiocarcinoma (CCA), and death. To compare outcomes, a random sample of PSC patients was selected in a 1:1 ratio matched for age of diagnosis and gender. Survival analyses were performed for comparisons using the Kaplan-Meier method, and log-rank test, and the cumulative incidence of cirrhosis and CCA was assessed using the competing risks regression method. RESULTS: A total of 61 patients were diagnosed with IgG4-SC during the study period. The median age of diagnosis was 66 years (IQR: 56–71 years), 85% were male, and the median follow-up was 6.1 years (IQR: 3.2–8.3 years). The pancreas was the most commonly involved extra-biliary organ (93%). Fifty-five patients received prednisone of whom 96% experienced complete or partial remission. Sixteen patients received rituximab as maintenance therapy, of whom 88% maintained remission. Three patients (5%) developed cirrhosis, and 2 patients (3%) developed CCA. Nine patients (15%) died; 2 due to cirrhosis, 2 due to CCA, 1 due to pancreatic cancer, and 4 due to non-hepatobiliary causes. Patients with IgG4-SC had significantly lower 5- and 10-year cumulative incidence of developing cirrhosis (5 y: 4% vs. 34%; 10 y: 6% vs. 43%; P < 0.001) and CCA (5 y: 3% vs. 17%; 10 y: 4% vs. 22%; P = 0.012) compared with PSC patients. Two patients in the PSC group underwent liver transplantation, while none in the IgG4-SC group. Overall 5- and 10-year survival was greater in the IgG4-SC cohort (5 y: 92% vs. 70%; 10 y: 77% vs. 57%; P = 0.02). CONCLUSION: Patients with IgG4-SC, the majority of whom received treatment, have a small potential risk of long-term hepatobiliary complications. Their risk of cirrhosis, CCA and death, was lower than in patients with PSC. The better outcome in the IgG4-SC group is likely due to the benefit of treatment. Surveillance in this population needs further assessment, especially the subset that does receive or respond to treatment.

Background: Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel diseases (IBD). Evidence suggests an association between the gut microbiome and PSC. However, the putative relationship between exposure to antibiotics and onset of PSC has never been reported. We observed 3 cases in which patients without antecedent liver or bowel issues developed symptoms leading to diagnosis of IBD and subsequently PSC after being exposed to doxycycline. We aimed to identify, through the PSC Partners national patient registry, additional cases of PSC in which there is a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. Areas of Uncertainty: The etiopathogenesis of PSC remains an enigma. Data Sources: We collected data from patients with PSC and PSC-IBD in which there seemed to be a temporal relationship between exposure to doxycycline and PSC. Time from doxycycline exposure to: (1) onset of PSC or PSC-IBD symptoms and (2) diagnosis of PSC were documented for each patient. Descriptive statistical analyses were performed. Results: We identified 6 additional patients with PSC or PSC-IBD in whom there was a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. The median age of these 9 patients was 20 years, 6 were female, and 7 had ulcerative colitis. The median time from doxycycline exposure to onset of first symptoms was 3 months, and median time from doxycycline exposure to diagnosis of PSC was 15 months. Therapeutic Hypothesis: We describe 9 cases of PSC and PSC-IBD in which there seem to be a temporal relationship between exposure to doxycycline and onset of PSC.

Primary sclerosing cholangitis (PSC) is a pathogenically complex, chronic, fibroinflammatory disorder of the bile ducts without known etiology or effective pharmacotherapy. Emerging in vitro and in vivo evidence support fundamental pathophysiologic mechanisms in PSC centered on enterohepatic circulation. To date, no studies have specifically interrogated the chemical footprint of enterohepatic circulation in PSC. Herein, we evaluated the metabolome and lipidome of portal venous blood and bile obtained at the time of liver transplantation in patients with PSC (n = 7) as compared to individuals with noncholestatic, end-stage liver disease (viral, metabolic, etc. (disease control, DC, n = 19)) and to nondisease controls (NC, living donors, n = 12). Global metabolomic and lipidomic profiling was performed on serum derived from portal venous blood (portal serum) and bile using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and differential mobility spectroscopy-mass spectroscopy (DMS-MS; complex lipid platform). The Mann–Whitney U test was used to identify metabolites that significantly differed between groups. Principal-component analysis (PCA) showed significant separation of both PSC and DC from NC for both portal serum and bile. Metabolite set enrichment analysis of portal serum and bile demonstrated that the liver-disease cohorts (PSC and DC) exhibited similar enrichment in several metabolite categories compared to NC. Interestingly, the bile in PSC was uniquely enriched for dipeptide and polyamine metabolites. Finally, analysis of patient-matched portal serum and biliary metabolome revealed that these biological fluids were more homogeneous in PSC than in DC or NC, suggesting aberrant bile formation and enterohepatic circulation. In summary, PSC and DC patients exhibited alterations in several metabolites in portal serum and bile, while PSC patients exhibited a unique bile metabolome. These specific alterations in PSC are amenable to hypothesis testing and, potentially, therapeutic pharmacologic manipulation.

Dominant strictures (DSs) of the biliary tree occur in approximately 50% of patients with primary sclerosing cholangitis (PSC) and may cause significant morbidity. Nevertheless, the definition and management of DSs lacks consensus. We aimed to better understand current perceptions and practices regarding PSC‐associated DSs. We conducted an anonymous, 23‐question, survey‐based study wherein electronic surveys were distributed to 131 faculty in the Division of Gastroenterology and Hepatology at the three Mayo Clinic campuses (Rochester, Scottsdale, and Jacksonville) as well as the affiliated practice network. Responses were aggregated and compared, where applicable, to practice guidelines of the American Association for the Study of Liver Diseases and European Association for the Study of the Liver. A total of 54 faculty (41.2%) completed the survey, of whom 24 (44.4%) were hepatologists, 21 (38.9%) gastroenterologists, and 9 (16.7%) advanced endoscopists. One of the major study findings was that there was heterogeneity among participants' definition, evaluation, management, and follow‐up of DSs in PSC. The majority of participant responses were in accordance with societal practice guidelines, although considerable variation was noted. Conclusion: Despite the prevalence and morbidity of DSs in PSC, clinical perceptions and practices vary widely among hepatologists, gastroenterologists, and advanced endoscopists who manage these patients, even within a single health care system. Further studies are needed to address these variations, develop general and evidence‐based consensus, and increase adherence to societal guidelines. ( Hepatology Communications 2018;2:836‐844)