Spontaneous perforation of the common bile duct: an uncommon complication of primary sclerosing cholangitis.

OBJECTIVES: To describe the MR features and prognosis of patients with an uncommon complication of primary sclerosing cholangitis (PSC) characterized by a spontaneous perforation of the common bile duct (CBD) resulting in a peri-biliary collection and a pseudo-cystic appearance of the CBD. METHODS: A single-center cohort of 263 patients with PSC who had at least two MRIs between 2003 and 2022 and a minimum follow-up of 1 year was retrospectively analyzed. MRI data (characteristics of CBD perforation and MR features of PSC) and clinical data were assessed. Analysis of survival without liver transplantation according to type of PSC (classical or CBD spontaneous perforation) was performed according to the Kaplan-Meier method and the curves were compared using the Log-Rank test. RESULTS: A total of nine (3.4%) PSC patients (5 males) had perforation of the CBD with a median age at diagnosis of 18 years compared to 33 years for the control group (p = 0.019). The peri-biliary collections were variable in appearance (fusiform or pedunculated), with a diameter ranging from 5 to 54 mm. All nine patients showed intra- and extra-hepatic bile duct involvement, dysmorphia, and high ANALI scores. The clinical course was characterized by numerous complications in most patients, and five patients (56%) underwent liver transplantation at a median time of 5 years from diagnosis, compared to 40 patients (16%) in the control group (p = 0.02). CONCLUSION: The spontaneous perforation of the common bile duct is an uncommon complication of primary sclerosing cholangitis that affects young patients and is associated with a poor prognosis. CLINICAL RELEVANCE STATEMENT: This uncommon complication of primary sclerosing cholangitis with perforation of the common bile duct resulting in a peri-biliary collection and a pseudo-cystic appearance of the common bile duct is characterized by a poor prognosis in younger patients. KEY POINTS: • Among 263 patients with primary sclerosing cholangitis (PSC), nine patients (3.6%) had an uncommon complication characterized on MRI by perforation of the common bile duct (CBD). • This perforation of the CBD was responsible in all nine cases for the formation of a peri-biliary collection, giving a pseudo-cystic appearance to the CBD. • The spontaneous perforation of the common bile duct is an uncommon complication of primary sclerosing cholangitis that affects young patients with a poor prognosis.

Protective potential of the gallbladder in primary sclerosing cholangitis.

Background & Aims: Gallbladder enlargement is common in patients with primary sclerosing cholangitis (PSC). The gallbladder may confer hepatoprotection against bile acid overload, through the sequestration and cholecystohepatic shunt of bile acids. The aim of this study was to assess the potential impact of the gallbladder on disease features and bile acid homeostasis in PSC. Methods: Patients with PSC from a single tertiary center who underwent liver MRI with three-dimensional cholangiography and concomitant analyses of serum bile acids were included. Gallbladder volume was measured by MRI and a cut-off of 50 ml was used to define gallbladder enlargement. Bile acid profiles and PSC severity, as assessed by blood tests and MRI features, were compared among patients according to gallbladder size (enlarged vs. normal-sized) or presence (removed vs. conserved). The impact of cholecystectomy was also assessed in the Abcb4 knockout mouse model of PSC. Results: Sixty-one patients with PSC, all treated with ursodeoxycholic acid (UDCA), were included. The gallbladder was enlarged in 30 patients, whereas 11 patients had been previously cholecystectomized. Patients with enlarged gallbladders had significantly lower alkaline phosphatase, a lower tauro-vs. glycoconjugate ratio and a higher UDCA vs. total bile acid ratio compared to those with normal-sized gallbladders. In addition, gallbladder volume negatively correlated with the hydrophobicity index of bile acids. Cholecystectomized patients displayed significantly higher aspartate aminotransferase and more severe bile duct strictures and dilatations compared to those with conserved gallbladder. In the Abcb4 knockout mice, cholecystectomy caused an increase in hepatic bile acid content and in circulating secondary bile acids, and an aggravation in cholangitis, inflammation and liver fibrosis. Conclusion: Altogether, our findings indicate that the gallbladder fulfills protective functions in PSC. Impact and implications: In patients with primary sclerosing cholangitis (PSC), gallbladder status impacts on bile acid homeostasis and disease features. We found evidence of lessened bile acid toxicity in patients with PSC and enlarged gallbladders and of increased disease severity in those who were previously cholecystectomized. In the Abcb4 knockout mouse model of PSC, cholecystectomy causes an aggravation of cholangitis and liver fibrosis. Overall, our results suggest that the gallbladder plays a protective role in PSC.

Portal fibroblasts with mesenchymal stem cell features form a reservoir of proliferative myofibroblasts in liver fibrosis.

BACKGROUND AND AIMS: In liver fibrosis, myofibroblasts derive from HSCs and as yet undefined mesenchymal cells. We aimed to identify portal mesenchymal progenitors of myofibroblasts. APPROACH AND RESULTS: Portal mesenchymal cells were isolated from mouse bilio-vascular tree and analyzed by single-cell RNA-sequencing. Thereby, we uncovered the landscape of portal mesenchymal cells in homeostatic mouse liver. Trajectory analysis enabled inferring a small cell population further defined by surface markers used to isolate it. This population consisted of portal fibroblasts with mesenchymal stem cell features (PMSCs), i.e., high clonogenicity and trilineage differentiation potential, that generated proliferative myofibroblasts, contrasting with nonproliferative HSC-derived myofibroblasts (-MF). Using bulk RNA-sequencing, we built oligogene signatures of the two cell populations that remained discriminant across myofibroblastic differentiation. SLIT2, a prototypical gene of PMSC/PMSC-MF signature, mediated profibrotic and angiogenic effects of these cells, which conditioned medium promoted HSC survival and endothelial cell tubulogenesis. Using PMSC/PMSC-MF 7-gene signature and slit guidance ligand 2 fluorescent in situ hybridization, we showed that PMSCs display a perivascular portal distribution in homeostatic liver and largely expand with fibrosis progression, contributing to the myofibroblast populations that form fibrotic septa, preferentially along neovessels, in murine and human liver disorders, irrespective of etiology. We also unraveled a 6-gene expression signature of HSCs/HSC-MFs that did not vary in these disorders, consistent with their low proliferation rate. CONCLUSIONS: PMSCs form a small reservoir of expansive myofibroblasts, which, in interaction with neovessels and HSC-MFs that mainly arise through differentiation from a preexisting pool, underlie the formation of fibrotic septa in all types of liver diseases.

Role of Angiogenesis in the Pathogenesis of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, exposing to the risk of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Angio-genesis is a complex process leading to the development of new vessels from pre-existing vessels. Angiogenesis is triggered by hypoxia and inflammation and is driven by the action of proangiogenic cytokines, mainly vascular endothelial growth factor (VEGF). In this review, we focus on liver angiogenesis associated with NAFLD and analyze the evidence of liver angiogenesis in animal models of NAFLD and in NAFLD patients. We also report the data explaining the role of angiogenesis in the progression of NAFLD and discuss the potential of targeting angiogenesis, notably VEGF, to treat NAFLD.

The Complementary Value of Magnetic Resonance Imaging and Vibration-Controlled Transient Elastography for Risk Stratification in Primary Sclerosing Cholangitis.

OBJECTIVES: Magnetic resonance (MR) risk scores and liver stiffness (LS) have individually been shown to predict clinical outcomes in primary sclerosing cholangitis (PSC). The aim of this study was to assess their complementary prognostic value. METHODS: Patients with PSC from 3 European centers with a 3-dimensional MR cholangiography available for central reviewing and a valid LS measurement assessed by vibration-controlled transient elastography by FibroScan performed within a 6-month interval were included in a longitudinal retrospective study. The MR score (Anali) without gadolinium (Gd) was calculated according to the formula: (1 × dilatation of intrahepatic bile ducts) + (2 × dysmorphy) + (1 × portal hypertension). The primary end point was survival without liver transplantation or cirrhosis decompensation. The prognostic values of LS and Anali score without Gd were assessed using Cox proportional hazard models. RESULTS: One hundred sixty-two patients were included. Over a total follow-up of 753 patient-years, 40 patients experienced an adverse outcome (4 liver transplantations, 6 liver-related deaths, and 30 cirrhosis decompensations). LS and Anali score without Gd were significantly correlated (ρ = 0.51, P < 0.001) and were independently associated with the occurrence of an adverse outcome. Optimal prognostic thresholds were 10.5 kPa for LS and 2 for the Anali score without Gd. Hazard ratios (95% confidence interval) were 2.07 (1.06-4.06) and 3.78 (1.67-8.59), respectively. The use in combination of these 2 thresholds allowed us to separate patients into low-, medium-, and high-risk groups for developing adverse outcomes. The 5-year cumulative rates of adverse outcome in these 3 groups were 8%, 16%, and 38% (P < 0.001), respectively. DISCUSSION: The combined use of MRI and vibration-controlled transient elastography permits easy risk stratification of patients with PSC.

Predictive criteria of response to endoscopic treatment for severe strictures in primary sclerosing cholangitis.

BACKGROUND: The aim of this study was to identify predictive criteria of improvement after endoscopic treatment (ET) for severe strictures of extrahepatic bile ducts in patients with primary sclerosing cholangitis (PSC). METHODS: PSC patients who had at least one ET for severe stricture were included. Features of magnetic resonance cholangiography (MRC), performed before ET, were evaluated according to a standard model of interpretation, and a radiologic qualitative score of probability of improvement after ET was built. Score 3 (likely) was given in case of severe common bile duct (CBD) stricture with marked dilatation without severe strictures of upstream ducts, Score 1 (unlikely) was given in case of severe multiple strictures of secondary ducts without biliary dilatation and Score 2 (undeterminate) was given to an intermediate pattern. The response to ET was assessed at 2 months (T2-response) from the last ET and at 12 months (T12-response) from inclusion. RESULTS: Thirty-one patients were included. All had severe stricture (reduction ≥ 75% of the diameter) of CBD and 50% had severe stricture of right and/or left hepatic duct (LHD) at MRC before ET. According to the qualitative score, 16 patients had Score 3, 7 had Score 1 and 9 had Score 2. T12-response was obtained in 50% of patients. In univariate analysis, short LHD strictures, bilirubin, transaminases, pruritus and Score 3 were associated with T12-response. Increased bilirubin and transaminases were independent predictive factors of T12-response (HR 24, 95% CI: 3.4-170.4, P = 0.001 and 23.8, 95% CI: 3.4-169.4, P = 0.002, respectively). CONCLUSION: MRC, together with biochemical features, may contribute to identify the PSC patients who are likely to be improved after ET for severe strictures of extrahepatic bile ducts.

Intrahepatic cystic biliary dilatation constitutes a significant prognostic factor in patients with primary sclerosing cholangitis.

AIMS: To evaluate the prognostic value of cystic dilatation (CD) of the intrahepatic biliary ducts in patients with primary sclerosing cholangitis (PSC). METHODS: A single-center cohort of 205 patients with PSC from 2003 to 2016 was analysed. CD was defined by quantitative and qualitative criteria. Radiological and clinical courses were assessed. A Kaplan-Meier analysis was used to estimate cumulative survival without liver transplantation (LT) from the date of PSC diagnosis. A log-rank test was performed to compare survival time of PSC patients with and without CD. RESULTS: A total of 15 (7.3%) PSC patients (12 males) with a median age of 23 years at diagnosis had CD. Five patients had one CD; seven patients had two or three CDs; and three patients had diffuse CD. CDs ranged in small diameter size from 12 to 32 mm. Radiological evolution of CD was markedly variable. However, a radiological worsening of PSC over time was observed in all patients. The clinical course was characterized by the occurrence of complications in most patients. Half of the patients with CD underwent LT at a median time of 40 months from diagnosis of CD and the median survival time from PSC diagnosis was significantly lower than in PSC without CD (10.7 vs. 23.4 years; HR 3.8, 95% confidence interval: 1.7-8.3, p = 0.001). CONCLUSIONS: CD in PSC is an unusual condition that mostly affects young patients. It is characterized by a rapid, unfavorable course and constitutes a significant prognostic factor. KEY POINTS: • Cystic dilatation of the intrahepatic biliary ducts affects young patients with primary sclerosing cholangitis and is characterized by a markedly variable radiological evolution. • Biliary wall inflammation, found in explanted livers, could be a key feature in the pathogenesis of cystic dilatation. • Cystic dilatation of the intrahepatic biliary ducts is characterized by an unfavorable course and constitutes a significant prognostic factor of primary sclerosing cholangitis.

Liver sinusoidal endothelial cells: Physiology and role in liver diseases.

Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells representing the interface between blood cells on the one side and hepatocytes and hepatic stellate cells on the other side. LSECs represent a permeable barrier. Indeed, the association of 'fenestrae', absence of diaphragm and lack of basement membrane make them the most permeable endothelial cells of the mammalian body. They also have the highest endocytosis capacity of human cells. In physiological conditions, LSECs regulate hepatic vascular tone contributing to the maintenance of a low portal pressure despite the major changes in hepatic blood flow occurring during digestion. LSECs maintain hepatic stellate cell quiescence, thus inhibiting intrahepatic vasoconstriction and fibrosis development. In pathological conditions, LSECs play a key role in the initiation and progression of chronic liver diseases. Indeed, they become capillarized and lose their protective properties, and they promote angiogenesis and vasoconstriction. LSECs are implicated in liver regeneration following acute liver injury or partial hepatectomy since they renew from LSECs and/or LSEC progenitors, they sense changes in shear stress resulting from surgery, and they interact with platelets and inflammatory cells. LSECs also play a role in hepatocellular carcinoma development and progression, in ageing, and in liver lesions related to inflammation and infection. This review also presents a detailed analysis of the technical aspects relevant for LSEC analysis including the markers these cells express, the available cell lines and the transgenic mouse models. Finally, this review provides an overview of the strategies available for a specific targeting of LSECs.

Portal myofibroblasts promote vascular remodeling underlying cirrhosis formation through the release of microparticles.

UNLABELLED: Liver fibrosis expanding from portal tracts and vascular remodeling are determinant factors in the progression of liver diseases to cirrhosis. In the present study, we examined the potential contribution of portal myofibroblasts (PMFs) to the vascular changes leading to cirrhosis. The analyses of liver cells based on the transcriptome of rat PMFs, compared to hepatic stellate cell HSC-derived myofibroblasts in culture, identified collagen, type XV, alpha 1 (COL15A1) as a marker of PMFs. Normal liver contained rare COL15A1-immunoreactive cells adjacent to the bile ducts and canals of Hering in the portal area. A marked increase in COL15A1 expression occurred together with that of the endothelial marker, von Willebrand factor, in human and rat liver tissue, at advanced stages of fibrosis caused by either biliary or hepatocellular injury. In cirrhotic liver, COL15A1-expressing PMFs adopted a perivascular distribution outlining vascular capillaries proximal to reactive ductules, within large fibrotic septa. The effect of PMFs on endothelial cells (ECs) was evaluated by in vitro and in vivo angiogenesis assays. PMF-conditioned medium increased the migration and tubulogenesis of liver ECs as well as human umbilical vein ECs and triggered angiogenesis within Matrigel plugs in mice. In coculture, PMFs developed intercellular junctions with ECs and enhanced the formation of vascular structures. PMFs released vascular endothelial growth factor (VEGF)A-containing microparticles, which activated VEGF receptor 2 in ECs and largely mediated their proangiogenic effect. Cholangiocytes potentiated the angiogenic properties of PMFs by increasing VEGFA expression and microparticle shedding in these cells. CONCLUSION: PMFs are key cells in hepatic vascular remodeling. They signal to ECs through VEGFA-laden microparticles and act as mural cells for newly formed vessels, driving scar progression from portal tracts into the parenchyma.

The emerging roles of microvesicles in liver diseases.

Microvesicles (MVs) are extracellular vesicles released by virtually all cells, under both physiological and pathological conditions. They contain lipids, proteins, RNAs and microRNAs and act as vectors of information that regulate the function of target cells. This Review provides an overview of the studies assessing circulating MV levels in patients with liver diseases, together with an insight into the mechanisms that could account for these changes. We also present a detailed analysis of the implication of MVs in key processes of liver diseases. MVs have a dual role in fibrosis as certain types of MVs promote fibrolysis by increasing expression of matrix metalloproteinases, whereas others promote fibrosis by stimulating processes such as angiogenesis. MVs probably enhance portal hypertension by contributing to intrahepatic vasoconstriction, splanchnic vasodilation and angiogenesis. As MVs can modulate vascular permeability, vascular tone and angiogenesis, they might contribute to several complications of cirrhosis including hepatic encephalopathy, hepatopulmonary syndrome and hepatorenal syndrome. Several results also suggest that MVs have a role in hepatocellular carcinoma. Although MVs represent promising biomarkers in patients with liver disease, methods of isolation and subsequent analysis must be standardized.