Therapeutic Inhibition of Inflammatory Monocyte Recruitment Reduces Steatohepatitis and Liver Fibrosis Hepatology (IF 13.246) Pub Date : 2017-09-21 Oliver Krenkel; Tobias Puengel; Olivier Govaere; Ali T. Abdallah; Jana C. Mossanen; Marlene Kohlhepp; Anke Liepelt; Eric Lefebvre; Tom Luedde; Claus Hellerbrand; Ralf Weiskirchen; Thomas Longerich; Ivan G. Costa; Quentin M. Anstee; Christian Trautwein; Frank Tacke
Macrophages are key regulators of liver fibrosis progression and regression in nonalcoholic steatohepatitis (NASH). Liver macrophages comprise resident phagocytes, Kupffer cells, and monocyte-derived cells, which are recruited via the chemokine receptor CCR2. We aimed at elucidating the therapeutic effects of inhibiting monocyte infiltration in NASH models by using cenicriviroc (CVC), an oral dual chemokine receptor CCR2/CCR5 antagonist that is under clinical evaluation. Human liver tissue from NASH patients were analyzed for CCR2+ macrophages and administration of CVC was tested in mouse models of steatohepatitis, liver fibrosis progression and fibrosis regression. In human liver from n=17 patients and n=4 controls, CCR2+ macrophages increased parallel to NASH severity and fibrosis stage, with a concomitant inflammatory polarization of these CD68+, portal monocyte-derived macrophages (MoMF). Similar to human disease, we observed a massive increase of hepatic MoMF in experimental models of steatohepatitis and liver fibrosis. Therapeutic treatment with CVC significantly reduced the recruitment of hepatic Ly- 6C+ MoMF in all models. In experimental steatohepatitis with obesity, therapeutic CVC application significantly improved insulin resistance and hepatic triglyceride levels. In fibrotic steatohepatitis, CVC treatment ameliorated histological NASH activity and hepatic fibrosis. CVC inhibited the infiltration of Ly-6C+ monocytes, without direct effects on macrophage polarization, hepatocyte fatty acid metabolism or stellate cell activation. Importantly, CVC did not delay fibrosis resolution after injury cessation. RNA sequencing analysis revealed that MoMF, but not Kupffer cells, specifically upregulate multiple growth factors and cytokines associated with fibrosis progression, while Kupffer cells activated pathways related to inflammation initiation and lipid metabolism. In conclusion, pharmacological inhibition of CCR2+ monocyte recruitment efficiently ameliorates insulin resistance, hepatic inflammation and fibrosis, corroborating the therapeutic potential of CVC in patients with NASH. This article is protected by copyright. All rights reserved.
A potent hepatitis B surface antigen response in subjects with inactive hepatitis B surface antigen carrier treated with pegylated-interferon alpha Hepatology (IF 13.246) Pub Date : 2017-08-26 Zhenhuan Cao; Yali Liu; Lina Ma; Junfeng Lu; Yi Jin; Shan Ren; Zhimin He; Chengli Shen; Xinyue Chen
Hepatitis B surface antigen (HBsAg) clearance represents a clinical cure, although the clearance rate is extremely low. The aim of this study was to evaluate the feasibility and safety profiles of pegylated-interferon α-2a (PEG-IFNα-2a) as a therapeutic option for inactive HBsAg carriers. There were 144 inactive HBsAg carriers enrolled and divided into a therapeutic group (102 subjects) and a control group (42 subjects). PEG-IFNα-2a and PEG-IFNα-2a combined with adefovir dipivoxil were used for treatment group subjects with hepatitis B virus DNA <20 IU/mL and 20 IU/mL ≤ hepatitis B virus DNA < 2,000 IU/mL, respectively. Total therapy duration was no more than 96 weeks. HBsAg clearance and seroconversion rates at therapeutic weeks 48 and 96 were used to evaluate the therapeutic efficacy. Per protocol analysis showed that the HBsAg clearance rate and seroconversion rate in the treatment group were 29.8% and 20.2% at week 48 and increased to 44.7% and 38.3% at week 96, respectively. However, the HBsAg clearance rate in the control group was 2.4% at weeks 48 and 96, and no subject achieved seroconversion. The quantitative HBsAg levels and changes during the early period of treatment (at week 12 and week 24) as well as the alanine aminotransferase elevation at week 12 were strong predictors of HBsAg clearance. The adverse events were similar to those with treatment for chronic hepatitis B patients. Conclusion: High rates of HBsAg clearance and seroconversion could be achieved by PEG-IFNα-2a-based treatments and the treatments were relatively safe for inactive HBsAg carriers. (Hepatology 2017;66:1058-1066).
Sofosbuvir and ribavirin in adolescents 12-17 years old with hepatitis C virus genotype 2 or 3 infection Hepatology (IF 13.246) Pub Date : 2017-08-26 Stefan Wirth; Philip Rosenthal; Regino P. Gonzalez‐Peralta; Maureen M. Jonas; William F. Balistreri; Chuan‐Hao Lin; Winita Hardikar; Kathryn Kersey; Benedetta Massetto; Bittoo Kanwar; Diana M. Brainard; Jiang Shao; Evguenia Svarovskaia; Brian Kirby; Ronen Arnon; Karen F. Murray; Kathleen B. Schwarz
Children with chronic hepatitis C virus infection have limited treatment options. We evaluated the all-oral combination of sofosbuvir and ribavirin in adolescents aged 12-17 with hepatitis C virus genotype 2 or 3 (ClinicalTrials.gov NCT02175758). Fifty-two patients received sofosbuvir 400 mg once daily and weight-based ribavirin twice daily for 12 (genotype 2) or 24 (genotype 3) weeks. The pharmacokinetics of sofosbuvir and its metabolite GS-331007 were evaluated by intensive plasma sampling at day 7 in the first 10 patients enrolled and by sparse sampling in all patients throughout treatment. The primary efficacy endpoint was the percentage of patients with a sustained virologic response 12 weeks after treatment (SVR12). The median age of patients was 15 years, and 75% had genotype 3. Eighty-three percent of patients were treatment-naive, and 73% were infected by vertical transmission. Forty percent were assessed as not having cirrhosis; the remainder did not have a cirrhosis determination. Overall, SVR12 was achieved by 98% of patients (51/52; 95% confidence interval, 90%-100%). SVR12 rates were 100% (13/13) for patients with genotype 2 and 97% (38/39) for those with genotype 3. The single patient who did not achieve SVR12 was lost to follow-up after achieving SVR4. The most commonly reported adverse events were nausea (27%) and headache (23%). When compared with the exposure in adults treated in phase 2 and 3 sofosbuvir studies, the area under the curve and maximum concentration for sofosbuvir and GS-331007 in adolescents were within predefined pharmacokinetic equivalence boundaries of 50%-200%. Conclusion: Sofosbuvir and ribavirin was safe and highly effective in adolescents with chronic hepatitis C virus genotype 2 or 3 infection. (Hepatology 2017;66:1102-1110).
Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma Hepatology (IF 13.246) Pub Date : 2017-08-26 Ander Arbelaiz; Mikel Azkargorta; Marcin Krawczyk; Alvaro Santos‐Laso; Ainhoa Lapitz; Maria J. Perugorria; Oihane Erice; Esperanza Gonzalez; Raul Jimenez‐Agüero; Adelaida Lacasta; Cesar Ibarra; Alberto Sanchez‐Campos; Juan P. Jimeno; Frank Lammert; Piotr Milkiewicz; Marco Marzioni; Rocio I.R. Macias; Jose J.G. Marin; Tushar Patel; Gregory J. Gores; Ibon Martinez; Félix Elortza; Juan M. Falcon‐Perez; Luis Bujanda; Jesus M. Banales
Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with poor prognosis. Several conditions, such as primary sclerosing cholangitis (PSC), are risk factors. Noninvasive differential diagnosis between intrahepatic CCA and hepatocellular carcinoma (HCC) is sometimes difficult. Accurate noninvasive biomarkers for PSC, CCA, and HCC are not available. In the search for novel biomarkers, serum extracellular vesicles (EV) were isolated from CCA (n = 43), PSC (n = 30), or HCC (n = 29) patients and healthy individuals (control, n = 32); and their protein content was characterized. By using nanoparticle tracking analysis, serum EV concentration was found to be higher in HCC than in all the other groups. Round morphology (by transmission electron microscopy), size (∼180 nm diameter by nanoparticle tracking analysis), and markers (clusters of differentiation 9, 63, and 81 by immunoblot) indicated that most serum EV were exosomes. Proteome profiles (by mass spectrometry) revealed multiple differentially expressed proteins among groups. Several of these proteins showed high diagnostic values with maximum area under the receiver operating characteristic curve of 0.878 for CCA versus control, 0.905 for CCA stage I-II versus control, 0.789 for PSC versus control, 0.806 for noncirhottic PSC versus control, 0.796 for CCA versus PSC, 0.956 for CCA stage I-II versus PSC, 0.904 for HCC versus control, and 0.894 for intrahepatic CCA versus HCC. Proteomic analysis of EV derived from CCA human cells in vitro revealed higher abundance of oncogenic proteins compared to EV released by normal human cholangiocytes. Orthotopic implant of CCA human cells in the liver of immunodeficient mice resulted in the release to serum of EV containing some similar human oncogenic proteins. Conclusion: Proteomic signatures found in serum EV of CCA, PSC, and HCC patients show potential usefulness as diagnostic tools. (Hepatology 2017;66:1125-1143).
Biases in the reporting of hepatocellular carcinoma tumor sizes on the liver transplant waiting list Hepatology (IF 13.246) Pub Date : 2017-08-26 Mariya L. Samoylova; Mark J. Nigrini; Jennifer L. Dodge; John P. Roberts
We investigated the possibility that patients with hepatocellular carcinoma (HCC) listed for liver transplant with tumors just outside stage T2 size criteria may be inaccurately reported as just meeting the tumor size criteria for transplant. The United Network for Organ Sharing/Standard Transplant Analysis and Research database identified 12,958 patients listed for liver transplants with HCC exception points from 2006 to 2013, 9,168 of whom were listed with one tumor. A logistic power peak function was fitted to the single-tumor size histogram, with the fitted values representing unbiased expected values. The difference between the observed and expected tumor counts for 2.0 cm and 5.0 cm was 238 (22%) and 66 (57%), respectively. This suggests that up to 304 (3.0%) patients with tumors outside of transplant criteria had their measurements recorded at the margins of eligibility. A risk-adjusted Poisson model evaluated the ratio of observed to expected HCC recurrence by tumor size. There were 435 HCC recurrences among 6,049 transplants. Only 2.0-cm tumors had observed to expected recurrence differing from 1 (ratio 0.73, 95% confidence interval 0.57-0.94), indicating a 27% lower than expected rate of recurrence. Conclusion: Higher than expected observed tumor counts at the lower transplant criteria margin were corroborated by lower than expected HCC recurrence, suggesting that tumor sizes at the margins of HCC transplant criteria may be subject to inaccurate reporting. (Hepatology 2017;66:1144-1150)
TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling Hepatology (IF 13.246) Pub Date : 2017-08-26 Tatyana V. Masyuk; Anatoliy I. Masyuk; Maria Lorenzo Pisarello; Brynn N. Howard; Bing Q. Huang; Pui‐Yuen Lee; Xavier Fung; Eduard Sergienko; Robert J. Ardecky; Thomas D.Y. Chung; Anthony B. Pinkerton; Nicholas F. LaRusso
Hepatic cystogenesis in polycystic liver disease is associated with increased levels of cyclic adenosine monophosphate (cAMP) in cholangiocytes lining liver cysts. Takeda G protein receptor 5 (TGR5), a G protein–coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with polycystic liver disease. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to (1) TGR5 agonists (taurolithocholic acid, oleanolic acid [OA], and two synthetic compounds), (2) a novel TGR5 antagonist (m-tolyl 5-chloro-2-[ethylsulfonyl] pyrimidine-4-carboxylate [SBI-115]), and (3) a combination of SBI-115 and pasireotide, a somatostatin receptor analogue. In vivo, we examined hepatic cystogenesis in OA-treated polycystic kidney rats and after genetic elimination of TGR5 in double mutant TGR5−/−;Pkhd1del2/del2 mice. Compared to control, expression of TGR5 and Gαs (but not Gαi and Gαq) proteins was increased 2-fold to 3-fold in cystic cholangiocytes in vitro and in vivo. In vitro, TGR5 stimulation enhanced cAMP production, cell proliferation, and cyst growth by ∼40%; these effects were abolished after TGR5 reduction by short hairpin RNA. OA increased cystogenesis in polycystic kidney rats by 35%; in contrast, hepatic cystic areas were decreased by 45% in TGR5-deficient TGR5−/−;Pkhd1del2/del2 mice. TGR5 expression and its colocalization with Gαs were increased ∼2-fold upon OA treatment. Levels of cAMP, cell proliferation, and cyst growth in vitro were decreased by ∼30% in cystic cholangiocytes after treatment with SBI-115 alone and by ∼50% when SBI-115 was combined with pasireotide. Conclusion: TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation; our data suggest that a TGR5 antagonist alone or concurrently with somatostatin receptor agonists represents a potential therapeutic approach in polycystic liver disease. (Hepatology 2017;66:1197-1218).
Plasma cystatin C is a predictor of renal dysfunction, acute-on-chronic liver failure, and mortality in patients with acutely decompensated liver cirrhosis Hepatology (IF 13.246) Pub Date : 2017-08-26 Daniel Markwardt; Lesca Holdt; Christian Steib; Andreas Benesic; Flemming Bendtsen; Mauro Bernardi; Richard Moreau; Daniel Teupser; Julia Wendon; Frederik Nevens; Jonel Trebicka; Elisabet Garcia; Marco Pavesi; Vicente Arroyo; Alexander L. Gerbes
The development of acute-on-chronic liver failure (ACLF) in patients with liver cirrhosis is associated with high mortality rates. Renal failure is the most significant organ dysfunction that occurs in ACLF. So far there are no biomarkers predicting ACLF. We investigated whether cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL) can predict development of renal dysfunction (RD), hepatorenal syndrome (HRS), ACLF, and mortality. We determined the plasma levels of CysC and NGAL in 429 patients hospitalized for acute decompensation of cirrhosis in the EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) study. The patients were followed for 90 days. Patients without RD or ACLF at inclusion but with development of either had significantly higher baseline concentrations of CysC and NGAL compared to patients without. CysC, but not NGAL, was found to be predictive of RD (odds ratio, 9.4; 95% confidence interval [CI], 1.8-49.7), HRS (odds ratio, 4.2; 95% CI, 1.2-14.8), and ACLF (odds ratio, 5.9; 95% CI, 1.3-25.9). CysC at day 3 was not found to be a better predictor than baseline CysC. CysC and NGAL were both predictive of 90-day mortality, with hazard ratios for CysC of 3.1 (95% CI, 2.1-4.7) and for NGAL of 1.9 (95% CI, 1.5-2.4). Conclusion: Baseline CysC is a biomarker of RD, HRS, and ACLF and an independent predictor of mortality in patients with acutely decompensated liver cirrhosis, though determining CysC at day 3 did not provide any benefit; while NGAL is also associated with short-term mortality, it fails to predict development of RD, HRS, and ACLF. Baseline CysC may help to identify patients at risk earlier and improve clinical management. (Hepatology 2017;66:1232-1241)
Targeting CCl4-induced liver fibrosis by RNA interference–mediated inhibition of cyclin E1 in mice Hepatology (IF 13.246) Pub Date : 2017-08-26 Jörg‐Martin Bangen; Linda Hammerich; Roland Sonntag; Maike Baues; Ute Haas; Daniela Lambertz; Thomas Longerich; Twan Lammers; Frank Tacke; Christian Trautwein; Christian Liedtke
Initiation and progression of liver fibrosis requires proliferation and activation of resting hepatic stellate cells (HSCs). Cyclin E1 (CcnE1) is the regulatory subunit of the cyclin-dependent kinase 2 (Cdk2) and controls cell cycle re-entry. We have recently shown that genetic inactivation of CcnE1 prevents activation, proliferation, and survival of HSCs and protects from liver fibrogenesis. The aim of the present study was to translate these findings into preclinical applications using an RNA interference (RNAi)-based approach. CcnE1-siRNA (small interfering RNA) efficiently inhibited CcnE1 gene expression in murine and human HSC cell lines and in primary HSCs, resulting in diminished proliferation and increased cell death. In C57BL/6 wild-type (WT) mice, delivery of stabilized siRNA using a liposome-based carrier targeted approximately 95% of HSCs, 70% of hepatocytes, and 40% of CD45+ cells after single injection. Acute CCl4-mediated liver injury in WT mice induced endogenous CcnE1 expression and proliferation of surviving hepatocytes and nonparenchymal cells, including CD45+ leukocytes. Pretreatment with CcnE1-siRNA reverted CcnE1 induction to baseline levels of healthy mice, which was associated with reduced liver injury, diminished proliferation of hepatocytes and leukocytes, and attenuated overall inflammatory response. For induction of liver fibrosis, WT mice were challenged with CCl4 for 4-6 weeks. Co-treatment with CcnE1-siRNA once a week was sufficient to continuously block CcnE1 expression and cell-cycle activity of hepatocytes and nonparenchymal cells, resulting in significantly ameliorated liver fibrosis and inflammation. Importantly, CcnE1-siRNA also prevented progression of liver fibrosis if applied after onset of chronic liver injury. Conclusion: Therapeutic targeting of CcnE1 in vivo using RNAi is feasible and has high antifibrotic activity. (Hepatology 2017;66:1242-1257).
Hepatitis B cure: From discovery to regulatory approval Hepatology (IF 13.246) Pub Date : 2017-08-01 Anna S. Lok; Fabien Zoulim; Geoffrey Dusheiko; Marc G. Ghany
The majority of persons currently treated for chronic hepatitis B require long-term or lifelong therapy. New inhibitors of hepatitis B virus entry, replication, assembly, or secretion and immune modulatory therapies are in development. The introduction of these novel compounds for chronic hepatitis B necessitates a standardized appraisal of the efficacy and safety of these treatments and definitions of new or additional endpoints to inform clinical trials. To move the field forward and to expedite the pathway from discovery to regulatory approval, a workshop with key stakeholders was held in September 2016 to develop a consensus on treatment endpoints to guide the design of clinical trials aimed at hepatitis B cure. The consensus reached was that a complete sterilizing cure, i.e., viral eradication from the host, is unlikely to be feasible. Instead, a functional cure characterized by sustained loss of hepatitis B surface antigen with or without hepatitis B surface antibody seroconversion, which is associated with improved clinical outcomes, in a higher proportion of patients than is currently achieved with existing treatments is a feasible goal. Development of standardized assays for novel biomarkers toward better defining hepatitis B virus cure should occur in parallel with development of novel antiviral and immune modulatory therapies such that approval of new treatments can be linked to the approval of new diagnostic assays used to measure efficacy or to predict response. Combination of antiviral and immune modulatory therapies will likely be needed to achieve functional hepatitis B virus cure. Limited proof-of-concept monotherapy studies to evaluate safety and antiviral activity should be conducted prior to proceeding to combination therapies. The safety of any new curative therapies will be paramount given the excellent safety of currently approved nucleos(t)ide analogues. (Hepatology 2017).
Glecaprevir/Pibrentasvir for HCV Genotype 3 Patients with Cirrhosis and/or Prior Treatment Experience: A Partially Randomized Phase III Clinical Trial Hepatology (IF 13.246) Pub Date : 2017-09-19 David Wyles; Fred Poordad; Stanley Wang; Laurent Alric; Franco Felizarta; Paul Y Kwo; Benedict Maliakkal; Kosh Agarwal; Tarek Hassanein; Frank Weilert; Samuel S Lee; Jens Kort; Sandra S Lovell; Ran Liu; Chih‐Wei Lin; Tami Pilot‐Matias; Preethi Krishnan; Federico J Mensa
Background: This study assessed the efficacy and safety of ribavirin (RBV)-free coformulated glecaprevir/pibrentasvir (G/P) in patients with hepatitis C virus (HCV) genotype (GT) 3 infection with either prior treatment experience and/or compensated cirrhosis, a patient population with limited treatment options.
CHOP-induced loss of intestinal epithelial stemness contributes to bile duct ligation-induced cholestatic liver injury Hepatology (IF 13.246) Pub Date : 2017-09-19 Runping Liu; Xiaojiaoyang Li; Zhiming Huang; Derrick Zhao; Bhagyalaxmi Sukka Ganesh; Guanhua Lai; William M. Pandak; Phillip B Hylemon; Jasmohan S Bajaj; Arun J Sanyal; Huiping Zhou
Impaired intestinal barrier function promotes the progression of various liver diseases including cholestatic liver disease. The close association of primary sclerosing cholangitis (PSC) with inflammatory bowel disease highlights the importance of the gut-liver axis. It has been reported that bile duct ligation (BDL)-induced liver fibrosis is significantly reduced in C/EBP homologous protein knock out (CHOP-/-) mice. However, the underlying mechanisms remain unclear. In the current study, we demonstrate that BDL induces striking and acute hepatic ER stress responses after 1 day, which return to normal after 3 days. No significant hepatocyte apoptosis is detected 7 to 14 days following BDL. However, the inflammatory response is significantly increased after 7 days, which is similar to what we found in human PSC liver samples. BDL-induced loss of stemness in intestinal stem cells (ISCs), disruption of intestinal barrier function, bacterial translocation, activation of hepatic inflammation and M2 macrophage polarization and liver fibrosis are significantly reduced in CHOP-/- mice. In addition, intestinal organoids derived from CHOP-/- mice contain more and longer crypt structures than those from WT mice, which is consistent with the upregulation of stem cell markers (Lgr5, Olfm4 and Sox9) and in vivo findings that CHOP-/- mice have longer villi and crypts as compared to WT mice. Similarly, the mRNA levels of CD14, IL-1β, TNF-α and MCP-1 are increased and stem cell proliferation is suppressed in the duodenum of cirrhotic patients. Conclusion: Activation of ER stress and subsequent loss of stemness of ISCs plays a critical role in BDL-induced systemic inflammation and cholestatic liver injury. Modulation of the ER stress response represents a potential therapeutic strategy for cholestatic liver diseases as well as other inflammatory diseases This article is protected by copyright. All rights reserved.
New pediatric percentiles of liver enzyme serum levels (ALT, AST, GGT): Effects of age, sex, BMI and pubertal stage Hepatology (IF 13.246) Pub Date : 2017-09-19 Sarah Bussler; Mandy Vogel; Diana Pietzner; Kristian Harms; Theresa Buzek; Melanie Penke; Norman Händel; Antje Körner; Ulrich Baumann; Wieland Kiess; Gunter Flemming
The present study aims to clarify the effects of sex, age, BMI and puberty on transaminase serum levels in children and adolescents and to provide new age- and sex-related percentiles for alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyltransferase (GGT). Venous blood and anthropometric data were collected from 4,126 cases. Excluded were cases of participants with potential hepatotoxic medication, with evidence of potential illness at the time of blood sampling and non-normal BMI (BMI < 10th or > 90th). The resulting data (N = 3,131 cases) were used for the calculations of ALT, AST, and GGT percentiles. Age- and sex-related reference intervals were established by using an LMSP-type method. Serum levels of transaminases follow age-specific patterns and relate to the onset of puberty. This observation is more pronounced in girls than in boys. The ALT percentiles showed similar shaped patterns in both sexes. Multivariate regression confirmed significant effects of puberty and BMI-SDS (β = 2.21) on ALT. Surprisingly, AST serum levels were negatively influenced by age (β = -1.42) and BMI-SDS (β = -0.15). The GGT percentiles revealed significant sex-specific differences, correlated positively with age (β = 0.37) and showed significant association with BMI-SDS (β = 1.16). Conclusion: Current reference values of ALT, AST and GGT serum levels were calculated for children between 11 months and 16.0 years, using modern analytical and statistical methods. This study extends the current knowledge about transaminases by revealing influences of age, sex, BMI, and puberty on the serum concentrations of all three parameters and has for these parameters one of the largest sample sizes published so far. This article is protected by copyright. All rights reserved.
MiRNA-506 promotes primary biliary cholangitis-like features in cholangiocytes and immune activation Hepatology (IF 13.246) Pub Date : 2017-09-18 Oihane Erice; Patricia Munoz‐Garrido; Javier Vaquero; Maria J. Perugorria; Maite G. Fernandez‐Barrena; Elena Saez; Alvaro Santos‐Laso; Ander Arbelaiz; Raul Jimenez‐Agüero; Joaquin Fernandez‐Irigoyen; Enrique Santamaria; Verónica Torrano; Arkaitz Carracedo; Meenakshisundaram Ananthanarayanan; Marco Marzioni; Jesus Prieto; Ulrich Beuers; Ronald P. Oude Elferink; Nicholas F. LaRusso; Luis Bujanda; Jose J.G. Marin; Jesus M. Banales
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease associated with autoimmune phenomena targeting intrahepatic bile duct cells (cholangiocytes). Although PBC etiopathogenesis still remains obscure, development of anti-mitochondrial auto-antibodies against pyruvate dehydrogenase complex-E2 (PDC-E2) is a common feature. MicroRNA (miR) dysregulation occurs in liver and immune cells of PBC patients, but their functional relevance is largely unknown. We previously reported that miR-506 is overexpressed in PBC cholangiocytes and directly targets both Cl–/HCO3– anion exchanger 2 (AE2) and type III inositol 1,4,5-trisphosphate receptor (InsP3R3), leading to cholestasis. Here, the regulation of miR-506 gene expression and its role in cholangiocyte pathophysiology and immune activation was studied. Several pro-inflammatory cytokines overexpressed in PBC livers [such as IL8, IL12, IL17, IL18 and TNFα] stimulated miR-506 promoter activity in human cholangiocytes, as revealed by luciferase reporter assays. Experimental overexpression of miR-506 in cholangiocytes dysregulated the cell proteomic profile (by mass spectrometry), affecting proteins involved in different biological processes including mitochondrial metabolism. In cholangiocytes, miR-506: i) induced dedifferentiation with downregulation of biliary and epithelial markers together with upregulation of mesenchymal, pro-inflammatory and pro-fibrotic markers; ii) impaired cell proliferation and adhesion; iii) increased oxidative and endoplasmic reticulum (ER) stress; iv) caused DNA damage; and v) sensitized to caspase-3-dependent apoptosis induced by cytotoxic bile acids. These events were also associated with impaired energy metabolism in mitochondria (proton leak and less ATP production) and PDC-E2 overexpression. Co-culture of miR-506 overexpressing cholangiocytes with PBC immunocytes induced activation and proliferation of PBC immunocytes. Conclusion: different pro-inflammatory cytokines enhance the expression of miR-506 in biliary epithelial cells. MiR-506 induces PBC-like features in cholangiocytes and promotes immune activation, representing a potential therapeutic target for PBC patients. This article is protected by copyright. All rights reserved.
Human Leukocyte Antigen Variants and Risk of Hepatocellular Carcinoma Modified by HCV Genotypes: A Genome-wide Association Study Hepatology (IF 13.246) Pub Date : 2017-09-16 Mei‐Hsuan Lee; Yu‐Han Huang; Hsuan‐Yu Chen; Charles Seik‐Soon Khor; Ya‐Hsuan Chang; Yu‐Ju Lin; Chin‐Lan Jen; Sheng‐Nan Lu; Hwai‐I Yang; Nao Nishida; Masaya Sugiyama; Masashi Mizokami; Yong Yuan; Gibert L'Italien; Katsushi Tokunaga; Chien‐Jen Chen
Background & aims: We conducted a genome-wide association study (GWAS) to discover genetic variants associated with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).
The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex-biased autoimmunity Hepatology (IF 13.246) Pub Date : 2017-09-16 Heekyong R. Bae; Deborah L. Hodge; Guo‐Xiang Yang; Patrick S.C. Leung; Sathi Babu Chodisetti; Julio C. Valencia; Michael Sanford; John M. Fenimore; Ziaur S.M. Rahman; Koichi Tsuneyama; Gary L. Norman; M. Eric Gershwin; Howard A. Young
We have reported a murine model of autoimmune cholangitis, generated by altering the AU rich element by deletion of the IFN-γ 3'UTR region (coined ARE-Del-/-), that has striking similarities to human primary biliary cholangitis (PBC) with female predominance. Previously, we suggested that the gender bias of autoimmune cholangitis was secondary to intense and sustained type I and II IFN signaling. Based on this thesis, and to define the mechanisms that lead to portal inflammation, we specifically addressed the hypothesis that type I IFNs are the driver of this disease. To accomplish these goals, we crossed ARE-Del-/- mice with IFN type I receptor alpha chain (Ifnar1) knockout mice. We report herein that loss of type I IFN receptor signaling in the double construct of ARE-Del-/- Ifnar1-/- mice dramatically reduces liver pathology and abrogated gender bias. More importantly, female ARE-Del-/- mice have an increased number of germinal center (GC) B cells as well as abnormal follicular formation, sites which have been implicated in loss of tolerance. Deletion of type I IFN signaling in ARE-Del-/- Ifnar1-/- mice corrects these GC abnormalities, including abnormal follicular structure. In conclusion, our data implicate type I IFN signaling as a necessary component of the gender bias of this murine model of autoimmune cholangitis. Importantly these data suggest that drugs that target the type I IFN signaling pathway would have potential benefit in the earlier stages of PBC. This article is protected by copyright. All rights reserved.
Solving doubts about L-Ornithine L-Aspartate for overt HE: whom and how to treat Hepatology (IF 13.246) Pub Date : 2017-09-16 Piero Amodio; Javier Ampuero
Randomized controlled trials about the treatment of bouts of overt hepatic encephalopathy (OHE) are difficult to design and interpret, since bouts of OHE i) are relatively short episodes in which the dynamic of the response to treatment is relevant, ii) their occurrence and treatment is frequently linked to precipitating events. The study by Sidhu et al. in this issue of Hepatology is a model of proper design and provides evidence that L-ornithine-L-aspartate infusion for 5 days is an effective add on treatment to speed up recovery from bouts of OHE in comparison with a placebo treatment that does not contain amino acid nutrients. This article is protected by copyright. All rights reserved.
Graft-infiltrating PD-L1hi cross-dressed dendritic cells regulate anti-donor T cell responses in mouse liver transplant tolerance Hepatology (IF 13.246) Pub Date : 2017-09-16 Yoshihiro Ono; Angelica Perez‐Gutierrez; Toshimasa Nakao; Helong Dai; Geoffrey Camirand; Osamu Yoshida; Shinichiro Yokota; Donna Beer Stolz; Mark A. Ross; Adrian E. Morelli; David A. Geller; Angus W. Thomson
While a key role of cross-dressing has been established in immunity to viral infection and more recently in the instigation of transplant rejection, its role in tolerance is unclear. Here, we investigated the role of intra-graft dendritic cells (DC) and cross-dressing in mouse major histocompatibility complex (MHC)-mismatched liver transplant tolerance that occurs without therapeutic immunosuppression. While donor interstitial DC diminished rapidly following transplantation, they were replaced in the liver by host DC that peaked on postoperative day (POD) 7 and persisted indefinitely. About 60% of these recipient DC displayed donor MHC class I, indicating cross-dressing. By contrast, only a very minor fraction (0-2%) of cross-dressed DC (CD-DC) was evident in the spleen. CD-DC sorted from liver grafts expressed much higher levels of T cell inhibitory programed death ligand 1 (PD-L1) and high levels of IL-10 compared with non CD-DC (nCD-DC) isolated from the graft. Concomitantly, high incidences of programed death protein 1 (PD-1)hi T cell immunoglobulin and mucin domain containing-3 (TIM-3)+ exhausted graft-infiltrating CD8+ T cells were observed. Importantly, unlike nCD-DC, the CD-DC failed to stimulate proliferation of allogeneic T cells but markedly suppressed anti-donor host T cell proliferation. CD-DC were much less evident in allografts from DNAX-activating protein of 12kDa (DAP12)-/- donors that were rejected acutely. Conclusion: These findings suggest that graft-infiltrating PD-L1hi CD-DC may play a key role in the regulation of alloimmunity and in the induction of liver transplant tolerance. This article is protected by copyright. All rights reserved.
Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma Hepatology (IF 13.246) Pub Date : 2017-09-15 Oriana Lo Re; Caterina Fusilli; Francesca Rappa; Matthias Van Haele; Julien Douet; Jana Pindjakova; Sura Wanessa Rocha; Illar Pata; Barbora Valčíková; Stjepan Uldrijan; Raymond S. Yeung; Christina Alves Peixoto; Tania Roskams; Marcus Buschbeck; Tommaso Mazza; Manlio Vinciguerra
Hepatocellular carcinomas (HCC) contain a sub-population of cancer stem cells (CSCs), which exhibit stem-cell like features and are responsible for tumor relapse, metastasis, and chemoresistance. The development of effective treatments for HCC will depend on a molecular-level understanding of the specific pathways driving CSC emergence and stemness. MacroH2A1 is a variant of the histone H2A and an epigenetic regulator of stem cell function, where it promotes differentiation and, conversely, acts as a barrier to somatic cell reprogramming. Here we focused on the role played by the histone variant macroH2A1 as a potential epigenetic factor promoting CSC differentiation. In human HCC sections we uncovered a significant correlation between low frequencies of macroH2A1 staining and advanced, aggressive HCC subtypes with poorly-differentiated tumor phenotypes. Using HCC cell lines we found that shRNA-mediated macroH2A1 knock-down induces acquisition of CSC-like features, including the growth of significantly larger and less-differentiated tumors when injected into nude mice. MacroH2A1-depleted HCC cells also exhibited reduced proliferation, resistance to chemotherapeutic agents, and stem-like metabolic changes consistent with enhanced hypoxia responses and increased glycolysis. The loss of macroH2A1 increased expression of a panel of stemness-associated genes, and drove hyper-activation of the NF-κBp65 pathway. Blocking phosphorylation of NF-κBp65 on Ser536 inhibited the emergence of CSC-like features in HCC cells knocked-down for macroH2A1. Conclusion: the absence of histone variant macroH2A1 confers a CSC-like phenotype to HCC cells in vitro and in vivo that depends on Ser536 phosphorylation of NF-κBp65. This pathway may hold valuable targets for the development of CSC-focused treatments for HCC. This article is protected by copyright. All rights reserved.
Impact of an electronic health record alert in primary care on increasing hepatitis c screening and curative treatment for baby boomers Hepatology (IF 13.246) Pub Date : 2017-09-14 Monica A. Konerman; Mary Thomson; Kristen Gray; Meghan Moore; Hetal Choxi; Elizabeth Seif; Anna S.F. Lok
Despite effective treatment for chronic hepatitis C, deficiencies in diagnosis and access to care preclude disease elimination. Screening of baby boomers remains low. The aims of this study were to assess the impact of an electronic health record–based prompt on hepatitis C virus (HCV) screening rates in baby boomers in primary care and access to specialty care and treatment among those newly diagnosed. We implemented an electronic health record–based “best practice advisory” (BPA) that prompted primary care providers to perform HCV screening for patients seen in primary care clinic (1) born between 1945 and 1965, (2) who lacked a prior diagnosis of HCV infection, and (3) who lacked prior documented anti-HCV testing. The BPA had associated educational materials, order set, and streamlined access to specialty care for newly diagnosed patients. Pre-BPA and post-BPA screening rates were compared, and care of newly diagnosed patients was analyzed. In the 3 years prior to BPA implementation, 52,660 baby boomers were seen in primary care clinics and 28% were screened. HCV screening increased from 7.6% for patients with a primary care provider visit in the 6 months prior to BPA to 72% over the 1 year post-BPA. Of 53 newly diagnosed patients, all were referred for specialty care, 11 had advanced fibrosis or cirrhosis, 20 started treatment, and 9 achieved sustained virologic response thus far. Conclusion: Implementation of an electronic health record–based prompt increased HCV screening rates among baby boomers in primary care by 5-fold due to efficiency in determining needs for HCV screening and workflow design. Streamlined access to specialty care enabled patients with previously undiagnosed advanced disease to be cured. This intervention can be easily integrated into electronic health record systems to increase HCV diagnosis and linkage to care. (Hepatology 2017).
NLRP3 inflammasome driven liver injury and fibrosis: Roles of IL- 17 and TNF Hepatology (IF 13.246) Pub Date : 2017-09-13 Alexander Wree; Matthew D. McGeough; Maria Eugenia Inzaugarat; Akiko Eguchi; Susanne Schuster; Casey D. Johnson; Carla A. Peña; Lukas J. Geisler; Bettina G Papouchado; Hal M. Hoffman; Ariel E. Feldstein
The NLRP3 inflammasome, a caspase-1 activation platform plays a key role in the modulation of liver inflammation and fibrosis. Here, we tested the hypothesis that interleukin 17 (IL-17) and tumor necrosis factor (TNF) are key cytokines involved in amplifying and perpetuating the liver damage and fibrosis resulting from NLRP3 activation. To address this hypothesis gain of function Nlrp3A350V knock-in mice were bred onto il17a and Tnf knockout backgrounds allowing for constitutive Nlrp3 activation in myeloid derived cells in mice deficient in IL-17 or TNF. Livers of Nlrp3A350V knock-in mice exhibited severe liver inflammatory changes characterized by infiltration with neutrophils, increased expression of CXCL1 and CXCL2 chemokines, activated inflammatory macrophages and elevated levels of IL-17 and TNF. Mutants with ablation of il17a signal showed fewer neutrophils when compared to intact Nlrp3A350V mutants, but still significant inflammatory changes when compared to the non-mutant il17a knockout littermates. The severe inflammatory changes associated with mutant Nlrp3 were almost completely rescued by Tnf knockout in association with a marked decrease in circulating IL-1β levels. Intact Nlrp3A350Vmutants showed changes of liver fibrosis, as evidenced by morphometric quantitation of Sirius red staining and increased mRNA levels of profibrotic genes including CTGF and TIMP-1. Il17a lacking mutants exhibited amelioration of the aforementioned fibrosis, while Tnf deficient mutants showed no signs of fibrosis when compared to littermate controls. Conclusion: Our study uncovers key roles for TNF, and to a lesser extent IL-17, as mediators of liver inflammation and fibrosis induced by constitutive NLRP3 inflammasome activation in myeloid derived cells. These findings may lead to novel therapeutic strategies aimed at halting the progression of liver injury and fibrogenesis in various liver pathogenesis driven by NLRP3 activation. This article is protected by copyright. All rights reserved.
Nuclear lamina genetic variants, including a truncated LAP2, in twins and siblings with nonalcoholic fatty liver disease Hepatology (IF 13.246) Pub Date : 2017-09-13 Graham F. Brady; Raymond Kwan; Peter J. Ulintz; Phirum Nguyen; Shirin Bassirian; Venkatesha Basrur; Alexey I. Nesvizhskii; Rohit Loomba; M. Bishr Omary
Nonalcoholic fatty liver disease (NAFLD) is becoming the major chronic liver disease in many countries. Its pathogenesis is multifactorial but twin and familial studies indicate significant heritability, which is not fully explained by currently-known genetic susceptibility loci. Notably, mutations in genes encoding nuclear lamina proteins, including lamins, cause lipodystrophy syndromes that include NAFLD. We hypothesized that variants in lamina-associated proteins predispose to NAFLD and used a candidate gene-sequencing approach to test for variants in 10 nuclear lamina-related genes in a cohort of 37 twin and sibling pairs: 21 individuals with, and 53 without, NAFLD. Twelve heterozygous sequence variants were identified in four lamina-related genes (ZMPSTE24/TMPO/SREBF1/SREBF2). The majority of NAFLD patients (>90%) had at least one variant, compared to <40% of controls (P<0.0001). When only insertions/deletions and changes in conserved residues were considered, the difference between the groups was similarly striking (>80% versus <25%; P<0.0001). Presence of a lamina variant segregated with NAFLD independent of the PNPLA3 I148M polymorphism. Several variants were found in TMPO, which encodes the lamina-associated polypeptide-2 (LAP2) that has not previously been associated with liver disease. One of these, a frameshift insertion that generates truncated LAP2, abrogated lamin-LAP2 binding, caused LAP2 mislocalization, altered endogenous lamin distribution, increased lipid droplet accumulation after oleic acid treatment in transfected cells, and led to cytoplasmic association with the ubiquitin-binding protein p62/SQSTM1. Conclusion: Novel variants in nuclear lamina-related genes were identified in a cohort of twins and siblings with NAFLD. One novel variant, which results in a truncated LAP2 protein and a dramatic phenotype in cell culture, represents the first association of TMPO/LAP2 variants with NAFLD and underscores the potential importance of the nuclear lamina in NAFLD. This article is protected by copyright. All rights reserved.
Cardiovascular predictors of death in patients with cirrhosis Hepatology (IF 13.246) Pub Date : 2017-09-13 Maurizio Cesari; Anna Chiara Frigo; Marta Tonon; Paolo Angeli
Cirrhotic cardiomyopathy is associated with poor outcomes in patients with cirrhosis. We investigated if subclinical cardiac morphologic and functional modifications can influence survival in cirrhotic patients during follow-up. A series of cirrhotic patients without cardiovascular or pulmonary disease underwent standard and tissue Doppler echocardiography to assess left ventricular (LV) geometry, systo/diastolic function and the main haemodynamic parameters. After baseline evaluation 115 cirrhotic patients were followed up for at least 6 years. During follow up 54 patients died (47%). On univariate analysis age, BSA, MELD, mean arterial pressure, heart rate, cardiac index, systemic vascular resistance index, the ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity (E/e') were associated with increased risk of death. In a Cox hazard regression analysis including these factors and other hypothesized important factors (but not MELD) increased age (p=0.04) and left atrial dimension (p=0.005), and lower BSA (p=0.03) were the strongest predictors of death. When MELD was included in the analysis the main predictors were MELD, age and BSA. When multivariate analysis was performed incorporating only cardiovascular parametres, increased E/e' (p=0.003) and heart rate (p= 0.03) and reduced mean blood pressure (p= 0.01) resulted significantly associated with poor prognosis. Conclusion: in a large cohort of cirrhotic patients and after a long follow-up MELD, age and BSA were the main predictors of death. Among cardiovascular parameters, left atrium enlargement, increased heart rate and E/e' and reduced mean blood pressure resulted independent predictors of death. This article is protected by copyright. All rights reserved.
Reassessing the Safety Concerns of Utilizing Blood Donations from Patients with Hemochromatosis Hepatology (IF 13.246) Pub Date : 2017-09-13 Adam C. Winters; Douglas Tremblay; Suzanne Arinsburg; John Mascarenhas; Thomas D. Schiano
Hereditary hemochromatosis (HH) is a genetic disorder of iron metabolism which may lead to iron overload. Clinical penetrance is low, however those afflicted may develop cirrhosis, hepatocellular carcinoma, diabetes mellitus and cardiomyopathy. Treatment involves regular phlebotomy to reduce the systemic iron burden. In many countries—including the United States—numerous blood centers do not accept donated blood obtained from HH patients during therapeutic phlebotomy and there are inconsistent positions regarding this globally. This refusal is borne out of a few concerns. First, there is a theoretical increase in the infectious risk of these blood products, particularly by siderophilic organisms such as Yersinia enterocolitica. Second, given the increased incidence of hepatitis C infection from non-voluntary donors in the 1970s, there is a concern that blood from HH donors may harbor additional risk given the non-voluntary nature of their presentation. In this review, we examine the existing biologic and clinical data concerning infectious risk and summarize clinical experience from centers allowing HH donors, and demonstrate that blood from HH patients is safe and should be allowed into the donor pool. We conclude that there is no convincing evidence to exclude this population from serving as blood donors. This article is protected by copyright. All rights reserved.
Complete response under sorafenib in patients with hepatocellular carcinoma. Relationship with dermatologic adverse events Hepatology (IF 13.246) Pub Date : 2017-09-12 Jordi Rimola; Álvaro Díaz‐González; Anna Darnell; María Varela; Fernando Pons; Manuel Hernandez‐Guerra; Manuel Delgado; Javier Castroagudin; Ana Matilla; Bruno Sangro; Carlos Rodriguez de Lope; Margarita Sala; Carmen Gonzalez; Carlos Huertas; Beatriz Minguez; Carmen Ayuso; Jordi Bruix; Maria Reig
Background-aims: The clinical benefit of sorafenib in patients with hepatocellular carcinoma (HCC) has been undervalued due to the absence of complete responses even though patients who develop early dermatologic reactions have shown very positive outcome. In addition, sorafenib is described as an antiangiogenic drug, but it also acts on immunological cells. Thus, the aim is to assess the complete response rate in a retrospective cohort of HCC patients treated with sorafenib and to describe the profile of the patients who achieve complete response for identifying factors related to this event and their connection with the immunological profile of sorafenib.
Organic Solute Transporter-beta (SLC51B) Deficiency in Two Brothers with Congenital Diarrhea and Features of Cholestasis Hepatology (IF 13.246) Pub Date : 2017-09-12 Mutaz Sultan; Anuradha Rao; Orly Elpeleg; Frédéric M. Vaz; Bassam Y Abu Libdeh; Saul J. Karpen; Paul A. Dawson
Primary bile acid malabsorption (PBAM) is associated with congenital diarrhea, steatorrhea, and a block in the intestinal return of bile acids in the enterohepatic circulation. Mutations in the ileal Na+-dependent bile acid transporter (ASBT; SLC10A2) can cause PBAM, but do not appear to account for most familial cases. Another major transporter involved in the intestinal reclamation of bile acids is the heteromeric Organic Solute Transporter alpha-beta (OSTα-OSTβ; SLC51A-SLC51B), which exports bile acid across the basolateral membrane. Here we report the first patients with OSTβ deficiency, clinically characterized by chronic diarrhea, severe fat soluble vitamin deficiency, and features of cholestatic liver disease including elevated serum gamma-glutamyltransferase activity. Whole exome sequencing revealed a homozygous single nucleotide deletion in codon 27 of SLC51B, resulting in a frameshift and premature termination at codon 50. Functional studies in transfected cells showed that the SLC51B mutation resulted in markedly reduced taurocholic acid uptake activity and reduced expression of the OSTα partner protein. Conclusion: The findings identify OSTβ deficiency as a new cause of congenital chronic diarrhea with features of cholestatic liver disease. These studies underscore OSTα-OSTβ's key role in the enterohepatic circulation of bile acids in humans. This article is protected by copyright. All rights reserved.
Contradictory Effects of Mitochondria- and Non-mitochondria-targeted Antioxidants on Hepatocarcinogenesis by Altering DNA Repair Hepatology (IF 13.246) Pub Date : 2017-09-12 Bibo Wang; Jing Fu; Ting Yu; An Xu; Wenhao Qin; Zhishi Yang; Yao Chen; Hongyang Wang
Conflicting effects of antioxidant supplementation on cancer prevention or promotion is of great concern to healthy people and cancer patients. Despite recent studies about antioxidants accelerating the progression of lung cancer and melanoma, it does not fully deny antioxidants for cancer prevention. Both tumor and antioxidants types influence the actual efficacy. However, little is known about the impact of different types of antioxidants on primary hepatocellular carcinoma (HCC), including non-mitochondrial- and mitochondrial-targeted antioxidants. Based on the mouse models of chemical hepatocarcinogenesis, we showed that administration of non-mitochondria-targeted antioxidants N-acetylcysteine (NAC) and the soluble vitamin E analog Trolox prevented tumorigenesis, whereas administration of mitochondria-targeted antioxidants SS-31 (the mitochondria targeted peptide) and Mito-Q (a derivative of ubiquinone) encouraged tumorigenesis. RNA sequencing revealed that NAC and SS-31 cause highly different changes in oxidation-reduction state and DNA damage response. Remarkably, in diethylnitrosamine (DEN)-treated primary hepatocytes, NAC and Trolox alleviated DNA damage by activating ATM/ATR for DNA repair while SS-31 and MitoQ aggravated damage by inactivating them. Interestingly, partial recovery of SS-31-scavengened mitochondrial ROS (mtROS) could alleviate SS-31-aggravated DNA damage. Localization of ATM between mitochondria and nuclei was changed after NAC and SS-31 treatment. Furthermore, blockage of p-ATR led to the recurrence of NAC-ameliorated DEN HCC. In contrast, reactivation of p-ATR blocked SS-31-promoted DEN HCC. These results demonstrate that the type of antioxidants plays a previously unappreciated role in hepatocarcinogenesis, and provide a mechanistic rationale for exploring the therapeutic use of antioxidants for liver cancer. This article is protected by copyright. All rights reserved.
The ASK1 Inhibitor Selonsertib in Patients with Nonalcoholic Steatohepatitis: A Randomized, Phase 2 Trial Hepatology (IF 13.246) Pub Date : 2017-09-11 Rohit Loomba; Eric Lawitz; Parvez S. Mantry; Saumya Jayakumar; Stephen H. Caldwell; Hays Arnold; Anna Mae Diehl; C. Stephen Djedjos; Ling Han; Robert P. Myers; G. Mani Subramanian; John G. McHutchison; Zachary D. Goodman; Nezam H. Afdhal; Michael R. Charlton
Inhibition of apoptosis signal-regulating kinase 1 (ASK1), a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis (NASH). We evaluated the safety and efficacy of selonsertib, a selective inhibitor of ASK1, alone or in combination with simtuzumab, in patients with NASH and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 weeks of open-label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once-weekly injections of 125 mg of simtuzumab, or simtuzumab alone. The effect of treatment was assessed by paired pre- and post-treatment liver biopsies, magnetic resonance elastography (MRE), and magnetic resonance imaging-estimated proton density fat fraction, quantitative collagen content, and noninvasive markers of liver injury. Due to the lack of effect of simtuzumab on histology or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. After 24 weeks of treatment, the proportion of patients with a ≥1-stage reduction in fibrosis in the 18-mg selonsertib group was 13 of 30 (43%; 95% CI, 26-63), in 6-mg selonsertib group, 8 of 27 (30%; 95% CI, 14-50), and in the simtuzumab-alone group, 2 of 10 (20%; 95% CI, 3-56). Improvement in fibrosis was associated with reductions in liver stiffness on MRE, and collagen content and lobular inflammation on liver biopsy, as well as improvements in serum biomarkers of apoptosis and necrosis. There were no significant differences in adverse events between the treatment groups.
A multifunctional nanocarrier for efficient TRAIL-based gene therapy against hepatocellular carcinoma with desmoplasia Hepatology (IF 13.246) Pub Date : 2017-09-08 Chun‐Hung Liu; Guann‐Gen Chern; Fu‐Fei Hsu; Kuan‐Wei Huang; Yun‐Chieh Sung; Hsi‐Chien Huang; Jiantai Timothy Qiu; Sheng‐Kai Wang; Chu‐Chi Lin; Chien‐Hsun Wu; Han‐Chung Wu; Jia‐Yu Liu; Yunching Chen
The anti-cancer efficacy of TNF-related apoptosis-inducing ligand (TRAIL)-based therapy is limited due to systemic toxicity, poor bioavailability, and the development of TRAIL-resistance. We developed a tumor-targeted LCPP (Lipid/Calcium/Phosphate/Protamine) nanoparticle (NP) to deliver TRAIL plasmid DNA (pDNA) into hepatocellular carcinoma (HCC) cells. TRAIL pDNA was encapsulated in a pH stimuli-responsive calcium phosphate (CaP) core, and protamine was added to facilitate nuclear delivery of pDNA. In addition, the intracellular release of Ca2+ from the CaP core overcame TRAIL resistance via calcium influx-dependent DR5 upregulation. TRAIL expression also attenuated fibrosis in the liver tissues surrounding HCCs by reverting activated hepatic stellate cells (HSCs) to a quiescent state or by directly inducing apoptosis in activated HSCs. Conclusion: TRAIL pDNA delivered by HCC-targeted LCPP NPs in combination with conventional sorafenib treatment attenuated HCC progression as well as liver fibrosis. Overall, our study presents an effective TRAIL-based cancer therapy that could be developed for clinical applications. This article is protected by copyright. All rights reserved.
Therapies for Advanced Stage Hepatocellular Carcinoma with Macrovascular invasion or Metastatic Disease: a Systematic Review and Meta-analysis Hepatology (IF 13.246) Pub Date : 2017-09-07 Richard S. Finn; Andrew X. Zhu; Farah Wigdan; Jehad Almasri; Feras Zaiem; Larry J Prokop; Mohammad Hassan Murad; Khaled Mohammed
Hepatocellular carcinoma (HCC) is a complex disease most commonly arising in the background of chronic liver disease. In the past two decades there has been a significant increase in our understanding of both the clinical and molecular heterogeneity of HCC. There has been a robust increase in clinical trial activity in patients with poor prognostic factors such as macrovascular invasion and extrahepatic spread. We aimed to synthesize the evidence for the treatment of patients with advanced HCC based on these baseline characteristics including patients with both Child-Pugh scores of A and B. A comprehensive search of several databases from each database inception to February 15th 2016, any language was conducted.We included 14 studies (3 randomized controlled studies (RCTs) and 11 observational studies).We included studies that compared sorafenib, transarterial bland embolisation/transarterial chemoembolization, yttrium-90/radiation therapy, ablation (or combination) and no therapy. Two RCTs comparing sorafenib to best supportive care demonstrated a consistent improvement in OS for patients with advanced HCC and MVI and/or EHS and Child Pugh-A liver disease (HR 0.66 (95% CI 0.51-0.87), I2= 0%). Several observational studies evaluated loco-regional therapies alone or in combination with other treatments and were limited by very low quality of evidence. This was true for both patients with EHS and MVI. Conclusion: In patients with advanced HCC and Child-Pugh A liver function, sorafenib is the only treatment that has been shown to improve overall survival in randomized studies. High quality data supporting the use of other treatment modalities in this setting, or in the setting of patients with less compensated (CP B) liver disease is lacking. This article is protected by copyright. All rights reserved.
Natural IgM initiates an inflammatory response important for both hepatic ischemia reperfusion injury and regeneration Hepatology (IF 13.246) Pub Date : 2017-09-07 Keely Marshall; Junfei Jin; Carl Atkinson; Ali Alawieh; Fei Qiao; Biao Lei; Kenneth D. Chavin; Songqing He; Stephen Tomlinson
Rationale: Complement plays a role in both hepatic ischemia reperfusion (IR) injury (IRI) and liver regeneration, but it is not clear how complement is activated in either process. We investigated the role of self-reactive IgM antibodies in activating complement after hepatic IR and liver resection.
Charting the transcriptional regulatory changes in mouse liver during fasting Hepatology (IF 13.246) Pub Date : 2017-08-17 Elodie Thierion; Duncan T Odom
In a recent paper: Goldstein I, Baek S, Presman DM, Paakinaho V, Swinstead EE, Hager GL. Transcription factor assisted loading and enhancer dynamics dictate the hepatic fasting response. Genome Res. 2017 Mar;27(3):427-39., the authors used a number of functional genomics approaches to explore the transcriptional regulatory dynamics that occur during hepatic fasting. They used chromatin landscape data to identify key fasting-related transcription factors, four of which were further investigated because they are known players of the fasting response: CEBPB (CCAAT enhancer binding-beta), CREB1 (cAMP responsive element binding protein I), GR (glucocorticoid receptor), and PPARA (peroxisome proliferator activated receptor alpha). The authors described two operating modules (GR-CREB1 and PPARA-GR) with synergistic effects driving gluconeogenesis through an assisted loading model and fatty acid oxidation/ketogenesis through a transcription factor cascade, respectively. Finally, using single-cell tracking, they confirmed that GR facilitates CREB1 binding to DNA. This article is protected by copyright. All rights reserved.
Projected increase in obesity and non-alcoholic steatohepatitis-related liver transplantation waitlist additions in the United States Hepatology (IF 13.246) Pub Date : 2017-08-17 Neehar D Parikh; Wesley J Marrero; Jingyuan Wang; Justin Steuer; Elliot B. Tapper; Monica Konerman; Amit G Singal; David W Hutton; Eunshin Byon; Mariel S Lavieri
Non-alcoholic steatohepatitis (NASH) cirrhosis is the fastest growing indication for liver transplantation (LT) in the US. We aimed to determine the temporal trend behind the rise in obesity and NASH-related additions to the LT waitlist in the US and make projections for future NASH burden on the LT waitlist. We used data from the Organ Procurement and Transplantation Network database from 2000-2014 to obtain the number of NASH-related LT waitlist additions. The obese population in the US from 2000-2014 was estimated using data from the US Census Bureau and the National Health and Nutrition Examination Survey. Based on obesity trends, we established a time lag between obesity prevalence and NASH-related waitlist additions. We used data from the US Census Bureau on population projections from 2016-2030 to forecast obesity estimates and NASH-related LT waitlist additions. From 2000-2014, the proportion of obese individuals significantly increased 44.9% and the number of NASH-related annual waitlist additions increased from 391 to 1605. Increase in obesity prevalence was strongly associated with LT waitlist additions 9 years later in derivation and validation cohorts (R2=0.9). Based on these data, annual NASH-related waitlist additions are anticipated to increase by 55.4% (1,354 to 2,104) between 2016 and 2030. There is significant regional variation in obesity rates and in the anticipated increase in NASH-related waitlist additions (p<0.01). Conclusion: We project a marked increase in demand for LT for NASH given population obesity trends. Continued public health efforts to curb obesity prevalence are needed to reduce the projected future burden of NASH. This article is protected by copyright. All rights reserved.
Radioembolization for Hepatocellular Carcinoma: Statistical Confirmation of Improved Survival in Responders by Landmark Analyses Hepatology (IF 13.246) Pub Date : 2017-08-18 Ahsun Riaz; Ahmed Gabr; Nadine Abouchaleh; Rehan Ali; Ali Alasadi; Ronald Mora; Laura Kulik; Kush Desai; Bartley Thornburg; Samdeep Mouli; Ryan Hickey; Frank H Miller; Vahid Yaghmai; Daniel Ganger; Robert J Lewandowski; Riad Salem
Does imaging response predict survival in hepatocellular carcinoma (HCC)? We studied the ability of post-therapeutic imaging response to predict overall survival. Over 14 years, 948 HCC patients were treated with radioembolization. Patients with baseline metastases, vascular invasion, multifocal disease, Child-Pugh>B7 and transplanted/resected were excluded. This created our homogenous study cohort of 134 Child-Pugh≤B7 patients with solitary HCC. Response (using European Association for Study of the Liver [EASL] and Response Evaluation Criteria in Solid Tumors 1.1 [RECIST 1.1] criteria) was associated with survival using Landmark and risk-of-death methodologies after reviewing 960 scans. In a sub-analysis, survival times of responders were compared to those of patients with stable disease (SD) and progressive disease (PD). Uni/multivariate survival analyses were performed at each Landmark. At the 3-month Landmark, responders survived longer than nonresponders by EASL (HR:0.46; CI:0.26-0.82; P=0.002) but not RECIST 1.1 criteria (HR:0.70; CI:0.37-1.32; P=0.32). At the 6-month Landmark, responders survived longer than nonresponders by EASL (HR:0.32; CI:0.15-0.77; P<0.001) and RECIST 1.1 criteria (HR:0.50; CI:0.29-0.87; P=0.021). At the 12-month Landmark, responders survived longer than nonresponders by EASL (HR:0.34; CI:0.15-0.77; P<0.001) and RECIST 1.1 criteria (HR:0.52;CI 0.27-0.98; P=0.049). At 6 months, risk of death was lower for responders by EASL (P<0.001) and RECIST 1.1 (P=0.0445). In sub-analyses, responders lived longer than patients with SD or PD. EASL response was a significant predictor of survival at 3, 6, and 12 month Landmarks on uni/multivariate analyses. Conclusion: Response to radioembolization in patients with solitary HCC can prognosticate improved survival. EASL necrosis criteria outperformed RECIST 1.1 size criteria in predicting survival. The therapeutic objective of radioembolization should be radiologic response and not solely to prevent progression. This article is protected by copyright. All rights reserved.
A miR-7/GAS6/TYRO3 axis regulates the growth and invasiveness of sorafenib-resistant cells in human hepatocellular carcinoma Hepatology (IF 13.246) Pub Date : 2017-08-18 TD Kabir; C Ganda; RM Brown; DJ Beveridge; KL Richardson; V Chaturvedi; P Candy; M Epis; L Wintle; F Kalinowski; C Kopp; LM Stuart; GC Yeoh; J George; PJ Leedman
Sorafenib remains the only approved drug for treating patients with advanced hepatocellular carcinoma (HCC). However, the therapeutic effect of sorafenib is transient and patients invariably develop sorafenib resistance (SR). Recently, TYRO3, a member of the TAM family of receptor tyrosine kinases, was identified as being aberrantly expressed in a significant proportion of HCC, however its role in SR is unknown. In this study, we generated two functionally distinct sorafenib resistant human Huh-7 HCC cell lines, in order to identify new mechanisms to abrogate acquired SR, as well as new potential therapeutic targets in HCC. Initially, we investigated the effects of a microRNA, miR-7, in both in vitro and in vivo preclinical models of human HCC and identified miR-7 as a potent tumour suppressor of human HCC. We identified TYRO3 as a new functional target of miR-7, which regulates proliferation, migration and invasion of Huh-7 cells via the PI3-Kinase/AKT pathway and is markedly elevated upon acquisition of SR. Furthermore, miR-7 effectively silenced TYRO3 expression in both sorafenib-sensitive and sorafenib-resistant Huh-7 cells inhibiting TYRO3/GAS6 mediated cancer cell migration and invasion. In conclusion, we identified a novel mechanism for acquiring SR in HCC which is via the aberrant expression of the TYRO3/PI3-Kinase/AKT signal transduction pathway, a mechanism that can be overcome by miR-7 over-expression. Taken together, these data suggest a potential role for miR-7 as an RNA-based therapeutic to treat refractory and drug resistant HCC. This article is protected by copyright. All rights reserved.
Epigenetic Regulation of Hepatitis B Virus Covalently Closed Circular DNA: Implications for Epigenetic Therapy against Chronic Hepatitis B Hepatology (IF 13.246) Pub Date : 2017-08-18 Xupeng Hong; Elena S. Kim; Haitao Guo
Hepatitis B virus (HBV) infection represents a significant public health burden worldwide. Although current therapeutics manage to control the disease progression, lifelong treatment and surveillance are required because drug resistance develops during treatment and reactivations frequently occur following medication cessation. Thus, the occurrence of hepatocellular carcinoma (HCC) is decreased but not eliminated. One major reason for the treatment failure is the inability to eradicate or inactivate the viral covalently closed circular DNA (cccDNA) which is a stable episomal form of viral genome decorated with host histones and non-histone proteins. Accumulating evidence suggests that epigenetic modifications of cccDNA contribute to viral replication and the outcome of chronic HBV infection. Here, we summarize the progress on HBV epigenetics research and the therapeutic implications for chronic HBV infection by learning from the epigenetic therapies for cancer and other viral diseases, which may open a new venue to cure the chronic hepatitis B. This article is protected by copyright. All rights reserved.
Self-assembled liver organoids recapitulate hepato-biliary organogenesis in vitro Hepatology (IF 13.246) Pub Date : 2017-08-23 Dipen Vyas; Pedro M. Baptista; Matthew Brovold; Emma Moran; Matthew Brovold; Brandon Gaston; Chris Booth; Michael Samuel; Anthony Atala; Shay Soker
Several 3D cell culture systems are currently available to create liver organoids. In general, these systems display better physiologic and metabolic aspects of intact liver tissue, compared with 2D culture systems. However, none of these reliably mimic human liver development, including parallel formation of hepatocyte and cholangiocyte anatomical structures. Here, we show that human fetal liver progenitor cells self-assemble inside acellular liver extracellular matrix (ECM) scaffolds to form 3D liver organoids that recapitulated several aspects of hepato-biliary organogenesis and resulted in concomitant formation of progressively more differentiated hepatocytes and bile duct structures. The duct morphogenesis process was interrupted by inhibiting Notch signaling, attempting to create a liver developmental disease model with a similar phenotype of Alagille syndrome. In the current study, we created an in vitro model of human liver development and disease, physiology and metabolism, supported by liver ECM substrata. We envision that it will be used in the future to study mechanisms of hepatic and biliary development, and for disease modeling and drug screening. This article is protected by copyright. All rights reserved.
Engaging hepatitis C infected patients in cost-effectiveness analyses: A literature review Hepatology (IF 13.246) Pub Date : 2017-08-23 T. Joseph Mattingly; Eleanor M. Perfetto; Sophia Johnson
Hepatic PPARγ coactivator 1β drives mitochondrial and anabolic signatures that contribute to hepatocellular carcinoma progression Hepatology (IF 13.246) Pub Date : 2017-08-31 Elena Piccinin; Claudia Peres; Elena Bellafante; Simon Ducheix; Claudio Pinto; Gaetano Villani; Antonio Moschetta
The peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1β (PGC-1 β) coactivator is a master regulator of mitochondrial biogenesis and oxidative metabolism as well as of antioxidant defense. Specifically in the liver PGC-1β also promotes de novo lipogenesis, thus sustaining cellular anabolic processes. Given the relevant pathogenic role of mitochondrial and fatty acid metabolism in hepatocarcinoma (HCC), here we pointed to PGC-1β as a putative novel transcriptional player in the development and progression of HCC. For this purpose, we generated both hepatic-specific PGC-1β overexpressing (LivPGC-1β) and PGC-1β knockout (LivPGC-1βKO) mice, and we challenged them with both chemical and genetic models of hepatic carcinogenesis. Our results demonstrate a pivotal role of PGC-1β in driving liver tumor development. Indeed, whereas mice overexpressing PGC-1β show greater tumor susceptibility, PGC-1β knockout mice are protected from carcinogenesis. High levels of PGC-1β are able to boost ROS scavenger expression, therefore limiting the detrimental ROS accumulation and, consequently, apoptosis. Moreover, it supports tumor anabolism, enhancing the expression of genes involved in fatty acid and triglyceride synthesis. Accordingly, the specific hepatic ablation of PGC-1β promotes the accumulation of ROS-driven macromolecule damage, finally limiting tumor growth . The present data elect hepatic PGC-1β as a transcriptional gatekeeper of mitochondrial function and redox status in HCC, orchestrating different metabolic programs that allow tumor progression. This article is protected by copyright. All rights reserved.
Pregnancy in Wilson disease – management and outcome Hepatology (IF 13.246) Pub Date : 2017-08-31 Jan Pfeiffenberger; Sandra Beinhardt; Daniel N Gotthardt; Nicola Haag; Clarissa Freissmuth; Ulrike Reuner; Annika Gauss; Wolfgang Stremmel; Michael L Schilsky; Peter Ferenci; Karl Heinz Weiss
Cystathionine β-synthase is required for body iron homeostasis Hepatology (IF 13.246) Pub Date : 2017-08-31 Yu‐Fu Zhou; Xiao‐Mei Wu; Gan Zhou; Ming‐dao Mu; Fa‐Li Zhang; Fe‐Mi Li; Christopher Qian; Fang Du; Wing‐Ho Yung; Zhong‐Ming Qian; Ya Ke
Cystathionine β-synthase (CBS) catalyzes the transsulfuration pathway and contributes, among other functions, to the generation of hydrogen sulfide (H2S). In view of the exceptionally high expression of CBS in the liver and the common interleukin-6 (IL-6) pathway utilized in the regulatory systems of H2S and hepcidin, we speculate that CBS is involved in body iron homeostasis. We found that CBS knock-out (CBS-/-) mice exhibited anemia and a significant increase in iron content in the serum, liver, spleen and heart, along with severe damage to the liver, displaying a hemochromatosis-like phenotype. A high level of hepatic and serum hepcidin was also found. A major cause of the systemic iron-overload is the reduced iron utilization due to suppressed erythropoiesis, which is consistent with an increase in IL-6 and the reduced expression of erythropoietin. Importantly, in the liver, an absence of CBS caused both a reduction in the transcriptional factor NRF2 and an upregulation of hepcidin that lead to a decrease in the iron export protein ferroportin 1. The resulting suppression of iron export exacerbates iron retention, causing damage to hepatocytes. Finally, administration of CBS-overexpressing adenovirus into CBS mutant mice could partially reverse the iron-related phenotype. Our findings thus point to a previously unknown, yet critical role of CBS in iron homeostasis of the body, and the liver in particular. It is likely that a hemochromatosis-like phenotype in patients can be induced by aberration not only in the expression of key molecules in the hepcidin pathway, but also in those related to CBS. This article is protected by copyright. All rights reserved.
Imaging for the Diagnosis of Hepatocellular Carcinoma: a Systematic Review and Meta-analysis Hepatology (IF 13.246) Pub Date : 2017-08-31 Lewis R. Roberts; Claude B. Sirlin; Feras Zaiem; Jehad Almasri; Larry J. Prokop; Julie Heimbach; M. Hassan Murad; Khaled Mohammed
Multiphasic computed tomography (CT) and magnetic resonance imaging (MRI) are both used for non-invasive diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis. To determine if there is a relative diagnostic benefit of one over the other, we synthesized evidence regarding the relative performances of CT, extracellular-contrast-enhanced-MRI, and gadoxetate-enhanced-MRI for diagnosis of HCC in patients with cirrhosis. We also assessed whether liver biopsy versus follow-up with the same versus alternative imaging is best for CT- or MRI-indeterminate liver nodules in patients with cirrhosis. We searched multiple databases from inception to April 27, 2016 for studies comparing CT with extracellular-contrast-enhanced-MRI or gadoxetate-enhanced-MRI in adults with cirrhosis and suspected HCC. Two reviewers independently selected studies and extracted data. Of 33 included studies, 19 were comprehensive, while 14 reported sensitivity only. For all tumor sizes, the 19 comprehensive comparisons showed significantly higher sensitivity (0.82 vs. 0.66) and lower negative likelihood ratio (0.20 vs. 0.37) for MRI over CT. The specificities of MRI vs. CT (0.91 vs. 0.92) and the positive likelihood ratios (8.8 vs. 8.1) were not different. All three modalities performed better for HCCs ≥2 cm. Performance was poor for HCCs <1 cm. No studies examined whether adults with cirrhosis and an indeterminate nodule are best evaluated using biopsy, repeated imaging or alternative imaging. Concerns about publication bias, inconsistent study results, low study quality, and clinical factors precluded support for exclusive use of either gadoxetate-enhanced or extracellular-contrast-enhanced MRI over CT. Conclusion: CT, extracellular-contrast-enhanced-MRI or gadoxetate-enhanced-MRI could not be definitively preferred for HCC diagnosis in patients with cirrhosis. In patients with cirrhosis and an indeterminate mass, there was insufficient data comparing biopsy to repeat cross-sectional imaging or,alternative imaging. This article is protected by copyright. All rights reserved.
Projections of primary liver cancer to 2030 in 30 countries worldwide Hepatology (IF 13.246) Pub Date : 2017-08-31 Patricia C. Valery; Mathieu Laversanne; Paul J. Clark; Jessica L. Petrick; Katherine A McGlynn; Freddie Bray
Primary liver cancer (PLC) is the sixth most common cancer worldwide and the second most common cause of cancer death. Future predictions can inform health planners and raise awareness of the need for cancer control action. We predicted the future burden of PLC in 30 countries around 2030. Incident cases of PLC (ICD-10 C22) were obtained from 30 countries for 1993-2007. We projected new PLC cases through to 2030 using age-period-cohort models (NORDPRED). Age-standardized incidence rates per 100,000 person-years were calculated by country and sex. Increases in new cases and rates of PLC are projected in both sexes. Among men, the largest increases in rates are in Norway (2.9% per annum), US whites (2.6%), and Canada (2.4%), and among women in the US (blacks 4.0%), Switzerland (3.4%), and Germany (3.0%). The projected declines are in China, Japan, Singapore, and parts of Europe (e.g. in Estonia, Czech Republic, Slovakia). A 35% increase in the number of new cases annually is expected compared to 2005. This increasing burden reflects both increasing rates (and the underlying prevalence of risk factors) and demographic changes. Japan is the only country with a predicted decline in the net number of cases and annual rates by 2030. Conclusion: Our reporting of a projected increase in PLC incidence to 2030 in 30 countries serves as a baseline for anticipated declines in the longer-term via the control of HBV and HCV infections through vaccination and treatment. However, the prospects that rising levels of obesity and its metabolic complications may lead to an increased increasing risk of PLC that potentially offset these gains, is a concern. This article is protected by copyright. All rights reserved.
Therapies for Patients with Hepatocellular Carcinoma Awaiting for Liver Transplantation: a Systematic Review and Meta-analysis Hepatology (IF 13.246) Pub Date : 2017-08-31 Laura Kulik; Julie K. Heimbach; Feras Zaiem; Jehad Almasri; Larry J Prokop; Zhen Wang; M. Hassan Murad; Khaled Mohammed
Patients with hepatocellular carcinoma (HCC) who are listed for liver transplantation are often treated while on the waiting list with loco-regional therapy (LRT) which is aimed at either preventing progression of HCC or reducing themeasurable disease burden of HCC in order to receive increased allocation priority. We aimed to synthesize evidence regarding the effectiveness of LRT in the management of patients with HCC who were on the liver transplant waitlist. We conducted a comprehensive search of multiple databases from 1996 to April 25, 2016, for studies that enrolled adults with cirrhosis awaiting liver transplantation and treated with bridging or down-staging therapies before liver transplantation. Therapies included trans-catheter arterial chemoembolization (TACE), trans-arterial radio-embolization (TARE), ablation or radiotherapy. We included both comparative and non-comparative studies. There were no randomized controlled trials identified. Results: For adults with T1 HCC and waitingfor liver transplantation there were only 2 non-randomized comparative studies, both with a high risk of bias, which reported the outcome of interest. In one series, the rate of dropout from all causes at 6 month in T1 HCC patients underwent loco-regional therapy was 5.3%, while in the other series of T1 HCC patients who did not receive loco-regional therapy, dropout rate at median follow up of 2.4 years and progression rate to T2 HCC was 30% and 88% respectively. For adults with T2 HCC awaiting liver transplantation, transplant with any bridging therapy showed a non-significant reduction in the risk of waitlist dropout due to progression (RR 0.32 (95% CI 0.06 - 1.85, I2 = 0%) and waitlist dropout from all causes (RR 0.38 (95% CI 0.060 - 2.370, I2=85.7%), compared to no therapy based on 3 comparative studies. The quality of evidence is very low due to high risk of bias, imprecision and inconsistency. There were 5 comparative studies which reported on post-transplant survival rates and 10 comparative studies which reported on post-transplant recurrence and there was no significant difference seen in either of these endpoints. For adults initially with stage T3 HCC who got LRT, there were 3 studies available reporting on transplant with any down-staging therapy versus no down-staging and this showed significant increase in 1year (2 studies (51, 52)(RR 1.11 (95% CI 1.01-1.23) and 5 year (1 study (52) (RR 1.17 (95% CI 1.03-1.32)post-LT survival rates for the patients who received LRT. The quality of evidence is very low due to serious risk of bias and imprecision.Conclusion: in patients with HCC listed for liver transplantation, the use of LRT is associated with a non-significant trend toward improved waitlist and post-transplant outcomes, though there is a high risk of selection bias in the available evidence. This article is protected by copyright. All rights reserved.
Continuous renal replacement therapy is associated with reduced serum ammonia levels and mortality in acute liver failure Hepatology (IF 13.246) Pub Date : 2017-08-31 Filipe S. Cardoso; Michelle Gottfried; Shannan Tujios; Jody C. Olson; Constantine J. Karvellas
Background: Hyperammonemia has been associated with intracranial hypertension and mortality in patients with acute liver failure (ALF). We evaluated the effect of renal replacement therapy (RRT) on serum ammonia level and outcomes in ALF.
Viral persistence, liver disease and host response in Hepatitis C-like virus rat model Hepatology (IF 13.246) Pub Date : 2017-08-31 Sheetal Trivedi; Satyapramod Murthy; Himanshu Sharma; Alex S. Hartlage; Arvind Kumar; Sashi Gadi; Peter Simmonds; Lokendra V. Chauhan; Troels K. H. Scheel; Eva Billerbeck; Peter D. Burbelo; Charles M. Rice; W. Ian Lipkin; Kurt Vandergrift; John M. Cullen; Amit Kapoor
The lack of a relevant, tractable, and immunocompetent animal model for hepatitis C virus (HCV) has severely impeded investigations of viral persistence, immunity and pathogenesis. In the absence of immunocompetent models with robust HCV infection, homolog hepaciviruses in their natural host could potentially provide useful surrogate models. We isolated a rodent hepacivirus (RHV) from wild rats (Rattus norvegicus), RHV-rn1, acquired the complete viral genome sequence and developed an infectious reverse genetics system. RHV-rn1 resembles HCV in genomic features including the pattern of polyprotein cleavage sites and secondary structures in the viral 5' and 3' UTRs. We used site-directed and random mutagenesis to determine that only the first of the two miR-122 seed sites in viral 5'UTR is required for viral replication and persistence in rats. Next, we used the clone derived virus progeny to infect several inbred and outbred rat strains. Our results determined that RHV-rn1 possesses several HCV-defining hallmarks: hepatotropism, propensity to persist, and the ability of induce gradual liver damage. Histological examination of liver samples revealed the presence of lymphoid aggregates, parenchymal inflammation and macro/micro vesicular steatosis in chronically infected rats. Gene expression analysis demonstrated that the intrahepatic response during RHV-rn1 infection in rats mirrors that of HCV infection, including persistent activation of interferon signaling pathways. Finally, we determined that the backbone drug of HCV direct acting antiviral (DAA) therapy, Sofosbuvir, effectively suppresses chronic RHV-rn1 infection in rats. Taken together, we developed RHV-rn1 infected rats as a fully immunocompetent and informative surrogate model to delineate the mechanisms of HCV-related viral persistence, immunity and pathogenesis. This article is protected by copyright. All rights reserved.
Performance Characteristics of Vibration-Controlled Transient Elastography for Evaluation of Non-Alcoholic Fatty Liver Disease Hepatology (IF 13.246) Pub Date : 2017-08-31 Raj Vuppalanchi; Mohammad S. Siddiqui; Mark L. Van Natta; Erin Hallinan; Danielle Brandman; Kris Kowdley; Brent A Neuschwander‐Tetri; Rohit Loomba; Srinivas Dasarathy; Manal Abdelmalek; Edward Doo; James A. Tonascia; David E. Kleiner; Arun J. Sanyal; Naga Chalasani
Background: Vibration-controlled transient elastography (VCTE) estimates liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) which are noninvasive assessments of hepatic fibrosis and steatosis respectively. However, prior VCTE studies reported high failure rate in patients with non-alcoholic fatty liver disease (NAFLD).
Significance of definitions of relapse after discontinuation of oral antivirals in HBeAg-negative chronic hepatitis B Hepatology (IF 13.246) Pub Date : 2017-08-31 George V Papatheodoridis; Spilios Manolakopoulos; Tung‐Hung Su; Spyros Siakavellas; Chun‐Jen Liu; Anastasia Kourikou; Hung‐Chih Yang; Jia‐Horng Kao
Relapses are observed in most HBeAg-negative chronic hepatitis B patients who discontinue nucleos(t)ide analogues (NAs), but the rates of relapse vary widely among studies and whether all patients with relapse need retreatment is unclear. The aim of this study was to assess the impact of different definitions on the rates of post-treatment relapse and therefore on the probability of retreatment in such patients who discontinued effective long-term NAs therapy. In total, 130 non-cirrhotic HBeAg-negative chronic hepatitis B patients before NAs were included. All had on-therapy virological remission for ≥24 months and close follow-up for ≥12 months after stopping NAs or until retreatment, which started on stringent predefined criteria. Relapses rates based on several predetermined definitions of virological and perhaps biochemical criteria were assessed. The median duration of therapy was 60 and of on-therapy virological remission 43 months. During a median off-NAs follow-up of 15 months, no patient experienced liver decompensation or died. Cumulative relapse rates ranged between 2%-49% at 3, 4%-73% at 6, 11%-82% at 12 and 16%-90% at 24 months, whereas cumulative retreatment rates were 15%, 22% and 40% at 6, 12 and 24 months after NAs discontinuation. No patient characteristic was independently associated with the probability of relapse based on at least two definitions or of retreatment. In conclusion, in HBeAg-negative chronic hepatitis B patients who discontinue NAs, the definition of relapse has great impact on the off-NAs relapse rates and potentially on the probability of retreatment. Regardless of definition, off-NAs relapses cannot be easily predicted by the patients' characteristics. A substantial proportion of such patients may not require retreatment if stringent criteria are adopted. This article is protected by copyright. All rights reserved.
Recent Developments of c-Met as a Therapeutic Target in Hepatocellular Carcinoma Hepatology (IF 13.246) Pub Date : 2017-09-01 Mohamed Bouattour; Eric Raymond; Shukui Qin; Ann‐Lii Cheng; Uz Stammberger; Giuseppe Locatelli; Sandrine Faivre
Aberrant c-Met activity is implicated in the development of hepatocellular carcinoma (HCC), suggesting that c-Met inhibition may have therapeutic potential. However, clinical trials of nonselective kinase inhibitors with c-Met activity (tivantinib, cabozantinib, foretinib, and golvatinib) in patients with HCC have failed so far to demonstrate significant efficacy. This is likely due to several factors, including trial design, lack of patient selection according to tumor c-Met status, and the prevalent off-target activity of these agents, which may mean that c-Met inhibition is incomplete. In contrast, selective c-Met inhibitors (tepotinib, capmatinib) can be dosed at a level predicted to achieve a complete inhibition of tumor c-Met activity. Moreover, results from early trials can be used to optimize the design of clinical trials of these agents. Preliminary results suggest that selective c-Met inhibitors have antitumor activity in HCC, with acceptable safety and tolerability in patients with Child-Pugh A liver function. Ongoing trials have been designed to assess the efficacy and safety of selective c-Met inhibition compared with standard therapy in patients with HCC selected based on tumor c-Met status. Thus, c-Met inhibition continues to be an active area of research in HCC, with well-designed trials in progress to investigate the benefit of selective c-Met inhibitors. This article is protected by copyright. All rights reserved.
Efficacy and Safety of Glecaprevir/Pibrentasvir in Japanese Patients with Chronic Genotype 2 Hepatitis C Virus Infection Hepatology (IF 13.246) Pub Date : 2017-09-02 Hidenori Toyoda; Kazuaki Chayama; Fumitaka Suzuki; Ken Sato; Tomofumi Atarashi; Tsunamasa Watanabe; Masanori Atsukawa; Atsushi Naganuma; Kazuo Notsumata; Yukio Osaki; Makoto Nakamuta; Koichi Takaguchi; Satoru Saito; Koji Kato; David Pugatch; Margaret Burroughs; Rebecca Redman; Katia Alves; Tami J. Pilot‐Matias; Rajneet K. Oberoi; Bo Fu; Hiromitsu Kumada
Glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor) (G/P), a coformulated once-daily, all oral, ribavirin (RBV)-free, direct-acting anti-viral (DAA) regimen was evaluated for safety and efficacy in Hepatitis C Virus GT2-infected Japanese patients, including those with compensated cirrhosis. CERTAIN-2 is a phase 3, open-label, multicenter study assessing the safety and efficacy of G/P (300/120mg) once daily (QD) in treatment-naïve and interferon (IFN) ± RBV treatment-experienced non-cirrhotic Japanese patients with GT2 infection. Patients were randomized 2:1 to receive 8 weeks of G/P (Arm A) or 12 weeks of sofosbuvir (400 mg QD) + RBV (600 -1000 mg weight-based, BID) (Arm B). The primary endpoint was non-inferiority of G/P compared to SOF+RBV by assessing sustained virologic response at post-treatment week 12 (SVR12) among patients in the intent-to-treat (ITT) population. SVR12 was also assessed in treatment-naïve and IFN ± RBV treatment-experienced patients with GT2 infection and compensated cirrhosis who received G/P for 12 weeks in the phase 3, open-label, multicenter CERTAIN-1 study. A total of 136 patients were enrolled in CERTAIN-2. SVR12 was achieved by 88/90 (97.8%) patients in Arm A and 43/46 (93.5%) patients in Arm B. No patient in Arm A experienced virologic failure, while two did in Arm B. The primary endpoint was achieved. In CERTAIN-1, 100% (18/18) of GT2-infected patients with compensated cirrhosis achieved SVR12. Treatment-emergent serious adverse events were experienced by two non-cirrhotic patients in each arm and no cirrhotic patient. Results demonstrate high efficacy and favorable tolerability of G/P in GT2-infected Japanese patients. This article is protected by copyright. All rights reserved.
Gene-disease associations identify a connectome with shared molecular pathways in human cholangiopathies Hepatology (IF 13.246) Pub Date : 2017-09-02 Zhenhua Luo; Anil G Jegga; Jorge A Bezerra
Cholangiopathies are a diverse group of progressive diseases whose primary cell targets are cholangiocytes. To identify shared pathogenesis and molecular connectivity among the three main human cholangiopathies (biliary atresia [BA], primary biliary cholangitis [PBC] and primary sclerosing cholangitis [PSC]), we built a comprehensive platform of published data on gene variants, gene expression and functional studies, and applied network-based analytics in search for shared molecular circuits. Mining the data platform with largest connected component and interactome analyses, we validated previously reported associations and identified essential- and hub-genes. In addition to disease-specific modules, we found a substantial overlap of disease neighborhoods, and uncovered a group of 34 core genes that are enriched for immune processes and abnormal intestine/hepatobiliary mouse phenotypes. Within this core, we identified a gene subcore containing STAT3, IL6, TNF and FOXP3 prominently placed in a regulatory connectome of genes related to cellular immunity and fibrosis. We also found substantial gene enrichment in the AGE-RAGE pathway, and showed that RAGE activation induced cholangiocyte proliferation. Conclusion: Human cholangiopathies share pathways enriched by immunity genes and a molecular connectome that links different pathogenic features of BA, PBC and PSC. This article is protected by copyright. All rights reserved.
Chronic Hepatitis C Increases the Risk of Chronic Kidney Disease (CKD) while Effective HCV Treatment Decreases the Incidence of CKD Hepatology (IF 13.246) Pub Date : 2017-09-05 Haesuk Park; Chao Chen; Wei Wang; Linda Henry; Robert L. Cook; David R. Nelson
We aimed to assess the risk of chronic kidney disease (CKD) in chronic hepatitis C virus (HCV) infected patients and the incidence reduction of CKD after receipt of HCV treatment. We also evaluated the risk of membranoproliferative glomerulonephritis (MPGN) and cryoglobulinemia in chronic HCV patients. A retrospective cohort analysis of the Truven Health MarketScan Database (2008-2015) in the United States was conducted. In a cohort of 56,448 HCV-infected patients and propensity score (1:3) matched 169,344 non-HCV patients, we examined the association of HCV infection with the incidence of CKD. Of 55,818 HCV patients, 6.6% (n=3666), 6.3% (n=3534), and 8.3% (n=4628) patients received either interferon-based dual, triple, or all-oral direct acting antiviral agents (DAA) therapy, respectively, whereas 79% of patients did not receive any HCV treatment. Cox proportional hazards models were used to compare the risk of developing CKD in HCV patients compared to non-HCV patients and treated patients compared to non-treated HCV patients. In a multivariate time-varying Cox regression model, HCV-infected patients had a 27% increased risk of CKD compared to non-HCV patients (hazard ratio (HR),1.27; 95% confidence interval (CI),1.18-1.37). Among HCV patients, individuals who received the minimally effective HCV treatment for dual, triple, or all-oral therapy had a 30% decreased risk of developing CKD (HR,0.70; 95% CI,0.55-0.88). In addition, HCV-infected patients experienced a twofold and a nearly 17-fold higher risk of MPGN (HR,2.23; 95% CI,1.84-2.71) and cryoglobulinemia (HR,16.91; 95% CI,12.00-23.81), compared to non-HCV patients.
Regression of hepatocellular adenomas and systemic inflammatory syndrome after cessation of estrogen therapy Hepatology (IF 13.246) Pub Date : 2017-07-18 Marie Sinclair; Anthony Schelleman; Daljean Sandhu; Peter W. Angus
We report a case of dramatic systemic inflammatory symptoms and biochemical signs of inflammation related to multiple hepatic adenomas that completely resolved after cessation of the oral contraceptive pill (OCP) and associated adenoma regression. This represents a case of dramatic symptoms that resolved after estrogen withdrawal alone. (Hepatology 2017;66:989–991).
Prevention and treatment of complications of selective internal radiation therapy: Expert guidance and systematic review Hepatology (IF 13.246) Pub Date : 2017-07-27 Bruno Sangro; Diego Martínez‐Urbistondo; Lourens Bester; Jose I. Bilbao; Douglas M. Coldwell; Patrick Flamen; Andrew Kennedy; Jens Ricke; Ricky A. Sharma
Selective internal radiation therapy (or radioembolization) by intra-arterial injection of radioactive yttrium-90-loaded microspheres is increasingly used for the treatment of patients with liver metastases or primary liver cancer. The high-dose beta-radiation penetrates an average of only 2.5 mm from the source, thus limiting its effects to the site of delivery. However, the off-target diversion of yttrium-90 microspheres to tissues other than the tumor may lead to complications. The most prominent of these complications include radiation gastritis and gastrointestinal ulcers, cholecystitis, radiation pneumonitis, and radioembolization-induced liver disease, which may occur despite careful pretreatment planning. Thus, selective internal radiation therapy demands an expert multidisciplinary team approach in order to provide comprehensive care for patients. This review provides recommendations to multidisciplinary teams on the optimal medical processes in order to ensure the safe delivery of selective internal radiation therapy. Based on the best available published evidence and expert opinion, we recommend the most appropriate strategies for the prevention, early diagnosis, and management of potential radiation injury to the liver and to other organs. (Hepatology 2017;66:969–982).
Pentraxin-3 modulates lipopolysaccharide-induced inflammatory response and attenuates liver injury Hepatology (IF 13.246) Pub Date : 2017-07-18 Luis Perea; Mar Coll; Lucia Sanjurjo; Delia Blaya; Adil El Taghdouini; Daniel Rodrigo‐Torres; José Altamirano; Isabel Graupera; Beatriz Aguilar‐Bravo; Marta Llopis; Julia Vallverdú; Joan Caballeria; Leo A. van Grunsven; Maria‐Rosa Sarrias; Pere Ginès; Pau Sancho‐Bru
Acute-on-chronic liver injury is characterized by an important inflammatory response frequently associated with endotoxemia. In this context, acute-phase proteins such as Pentraxin-3 (PTX3) are released; however, little is known about their role in chronic liver disease. The aim of this study was to elucidate the role of PTX3 in liver injury. The role of PTX3 was evaluated in cultured human cells, liver tissue slices, and mice with acute-on-chronic liver injury. PTX3 expression was assessed in tissue and serum samples from 54 patients with alcoholic hepatitis. PTX3 expression was up-regulated in animal models of liver injury and strongly induced by lipopolysaccharide (LPS). Liver cell fractionation showed that macrophages and activated hepatic stellate cells were the main cell types expressing PTX3 in liver injury. Ex vivo and in vivo studies showed that PTX3 treatment attenuated LPS-induced liver injury, inflammation, and cell recruitment. Mechanistically, PTX3 mediated the hepatic stellate cell wound-healing response. Moreover, PTX3 modulated LPS-induced inflammation in human primary liver macrophages and peripheral monocytes by enhancing a TIR domain–containing adapter-inducing interferon–dependent response and favoring a macrophage interleukin-10-like phenotype. Additionally, hepatic and plasma PTX3 levels were increased in patients with alcoholic hepatitis, a prototypic acute-on-chronic condition; and its expression correlated with disease severity scores, endotoxemia, infections, and short-term mortality, thus suggesting that expression of PTX3 found in patients could be a counterregulatory response to injury. Conclusion: Experimental and human evidence suggests that, in addition to being a potential biomarker for alcoholic hepatitis, PTX3 participates in the wound-healing response and attenuates LPS-induced liver injury and inflammation; therefore, administration of PTX3 could be a promising therapeutic strategy in acute-on-chronic conditions, particularly those associated with endotoxemia. (Hepatology 2017;66:953–968).
Sirtuin 3 acts as a negative regulator of autophagy dictating hepatocyte susceptibility to lipotoxicity Hepatology (IF 13.246) Pub Date : 2017-07-20 Songtao Li; Xiaobing Dou; Hua Ning; Qing Song; Wei Wei; Ximei Zhang; Chen Shen; Jiaxin Li; Changhao Sun; Zhenyuan Song
Lipotoxicity induced by saturated fatty acids (SFAs) plays a central role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD); however, the exact mechanisms remain to be fully elucidated. Sirtuin 3 (SIRT3) is a nicotinamide adenine dinucleotide–dependent deacetylase located primarily inside mitochondria. In this study, we demonstrated that an SFA-rich high-fat diet (HFD) was more detrimental to the liver than an isocaloric unsaturated HFD rich in fatty acids. Unexpectedly, SIRT3 expression and activity were significantly elevated in the livers of mice exposed to the SFA-rich HFD. Using cultured HepG2 and AML-12 hepatocytes, we demonstrated that unlike monounsaturated fatty acids, SFAs up-regulate SIRT3 expression and activity. SIRT3 overexpression renders both the liver and hepatocytes susceptible to palmitate-induced cell death, which can be alleviated by SIRT3 small interfering RNA (siRNA) transfection. In contrast, SIRT3 suppression protects hepatocytes from palmitate cytotoxicity. Further studies revealed that SIRT3 acts as a negative regulator of autophagy, thereby enhancing the susceptibility of hepatocytes to SFA-induced cytotoxicity. Mechanistic investigations revealed that SIRT3 overexpression causes manganese superoxide dismutase deacetylation and activation, which depleted intracellular superoxide contents, leading to adenosine monophosphate–activated protein kinase (AMPK) inhibition and mammalian target of rapamycin C1 activation, resulting in autophagy suppression. In contrast, SIRT3 siRNA gene silencing enhanced autophagy flux. A similar result was observed in the liver tissue of SIRT3 knockout mice. Conclusion: Our data indicate that SIRT3 is a negative regulator of autophagy whose activation by SFAs contributes to lipotoxicity in hepatocytes and suggest that restraining SIRT3 overactivation can be a potential therapeutic choice for the treatment of NAFLD as well as other metabolic disorders, with lipotoxicity being the principal pathomechanism. (Hepatology 2017;66:936–952).
Pentamidine blocks hepatotoxic injury in mice Hepatology (IF 13.246) Pub Date : 2017-07-20 Enpeng Zhao; Ghulam Ilyas; Francesca Cingolani; Jae Ho Choi; François Ravenelle; Kathryn E. Tanaka; Mark J. Czaja
Toxin-induced liver diseases lack effective therapies despite increased understanding of the role factors such as an overactive innate immune response play in the pathogenesis of this form of hepatic injury. Pentamidine is an effective antimicrobial agent against several human pathogens, but studies have also suggested that this drug inhibits inflammation. This potential anti-inflammatory mechanism of action, together with the development of a new oral form of pentamidine isethionate VLX103, led to investigations of the effectiveness of this drug in the prevention and treatment of hepatotoxic liver injury. Pretreatment with a single injection of VLX103 in the d-galactosamine (GalN) and lipopolysaccharide (LPS) model of acute, fulminant liver injury dramatically decreased serum alanine aminotransferase levels, histological injury, the number of terminal deoxynucleotide transferase–mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive cells and mortality compared with vehicle-injected controls. VLX103 decreased GalN/LPS induction of tumor necrosis factor (TNF) but had no effect on other proinflammatory cytokines. VLX103 prevented the proinflammatory activation of cultured hepatic macrophages and partially blocked liver injury from GalN/TNF. In GalN/LPS-treated mice, VLX103 decreased activation of both the mitochondrial death pathway and downstream effector caspases 3 and 7, which resulted from reduced c-Jun N-terminal kinase activation and initiator caspase 8 cleavage. Delaying VLX103 treatment for up to 3 hours after GalN/LPS administration was still remarkably effective in blocking liver injury in this model. Oral administration of VLX103 also decreased hepatotoxic injury in a second more chronic model of alcohol-induced liver injury, as demonstrated by decreased serum alanine and aspartate aminotransferase levels and numbers of TUNEL-positive cells. Conclusion: VLX103 effectively decreases toxin-induced liver injury in mice and may be an effective therapy for this and other forms of human liver disease. (Hepatology 2017;66:922–935).
PTEN Down-Regulation Promotes β-Oxidation to Fuel Hypertrophic Liver Growth After Hepatectomy in Mice Hepatology (IF 13.246) Pub Date : 2017-07-20 Ekaterina Kachaylo; Christoph Tschuor; Nicolas Calo; Nathalie Borgeaud; Udo Ungethüm; Perparim Limani; Anne‐Christine Piguet; Jean‐Francois Dufour; Michelangelo Foti; Rolf Graf; Pierre A. Clavien; Bostjan Humar
In regenerating liver, hepatocytes accumulate lipids before the major wave of parenchymal growth. This transient, regeneration-associated steatosis (TRAS) is required for liver recovery, but its purpose is unclear. The tumor suppressor phosphatase and tensin homolog (PTEN) is a key inhibitor of the protein kinase B/mammalian target of rapamycin axis that regulates growth and metabolic adaptations after hepatectomy. In quiescent liver, PTEN causes pathological steatosis when lost, whereas its role in regenerating liver remains unknown. Here, we show that PTEN down-regulation promotes liver growth in a TRAS-dependent way. In wild-type mice, PTEN reduction occurred after TRAS formation, persisted during its disappearance, and correlated with up-regulated β-oxidation at the expense of lipogenesis. Pharmacological modulation revealed an association of PTEN with TRAS turnover and hypertrophic liver growth. In liver-specific Pten–/– mice shortly after induction of knockout, hypertrophic regeneration was accelerated and led to hepatomegaly. The resulting surplus liver mass was functional, as demonstrated by raised survival in a lethal model of resection-induced liver failure. Indirect calorimetry revealed lipid oxidation as the primary energy source early after hepatectomy. The shift from glucose to lipid usage was pronounced in Pten–/– mice and correlated with the disappearance of TRAS. Partial inhibition of β-oxidation led to persisting TRAS in Pten–/– mice and abrogated hypertrophic liver growth. PTEN down-regulation may promote β-oxidation through β-catenin, whereas hypertrophy was dependent on mammalian target of rapamycin complex 1. Conclusion: PTEN down-regulation after hepatectomy promotes the burning of TRAS-derived lipids to fuel hypertrophic liver regeneration. Therefore, the anabolic function of PTEN deficiency in resting liver is transformed into catabolic activities upon tissue loss. These findings portray PTEN as a node coordinating liver growth with its energy demands and emphasize the need of lipids for regeneration. (Hepatology 2017;66:908–921).
Statins decrease the risk of decompensation in hepatitis B virus– and hepatitis C virus–related cirrhosis: A population-based study Hepatology (IF 13.246) Pub Date : 2017-05-08 Fu‐Ming Chang; Yen‐Po Wang; Hui‐Chu Lang; Chia‐Fen Tsai; Ming‐Chih Hou; Fa‐Yauh Lee; Ching‐Liang Lu
Statin use decreases the risk of decompensation and mortality in patients with cirrhosis due to hepatitis C virus (HCV). Whether this beneficial effect can be extended to cirrhosis in the general population or cirrhosis due to other causes, such as hepatitis B virus (HBV) infection or alcohol, remains unknown. Statin use also decreases the risk of hepatocellular carcinoma (HCC) in patients with chronic HBV and HCV infection. It is unclear whether the effect can be observed in patients with pre-existing cirrhosis. The goal of this study was to determine the effect of statin use on rates of decompensation, mortality, and HCC in HBV-, HCV-, and alcohol-related cirrhosis. Patients with cirrhosis were identified from a representative cohort of Taiwan National Health Insurance beneficiaries from 2000 to 2013. Statin users, defined as having a cumulative defined daily dose (cDDD) ≥28, were selected and served as the case cohort. Statin nonusers (<28 cDDD) were matched through propensity scores. The association between statin use and risk of decompensation, mortality, and HCC were estimated. A total of 1350 patients with cirrhosis were enrolled. Among patients with cirrhosis, statin use decreased the risk of decompensation, mortality, and HCC in a dose-dependent manner (P for trend <0.0001, <0.0001, and 0.009, respectively). Regression analysis revealed a lower risk of decompensation among statin users with cirrhosis due to chronic HBV (adjusted hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.25-0.62) or HCV infection (HR, 0.51; 95% CI, 0.29-0.93). The lowered risk of decompensation was of borderline significance among statin users with alcohol-related cirrhosis (HR, 0.69; 95% CI, 0.45-1.07). Conclusion: Statin use decreases the decompensation rate in both HBV- and HCV-related cirrhosis. Of borderline significance is a decreased decompensation rate in alcohol-related cirrhosis. (Hepatology 2017;66:896–907).
Autoreactive monoclonal antibodies from patients with primary biliary cholangitis recognize environmental xenobiotics Hepatology (IF 13.246) Pub Date : 2017-07-20 Toshihiro Tanaka; Weici Zhang; Ying Sun; Zongwen Shuai; Asiya Seema Chida; Thomas P. Kenny; Guo‐Xiang Yang; Ignacio Sanz; Aftab Ansari; Christopher L. Bowlus; Gregory C. Ippolito; Ross L. Coppel; Kazuichi Okazaki; Xiao‐Song He; Patrick S.C. Leung; M. Eric Gershwin
A major problem in autoimmunity has been identification of the earliest events that lead to breach of tolerance. Although there have been major advances in dissecting effector pathways and the multilineage immune responses to mitochondrial self-antigens in primary biliary cholangitis, the critical links between environmental factors and tolerance remain elusive. We hypothesized that environmental xenobiotic modification of the E2 subunit of the pyruvate dehydrogenase (PDC-E2) inner lipoyl domain can lead to loss of tolerance to genetically susceptible hosts. Previously we demonstrated that serum anti-PDC-E2 autoantibodies cross-react with the chemical xenobiotics 2-octynoic acid and 6,8-bis (acetylthio) octanoic acid and further that there is a high frequency of PDC-E2-specific peripheral plasmablasts. Herein we generated 104 recombinant monoclonal antibodies (mAbs) based on paired heavy-chain and light-chain variable regions of individual plasmablasts derived from primary biliary cholangitis patients. We identified 32 mAbs reactive with native PDC-E2, including 20 specific for PDC-E2 and 12 cross-reactive with both PDC-E2 and 2-octynoic acid and 6,8-bis (acetylthio) octanoic acid. A lower frequency of replacement somatic hypermutations, indicating a lower level of affinity maturation, was observed in the complementarity-determining regions of the cross-reactive mAbs in comparison to mAbs exclusively recognizing PDC-E2 or those for irrelevant antigens. In particular, when the highly mutated heavy-chain gene of a cross-reactive mAb was reverted to the germline sequence, the PDC-E2 reactivity was reduced dramatically, whereas the xenobiotic reactivity was retained. Importantly, cross-reactive mAbs also recognized lipoic acid, a mitochondrial fatty acid that is covalently bound to PDC-E2. Conclusion: Our data reflect that chemically modified lipoic acid or lipoic acid itself, through molecular mimicry, is the initial target that leads to the development of primary biliary cholangitis. (Hepatology 2017;66:885–895)
The role of long noncoding RNA H19 in gender disparity of cholestatic liver injury in multidrug resistance 2 gene knockout mice Hepatology (IF 13.246) Pub Date : 2017-07-20 Xiaojiaoyang Li; Runping Liu; Jing Yang; Lixin Sun; Luyong Zhang; Zhenzhou Jiang; Puneet Puri; Emily C. Gurley; Guanhua Lai; Yuping Tang; Zhiming Huang; William M. Pandak; Phillip B. Hylemon; Huiping Zhou
The multidrug resistance 2 knockout (Mdr2–/–) mouse is a well-established model of cholestatic cholangiopathies. Female Mdr2–/– mice develop more severe hepatobiliary damage than male Mdr2–/– mice, which is correlated with a higher proportion of taurocholate in the bile. Although estrogen has been identified as an important player in intrahepatic cholestasis, the underlying molecular mechanisms of gender-based disparity of cholestatic injury remain unclear. The long noncoding RNA H19 is an imprinted, maternally expressed, and estrogen-targeted gene, which is significantly induced in human fibrotic/cirrhotic liver and bile duct–ligated mouse liver. However, whether aberrant expression of H19 accounts for gender-based disparity of cholestatic injury in Mdr2–/– mice remains unknown. The current study demonstrated that H19 was markedly induced (∼200-fold) in the livers of female Mdr2–/– mice at advanced stages of cholestasis (100 days old) but not in age-matched male Mdr2–/– mice. During the early stages of cholestasis, H19 expression was minimal. We further determined that hepatic H19 was mainly expressed in cholangiocytes, not hepatocytes. Both taurocholate and estrogen significantly activated the extracellular signal–regulated kinase 1/2 signaling pathway and induced H19 expression in cholangiocytes. Knocking down H19 not only significantly reduced taurocholate/estrogen-induced expression of fibrotic genes and sphingosine 1-phosphate receptor 2 in cholangiocytes but also markedly reduced cholestatic injury in female Mdr2–/– mice. Furthermore, expression of small heterodimer partner was substantially inhibited at advanced stages of liver fibrosis, which was reversed by H19 short hairpin RNA in female Mdr2–/– mice. Similar findings were obtained in human primary sclerosing cholangitis liver samples. Conclusion: H19 plays a critical role in the disease progression of cholestasis and represents a key factor that causes the gender disparity of cholestatic liver injury in Mdr2–/– mice. (Hepatology 2017;66:869–884).
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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