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Seminars in Liver Disease

Franco Trevisani, Francesca Garuti, Andrea Neri
Reliable biomarkers are of great clinical value in predicting cancer occurrence/recurrence, anticipating its detection at an asymptomatic stage, supporting the radiological diagnosis, stratifying patients for prognosis and proper therapy, and measuring the response to treatment. Despite the plethora of biomarkers proposed for hepatocellular carcinoma (HCC), the first one identified, α-fetoprotein (AFP), remains the most utilized. 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...
March 8, 2019: Seminars in Liver Disease
Raj A Shah, Kris V Kowdley
Pruritus 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 circuitry is paramount to guiding the search for definitive treatment...
March 8, 2019: Seminars in Liver Disease
Anup Ramachandran, Hartmut Jaeschke
Acetaminophen (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...
March 8, 2019: Seminars in Liver Disease
Ramy Younes, Elisabetta Bugianesi
Nonalcoholic 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 understood, but they may include a more dysfunctional fat (visceral obesity, differences in adipocyte differentiation and altered lipid turnover), altered body composition (decreased muscle mass), a genetic background, not limited to patatin-like phospholipase domain-containing protein 3 (PNPLA3) C > G polymorphisms, epigenetic changes occurring early in life and a different pattern of gut microbiota...
January 17, 2019: Seminars in Liver Disease
Francesco Dituri, Serena Mancarella, Antonio Cigliano, Annarita Chieti, Gianluigi Giannelli
Therapeutic 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 several malignancy traits...
December 26, 2018: Seminars in Liver Disease
Kento Fukano, Senko Tsukuda, Koichi Watashi, Takaji Wakita
Identification 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-based technologies that target NTCP has identified a variety of unique small molecules that interfere with viral entry...
February 2019: Seminars in Liver Disease
Yoon Mee Yang, So Yeon Kim, Ekihiro Seki
Hepatocellular 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, Th17 cells, and B cells, can also stimulate HCC development...
February 2019: Seminars in Liver Disease
Sabine K Urban, Tudor Mocan, Hanna Sänger, Veronika Lukacs-Kornek, Miroslaw Kornek
Extracellular 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 disease, alcoholic hepatitis, or acute liver failure, it has been shown that extracellular vesicle (EV) surface profiling can be useful for disease diagnosis and prognosis...
February 2019: Seminars in Liver Disease
Beverley Kok, Juan G Abraldes
The 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 use in the context of hepatocellular carcinoma and drug development and dose adjustment...
February 2019: Seminars in Liver Disease
Melody J Xu, Mary Feng
Hepatocellular 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 indications in HCC from locally advanced unresectable disease to bridge therapy for liver transplant candidates...
February 2019: Seminars in Liver Disease
Venancio Avancini Ferreira Alves, Jordi Rimola
Hepatic angiosarcoma and epithelioid hemangioendothelioma (EHE) might be clinically considered a spectrum since, although more frequently presenting indolent behavior, EHE occasionally evolves to high-grade neoplasms. However, in most circumstances, pathological and immunohistochemical patterns define this differential diagnosis. More recently, molecular pathways for angiosarcoma and for EHE from other organs and from soft tissue have been proved different, paving the way for future morpho-molecular assessment of their hepatic counterpart...
February 2019: Seminars in Liver Disease
Veronica Ranieri, Kathy McKay, Martine Walmsley, Robert Senior, Douglas Thorburn, Eilis Kennedy
Primary sclerosing cholangitis (PSC) is a chronic liver disease resulting from the inflammation and scarring of an individual's hepatic bile ducts. With no curative treatment available and a risk of potentially severe complications and death, it is likely that those diagnosed with the illness may experience impairments in their psychological wellbeing. The aim of this scoping review is to locate, chart, and summarize all available literature on how PSC affects mental health and psychological wellbeing, as well as the factors that may or may not impact on the psychological wellbeing of those who have this diagnosis...
February 2019: Seminars in Liver Disease
Massimiliano Salati, Chiara Braconi
Cholangiocarcinomas (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 ...
December 7, 2018: Seminars in Liver Disease
Yu-Yang Lin, Ching-Ting Tan, Chia-Wei Chen, Da-Liang Ou, Ann-Lii Cheng, Chiun Hsu
Multikinase inhibitors with antiangiogenic properties used to be standard therapy for patients with advanced hepatocellular carcinoma (HCC). Recently, several antiangiogenic agents (lenvatinib, cabozantinib, and ramucirumab) have demonstrated antitumor activity for advanced HCC in randomized controlled trials. However, the landscape of drug development for HCC may change dramatically with the advent of immune checkpoint inhibitor therapy, particularly the anti-programmed cell death-1 (anti-PD1) agents. In addition, early-phase clinical trials of combination of anti-PD-1 and antiangiogenic agents have shown very promising anti-tumor activity in patients with advanced HCC...
November 2018: Seminars in Liver Disease
Brian A Nadeau, Leslie A Fecher, Scott R Owens, Nataliya Razumilava
Immune checkpoint inhibition targeted against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has shown clinically significant survival benefit when used to treat multiple types of advanced cancer. These drugs have gained approval by the US Food and Drug Administration and their indications continue to increase. Checkpoint inhibitor therapy is associated with a unique side-effect profile characterized as immune-related adverse events (irAEs), which can result in significant morbidity and rarely mortality...
November 2018: Seminars in Liver Disease
Ammar Hassan, Robert J Fontana
Exertional heat stroke most commonly develops following prolonged levels of aerobic activity in a warm or humid environment. Hypoperfusion of the vital organs along with activation of the inflammasome can lead to progressive and potentially fatal multiorgan failure including acute liver failure. In the United States, herbal and dietary supplements that are marketed to improve performance, strength, and weight loss are increasingly being used by both amateur and professional athletes. Consumption of bodybuilding supplements that contain androgenic anabolic steroids can lead to adverse hepatic effects ranging from asymptomatic serum aminotransferase elevations to severe cholestatic hepatitis with prolonged jaundice...
November 2018: Seminars in Liver Disease
Chetana Lim, Eylon Lahat, Michael Osseis, Dobromir Sotirov, Chady Salloum, Daniel Azoulay
Neuroendocrine tumors are slow-growing tumors and associated with prolonged overall survival even in the presence of untreated liver metastases. The presence of liver metastases may be responsible for severe symptoms with impairment of quality of life. Liver resection has been proposed to achieve better symptom control and/or improve overall survival, but this concerns less than 20% of patients with liver metastases. In addition, the chance to be really cured after liver resection is around 40%, which prompts consideration of liver transplantation as the only potential curative treatment...
November 2018: Seminars in Liver Disease
Zhuan Li, Steven A Weinman
Macrophages are innate immune cells with diverse functions including clearing infectious agents, inducing inflammation and fibrosis, resolving fibrosis, and restoring tissue integrity. Liver macrophages consist of both resident Kupffer cells and infiltrating macrophages. They have heterogeneous highly plastic phenotypes, and they change their phenotypes rapidly in response to a diverse array of signals present in the injured or recovering liver. Cell death by apoptosis, necroptosis, or pyroptosis is a common response of liver macrophages to infectious and toxic insults...
November 2018: Seminars in Liver Disease
Verena Keitel, Dieter Häussinger
TGR5 (GPBAR1) is a G protein-coupled receptor activated by primary and secondary bile acids, which is expressed in different nonparenchymal cells of the liver, such as sinusoidal endothelial cells, Kupffer cells, cholangiocytes as well as activated hepatic stellate cells. In liver, TGR5 modulates microcirculation, inflammation, regeneration, biliary secretion and proliferation as well as gallbladder filling. Absence of TGR5 renders mice more susceptible toward infectious, inflammatory, metabolic as well as cholestatic liver injuries...
November 2018: Seminars in Liver Disease
Anne S Henkel
Activation of the hepatic unfolded protein response (UPR), a highly conserved cellular response to endoplasmic reticulum (ER) stress, is a firmly established feature of nonalcoholic fatty liver disease (NAFLD). ER stress is now widely accepted as both a cause and a consequence of hepatic steatosis. Moreover, the accumulation of hepatic lipids induces ER stress, which, in turn, disrupts hepatic lipid metabolism thus creating a vicious cycle that potentiates hepatic lipid accumulation. Additionally, there is interplay between the UPR and the inflammatory cascades associated with progressive nonalcoholic steatohepatitis...
November 2018: Seminars in Liver Disease
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