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Human immunodeficiency virus (HIV) and hepatitis-B virus (HBV) infections are weighty public health challenges, especially in the African continent. The direct carcinogenic effect of HBV means that it remains a potent cause of early-onset hepatocellular carcinoma (HCC) in Sub-Saharan Africa (SSA), where it causes significant morbidity and mortality. The presence of HIV infection in HBV-infected patients poses a complicating factor, as coinfection has been shown to hasten the progression of liver disease to cirrhosis and HCC, and often resulting in early-age hepatocarcinogenesis with consequent late diagnosis and lower survival. In this review, we discuss this unique conundrum, the epidemiology of HIV-HBV coinfection in SSA, its effect on liver disease and development of HCC, as well as practices and barriers to HCC surveillance in this distinct population. We propose a way forward to curb this considerable health burden focusing on reduction of disease stigma, the need for easy-to-measure biomarkers, and implementation of large prospective studies in this population. LESS      Full article

Over the last decade, we have been facing a new aetiology responsible for the development of HCC - the non-alcoholic fatty liver disease (NAFLD). The prevalence of HCC development in this group is higher than that observed in the general population and in non-cirrhotic subjects with other causes of liver disease. Conventional ultrasound (US) is the first-line tool for HCC surveillance, but, in this population, it has a decreased diagnostic accuracy due to several particular features, including obesity and steatosis. Contrast-enhanced ultrasound (CEUS) appeared as a new branch of US due to its ability to depict the vascular architecture of all types of focal lesions (FLs). Nevertheless, CEUS has several limitations besides those inherited from US, which renders this method unreliable as the first-line HCC diagnostic tool and for HCC staging. Artificial intelligence eliminates operator limitations, which has led to an increased sensitivity and specificity of US. However, this approach is still in its early stages and more data are needed. Consequently, the purpose of the current study is to highlight the strengths and limits of US, along with its alternatives to HCC screening in NAFLD population. LESS      Full article

Nonalcoholic fatty liver disease (NAFLD) is the major contributor to the global burden of chronic liver diseases and ranges from simple and reversible steatosis to nonalcoholic steatohepatitis (NASH), which may progress into cirrhosis and hepatocellular carcinoma (HCC). HCC represents the most common liver cancer, and it is a leading cause of death worldwide with an increasing trend for the future. Due to late diagnosis, non-responsiveness to systemic therapy, and high cancer heterogeneity, the treatment of this malignancy is challenging. To date, liver biopsy and ultrasound (US) are the gold standard procedures for HCC diagnosis and surveillance, although they are not suitable for mass screening. Therefore, it is impelling to find new, less invasive diagnostic strategies able to detect HCC at an early stage as well as monitor tumor progression and recurrence. Common and rare inherited variations that boost the switching from NASH to liver cancer may help to predict tumor onset. Furthermore, epigenetic changes which reflect intertumoral heterogeneity occur early in tumorigenesis and are highly stable under pathologic conditions. The severity of hepatic injuries can be detected through the analysis of cell circulating tumor DNAs (ctDNAs), microRNAs (miRNAs), and noncoding RNAs (ncRNAs), which are involved in several pathological processes that feature cancer, including cell growth, survival, and differentiation, thus representing appealing biomarkers for HCC. Therefore, this review discusses the current options for HCC surveillance, focusing on the role of genetic and epigenetic biomarkers as new strategies to refine HCC management. LESS      Full article

Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy. In the clinic, therapeutic resistance is largely attributed to tumor heterogeneity. Growing evidence indicates that cancer stem cells (CSCs) are the major source of tumor heterogeneity. Hence, uncovering the resistance mechanisms associated with CSC properties is essential for developing effective therapeutics. CSCs resemble embryonic stem cells. Embryonic development-related genes and signaling pathways are usually abnormally active and function as oncofetal drivers in HCC. Multiple strategies have been applied to identify oncofetal drivers. The mechanisms of CSC resistance could also provide reliable biomarkers to predict treatment failure. Precisely targeting these specific CSC properties may be effective in preventing or annihilating therapy resistance. This review provides an overview of drug resistance mechanisms associated with CSC traits and summarize therapeutic strategies against drug resistance. LESS      Full article

Liver transplantation is the only potentially curative option for unresectable hepatoblastoma. The introduction of platinum-based chemotherapy drastically improved the survival outcomes of patients with hepatoblastoma. However, the use of neoadjuvant chemotherapy and the optimal number of cycles required in patients listed for liver transplantation, as well as the potential use of adjuvant chemotherapy, remain unclear. Additionally, the shortage of donor liver grafts, along with the lack of clear consensus on the management of metastatic hepatoblastoma, makes the decision on whether to proceed to liver transplantation even more complex and challenging. Technological advances may optimize intraoperative imaging of both the primary tumor and metastatic sites, thus facilitating complete resection. Such improvements, along with the wider use of social media platforms to increase public awareness, could potentially pave the way for more optimal implementation of liver transplantation for the treatment of patients with unresectable hepatoblastoma. LESS      Full article

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder worldwide. It comprises a spectrum of conditions that range from steatosis to non-alcoholic steatohepatitis, with progression to cirrhosis and hepatocellular carcinoma. Currently, there is no FDA-approved pharmacological treatment for NAFLD. The pathogenesis of NAFLD involves genetic and environmental/host factors, including those that cause changes in intestinal microbiota and their metabolites. In this review, we discuss recent findings on the relationship(s) of microbiota signature with severity of NAFLD and the role(s) microbial metabolites in NAFLD progression. We discuss how metabolites may affect NAFLD progression and their potential to serve as biomarkers for NAFLD diagnosis or therapeutic targets for disease management. LESS      Full article

The COVID-19 pandemic has led to the greatest worldwide health crisis in decades. The number of infected patients with severe SARS-CoV-2 (COVID-19) disease has overwhelmed the capacity of almost all health care systems around world. Hypoalbuminemia has now been reported in patients with severe disease seeking help in the emergency room because of COVID-19 infection. In the past, hypoalbuminemia was considered to be a negative prognostic marker, not only in patients with chronic liver disease, but also in patients with SARS and MERS infections. Albumin is the major serum protein synthesized by the liver. A low serum albumin level is an ominous clinical sign. Introduction of amino acids to a patient’s diet is of fundamental importance to hepatic albumin synthesis in different clinical situations. This highlights the importance of nutritional support during the early phases of COVID-19-infection. Furthermore, albumin synthesis in the hepatocyte is downregulated at a pretranslational level by the direct interaction of the major acute-phase cytokines which are released into the circulation during the cytokine “storm” induced by the viral effects on the lungs. Both mechanisms contribute to severe hypoalbuminemia which, combined with massive fluid losses due to the fever, is responsible for severe hypovolemia and shock commonly observed in patients with COVID-19 in critical care settings. LESS      Full article

Currently, alcoholic liver disease (ALD) is one of the most prevalent chronic liver diseases worldwide, representing one of the main etiologies of cirrhosis and hepatocellular carcinoma (HCC). Although we do not know the exact mechanisms by which only a selected group of patients with ALD progress to the final stage of HCC, the role of the gut microbiota within the progression to HCC has been intensively studied in recent years. To date, we know that alcohol-induced gut dysbiosis is an important feature of ALD with important repercussions on the severity of this disease. In essence, an increased metabolism of ethanol in the gut induced by an excessive alcohol consumption promotes gut dysfunction and bacterial overgrowth, setting a leaky gut. This causes the translocation of bacteria, endotoxins, and ethanol metabolites across the enterohepatic circulation reaching the liver, where the recognition of the pathogen-associated molecular patterns via specific Toll-like receptors of liver cells will induce the activation of the nuclear factor kappa-B pathway, which releases pro-inflammatory cytokines and chemokines. In addition, the mitogenic activity of hepatocytes will be promoted and cellular apoptosis will be inhibited, resulting in the development of HCC. In this context, it is not surprising that microbiota-regulating drugs have proven effectiveness in prolonging the overall survival of patients with HCC, making attractive the implementation of these drugs as co-adjuvant for HCC treatment. LESS      Full article

Hepatocellular carcinoma (HCC) is the fifth most widespread cancer responsible for one fourth of cancer-related deaths globally. Persistent infection with hepatitis B virus (HBV) remains the main cause of HCC summing up to 50% of its causative etiology. Our recent studies, supported by findings from others, uncovered that HBV and its close relative woodchuck hepatitis virus (WHV) integrate into hepatocyte genome almost immediately, hence in minutes after infection. Retrotransposons and genes with translocation potential were found to be frequent sites of HBV insertions, suggesting a mechanism of HBV DNA spread across liver genome from the earliest stages after virus invasion. Many other genes were identified as the sites of early hepadnavirus merges in human hepatocyte-like lines infected de novo with HBV and in natural woodchuck WHV infection model. It was uncovered that head-to-tail joins (HTJs) prevail among the earliest virus-host fusions, implying their formation via the non-homologous-end-joining (NHEJ) pathway. Overlapping homologous junctions resulting from the micro-homology-mediated-overlapping-joining (MHMOJ) were rarely detected. Formation of the initial HTJs coincided with strong induction of reactive oxygen species (ROS) and transient appearance of inducible nitric oxide (iNOS). This was accompanied by cell DNA damage and activation of the poly(ADP-ribose) polymerase 1 (PARP1)-mediated host DNA repair machinery, which may explain predominant HTJ format of the first virus-host fusions. Identification of initial integration sites and resulting alterations in hepatocyte phenotype may pave a way to discovery of reliable markers of HBV-triggered HCC, including HCC resulting from occult HBV infection. Our research strongly argues that HBV is an ultimate human carcinogen capable of initiation of a pro-oncogenic process immediately after first contact with a susceptible host. LESS      Full article