Cholangiopathies encompass various biliary diseases affecting the biliary epithelium, resulting in cholestasis, inflammation, fibrosis, and ultimately liver cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most important progressive cholangiopathies in adults. Much research has broadened the scope of disease biology to genetic risk, epigenetic changes, dysregulated mucosal immunity, altered biliary epithelial cell function, and dysbiosis, all of which interact and arise in the context of ill-defined environmental triggers. An in-depth understanding of the molecular pathogenesis of these cholestatic diseases will help clinicians better prevent and treat diseases. In this review, we focus on the main underlying mechanisms of disease initiation and progression, and novel targeted therapeutics beyond currently approved treatments.
Background and Aim: Acute variceal bleeding (AVB) is a fatal adverse event of cirrhosis, and endoscopic band ligation (EBL) is the standard treatment for AVB. We developed a novel bedside risk-scoring model to predict the 6-week mortality in cirrhotic patients undergoing EBL for AVB. Methods: Cox regression analysis was used to assess the relationship of clinical, biological, and endoscopic variables with the 6-week mortality risk after EBL in a derivation cohort (n = 1373). The primary outcome was the predictive accuracy of the new model for the 6-week mortality in the validation cohort. Moreover, we tested the adequacy of the mortality risk-based stratification and the discriminative performance of our new model in comparison with the Child-Turcotte-Pugh (CTP) and the model for end-stage liver disease scores in the validation cohort (n = 200). Results: On multivariate Cox regression analysis, five objective variables (use of betablockers, hepatocellular carcinoma, CTP class C, hypovolemic shock at initial presentation, and history of hepatic encephalopathy) were scored to generate a 12-point risk-prediction model. The model stratified the 6-week mortality risk in patients as low (3.5%), intermediate (21.1%), and high (53.4%) (P < 0.001). Time-dependent area under the receiver operating characteristic curve for 6-week mortality showed that this model was a better prognostic indicator than the CTP class alone in the derivation (P < 0.001) and validation (P < 0.001) cohorts. Conclusions: A simplified scoring model with high potential for generalization refines the prediction of 6-week mortality in high-risk cirrhotic patients, thereby aiding the targeting and individualization of treatment strategies for decreasing the mortality rate.
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