The farnesoid X receptor (FXR) is a nuclear bile acid receptor involved in bile acid homeostasis, hepatic and intestinal inflammation, liver fibrosis, and cardiovascular disease. We studied the ...effect of short‐term treatment with obeticholic acid (INT‐747), a potent selective FXR agonist, on intrahepatic hemodynamic dysfunction and signaling pathways in different rat models of cirrhotic portal hypertension (PHT). For this, thioacetamide (TAA)‐intoxicated and bile‐duct–ligated (BDL) rats were used as models. After gavage of two doses of 30 mg/kg of INT‐747 or vehicle within 24 hours, in vivo hemodynamics were assessed. Additionally, we evaluated the direct effect of INT‐747 on total intrahepatic vascular resistance (IHVR) and intrahepatic vascular tone (endothelial dysfunction and hyperresponsiveness to methoxamine) by means of an in situ liver perfusion system and on hepatic stellate cell contraction in vitro. FXR expression and involved intrahepatic vasoactive pathways (e.g., endothelial nitric oxide synthase eNOS, Rho‐kinase, and dimethylarginine dimethylaminohydrolase DDAH) were analyzed by immunohistochemistry, reverse‐transcriptase polymerase chain reaction, or western blotting. In both cirrhotic models, FXR expression was decreased. Treatment with INT‐747 in TAA and BDL reactivated the FXR downstream signaling pathway and decreased portal pressure by lowering total IHVR without deleterious systemic hypotension. In the perfused TAA and BDL cirrhotic liver, INT‐747 improved endothelial vasorelaxation capacity, but not hyperresponsiveness. In both groups, this was associated with an increased eNOS activity, which, in TAA, related to down‐regulation of Rho‐kinase and in BDL to up‐regulation of DDAH‐2. Conclusion: FXR agonist INT‐747 improves PHT in two different rat models of cirrhosis by decreasing IHVR. This hemodynamic effect relates to increased intrahepatic eNOS activity by pathways that differ depending on the etiology of cirrhosis. (Hepatology 2014;59:2286–2298)
Bacterial translocation (BTL) drives pathogenesis and complications of cirrhosis. Farnesoid X-activated receptor (FXR) is a key transcription regulator in hepatic and intestinal bile metabolism. We ...studied potential intestinal FXR dysfunction in a rat model of cholestatic liver injury and evaluated effects of obeticholic acid (INT-747), an FXR agonist, on gut permeability, inflammation, and BTL. Rats were gavaged with INT-747 or vehicle during 10 days after bile-duct ligation and then were assessed for changes in gut permeability, BTL, and tight-junction protein expression, immune cell recruitment, and cytokine expression in ileum, mesenteric lymph nodes, and spleen. Auxiliary in vitro BTL-mimicking experiments were performed with Transwell supports. Vehicle-treated bile duct–ligated rats exhibited decreased FXR pathway expression in both jejunum and ileum, in association with increased gut permeability through increased claudin-2 expression and related to local and systemic recruitment of natural killer cells resulting in increased interferon-γ expression and BTL. After INT-747 treatment, natural killer cells and interferon-γ expression markedly decreased, in association with normalized permeability selectively in ileum (up-regulated claudin-1 and occludin) and a significant reduction in BTL. In vitro , interferon-γ induced increased Escherichia coli translocation, which remained unaffected by INT-747. In experimental cholestasis, FXR agonism improved ileal barrier function by attenuating intestinal inflammation, leading to reduced BTL and thus demonstrating a crucial protective role for FXR in the gut–liver axis.
In the management of gastric outlet obstruction (GOO), EUS-guided gastroenterostomy (EUS-GE) seems to be safe and more effective than enteral stent placement. However, comparisons with laparoscopic ...GE (L-GE) are scarce. Our aim was to perform a propensity score–matched comparison between EUS-GE and L-GE.
An international, multicenter, retrospective analysis was performed of consecutive EUS-GE and L-GE procedures in 3 academic centers (January 2015 to May 2020) using propensity score matching to minimize selection bias. A standard maximum propensity score difference of .1 was applied, also considering underlying disease and oncologic staging.
Overall, 77 patients were treated with EUS-GE and 48 patients with L-GE. By means of propensity score matching, 37 patients were allocated to both groups, resulting in 74 (1:1) matched patients. Technical success was achieved in 35 of 37 EUS-GE–treated patients (94.6%) versus 100% in the L-GE group (P = .493). Clinical success, defined as eating without vomiting or GOO Scoring System ≥2, was achieved in 97.1% and 89.2%, respectively (P = .358). Median time to oral intake (1 interquartile range {IQR}, .3-1.0 vs 3 IQR, 1.0-5.0 days, P < .001) and median hospital stay (4 IQR, 2-8 vs 8 IQR, 5.5-20 days, P < .001) were significantly shorter in the EUS-GE group. Overall (2.7% vs 27.0%, P = .007) and severe (.0% vs 16.2%, P = .025) adverse events were identified more frequently in the L-GE group.
For patients with GOO, EUS-GE and L-GE showed almost identical technical and clinical success. However, reduced time to oral intake, shorter median hospital stay, and lower rate of adverse events suggest that the EUS-guided approach might be preferable.
Hepatic inflammation drives hepatic stellate cells (HSC), resulting in liver fibrosis. The Farnesoid-X receptor (FXR) antagonizes inflammation through NF-κB inhibition. We investigated preventive and ...therapeutic effects of FXR agonist obeticholic acid (OCA) on hepatic inflammation and fibrosis in toxic cirrhotic rats. Cirrhosis was induced by thioacetamide (TAA) intoxication. OCA was given during or after intoxication with vehicle-treated rats as controls. At sacrifice, fibrosis, hemodynamic and biochemical parameters were assessed. HSC activation, cell turn-over, hepatic NF-κB activation, pro-inflammatory and pro-fibrotic cytokines were determined. The effect of OCA was further evaluated in isolated HSC, Kupffer cells, hepatocytes and liver sinusoidal endothelial cells (LSEC). OCA decreased hepatic inflammation and fibrogenesis during TAA-administration and reversed fibrosis in established cirrhosis. Portal pressure decreased through reduced intrahepatic vascular resistance. This was paralleled by decreased expression of pro-fibrotic cytokines (transforming growth-factor β, connective tissue growth factor, platelet-derived growth factor β-receptor) as well as markers of hepatic cell turn-over, by blunting effects of pro-inflammatory cytokines (e.g. monocyte chemo-attractant protein-1). In vitro, OCA inhibited both LSEC and Kupffer cell activation; while HSC remained unaffected. This related to NF-κB inhibition via up-regulated IκBα. In conclusion, OCA inhibits hepatic inflammation in toxic cirrhotic rats resulting in decreased HSC activation and fibrosis.
Cholangiocellular carcinoma (CC) originates from topographically heterogeneous cholangiocytes. The cylindrical mucin‐producing cholangiocytes are located in large bile ducts and the cuboidal ...non–mucin‐producing cholangiocytes are located in ductules containing bipotential hepatic progenitor cells (HPCs). We investigated the clinicopathological and molecular features of 85 resected CCs (14 hilar CCs so‐called Klatskin tumor, 71 intrahepatic CCs ICCs including 20 cholangiolocellular carcinomas CLCs, which are thought to originate from HPCs) and compared these with the different cholangiocyte phenotypes, including HPCs. Immunohistochemistry was performed with biliary/HPC and hepatocytic markers. Gene expression profiling was performed in different tumors and compared with nonneoplastic different cholangiocyte phenotypes obtained by laser microdissection. Invasion and cell proliferation assay were assessed using different types of CC cell lines: KMC‐1, KMCH‐1, and KMCH‐2. Among 51 ICCs, 31 (60.8%) contained only mucin‐producing CC features (muc‐ICCs), whereas 39.2% displayed histological diversity: focal hepatocytic differentiation and ductular areas (mixed‐ICCs). Clinicopathologically, muc‐ICCs and hilar CCs showed a predominantly (peri‐)hilar location, smaller tumor size, and more lymphatic and perineural invasion compared with mixed‐ICCs and CLCs (predominantly peripheral location, larger tumor size, and less lymphatic and perineural invasion). Immunoreactivity was similar in muc‐ICCs and hilar CCs and in mixed‐ICCs and CLCs. S100P and MUC1 were significantly up‐regulated in hilar CCs and muc‐ICCs compared with mixed‐ICCs and CLCs, whereas NCAM1 and ALB tended to be up‐regulated in mixed‐ICCs and CLCs compared with other tumors. KMC‐1 showed significantly higher invasiveness than KMCH‐1 and KMCH‐2. Conclusion: Muc‐ICCs had a clinicopathological, immunohistochemical, and molecular profile similar to that of hilar CCs (from mucin‐producing cholangiocytes), whereas mixed‐ICCs had a profile similar to that of CLCs (thought to be of HPC origin), possibly reflecting their respective cells of origin. (HEPATOLOGY 2012;55:1876–1888)
Background and study aim
Indeterminate biliary strictures and difficult bile duct stones remain clinically arduous and challenging situations. We aimed to evaluate the utility of the single-operator ...cholangioscopy (SOC)-system SpyGlass in both conditions in a single-center biliopancreatic interventional unit and in perspective of available aggregated literature.
Methods
Usefulness of SOC was assessed for the above-mentioned indications by means of the combination of successful procedural completion, clinical success and incidence of procedure-related adverse events in our own prospective cohort from 3/2010 to 7/2014 and all available literature till 6/2015.
Results
Our single-center cohort constituted of 84 patients undergoing SpyGlass either for indeterminate strictures (
n
= 45) or difficult stones (
n
= 39). In addition, a comprehensive literature review yielded 851 patients (from 15 series) for either stenosis (
n
= 646, 75.9 %) and difficult stones (
n
= 205, 24.1 %). In our series, overall procedural success amounted to 85.7 % (with 88.9 % for stenosis or 82.1 % for stones) compared to 90.7, 91.5 and 88.3 % in overall literature, respectively. Sensitivity, specificity and accuracy for
visual diagnosis
in our cohort added up to 83.3, 82.9 and 82.9 % compared to 90.8, 90.9 and 90.8 % in the pooled analysis. Respective figures for
SOC
-
directed biopsies
totaled 85.7, 100 and 95.7 % in our cohort and 72.4, 100 and 84 % overall. Overall procedure-related complications varied between 9.4 and 21.4 %.
Conclusions
The SOC-platform SpyGlass can be considered useful in the context of indeterminate biliary strictures and difficult-to-remove biliary stones. In both, SpyGlass-assisted intervention is associated with high procedural success and alters clinical outcome compared to conventional approaches with an acceptable safety profile.
Endoscopic duodenal stenting is the current standard treatment for malignant gastric outlet obstruction (GOO) in patients with limited life expectancy. However, duodenal stenting is prone to stent ...dysfunction. Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) is a novel technique with potentially superior stent patency. We compared clinical success, safety, and stent dysfunction of EUS-GE and duodenal stenting in patients with malignant GOO using propensity score matching.
This international, multicenter, retrospective study analyzed consecutive patients undergoing EUS-GE or duodenal stenting for GOO between 2015 and 2021 in three European centers. Primary outcomes were clinical success (GOO scoring system GOOSS ≥ 2) and stent dysfunction (GOOSS ≤ 1 after initial clinical success). A propensity score matching (1:1) analysis was performed using age, sex, underlying disease, disease stage, ascites, and peritoneal carcinomatosis as variables.
214 patients underwent EUS-GE (n = 107) or duodenal stenting (n = 107). After propensity score matching, 176 patients were matched and compared. Technical success rates for EUS-GE and duodenal stenting were 94 % (95 %CI 89 %-99 %) vs. 98 % (95 %CI 95 %-100 %), respectively (
= 0.44). Clinical success rates were 91 % (95 %CI 85 %-97 %) vs. 75 % (95 %CI 66 %-84 %;
= 0.008). Stent dysfunction occurred in 1 % (95 %CI 0-4 %) vs. 26 % (95 %CI 15 %-37 %) of patients (
< 0.001). Adverse event rate was 10 % (95 %CI 4 %-17 %) vs. 21 % (95 %CI 12 %-29 %;
= 0.09).
EUS-GE had higher clinical success and lower stent dysfunction, with similar safety, compared with duodenal stenting, suggesting that EUS-GE may be preferred over duodenal stenting in patients with malignant GOO.
ACLF is a specific, but complex and multifactorial form of acute decompensation of cirrhosis and is characterized by an extraordinary dynamic natural course, rapidly evolving organ failure, and high ...short-term mortality. Dysbalanced immune function is central to its pathogenesis and outcome with an initial excessive systemic inflammatory response that drives organ failure and mortality. Later in its course, immuno-exhaustion/immunoparalysis prevails predisposing the patient to secondary infectious events and reescalation in end-organ dysfunction and mortality. The management of patients with ACLF is still poorly defined. However, as its pathophysiology is gradually being unravelled, potential therapeutic targets emerge that warrant further study such as restoring or substituting albumin via plasma exchange or via albumin dialysis and evaluating usefulness of TLR4 antagonists, modulators of gut dysbiosis (pre- or probiotics), and FXR-agonists.
Refractory hepatic encephalopathy (HE) remains a major cause of morbidity in cirrhosis patients. Large spontaneous portosystemic shunts (SPSSs) have been previously suggested to sustain HE in these ...patients. We aimed to retrospectively assess the efficacy and safety of patients treated with embolization of large SPSSs for the treatment of chronic therapy‐refractory HE in a European multicentric working group and to identify patients who may benefit from this procedure. Between July 1998 and January 2012, 37 patients (Child A6‐C13, MELD Model of Endstage Liver Disease 5‐28) with refractory HE were diagnosed with single large SPSSs that were considered eligible for embolization. On a short‐term basis (i.e., within 100 days after embolization), 22 out of 37 patients (59.4%) were free of HE (P < 0.001 versus before embolization) of which 18 (48.6% of patients overall) remained HE‐free over a mean follow‐up period of 697 ± 157 days (P < 0.001 versus before embolization). Overall, we noted improved autonomy, decreased number of hospitalizations, and severity of the worst HE episode after embolization in three‐quarters of the patients. Logistic regression identified the MELD score as strongest positive predictive factor of HE recurrence with a cutoff of 11 for patient selection. As to safety, we noted one major nonlethal procedure‐related complication. There was no significant increase in de novo development or aggravation of preexisting varices, portal hypertensive gastropathy, or ascites. Conclusion: This multicenter European cohort study demonstrated a role for large SPSSs in chronic protracted or recurrent HE and substantiated the effectiveness and safety of embolization of these shunts, provided there is sufficient functional liver reserve. (HEPATOLOGY 2013;57:2448–2457)
Benign biliary strictures (BBS) are complications of chronic pancreatitis (CP). Endotherapy using multiple plastic stents (MPS) or a fully covered self-expanding metal stent (FCSEMS) are acceptable ...treatment options for biliary obstructive symptoms in these patients.
Patients with symptomatic CP-associated BBS enrolled in a multicenter randomized noninferiority trial comparing 12-month treatment with MPS vs FCSEMS. Primary outcome was stricture resolution status at 24 months, defined as absence of restenting and 24-month serum alkaline phosphatase not exceeding twice the level at stenting completion. Secondary outcomes included crossover rate, numbers of endoscopic retrograde cholangiopancreatography (ERCPs) and stents, and stent- or procedure-related serious adverse events.
Eighty-four patients were randomized to MPS and 80 to FCSEMS. Baseline technical success was 97.6% for MPS and 98.6% for FCSEMS. Eleven patients crossed over from MPS to FCSEMS, and 10 from FCSEMS to MPS. For MPS vs FCSEMS, respectively, stricture resolution status at 24 months was 77.1% (54/70) vs 75.8% (47/62) (P = .008 for noninferiority intention-to-treat analysis), mean number of ERCPs was 3.9 ± 1.3 vs 2.6 ± 1.3 (P < .001, intention-to-treat), and mean number of stents placed was 7.0 ± 4.4 vs 1.3 ± .6 (P < .001, as-treated). Serious adverse events occurred in 16 (19.0%) MPS and 19 (23.8%) FCSEMS patients (P = .568), including cholangitis/fever/jaundice (9 vs 7 patients respectively), abdominal pain (5 vs 5), cholecystitis (1 vs 3) and post-ERCP pancreatitis (0 vs 2). No stent- or procedure-related deaths occurred.
Endotherapy of CP-associated BBS has similar efficacy and safety for 12-month treatment using MPS compared with a single FCSEMS, with FCSEMS requiring fewer ERCPs over 2 years. (ClinicalTrials.gov, Number: NCT01543256.)
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For benign biliary stricture secondary to chronic pancreatitis, 12-month endotherapy using a single fully covered self-expandable metal stent has similar efficacy and safety and requires fewer procedural interventions than multiple plastic stents.
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