Endoplasmic Reticulum Stress in Metabolic Liver Diseases and Hepatic Fibrosis
Semin Liver Dis DOI: 10.1055/s-0039-1681032Endoplasmic reticulum (ER) stress is a major contributor to liver disease and hepatic fibrosis, but the role it plays varies depending on the cause and progression of the disease. Furthermore, ER stress plays a distinct role in hepatocytes versus hepatic stellate cells (HSCs), which adds to the complexity of understanding ER stress and its downstream signaling through the unfolded protein response (UPR) in liver disease. Here, the authors focus on the current literature of ER stress in nonalcoholic and alcoholic fatty liver diseases, how ER stress impacts hepatocyte injury, and th...
Source: Seminars in Liver Disease - March 24, 2019 Category: Gastroenterology Authors: Maiers, Jessica L. Malhi, Harmeet Tags: Review Article Source Type: research
Prevention of Hepatocellular Carcinoma by Statins: Clinical Evidence and Plausible Mechanisms
Semin Liver Dis DOI: 10.1055/s-0039-1679956Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are widely used to treat hypercholesterolemia for primary and secondary prevention of cardiovascular disease. Statins inhibit HMG-CoA reductase, the rate-limiting step in cholesterol synthesis, and modulate the downstream signaling of the mevalonate pathway. In addition to the primary effect, the antitumor effect of statins can be associated with mevalonate pathway-mediated and nonmevalonate pathway-mediated mechanisms, which improve endothelial function and lead to proapoptotic, antiproliferative, a...
Source: Seminars in Liver Disease - March 24, 2019 Category: Gastroenterology Authors: Kim, Gyuri Kang, Eun Seok Tags: Review Article Source Type: research
Liver Cancer Gene Discovery Using Gene Targeting, Sleeping Beauty, and CRISPR/Cas9
Semin Liver Dis DOI: 10.1055/s-0039-1678725Hepatocellular carcinoma (HCC) is a devastating and prevalent cancer with limited treatment options. Technological advances have enabled genetic screens to be employed in HCC model systems to characterize genes regulating tumor initiation and growth. Relative to traditional methods for studying cancer biology, such as candidate gene approaches or expression analysis, genetic screens have several advantages: they are unbiased, with no a priori selection; can directly annotate gene function; and can uncover gene–gene interactions. In HCC, three main types of screens have been cond...
Source: Seminars in Liver Disease - March 24, 2019 Category: Gastroenterology Authors: Kieckhaefer, Julia E. Maina, Flavio Wells, Rebecca G. Wangensteen, Kirk J. Tags: Review Article Source Type: research
Hepatocellular Carcinoma Risk Stratification by Genetic Profiling in Patients with Cirrhosis
Semin Liver Dis DOI: 10.1055/s-0039-1681031Prediction of future hepatocellular carcinoma (HCC) risk in the sizable chronic liver disease population is an urgent unmet need to enable regular HCC screening for early detection. Germline deoxyribonucleic acid polymorphisms likely represent etiology-specific host factors that determine HCC susceptibility, including single nucleotide polymorphisms in EGF, IFNL3, MICA, and TLL1 in hepatitis C with or without active viral infection, and PNPLA3, TM6SF2, and MBOAT7 in metabolic liver diseases. Transcriptome-based prognostic liver signature in diseased liver tissue has been associate...
Source: Seminars in Liver Disease - March 24, 2019 Category: Gastroenterology Authors: Fujiwara, Naoto Hoshida, Yujin Tags: Review Article Source Type: research
Alpha-fetoprotein for Diagnosis, Prognosis, and Transplant Selection
This article reviews the lights and shadows of AFP as a surveillance test for patients at risk of HCC, and as a diagnostic test for those with chronic liver disease and a suspected hepatic mass. Moreover, the article scrutinizes the large body of evidence supporting the prognostic relevance of AFP in patients undergoing both curative and palliative treatment of HCC and the growing importance attributed to this biomarker (as a static or a dynamic variable) in the selection of potential candidates for liver transplantation. In fact, the inclusion of AFP among transplant criteria would improve the ability of identifying poor ...
Source: Seminars in Liver Disease - March 7, 2019 Category: Gastroenterology Authors: Trevisani, Franco Garuti, Francesca Neri, Andrea Tags: Review Article Source Type: research
Mechanisms and Treatments of Pruritus in Primary Biliary Cholangitis
Semin Liver Dis DOI: 10.1055/s-0039-1679918Pruritus is a frustrating and sometimes debilitating symptom that commonly accompanies primary biliary cholangitis (PBC). The mechanism by which this symptom manifests remains elusive but extensive research has now shown that the itch is not just “weak pain” as had been the commonly held belief for decades. As this research now shines a light on the many diverse paths by which pruritus might be experienced, the necessity for a comprehensive approach to the symptom becomes clear. Understanding the interplay between the pathophysiology of PBC and delicately balanced neural circu...
Source: Seminars in Liver Disease - March 7, 2019 Category: Gastroenterology Authors: Shah, Raj A. Kowdley, Kris V. Tags: Review Article Source Type: research
Acetaminophen Hepatotoxicity
Semin Liver Dis DOI: 10.1055/s-0039-1679919Acetaminophen (APAP) is one of the most popular and safe pain medications worldwide. However, due to its wide availability, it is frequently implicated in intentional or unintentional overdoses where it can cause severe liver injury and even acute liver failure (ALF). In fact, APAP toxicity is responsible for 46% of all ALF cases in the United States. Early mechanistic studies in mice demonstrated the formation of a reactive metabolite, which is responsible for hepatic glutathione depletion and initiation of the toxicity. This insight led to the rapid introduction of N-acetylcyste...
Source: Seminars in Liver Disease - March 7, 2019 Category: Gastroenterology Authors: Ramachandran, Anup Jaeschke, Hartmut Tags: Review Article Source Type: research
NASH in Lean Individuals
Semin Liver Dis DOI: 10.1055/s-0038-1677517Nonalcoholic fatty liver disease (NAFLD) is generally associated with obesity and the related comorbidities but it can also develop in subjects with a body mass index (BMI) within the ethnic-specific cutoff of 25 kg/m2 BMI in Caucasian and 23 kg/m2 in Asian subjects, the so-called “lean” NAFLD. This sub-phenotype of NAFLD patients has been described across populations of different ethnicity, particularly in Asia, but it can be diagnosed in 10 to 20% of nonobese Americans and Caucasians. Pathophysiological mechanisms underpinning the “lean” phenotype are not completely unde...
Source: Seminars in Liver Disease - January 17, 2019 Category: Gastroenterology Authors: Younes, Ramy Bugianesi, Elisabetta Tags: Review Article Source Type: research
Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets
Semin Liver Dis DOI: 10.1055/s-0038-1676806Hepatocellular carcinoma (HCC) is associated with chronic inflammation and fibrosis arising from different etiologies, including hepatitis B and C and alcoholic and nonalcoholic fatty liver diseases. The inflammatory cytokines tumor necrosis factor-α and interleukin-6 and their downstream targets nuclear factor kappa B (NF-κB), c-Jun N-terminal kinase (JNK), and signal transducer and activator of transcription 3 drive inflammation-associated HCC. Further, while adaptive immunity promotes immune surveillance to eradicate early HCC, adaptive immune cells, such as CD8+ T cells, Th1...
Source: Seminars in Liver Disease - January 17, 2019 Category: Gastroenterology Authors: Yang, Yoon Mee Kim, So Yeon Seki, Ekihiro Tags: Review Article Source Type: research
Extracellular Vesicles in Liver Diseases: Diagnostic, Prognostic, and Therapeutic Application
Semin Liver Dis DOI: 10.1055/s-0038-1676122Extracellular vesicles, comprising exosomes, microvesicles, and apoptotic bodies, represent an emerging field in disease diagnostics and prognosis. They can be isolated from peripheral blood of patients as well as from other body fluids and can therefore be considered a minimally invasive liquid biopsy screening tool. Especially their surface antigen composition can reveal information about disease backgrounds. For several liver diseases, including fatal hepatocellular and cholangiocellular carcinoma as well as other nonmalignant liver disorders such as nonalcoholic fatty liver di...
Source: Seminars in Liver Disease - January 17, 2019 Category: Gastroenterology Authors: Urban, Sabine K. Mocan, Tudor S änger, Hanna Lukacs-Kornek, Veronika Kornek, Miroslaw Tags: Review Article Source Type: research
Concept of Viral Inhibitors via NTCP
Semin Liver Dis DOI: 10.1055/s-0038-1676804Identification of sodium taurocholate cotransporting polypeptide (NTCP) as an entry receptor for hepatitis B and D viruses (HBV and HDV) has not only promoted our understanding of the mechanism underlying the viral entry process, but also provided cell culture models supporting viral infection. These models have greatly facilitated cell-based chemical screening for the discovery of entry inhibitors, and mode of action studies using such inhibitors have shown the advantages of NTCP as a drug target. Furthermore, in vitro chemical screening by application of high-throughput affinity...
Source: Seminars in Liver Disease - January 17, 2019 Category: Gastroenterology Authors: Fukano, Kento Tsukuda, Senko Watashi, Koichi Wakita, Takaji Tags: Review Article Source Type: research
Child –Pugh Classification: Time to Abandon?
Semin Liver Dis DOI: 10.1055/s-0038-1676805The Child–Pugh classification is one of the commonest and oldest bedside tools utilized in estimating prognosis in patients with cirrhosis. However, its usage as a risk prediction tool or indeed a decision-making tool should be revisited. In this review, we discuss some inherent issues with the Child–Pugh classification and present a few contexts in which the current usage of Child–Pugh warrants reassessment, elaborating on its utility in acute variceal bleeding, specifically its role in decision-making on early transjugular intrahepatic portosystemic shunt, as well as its u...
Source: Seminars in Liver Disease - January 11, 2019 Category: Gastroenterology Authors: Kok, Beverley Abraldes, Juan G. Tags: Review Article Source Type: research
TGF- β as Multifaceted Orchestrator in HCC Progression: Signaling, EMT, Immune Microenvironment, and Novel Therapeutic Perspectives
Semin Liver Dis DOI: 10.1055/s-0038-1676121Therapeutic attempts to treat hepatocellular carcinoma (HCC) frequently result in a poor response or treatment failure. The efficacy of approved drugs and survival expectancies is affected by an ample degree of variability that can be explained at least in part by the enormous between-patient cellular and molecular heterogeneity of this neoplasm. Transforming growth factor-β (TGF-β) is hyperactivated in a large fraction of HCCs, where it influences complex interactive networks covering multiple cell types and a plethora of other local soluble ligands, ultimately establishing sev...
Source: Seminars in Liver Disease - December 26, 2018 Category: Gastroenterology Authors: Dituri, Francesco Mancarella, Serena Cigliano, Antonio Chieti, Annarita Giannelli, Gianluigi Tags: Review Article Source Type: research
Radiation Therapy in HCC: What Data Exist and What Data Do We Need to Incorporate into Guidelines?
Semin Liver Dis DOI: 10.1055/s-0038-1676098Hepatocellular carcinoma (HCC) is a complex and diverse disease, with choice of treatment dependent on a patient's disease burden, location of disease, underlying liver function, and performance status. While radiation therapy (RT) was historically omitted from treatment algorithms, immense technological advances over the past several decades have enabled introduction of RT as an effective and safe treatment option for patients with HCC. Growing prospective and retrospective evidence supports the use of RT, particularly stereotactic body radiotherapy (SBRT), for a wide range of in...
Source: Seminars in Liver Disease - December 7, 2018 Category: Gastroenterology Authors: Xu, Melody J. Feng, Mary Tags: Review Article Source Type: research
Noncoding RNA in Cholangiocarcinoma
Semin Liver Dis DOI: 10.1055/s-0038-1676097Cholangiocarcinomas (CCAs) are tumors with a dismal prognosis. Early diagnosis is a key challenge because of the lack of specific symptoms, and the curability rate is low due to the difficulty in achieving a radical resection and the intrinsic chemoresistance of CCA cells. Noncoding RNAs (ncRNAs) are transcripts that are not translated into proteins but exert their functional role by regulating the transcription and translation of other genes. The discovery of the first ncRNA dates back to 1993 when the microRNA (miRNA) lin-4 was discovered in Caenorhabditis elegans. Only 10 years...
Source: Seminars in Liver Disease - December 7, 2018 Category: Gastroenterology Authors: Salati, Massimiliano Braconi, Chiara Tags: Review Article Source Type: research
