TAM Receptors in the Pathophysiology of Liver Disease

TAM receptors (Tyro3, Axl and MerTK) are a family of tyrosine kinase receptors that are expressed in a variety of cell populations, including liver parenchymal and non-parenchymal cells. These receptors are vital for immune homeostasis, as they regulate the innate immune response by suppressing inflammation via toll-like receptor inhibition and by promoting tissue resolution through efferocytosis. However, there is increasing evidence indicating that aberrant TAM receptor signaling may play a role in pathophysiological processes in the context of liver disease. This review will explore the roles of TAM receptors and their ligands in liver homeostasis as well as a variety of disease settings, including acute liver injury, steatosis, fibrosis, cirrhosis-associated immune dysfunction and hepatocellular carcinoma. A better understanding of our current knowledge of TAM receptors in liver disease may identify new opportunities for disease monitoring as well as novel therapeutic targets. Nonetheless, this review also aims to highlight areas where further research on TAM receptor biology in liver disease is required.

Cellular and Molecular Mechanisms Underlying Scope and Limitation of Ongoing and Innovative Therapies for Treating Chronic Hepatitis B

Millions of people of the world suffer from chronic hepatitis B (CHB), a pathological entity in which the patients are chronically infected with hepatitis B virus (HBV) and express hepatitis B surface antigen (HBsAg) and HBV DNA, as well as evidence of liver damages. Considerable numbers of CHB patients develop cirrhosis of the liver and hepatocellular carcinoma if untreated. Two groups of drugs (interferons and nucleoside analogs) are used to treat CHB patients, but both are endowed with considerable adverse effects, increased costs, extended duration of therapy, and limited efficacy. Thus, there is a pressing need to develop new and innovative therapeutics for CHB patients, and many such drugs have been developed during the last four decades. Some of these drugs have inspired considerable optimism to be a game-changer for the treatment of CHB. Here, we first discuss why ongoing therapeutics such as interferon and nucleoside analogs could not stand the test of time. Next, we dissect the scope and limitation of evolving therapies for CHB by dissecting the cellular and molecular mechanisms of some of these innovative therapeutics.

Biliary hCGβ Is a Potential Novel Marker for Prediction of Biliary Neoplasia in Primary Sclerosing Cholangitis Patients

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease, which is associated with an increased risk of cholangiocarcinoma (CCA). Novel markers, to complement or replace CA19-9, are urgently needed for the screening of PSC-associated biliary neoplasia. Previous studies have suggested that serum trypsinogen-2 and human chorionic gonadotropin β-subunit (hCGβ) may serve as such markers. Using highly specific in-house immunoassays, we studied trypsin(ogen)-2 and -3, SPINK1 and hCGβ in bile samples of 214 patients, referred for endoscopic retrograde cholangiography. We found that biliary trypsinogen-2 was decreased (p = 0.027) and hCGβ was elevated (p < 0.001) in PSC patients who were diagnosed 1.6 years (median, range 0.1–8.8 years) later with CCA or in whom biliary dysplasia was observed at least twice in brush cytology (n = 11) as compared to PSC patients without CCA or repeated dysplasia (n = 171). The other studied markers did not show significant differences between these groups. Our results warrant further evaluation of hCGβ as a predictive marker for PSC-associated biliary neoplasia.

Predictive Factors for Hepatocellular Carcinoma Development after Direct-Acting Antiviral Treatment of HCV

Chronic hepatitis C virus infection is still one of the major risk factors for the development of hepatocellular carcinoma (HCC), the most frequent type of primary liver cancer. Direct-acting antivirals have substantially improved the cure rate of the virus, but the risk of hepatitis C virus-related HCC remains high, mainly in patients with advanced liver fibrosis and cirrhosis. HCC is often asymptomatic and, therefore, remains undetected until the late tumor stage, which is associated with poor survival rates. Therefore, to improve the surveillance programs following HCV eradication, there is a need to summarize predictive factors or potential biomarkers, to specifically identify patients likely to develop HCC after direct-acting antiviral treatment. This review outlines the most recent data about different predictive factors for HCC development after direct-acting antiviral treatment of hepatitis C virus-infected patients, to improve the clinical management of patients with chronic hepatitis C virus.

Statistical Machine Learning Approaches to Liver Disease Prediction

Medical diagnoses have important implications for improving patient care, research, and policy. For a medical diagnosis, health professionals use different kinds of pathological methods to make decisions on medical reports in terms of the patients’ medical conditions. Recently, clinicians have been actively engaged in improving medical diagnoses. The use of artificial intelligence and machine learning in combination with clinical findings has further improved disease detection. In the modern era, with the advantage of computers and technologies, one can collect data and visualize many hidden outcomes such as dealing with missing data in medical research. Statistical machine learning algorithms based on specific problems can assist one to make decisions. Machine learning (ML), data-driven algorithms can be utilized to validate existing methods and help researchers to make potential new decisions. The purpose of this study was to extract significant predictors for liver disease from the medical analysis of 615 humans using ML algorithms. Data visualizations were implemented to reveal significant findings such as missing values. Multiple imputations by chained equations (MICEs) were applied to generate missing data points, and principal component analysis (PCA) was used to reduce the dimensionality. Variable importance ranking using the Gini index was implemented to verify significant predictors obtained from the PCA. Training data (ntrain=399) for learning and testing data (ntest=216) in the ML methods were used for predicting classifications. The study compared binary classifier machine learning algorithms (i.e., artificial neural network, random forest (RF), and support vector machine), which were utilized on a published liver disease data set to classify individuals with liver diseases, which will allow health professionals to make a better diagnosis. The synthetic minority oversampling technique was applied to oversample the minority class to regulate overfitting problems. The RF significantly contributed (p<0.001) to a higher accuracy score of 98.14% compared to the other methods. Thus, this suggests that ML methods predict liver disease by incorporating the risk factors, which may improve the inference-based diagnosis of patients.

Redrawing the Map to Novel DILI Biomarkers in Circulation: Where Are We, Where Should We Go, and How Can We Get There?

Circulating biomarkers of drug-induced liver injury (DILI) have been a focus of research in hepatology over the last decade, and several novel DILI biomarkers that hold promise for certain applications have been identified. For example, glutamate dehydrogenase holds promise as a specific biomarker of liver injury in patients with concomitant muscle damage. It may also be a specific indicator of mitochondrial damage. In addition, microRNA-122 is sensitive for early detection of liver injury in acetaminophen overdose patients. However, recent events in the field of DILI biomarker research have provided us with an opportunity to step back, consider how biomarker discovery has been done thus far, and determine how to move forward in a way that will optimize the discovery process. This is important because major challenges remain in the DILI field and related areas that could be overcome in part by new biomarkers. In this short review, we briefly describe recent progress in DILI biomarker discovery and development, identify current needs, and suggest a general approach to move forward.

Noncoding RNAs Interactions in Hepatic Stellate Cells during Hepatic Fibrosis

Hepatic fibrosis is a reversible wound healing process following liver injury. Although this process is necessary for maintaining liver integrity, severe excessive extracellular matrix accumulation (ECM) could lead to permanent scar formation and destroy the liver structure. The activation of hepatic stellate cells (HSCs) is a key event in hepatic fibrosis. Previous studies show that most antifibrotic therapies focus on the apoptosis of HSCs and the prevention of HSC activation. Noncoding RNAs (ncRNAs) play a substantial role in HSC activation and are likely to be biomarkers or therapeutic targets for the treatment of hepatic fibrosis. This review summarizes and discusses the previously reported ncRNAs, including the microRNAs, long noncoding RNAs, and circular RNAs, highlighting their regulatory roles and interactions in the signaling pathways that regulate HSC activation in hepatic fibrosis.

Fructose Consumption and Hepatocellular Carcinoma Promotion

Hepatocellular carcinoma (HCC) accounts for 85% of primary liver cancer, the third most common cause of cancer-related deaths worldwide. Its incidence has been increasing in both men and women. In Western countries, high-calorie diets, mainly rich in carbohydrates such as fructose, represent a significant concern due to their repercussions on the population’s health. A high-fructose diet is related to the development of Metabolic-Associated Fatty Liver Disease (MAFLD), formerly named Non-Alcoholic Fatty Liver Disease (NAFLD), and the progression of HCC as it potentiates the lipogenic pathway and the accumulation of lipids. However, fructose metabolism seems to be different between the stages of the disease, carrying out a metabolic reprogramming to favor the proliferation, inflammation, and metastatic properties of cancer cells in HCC. This review focuses on a better understanding of fructose metabolism in both scenarios: MAFLD and HCC.

Na+-Taurocholate Co-Transporting Polypeptide (NTCP) in Livers, Function, Expression Regulation, and Potential in Hepatitis B Treatment

Chronic hepatitis B virus (HBV) infection has become one of the leading causes of liver cirrhosis and hepatocellular carcinoma globally. The discovery of sodium taurocholate co-transporting polypeptide (NTCP), a solute carrier, as a key receptor for HBV and hepatitis D virus (HDV) has opened new avenues for HBV treatment. Additionally, it has led researchers to generate hepatoma cell lines (including HepG2-NTCP and Huh-7-NTCP) susceptible to HBV infection in vitro, hence, paving the way to develop and efficiently screen new and novel anti-HBV drugs. This review summarizes the history, function and critical findings regarding NTCP as a viral receptor for HBV/HDV, and it also discusses recently developed drugs targeting NTCP.

Prevalence of Hepatitis B Serum Markers in Young Military Recruits in Greece: A Comparison Study between 2005 and 2019 Cohorts

Background: The prevalence of hepatitis B (HBV) varies among countries. Although an overall reduction has been described in Greece, data are limited. Methods: We reviewed the HBsAg/anti-HBc/anti-HBs seroprevalence among military recruits and compared data between 2005 and 2019. The study included 2001 (group 1) and 1629 (group 2) male recruits in 2019 and 2005, respectively. Age and descent were recorded. Results: The prevalence of HBsAg, anti-HBc and anti-HBs positivity in group1 vs. group 2 was estimated as: 0.2%, 1.3% and 67% vs. 0.4%, 1.6% and 62%, respectively. Only anti-HBs positivity achieved a statistically significant difference between the two groups (p = 0.007). HBsAg and anti-HBc were more frequently positive in non-Greeks than in Greeks (9/237 (4%) vs. 2/3393 (0.06%), p < 0.001), (26/237 (11%) vs. 26/3393 (0.8%), p < 0.001 respectively), while anti-HBs was more frequently positive in Greeks than in non-Greeks (84/164 (51%) vs. 1461/2213 (66%), p < 0.001). Conclusions: Our data suggest a further reduction in HBV prevalence in Greece about 20 years after the adoption of the National HBV Immunization Program, with Greek participants experiencing a more effective HBV Immunization Program than non-Greeks.