Joaquin Cabezas

Barriers to HCV treatment in the era of triple therapy: a prospective multi-centred study in clinical practice

(i) To describe the demographic, clinical, virological and histological characteristics of the patients undergoing evaluation for indication of triple therapy against hepatitis C virus genotype 1, and to identify the reasons why candidate patients are excluded; and (ii) to evaluate the characteristics of the healthcare environment related to treatment.

Plasma betatrophin levels in patients with liver cirrhosis

AIM To investigate the plasma levels of betatrophin in patients with cirrhosis. METHODS Forty patients diagnosed at the clinic with liver cirrhosis according to biological, ultrasonographic, or histological criteria were included. The severity of cirrhosis was classified according to Pughs modification of Childs classification and MELD score. Insulin resistance (IR) was assessed by the Homeostasis Model Assessment. A total of 20 patients showed a MELD score higher than 14. The control group consisted in 15 sex-and aged-matched subjects. Fasting blood samples were obtained for subsequent analysis. Serum insulin was determined by Liaison automated immune chemiluminiscence assay (DiaSorin S.p.A.) using a sandwich assay. The sensitivity of the assay was 0.2 μU/mL. The intra and interassay variation coefficients were < 4% and < 10%, respectively. The normal values were between 2 and 17 μU/mL. Human active betatrophin was analyzed by specific quantitative sandwich ELISA (Aviscera Bioscience). The sensitivity of the assay was 0.4 ng/mL, and the intra and interassay reproducibility were < 6% and < 10%, respectively. RESULTS Plasma betatrophin levels were significantly increased in patients with cirrhosis compared with those in healthy subjects (P = 0.0001). Betatrophin levels were also associated with disease severity, being higher in Child-Pugh C patients compared to Child-Pugh B (P < 0.0005) and in patients who displayed a MELD score higher than 14 points compared to patients with lower punctuation (P = 0.01). In addition, we found a positive correlation between plasma betatrophin levels and the severity of cirrhosis according to Child-Pugh classification (r = 0.53; P < 0.01) or MELD score (r = 0.45; P < 0.01). In the overall cohort, a moderate correlation between serum betatrophin and plasmatic bilirrubin (r = 0.39; P < 0.01) has been observed, as well as an inverse correlation between betatrophin and albumin (r = -0.41; P < 0.01) or prothrombin time (r = -0.44; P <0.01). Moreover, insulin resistance was observed in 82.5% of the cirrhotic patients. In this group of patients, betatrophin levels were significantly higher than those in the group of patients without IR (P < 0.05). CONCLUSION Plasma betatrophin is increased in patients with cirrhosis. This increase is related to the severity of cirrhosis, as well as with the emergence of insulin resistance.

Disparities between research attention and burden in liver diseases: implications on uneven advances in pharmacological therapies in Europe and the USA

Objectives Effective oral therapies for hepatitis B and C have recently been developed, while there are no approved pharmacological therapies for alcoholic and non-alcoholic fatty liver diseases (ALD and NAFLD). We hypothesise that fewer advances in fatty liver diseases could be related to disparities in research attention. Methods We developed the Attention-to-Burden Index (ABI) that compares the research activities during 2010–2014, and an estimate of disease burden of these 4 major liver diseases. The resulting ratio reflects either overattention (positive value) or inadequate attention (negative value) compared with disease burden. The mean research attention and disease burden were calculated from 5 and 6 different parameters, respectively. The efficacy rate of current pharmacological therapies was assessed from published clinical trials. Findings The mean research attention for hepatitis B and C was 31% and 47%, respectively, while NAFLD and ALD received 17% and 5%. The overall burden was 5% and 28% for hepatitis B and C, and 17% and 50% for NAFLD and ALD. The calculated ABI for hepatitis B and C revealed a +6.7-fold and +1.7-fold overattention, respectively. NAFLD received an appropriate attention compared with its burden, while ALD received marked inadequate attention of −9.7-fold. The efficacy rate of current pharmacological agents was 72% for hepatitis B, 89% for hepatitis C, 25% for non-alcoholic steatohepatitis and 13% for alcoholic hepatitis. Importantly, we found a positive correlation between the mean attention and the efficacy rate of current therapies in these 4 major liver diseases. Interpretation There are important disparities between research attention and disease burden among the major liver diseases. While viral hepatitis has received considerable attention, there is a marked inadequate attention to ALD. There is a critical need to increase awareness of ALD in the liver research community.

Nonalcoholic Fatty Liver Disease: A Pathological View

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder of our times. The spectrum of this disease goes from steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. NAFLD can appear in the context of many condi‐ tions. Probably, NAFLD could be a component of metabolic syndrome, with its complete phenotypic expression: insulin resistance, obesity, type 2 diabetes, hypertension, hypercho‐ lesterolemia, and hypertriglyceridemia.

Epigenetics in Liver Fibrosis

Liver fibrosis is a common consequence of chronic liver injury and is a key determinant of liver-associated morbidity and mortality. Identification of new mechanisms of fibrosis, including disease-specific molecular drivers, remains relevant to reveal novel biomarkers and therapeutic targets. Recently, greater accessibility to more advanced molecular methods that can assess changes in epigenetic regulation has stimulated more research investigating the epigenetic landscape of liver fibrosis. Such studies have revealed changes in DNA methylation, histone acetylation, and microRNAs that regulate the fibrogenic response to injury including hepatic stellate cell activation. The aim of this review is to briefly introduce the general mechanisms and epigenetic regulation of liver fibrosis and to familiarize the reader with the chief epigenetic mechanisms implicated as drivers of liver fibrosis.

Reduced Impact of Renal Failure on the Outcome of Patients with Alcoholic Liver Disease Undergoing Liver Transplantation

Pretransplant renal failure is commonly reported to be a poor prognostic indicator affecting survival after liver transplantation (LT). However, whether the impact of renal failure on patient outcome varies according to the aetiology of the underlying liver disease is largely unknown.

Computerized Physician Order Entry–Based System Improves Hepatitis B Virus Screening in Patients Undergoing Chemotherapy

TO THE EDITOR: In the clinical opinion update by Hwang et al, the authors reviewed the most important issues related to hepatitis B virus (HBV) screening in patients who are about to receive cytotoxic chemotherapy for the treatment of malignant diseases. This update notes the importance of screening all patients who are going to be treated with anti-CD20 therapy. The authors also point out that this screening should be extended to patients with high risk factors for HBV infection. Then, when a patient who is hepatitis B surface antigen (HBsAg) positive/hepatitis B core antibody (anti-HBc) positive is identified, antiviral treatment should be started just before or at the same time as chemotherapy. In contrast, patients who are HBsAg negative/anti-HBc positive could be carefully observed with ALT and HBV-DNA levels. In the article by Hwang et al, Spain is included as a country with HBV prevalence greater than 2%. We believe this statement is currently obsolete and should be corrected. Because of the universal vaccination program started circa 1992, the HBV prevalence in Spain is now approximately 0.7% (HBsAg positive). However, this 0.7% prevalence in HBsAg does not disqualify, in our opinion, a universal HBsAg screening for all patients scheduled to receive systemic cancer therapy. As Hwang et al succinctly mentioned, previous studies have shown that universal screening for HBsAg is not only cost effective but actually cost saving when compared with no screening or screening only high-risk individuals before starting chemotherapy, particularly when the prevalence of HBsAg in the low-risk population is greater than 0.20%. Finally, one aspect that we miss in this special article is the mention of currently available innovative strategies to facilitate this HBV screening in the hospital setting, where the majority of immunosuppressive therapies are prescribed. We are referring specifically to the use of the computerized physician order entry–based (CPOE) systems that apply to this subject. As we previously have demonstrated, the use of this CPOE system in our hospital increased theHBV screening rate from less than 50% to 94% forHBsAg and from less than 30% to 85% for anti-HBc in patients for whom a biologic drug was prescribed. In conclusion, we consider it reasonable to recommend universal HBsAg (and anti-HBc) screening for all patients scheduled to receive systemic cancer therapies or other immunosuppressive therapies, adding when available or feasible the potential benefits of new tools such as CPOE systems together with educational efforts to improve the HBV screening rates.

Paritaprevir/r/Ombitasvir + Dasabuvir 8 weeks in HCV-genotype 1b with mild-moderate fibrosis: Results from a Real World Cohort

The interferon‐free regimen paritaprevir/ritonavir, ombitasvir + dasabuvir (PTV/r/OBV/DSV) has shown high efficacy in patients with hepatitis C virus (HCV) genotype 1b infection when administered for 8 or 12 weeks, but data regarding the 8‐week treatment are scarce. The aim of our study was to assess the efficacy and safety of the 8‐week administration of PTV/r/OBV/DSV in a real‐world cohort.

Erratum: Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis (Cell Metabolism (2018) 27(2) (339–350.e3)(S1550413118300561)(10.1016/j.cmet.2018.01.007))

Megan N. Roberts, Marita A. Wallace, Alexey A. Tomilov, Zeyu Zhou, George R. Marcotte, Dianna Tran, Gabriella Perez, Elena Gutierrez-Casado, Shinichiro Koike, Trina A. Knotts, Denise M. Imai, Stephen M. Griffey, Kyoungmi Kim, Kevork Hagopian, Marissa Z. McMackin, Fawaz G. Haj, Keith Baar, Gino A. Cortopassi, Jon J. Ramsey,* and Jose Alberto Lopez-Dominguez* *Correspondence: jjramsey@ucdavis.edu (J.J.R.), jlopez-dominguez@buckinstitute.org (J.A.L.-D.) https://doi.org/10.1016/j.cmet.2018.04.005

TLR7-let-7 Signaling Contributes to Ethanol-Induced Hepatic Inflammatory Response in Mice and in Alcoholic Hepatitis

Background Toll‐like receptor 7 (TLR7) is an endosomal TLR that is activated by single‐stranded RNA, including endogenous microRNAs (e.g., let‐7b). Increased hepatic expression of TLRs, microRNAs, and inflammatory mediators is linked to ethanol (EtOH) exposure and to alcoholic liver disease (ALD). ALD invovles chronic hepatic inflammation that can progress to alcoholic hepatitis (AH), a particularly severe form of ALD. This study aimed to investigate TLR7 expression in patients with different liver disease phenotypes and in mouse liver following alcohol exposure. Methods Hepatic mRNA expression was determined by RNA sequencing of liver tissue from patients with liver disease or normal liver tissue. Mice were exposed to subchronic EtOH followed by administration of the TLR7 agonist imiquimod. Primary human hepatocytes were exposed to EtOH or imiquimod in vitro. Results RNAseq analysis revealed that hepatic expression of TLR7 and let‐7b microRNA, an endogenous TLR7 ligand, was significantly increased in AH patients. Hepatic expression of TLR7 and let‐7b positively correlated with hepatic IL‐8 mRNA expression. In mice, EtOH increased hepatic TLR7 mRNA expression and enhanced imiquimod‐induced expression of the pro‐inflammatory mediators TNF α, MCP‐1, and iNOS. In vitro, EtOH significantly increased hepatocyte TLR7 mRNA and the TLR7 agonist, imiquimod, induced hepatocyte expression of TNF α and IL‐8 mRNA. EtOH also increased the release of let‐7b in microvesicles from hepatocytes, suggesting that EtOH can increase the expression of both the receptor and its endogenous ligand. Conclusions These studies suggest that increased TLR7 signaling caused by increased expression of TLR7 and its endogenous ligand let‐7b may contribute to the enhanced inflammatory response associated with AH.