Non-alcoholic fatty liver disease (NAFLD) and its complications are an expanding health problem associated with the metabolic syndrome. Liver sinusoidal endothelial cells (LSECs) are highly ...specialized endothelial cells localized at the interface between the blood derived from the gut and the adipose tissue on the one side, and other liver cells on the other side. In physiological conditions, LSECs are gatekeepers of liver homeostasis. LSECs display anti-inflammatory and anti-fibrogenic properties by preventing Kupffer cell and hepatic stellate cell activation and regulating intrahepatic vascular resistance and portal pressure. This review focusses on changes occurring in LSECs in NAFLD and on their consequences on NAFLD progression and complications. Capillarization, namely the loss of LSEC fenestrae, and LSEC dysfunction, namely the loss of the ability of LSECs to generate vasodilator agents in response to increased shear stress both occur early in NAFLD. These LSEC changes favour steatosis development and set the stage for NAFLD progression. At the stage of non-alcoholic steatohepatitis, altered LSECs release inflammatory mediators and contribute to the recruitment of inflammatory cells, thus promoting liver injury and inflammation. Altered LSECs also fail to maintain hepatic stellate cell quiescence and release fibrogenic mediators, including Hedgehog signalling molecules, promoting liver fibrosis. Liver angiogenesis is increased in NAFLD and contributes to liver inflammation and fibrosis, but also to hepatocellular carcinoma development. Thus, improving LSEC health appears to be a promising approach to prevent NAFLD progression and complications.
Extracellular vesicles are membrane-bound vesicles containing proteins, lipids, RNAs and microRNAs. They can originate from both healthy and stressed cells, and provide a snapshot of the cell of ...origin in physiological and pathological circumstances. Various processes that may give rise to the release of extracellular vesicles occur in liver diseases, including hepatocyte apoptosis, hepatic stellate cell activation, liver innate immune system activation, systemic inflammation, and organelle dysfunction (mitochondrial dysfunction and endoplasmic reticulum stress). Numerous studies have therefore investigated the potential role of extracellular vesicles as biomarkers in liver diseases. This review provides an overview of the methods that can be used to measure extracellular vesicle concentrations in clinical settings, ranging from plasma preparation to extracellular vesicle measurement techniques, as well as looking at the challenges of using extracellular vesicles as biomarkers. We also provide a comprehensive review of studies that test extracellular vesicles as diagnostic, severity and prognostic biomarkers in various liver diseases, including non-alcoholic and alcoholic steatohepatitis, viral hepatitis B and C infections, cirrhosis, primary liver cancers, primary sclerosing cholangitis and acute liver failure. In particular, extracellular vesicles could be useful tools to evaluate activity and fibrosis in non-alcoholic fatty liver disease, predict risk of hepatitis B virus reactivation, predict complications and mortality in cirrhosis, detect early hepatocellular carcinoma, detect malignant transformation in primary sclerosing cholangitis and predict outcomes in acute liver failure. While most studies draw on data derived from pilot studies, which still require clinical validation, some extracellular vesicle subpopulations have already been evaluated in solid prospective studies.
Autophagy is a self-eating catabolic pathway that contributes to liver homeostasis through its role in energy balance and in the quality control of the cytoplasm, by removing misfolded proteins, ...damaged organelles and lipid droplets. Autophagy not only regulates hepatocyte functions but also impacts on non-parenchymal cells, such as endothelial cells, macrophages and hepatic stellate cells. Deregulation of autophagy has been linked to many liver diseases and its modulation is now recognized as a potential new therapeutic strategy. Indeed, enhancing autophagy may prevent the progression of a number of liver diseases, including storage disorders (alpha-1 antitrypsin deficiency, Wilson's disease), acute liver injury, non-alcoholic steatohepatitis and chronic alcohol-related liver disease. Nevertheless, in some situations such as fibrosis, targeting specific liver cells must be considered, as autophagy displays opposing functions depending on the cell type. In addition, an optimal therapeutic time-window should be identified, since autophagy might be beneficial in the initial stages of disease, but detrimental at more advanced stages, as in the case of hepatocellular carcinoma. Finally, identifying biomarkers of autophagy and methods to monitor autophagic flux in vivo are important steps for the future development of personalized autophagy-targeting strategies. In this review, we provide an update on the regulatory role of autophagy in various aspects of liver pathophysiology, describing the different strategies to manipulate autophagy and discussing the potential to modulate autophagy as a therapeutic strategy in the context of liver diseases.
Abstract 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 aging, 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.
Membrane vesicles released in the extracellular space are composed of a lipid bilayer enclosing soluble cytosolic material and nuclear components. Extracellular vesicles include apoptotic bodies, ...exosomes, and microvesicles (also known previously as microparticles). Originating from different subcellular compartments, the role of extracellular vesicles as regulators of transfer of biological information, acting locally and remotely, is now acknowledged. Circulating vesicles released from platelets, erythrocytes, leukocytes, and endothelial cells contain potential valuable biological information for biomarker discovery in primary and secondary prevention of coronary artery disease. Extracellular vesicles also accumulate in human atherosclerotic plaques, where they affect major biological pathways, including inflammation, proliferation, thrombosis, calcification, and vasoactive responses. Extracellular vesicles also recapitulate the beneficial effect of stem cells to treat cardiac consequences of acute myocardial infarction, and now emerge as an attractive alternative to cell therapy, opening new avenues to vectorize biological information to target tissues. Although interest in microvesicles in the cardiovascular field emerged about 2 decades ago, that for extracellular vesicles, in particular exosomes, started to unfold a decade ago, opening new research and therapeutic avenues. This Review summarizes current knowledge on the role of extracellular vesicles in coronary artery disease, and their emerging potential as biomarkers and therapeutic agents.
The diagnosis of alcoholic hepatitis (AH) often requires a transjugular liver biopsy (TJLB), a procedure that is not always readily accessible. We analyzed plasma biomarkers to estimate the presence ...of histological features of AH among patients with clinical suspicion of AH. Using enzyme‐linked immunosorbent assay, we tested M65 and M30 (circulating fragments of cytokeratin‐18) and their respective fraction carried by microvesicles (MVs), CCL20 and TREM1. Leukocyte, platelet, and endothelial‐derived MVs were quantified by way of flow cytometry. Test and validation cohorts prospectively included patients with clinical features of AH undergoing TJLB. In the test cohort, 46 of 83 (55%) patients showed histological features of AH. Age, bilirubin, INR, and creatinine (ABIC) score was B or C in 83%. Patients with histologically proven AH had higher levels of total and MV‐bound M65 and total and MV‐bound M30 and CCL20 than those without (P < 0.001 for all tests). Levels of TREM‐1 and of subpopulations of MVs were not different between groups. M65 and M30 both had an area under the receiver operating characteristics curve of 0.84 to estimate the presence of AH. For M65, a cutoff of 2000 IU/L had a positive predictive value of 91%, whereas a cutoff of 641 IU/L had a negative predictive value of 88%. In the validation cohort, AH was histologically confirmed in 48 of 68 (71%) patients. ABIC score was B or C in 69% of patients. For M65, the above cutoffs had a diagnostic accuracy of 81%. Even better results were obtained in patients with suspicion of severe AH (ABIC B or C) in both cohorts. Conclusion: Plasma levels of cytokeratin‐18 fragments are reliable noninvasive markers of AH. Using the proposed cutoffs for M65, two thirds of TJLB can be avoided, which can be useful in centers where this technique is not readily available. (Hepatology 2017;66:555–563).
Beta‐blockers may have a negative impact on survival in patients with cirrhosis and refractory ascites. The aim of this study was to evaluate the effect of the administration of beta‐blockers on ...long‐term survival in patients with cirrhosis and refractory ascites. We performed a single‐center, observational, case‐only, prospective study of patients with cirrhosis and refractory ascites who did or did not receive beta‐blockers for the prevention of gastrointestinal bleeding; 151 patients were included. The mean Model for End‐Stage Liver Disease score was 18.8 ± 4.1. All patients regularly underwent large‐volume paracentesis and intravenous albumin administration. Seventy‐seven patients (51%) were treated with propranolol (113 ± 46 mg/day). The median follow‐up for the whole group was 8 months. The median survival time was 10 months 95% confidence interval (CI) = 8‐12 months. The probability of survival at 1 year was 41% (95% CI = 33%‐49%). The clinical characteristics and laboratory values at enrolment were not significantly different between patients who were receiving propranolol and those who were not. The median survival time was 20.0 months (95% CI = 4.8‐35.2 months) in patients not treated with propranolol and 5.0 months (95% CI = 3.5‐6.5 months) in those treated with propranolol (P = 0.0001). The 1‐year probability of survival was significantly lower in patients who received propranolol 19% (95% CI = 9%‐29%) versus those who did not 64% (95% CI = 52%‐76%), P < 0.0001. The independent variables of mortality were Child‐Pugh class C, hyponatremia and renal failure as causes of refractory ascites, and beta‐blocker therapy. Conclusion: The use of beta‐blockers is associated with poor survival in patients with refractory ascites. These results suggest that beta‐blockers should be contraindicated in these patients. HEPATOLOGY 2010
Disorders of glucose metabolism, namely glucose intolerance and diabetes, are frequent in patients with chronic liver diseases. In patients with cirrhosis, diabetes can be either a classical type 2 ...diabetes mellitus or the so‐called hepatogenous diabetes, i.e. a consequence of liver insufficiency and portal hypertension. This review article provides an overview of the possible pathophysiological mechanisms explaining diabetes in patients with cirrhosis. Cirrhosis is associated with portosystemic shunts as well as reduced hepatic mass, which can both impair insulin clearance by the liver, contributing to peripheral insulin resistance through insulin receptors down‐regulation. Moreover, cirrhosis is associated with increased levels of advanced‐glycation‐end products and hypoxia‐inducible‐factors, which may play a role in the development of diabetes. This review also focuses on the clinical implications of diabetes in patients with cirrhosis. First, diabetes is an independent factor for poor prognosis in patients with cirrhosis. Specifically, diabetes is associated with the occurrence of major complications of cirrhosis, including ascites and renal dysfunction, hepatic encephalopathy and bacterial infections. Diabetes is also associated with an increased risk of hepatocellular carcinoma in patients with chronic liver diseases. Last, the management of patients with concurrent diabetes and liver disease is also addressed. Recent findings suggest a beneficial impact of metformin in patients with chronic liver diseases. Insulin is often required in patients with advanced cirrhosis. However, the favourable impact of controlling diabetes in patients with cirrhosis has not been demonstrated yet.
The prevention and management of bleeding and thrombosis in patients with cirrhosis poses several difficult clinical questions. These Clinical Practice Guidelines have been developed to provide ...practical guidance on debated topics, including current views on haemostasis in liver disease, controversy regarding the need to correct thrombocytopenia and abnormalities in the coagulation system in patients undergoing invasive procedures, and the need for thromboprophylaxis in hospitalised patients with haemostatic abnormalities. Multiple recommendations in this document are based on interventions that the panel feels are not useful, even though widely applied in clinical practice.
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