Aberrant hepatic trafficking of gut-derived T cells is not specific to primary sclerosing cholangitis.

BACKGROUND AND AIMS: The "gut homing" hypothesis suggests the pathogenesis of primary sclerosing cholangitis (PSC) is driven by aberrant hepatic expression of gut adhesion molecules and subsequent recruitment of gut-derived T cells to the liver. However, inconsistencies lie within this theory including an absence of investigations and comparisons with other chronic liver diseases (CLD). Here, we examine "the gut homing theory" in patients with PSC with associated inflammatory bowel disease (PSC-IBD) and across multiple inflammatory liver diseases. APPROACH AND RESULTS: Expression of MAdCAM-1, CCL25, and E-Cadherin were assessed histologically and using RT-PCR on explanted liver tissue from patients with CLD undergoing OLT and in normal liver. Liver mononuclear cells were isolated from explanted tissue samples and the expression of gut homing integrins and cytokines on hepatic infiltrating gut-derived T cells was assessed using flow cytometry. Hepatic expression of MAdCAM-1, CCL25 and E-Cadherin was up-regulated in all CLDs compared with normal liver. There were no differences between disease groups. Frequencies of α4ß7, αEß7, CCR9, and GPR15 expressing hepatic T cells was increased in PSC-IBD, but also in CLD controls, compared with normal liver. ß7 expressing hepatic T cells displayed an increased inflammatory phenotype compared with ß7 negative cells, although this inflammatory cytokine profile was present in both the inflamed and normal liver. CONCLUSIONS: These findings refute the widely accepted "gut homing" hypothesis as the primary driver of PSC and indicate that aberrant hepatic recruitment of gut-derived T cells is not unique to PSC, but is a panetiological feature of CLD.

Residual risk of liver disease after hepatitis C virus eradication.

Treatment of hepatitis C with direct-acting antivirals is safe and highly efficacious, resulting in viral clearance (sustained virological response [SVR]) in the vast majority of patients. Although SVR is mostly permanent and associated with a significant reduction of liver morbidity and mortality, some patients may still suffer from a major risk of progressive liver damage, potentially leading to severe complications - including liver decompensation, hepatocellular carcinoma and death. This concise review discusses some of the most important features of residual liver disease in patients with chronic hepatitis C who have achieved SVR after antiviral therapy.

EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis - 2021 update.

Non-invasive tests are increasingly being used to improve the diagnosis and prognostication of chronic liver diseases across aetiologies. Herein, we provide the latest update to the EASL Clinical Practice Guidelines on the use of non-invasive tests for the evaluation of liver disease severity and prognosis, focusing on the topics for which relevant evidence has been published in the last 5 years.

CystAnalyser: A new software tool for the automatic detection and quantification of cysts in Polycystic Kidney and Liver Disease, and other cystic disorders.

The Polycystic Kidney Disease (PKD) is characterized by progressive renal cyst development and other extrarenal manifestation including Polycystic Liver Disease (PLD). Phenotypical characterization of animal models mimicking human diseases are commonly used, in order to, study new molecular mechanisms and identify new therapeutic approaches. The main biomarker of disease progression is total volume of kidney and liver in both human and mouse, which correlates with organ function. For this reason, the estimation of the number and area of the tissue occupied by cysts, is critical for the understanding of physiological mechanisms underlying the disease. In this regard, cystic index is a robust parameter commonly used to quantify the severity of the disease. To date, the vast majority of biomedical researchers use ImageJ as a software tool to estimate the cystic index by quantifying the cystic areas of histological images after thresholding. This tool has imitations of being inaccurate, largely due to incorrectly identifying non-cystic regions. We have developed a new software, named CystAnalyser (register by Universidade de Santiago de Compostela-USC, and Fundación Investigación Sanitaria de Santiago-FIDIS), that combines automatic image processing with a graphical user friendly interface that allows investigators to oversee and easily correct the image processing before quantification. CystAnalyser was able to generate a cystic profile including cystic index, number of cysts and cyst size. In order to test the CystAnalyser software, 795 cystic kidney, and liver histological images were analyzed. Using CystAnalyser there were no differences calculating cystic index automatically versus user input, except in specific circumstances where it was necessary for the user to distinguish between mildly cystic from non-cystic regions. The sensitivity and specificity of the number of cysts detected by the automatic quantification depends on the type of organ and cystic severity, with values 76.84-78.59% and 76.96-89.66% for the kidney and 87.29-93.80% and 63.42-86.07% for the liver. CystAnalyser, in addition, provides a new tool for estimating the number of cysts and a more specific measure of the cystic index than ImageJ. This study proposes CystAnalyser is a new robust and freely downloadable software tool for analyzing the severity of disease by quantifying histological images of cystic organs for routine biomedical research. CystAnalyser can be downloaded from https://citius.usc.es/transferencia/software/cystanalyser (for Windows and Linux) for research purposes.

Point Shear Wave Elastography for Assessing Liver Stiffness in Chronic Liver Diseases of Different Etiologies Compared to Biopsy.

BACKGROUND: Point shear-wave elastography (pSWE) is a new method to assess the degree of liver fibrosis. It has been shown to be effective in detecting stiffness in viral hepatitis. OBJECTIVES: To determine the feasibility of pSWE for assessing liver stiffness and fibrosis in liver diseases of different etiologies. METHODS: This prospective single-center study included a population of adult patients with chronic liver diseases from different etiologies, who were scheduled for liver biopsy, and a control group of healthy adults who prospectively underwent pSWE. Ten consecutive pSWE measurements of the liver were performed using a Philips iU22 ultrasound system. Stiffness degree was compared to liver biopsy results. Fibrosis degree was staged according to METAVIR scoring system. RESULTS: The study group was comprised of 202 patients who underwent liver biopsy and pSWE test and a control group consisting of 14 healthy adults who underwent pSWE for validation. In the study group, the median stiffness was 5.35 ± 3.37 kilopascal (kPa). The median stiffness for F0-1, F2, F3, and F4 as determined by liver biopsy results were 4.9 kPa, 5.4 kPa, 5.7 kPa, and 8 kPa, respectively. The median stiffness in the control group was 3.7 ± 0.6 kPa. Subgroup analyses were conducted for viral hepatitis vs. non-viral hepatitis and steatohepatitis vs. non-steatohepatitis groups. CONCLUSIONS: pSWE is a reproducible method for assessing liver stiffness and is in a linear relationship with fibrosis degree as seen in pathology. Compared with patients with non-significant fibrosis, healthy controls showed significantly lower values.

Extracellular vesicles as biomarkers in liver diseases: A clinician's point of view.

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.

Global liver disease burdens and research trends: Analysis from a Chinese perspective.

Liver diseases affect millions of people worldwide. In most developed countries, the incidence of viral hepatitis is waning as a result of modern advances in disease prevention, diagnosis, and therapies. Expanded programmes for systematic immunisation against hepatitis B virus have also significantly brought down the number of new cases in many countries, including China. In contrast, with the improvement in living standards, the prevalence of metabolic liver diseases including non-alcoholic fatty liver disease and alcohol-related liver disease is set to rise, ultimately leading to more cases of end-stage liver diseases (liver failure, cirrhosis, and liver cancer). Over the past 30 years, visionary governments of major nations have provided strong incentives for basic/clinical research, vaccination programmes, and drug discovery and development in the field of hepatology. To get rid of her unflattering title as the "leader in liver diseases", China has also made a serious effort to initiate nationwide preventive measures for liver diseases, global partnerships, and mentoring programmes for young hepatologists. Instrumental to such progress is the continuous support of the National Natural Science Foundation of China (NSFC), which has helped hepatology to thrive in virtually all research directions within the country. In this article, we seek to provide stimulating glimpses into the evolving liver disease epidemiology, institutional research profiles, funding landscape, and drug development trends in China, with an attempt to compare her status and achievements with those of the United States, European countries, and Japan.

Gut microbiota in liver disease: too much is harmful, nothing at all is not helpful either.

The intestinal microbiome plays a major role in the pathogenesis of liver disease, with a hallmark event being dysbiosis, or an imbalance of pathobionts and beneficial bacteria with the associated deleterious effects on their host. Reducing the number of intestinal bacteria with antibiotic treatment is generally advantageous in experimental liver diseases. Complete absence of intestinal microbiota as in germ-free rodents can be protective in autoimmune hepatitis and hepatic tumors induced by chemicals, or it can exacerbate disease as in acute toxic liver injury and liver fibrosis/cirrhosis. In alcoholic liver disease, nonalcoholic fatty liver disease, and autoimmune cholangiopathies, germ-free status can be associated with worsened or improved hepatic phenotype depending on the experimental model and type of rodent. Some of the unexpected outcomes can be explained by the limitations of rodents raised in a germ-free environment including a deficient immune system and an altered metabolism of lipids, cholesterol, xenobiotics/toxins, and bile acids. Given these limitations and to advance understanding of the interactions between host and intestinal microbiota, simplified model systems such as humanized gnotobiotic mice, or gnotobiotic mice monoassociated with a single bacterial strain or colonized with a defined set of microbes, are unique and useful models for investigation of liver disease in a complex ecosystem.

Role of US LI-RADS in the LI-RADS Algorithm.

The US Liver Imaging Reporting and Data System (LI-RADS) was released in 2017 and is the newest of the four American College of Radiology (ACR) LI-RADS algorithms. US LI-RADS provides standardized terminology, technical recommendations, and a reporting framework for US examinations performed for screening or surveillance in patients at risk for developing hepatocellular carcinoma (HCC). The appropriate patient population for screening and surveillance includes individuals who are at risk for developing HCC but do not have known or suspected cancer. This includes patients with cirrhosis from any cause and subsets of patients with chronic hepatitis B virus infection in the absence of cirrhosis. In an HCC screening or surveillance study, US LI-RADS recommends assigning two scores that apply to the entire study: the US category, which determines follow-up, and a visualization score, which communicates the expected level of sensitivity of the examination but does not affect management. Three US categories are possible: US-1 negative, a study with no evidence of HCC; US-2 subthreshold, a study in which an observation less than 10 mm is depicted that is not definitely benign; and US-3 positive, a study in which an observation greater than or equal to 10 mm or a new thrombus in vein is identified, for which diagnostic contrast material-enhanced imaging is recommended. Three visualization scores are possible: A (no or minimal limitations), B (moderate limitations), and C (severe limitations). ©RSNA, 2019.

Burden of liver disease in Europe: Epidemiology and analysis of risk factors to identify prevention policies.

The burden of liver disease in Europe continues to grow. We aimed to describe the epidemiology of liver diseases and their risk factors in European countries, identifying public health interventions that could impact on these risk factors to reduce the burden of liver disease. As part of the HEPAHEALTH project we extracted information on historical and current prevalence and mortality from national and international literature and databases on liver disease in 35 countries in the World Health Organization European region, as well as historical and recent prevalence data on their main determinants; alcohol consumption, obesity and hepatitis B and C virus infections. We extracted information from peer-reviewed and grey literature to identify public health interventions targeting these risk factors. The epidemiology of liver disease is diverse, with variations in the exact composition of diseases and the trends in risk factors which drive them. Prevalence and mortality data indicate that increasing cirrhosis and liver cancer may be linked to dramatic increases in harmful alcohol consumption in Northern European countries, and viral hepatitis epidemics in Eastern and Southern European countries. Countries with historically low levels of liver disease may experience an increase in non-alcoholic fatty liver disease in the future, given the rise of obesity across most European countries. Liver disease in Europe is a serious issue, with increasing cirrhosis and liver cancer. The public health and hepatology communities are uniquely placed to implement measures aimed at reducing their causes: harmful alcohol consumption, child and adult obesity, and chronic infection with hepatitis viruses, which will in turn reduce the burden of liver disease.

Factors influencing on health-related quality of life in South Korean with chronic liver disease.

BACKGROUND: The objective of this study was to determine health-related quality of life (HRQoL) among chronic liver disease (CLD) subjects in South Korea using EuroQol five-dimension questionnaire (EQ-5D). METHOD: The sample consisted of 139 subjects with CLD from the sixth Korean National Health and Nutrition Examination Survey (KNHNES VI). Data were analyzed using SPSS program for descriptive statistics, t-test, ANOVA, Scheffe's test and hierarchical multiple regression. RESULTS: Results indicated that marital status (P < 0.01), occupation (P < 0.01), basic livelihood security recipient status (P < 0.05), hepatocellular carcinoma (P < 0.05), subjective health status (P < 0.01), and depression (P < 0.001) were significant predictors of HRQoL. Health behaviors (alcohol intake, sleep duration) variables were insignificant. CONCLUSION: In conclusion, marital status, occupation, basic livelihood security recipient status (BLSRS), hepatocellular carcinoma (HCC), subjective health status (SHS), and depression were confirmed to be factors affecting the HRQoL. We should be provide to continuous monitoring and education of adequate alcohol intake for patients with CLD. Findings of this study might be used to develop community based health programs and policies for CLD.

Change in nomenclature for the immunologic synapse from Troxis Necrosis to trogocytosis.

The immunologic synapse mechanism of liver necrosis was termed Troxis Necrosis meaning "nibbling". (Wang MX et al. and French SW. Exp Mol Pathol 2001, 71: 137-146). This mechanism of liver injury was first named "Piecemeal Necrosis" by Hans Popper. It is involved in autoimmune hepatitis, HCV, HBV, primary biliary cirrhosis and steatohepatitis. This process involves the T cell receptor (TCR) which binds to the hepatocyte antigen presenting major histocompatibility complex (MHC) on the hepatocytic plasma membrane which quickly leads to the removal of the complex from the liver and uptake by the CD4 lymphocyte. This process is performed by the immunologic synapse now called trogocytosis meaning "gnaw" (Martinez-Martin N et al., Immunity 2011, 35: 208-222 and Dustin ML, Cancer Immunol Res 2014, 2: 1023-1033). The repeated episodes of uptake of the hepatocyte bite by bite causes the hepatocyte to slowly disappear like the Cheshire cat. This immunological synapse process is also involved in drug hepatitis, Hashimoto's thyroiditis, type I diabetes, autoimmune adrenalitis, autoimmune gastritis and cancer therapy. Treatment of Alzheimer's disease is also now being studied with PD-L1 antibody as used in the treatment of cancer allowing recruitment of disease modifying leukocytes to the sites of brain pathology (Schwartz M. Science 2017, 357: 254-255). Acknowledgement: Supported by a Grant from NIAAAUO1-021898.

Genetics of liver disease: From pathophysiology to clinical practice.

Paralleling the first 30 years of the Journal of Hepatology we have witnessed huge advances in our understanding of liver disease and physiology. Genetic advances have played no small part in that. Initial studies in the 1970s and 1980s identified the strong major histocompatibility complex associations in autoimmune liver diseases. During the 1990 s, developments in genomic technologies drove the identification of genes responsible for Mendelian liver diseases. Over the last decade, genome-wide association studies have allowed for the dissection of the genetic susceptibility to complex liver disorders, in which also environmental co-factors play important roles. Findings have allowed the identification and elaboration of pathophysiological processes, have indicated the need for reclassification of liver diseases and have already pointed to new disease treatments. In the immediate future genetics will allow further stratification of liver diseases and contribute to personalized medicine. Challenges exist with regard to clinical implementation of rapidly developing technologies and interpretation of the wealth of accumulating genetic data. The historical perspective of genetics in liver diseases illustrates the opportunities for future research and clinical care of our patients.

Diagnosis and Management of Hepatitis C.

Hepatitis C virus (HCV) infection, a major cause of chronic liver disease and cirrhosis, is predominantly transmitted by exposure to blood or body fluids. The infection progresses to a chronic state in 80% of patients, whereas the virus clears completely after the acute infection in 20% of patients. Screening for HCV with an anti-HCV antibody test is recommended for all adults at high risk of infection, and one-time screening is recommended in adults born between 1945 and 1965. If the anti-HCV antibody test result is positive, current infection should be confirmed with a qualitative HCV RNA test. In patients with confirmed HCV infection, quantitative HCV RNA testing and testing for HCV genotype is recommended. An assessment of the degree of liver fibrosis with liver biopsy or noninvasive testing is necessary to determine the urgency of treatment. Treatment of patients with chronic HCV infection should be considered based on genotype, extent of fibrosis or cirrhosis, prior treatment, comorbidities, and potential adverse effects. The goal of therapy is to reduce all-cause mortality and liver-associated complications. Although interferon-based regimens have been the mainstay of treatment for HCV infection, the U.S. Food and Drug Administration recently approved two combination-pill interferon-free treatments (ledipasvir plus sofosbuvir, and ombitasvir/paritaprevir/ritonavir plus dasabuvir) for chronic HCV genotype 1.

[Features Interaction Lasso for Liver Disease Classification].

To solve the complex interaction problems of hepatitis disease classification, we proposed a lasso method (least absolute shrinkage and selection operator method) with feature interaction. First, lasso penalized function and hierarchical convex constraint were added to the interactive model which is newly defined. Then the model was solved with the convex optimal method combining Karush-Kuhn-Tucker (KKT) condition with generalized gradient descent. Finally, the sparse solution of the main effect features and interactive features were derived, and the classification model was implemented. The experiments were performed on two liver data sets and proved that features interaction contributed to the classification of liver diseases. The experimental results showed that the feature interaction lasso method was of strong explanatory ability, and its effectiveness and efficiency were superior to those of lasso, of all pair-wise lasso, support vector machine (SVM) method, K nearest neighbor (KNN) method, linear discriminant analysis (LDA) classification method, etc.

[DETERMINING THE DEGREE OF LIVER DYSFUNCTION IN CHILDREN WITH POSITIONS OF THE INTERNATIONAL CLASSIFICATION OF FUNCTIONING, DISABILITY AND HEALTH (ICF)].

METHODS: Based on a retrospective analysis of biochemical blood parameters which characterize the role of liver function in the metabolism of proteins, fats and carbohydrates (considered indicators of ALT, AST, De Ritis coefficient, bilirubin, albumin, fibrinogen, prothrombin, transferrin, ceruloplasmin, cholesterol, urea, ammonia, glucose, lactate) in 95 children without liver pathology, 15 children who died of liver failure, 295 patients with various liver diseases who were treated in the SCCH, a scale system was developed as a support tool to assess liver dysfunction. RESULTS: Each biochemical indicator was assessed on a five-point scale. The level of a biochemical indicator, which corresponded to the absence of disorders, was estimated as 4 points, corresponding to "insignificant disorders"--as 3 points, "moderate disorders"--as 2 points, "severe disorders"--as 1 point, "absolute disorders"--as 0 points. The total score is the estimate of the degree of liver dysfunction. According to the recommendations of the International Classification of Functioning, Limitations of vital activities and Health, the decrease of the number of points on 0-4% (54-56 points) corresponds to the absence of the liver dysfunction, on 5-24% (43-53 points)--insignificant disorders of liver function, on 25-49% (29-42 points)--moderate hepatic impairment, on 50-95% (3-28 points)--severe disturbances of liver function, on 96-100% (0-2 points)--absolute dysfunction of the liver. CONCLUSIONS: A scoring system of assessing liver dysfunction can be applied at any stage of the examination and treatment of children of any age, as used in biochemical parameters do not depend on the age of the patient. It is an objective criterion for assessing the degree of liver dysfunction and can be used to assess the severity of the pathological process in the dynamics determining the prognosis of the disease and can be the criterion of the indications for liver transplantation, and also used during the of medico-social expert examination.

Hepatocellular benign tumors-from molecular classification to personalized clinical care.

Focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) are benign hepatocellular tumors that develop most frequently in women without cirrhosis. Genomic approaches have identified signaling pathways related to these benign hepatocyte proliferations. FNH, a polyclonal lesion, is characterized by local vascular abnormalities and heterogeneous activation of Wnt/ß-catenin and transforming growth factor ß signaling. Four major subgroups of HCAs have been identified based on mutations in specific oncogenes and tumor suppressor genes. Each molecular subtype of HCA has been associated with specific pathways, providing new information about benign tumorigenesis. Key features include metabolic alterations (induced by defects in HNF1A), oncogene-induced inflammation (activation of JAK-STAT signaling in inflammatory adenomas), and an association between activation of Wnt/ß-catenin signaling and progression of HCAs in hepatocellular carcinomas. Benign hepatocellular tumors can be classified using immunohistochemical analyses. Studies of genotypes and phenotypes of FNH and HCAs have led to the identification of risk factors and improved invasive and noninvasive diagnostic techniques, evaluation of prognosis, and treatment. We review the molecular pathways involved in benign hepatocyte proliferation and discuss how this basic knowledge has been progressively translated into personalized clinical care.

m-RECIST at 1 month and Child A are survival predictors after percutaneous ethanol injection of hepatocellular carcinoma.

BACKGROUND AND AIMS: Percutaneous ethanol injection (PEI) is a well-established therapeutic option in patients with cirrhosis and hepatocellular carcinoma (HCC). The modified-Response Evaluation Criteria in Solid Tumors (m-RECIST) are an important tool for the assessment of HCC response to therapy. The aim was to evaluate whether HCC response according to the m-RECIST criteria could be an effective predictor of long-term survival in Barcelona Clinic Liver Cancer (BCLC) stage 0 and A HCC patients undergoing PEI. MATERIAL AND METHODS: 79 patients were followed-up for median time of 26.8 months. HCC diagnosis was based on the current guidelines of the American Association for Study of the Liver Diseases (AASLD) and European Association for Study of the Liver (EASL). Patient survival was calculated from the first PEI session to the end of the follow-up. RESULTS: The 1-, 3-, and 5-year overall survival rates were 79, 48 and 37%, respectively. In the multivariate analysis, Child-Pugh-Turcotte (CPT) (p = 0.022) and the response to m-RECIST criteria (p = 0.016) were associated with patient survival. CPT A patients who achieved Complete Response (CR) 1 month after PEI presented a 5-year survival rate of 55%. By contrast, the worst scenario, the group with CPT B but without CR had a 5-year survival rate of 9%, while the group with either CPT A or CR as a survival predictor had a 5-year survival rate of 31%. In conclusion, in BCLC stage 0 and A HCC-patients, m-RECIST at 1 month and Child A may predict survival rates after PEI.