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Liver fibrosis reflects tissue scarring in the liver due to the accumulation of excessive extracellular matrix in response to chronically persistent liver injury. Hepatocyte cell death can trigger capillarization of liver sinusoidal endothelial cells, stimulation of immune cells including macrophages and Kupffer cells, and activation of hepatic stellate cells (HSCs), resulting in progression of liver fibrosis. Liver cirrhosis is the terminal state of liver fibrosis and is associated with severe complications, such as liver failure, portal hypertension, and liver cancer. Nevertheless, effective therapy for cirrhosis has not yet been established, and liver transplantation is the only radical treatment for severe cases. Studies investigating HSC activation and regulation of collagen production in the liver have made breakthroughs in recent decades that have advanced the knowledge regarding liver fibrosis pathophysiology. In this review, we summarize molecular mechanisms of liver fibrosis and discuss the development of novel anti-fibrotic therapies.

BackgroundIt is unclear whether hepatocyte function and/or portal hypertension improves if a sustained virologic response (SVR) is achieved with direct-acting antivirals in patients with decompensated hepatitis C-related cirrhosis.MethodsWe examined the safety and efficacy of a 12-week course of sofosbuvir/velpatasvir (SOF/VEL) in 20 patients with decompensated hepatitis C-related cirrhosis. We also investigated changes in the hepatocyte receptor index (LHL15) and blood clearance index (HH15) by Tc-99 m-galactosyl human serum albumin scintigraphy, liver stiffness measurement (LSM) by transient elastography, and hepatic venous pressure gradient (HVPG) in patients who achieved an SVR at 24 weeks after treatment (SVR24).ResultsOne patient discontinued treatment because of rectal variceal hemorrhage, and 19 patients completed treatment. SVR24 was achieved in 17 patients (89%). Median LHL15 increased from 0.72 pre-treatment to 0.82 after SVR24 (p = 0.012), and median HH15 decreased from 0.82 pre-treatment to 0.76 after SVR24 (p = 0.010). The percentage of patients with LSM ≥ 20 kPa was 90% before treatment and remained at 90% after SVR24. However, the percentage with severe portal hypertension (defined as HVPG ≥ 12 mmHg) decreased from 92% pre-treatment to 58% after SVR24 (p = 0.046). Patients with a decreased HVPG from pre-treatment to after SVR24 had a smaller pre-treatment spleen volume than those with an increased HVPG (median, 252 vs. 537 mL, p = 0.028).ConclusionAchieving SVR24 with SOF/VEL treatment in patients with decompensated hepatitis C-related cirrhosis can be expected to improve hepatocyte function and portal hypertension on short-term follow-up.

In hepatocellular carcinoma (HCC), the clinical significance of soluble immune checkpoint protein levels as predictors of patient outcomes or therapeutic responses has yet to be defined. This study profiled the baseline levels of sixteen soluble checkpoint proteins and their changes following sorafenib treatment for HCC. Plasma samples were obtained from 53 patients with advanced HCC at baseline, week 1, 2 and 4 of sorafenib treatment and tested the concentrations of 16 soluble checkpoint proteins using multiplexed fluorescent bead-based immunoassays. Multivariate analysis showed high sBTLA levels at baseline were an independent predictor of poor overall survival (p = 0.038). BTLA was highly expressed in T cells and macrophages in peritumoral areas. At week 2, sCD27 levels were decreased compared to baseline. By contrast, the concentrations of most inhibitory proteins, including sBTLA, sLAG-3, sCTLA-4, sPD-1, sCD80, sCD86 and sPD-L1, had significantly increased. The fold-changes of soluble checkpoint receptors and their ligands, including sCTLA-4 with sCD80/sCD86, sPD-1 with sPD-L1; and the fold-changes of sCTLA-4 with sBTLA or sPD-1 were positively correlated. sBTLA may be a good biomarker for predicting overall survival in HCC patients. Sorafenib treatment in patients with advanced HCC revealed dynamic changes of soluble checkpoint protein levels.

Soluble immune checkpoint molecules are emerging novel mediators of immune regulation. However, it is unclear whether soluble immune checkpoint proteins affect the development of hepatocellular carcinoma (HCC) during nucleos(t)ide analogue (NA) treatment in patients with chronic hepatitis B virus infection. This study included 122 NA-naïve patients who received NA therapy. We assessed the associations of clinical factors, including soluble immune checkpoint proteins, with HCC development during NA treatment. The baseline serum concentrations of 16 soluble immune checkpoint proteins were measured using multiplexed fluorescent bead-based immunoassay. In total, 13 patients developed HCC during the follow-up period (median duration, 4.3 years). Of the 16 proteins, soluble inducible T-cell co-stimulator (≥ 164.71 pg/mL; p  = 0.014), soluble programmed cell death-1 (sPD-1) (≤ 447.27 pg/mL; p  = 0.031), soluble CD40 (≤ 493.68 pg/mL; p  = 0.032), and soluble herpes virus entry mediator (≤ 2470.83 pg/mL; p  = 0.038) were significantly associated with HCC development (log-rank test). In multivariate analysis, an sPD-1 level ≤ 447.27 pg/mL ( p  = 0.014; hazard ratio [HR], 4.537) and α-fetoprotein level ≥ 6.4 ng/mL ( p  = 0.040; HR, 5.524) were independently and significantly associated with HCC development. Pre-treatment sPD-1 is a novel predictive biomarker for HCC development during NA treatment.

Stress can affect our body and is known to lead to some diseases. However, the influence on the development of nonalcohol fatty liver disease (NAFLD) remains unknown. This study demonstrated that chronic restraint stress attenuated hepatic lipid accumulation via elevation of hepatic β-muricholic acid (βMCA) levels in the development of nonalcoholic steatohepatitis (NASH) in mice. Serum cortisol and corticosterone levels, i.e., human and rodent stress markers, were correlated with serum bile acid levels in patients with NAFLD and methionine- and choline-deficient (MCD) diet-induced mice, respectively, suggesting that stress is related to bile acid (BA) homeostasis in NASH. In the mouse model, hepatic βMCA and cholic acid (CA) levels were increased after the stress challenge. Considering that a short stress enhanced hepatic CYP7A1 protein levels in normal mice and corticosterone increased CYP7A1 protein levels in primary mouse hepatocytes, the enhanced Cyp7a1 expression was postulated to be involved in the chronic stress-increased hepatic βMCA level. Interestingly, chronic stress decreased hepatic lipid levels in MCD-induced NASH mice. Furthermore, βMCA suppressed lipid accumulation in mouse primary hepatocytes exposed to palmitic acid/oleic acid, but CA did not. In addition, Cyp7a1 expression seemed to be related to lipid accumulation in hepatocytes. In conclusion, chronic stress can change hepatic lipid accumulation in NASH mice, disrupting BA homeostasis via induction of hepatic Cyp7a1 expression. This study discovered a new βMCA action in the liver, indicating the possibility that βMCA is available for NAFLD therapy. Chronic stress can change hepatic lipid accumulation via elevation of hepatic β-muricholic acid levels in nonalcoholic steatohepatitis mice, disrupting bile acid homeostasis by induction of hepatic Cyp7a1 expression. This study describes a new role βMCA in the liver, indicating its potential usefulness for nonalcohol fatty liver disease therapy.

Aim The purpose of this study was to evaluate the predictors of deterioration of the Child‐Pugh classification 1 month after transcatheter arterial chemo‐embolization (TACE) in patients with treatment‐naive hepatocellular carcinoma (HCC). Methods Between 2010 and 2020, consecutive patients who underwent conventional TACE using epirubicin as the initial treatment were enrolled. Patients with Barcelona Clinic Liver Cancer stage‐0, A or B and Child‐Pugh class A were included. The Child‐Pugh score was evaluated before treatment and 1 month after TACE. The following variables were analyzed by univariate and multivariate analyses as predictors of deterioration of the Child‐Pugh class from A to B: age, sex, etiology, serum albumin, bilirubin, prothrombin time (PT), encephalopathy, ascites, largest tumor diameter, tumor number, tumor location, α‐fetoprotein, protein induced by vitamin K absence or antagonist‐II, epirubicin dosage, ethiodized oil dosage, and number of treated liver segments. Results A total of 152 patients were retrospectively enrolled. The deterioration rate of the Child‐Pugh class from A to B was 8.6%. Multivariable analysis showed that serum albumin ≤ 3.8 g/dL, PT ≤ 80%, and largest tumor diameter ≥ 3.8 cm were predictors of deterioration of the Child‐Pugh class. The deterioration rate to Child‐Pugh class B was 0% in patients with up to one of these factors, 14.3% in those with two factors, and 70% in those with three factors. Conclusions A combination of serum albumin ≤ 3.8 g/dL, PT ≤ 80%, and largest tumor diameter ≥ 3.8 cm can predict the immediate deterioration of the Child‐Pugh classification from A to B following TACE.

Cholangiocarcinoma (CC) has a poor prognosis and different driver genes depending on the site of onset. Intrahepatic CC is the second‐most common liver cancer after hepatocellular carcinoma, and novel therapeutic targets are urgently needed. The present study was conducted to identify novel therapeutic targets by exploring differentially regulated genes in human CC. MicroRNA (miRNA) and mRNA microarrays were performed using tissue and serum samples obtained from 24 surgically resected hepatobiliary tumor cases, including 10 CC cases. We conducted principal component analysis to identify differentially expressed miRNA, leading to the identification of miRNA‐3648 as a differentially expressed miRNA. We used an in silico screening approach to identify its target mRNA, the tumor suppressor Sloan Kettering Institute (SKI). SKI protein expression was decreased in human CC cells overexpressing miRNA‐3648, endogenous SKI protein expression was decreased in human CC tumor tissues, and endogenous SKI mRNA expression was suppressed in human CC cells characterized by rapid growth. SKI‐overexpressing OZ cells (human intrahepatic CC cells) showed upregulation of cyclin‐dependent kinase inhibitor p21 mRNA and protein expression and suppressed cell proliferation. Nuclear expression of CDT1 (chromatin licensing and DNA replication factor 1), which is required for the G1/S transition, was suppressed in SKI‐overexpressing OZ cells. SKI knockdown resulted in the opposite effects. Transgenic p21‐luciferase was activated in SKI‐overexpressing OZ cells. These data indicate SKI involvement in p21 transcription and that SKI–p21 signaling causes cell cycle arrest in G1, suppressing intrahepatic CC cell growth. Therefore, SKI may be a potential therapeutic target for intrahepatic CC. We analyzed clinical intrahepatic cholangiocarcinoma (CC) samples, focusing on the microRNA‐3648 and its target mRNA, the tumor suppressor Sloan Kettering Institute (SKI). We found that SKI was involved in the transcription of the cyclin‐dependent kinase inhibitor p21. SKI–p21 signaling may act as a brake, preventing cell cycle progression in G1 phase, resulting in the suppression of CC cell growth.

Background and Aim We evaluated the efficacy of rechallenge transcatheter arterial chemoembolization (TACE) after lenvatinib (LEN) treatment in patients with previous TACE failure/refractoriness. Methods We enrolled 63 consecutive patients with a history of TACE failure/refractoriness prior to LEN treatment as a first‐line systemic therapy. We reviewed the clinical backgrounds and courses of the patients. Results In total, 25 patients underwent rechallenge TACE after LEN due to LEN‐refractoriness (17 cases) or intolerance (8 cases). A complete or partial response was obtained for 13 (65.0%) of the 20 patients whose therapeutic effects were determined. The survival rate of patients who underwent rechallenge TACE was significantly higher than that of patients who did not undergo rechallenge TACE (median survival time, not reached vs 403 days, P = 0.015). Rechallenge TACE significantly reduced the risk of death in univariate (hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.08–0.69, P = 0.008) and multivariate analyses (HR 0.26, 95% CI 0.08–0.80, P = 0.019). If complete or partial response was obtained by rechallenge TACE, the median survival time of these patients was significantly longer than those of the progressive disease (PD) group (P = 0.05), and the median survival time of the PD group after rechallenge TACE was not different from that of the group who did not undergo rechallenge TACE (P = 0.36). We did not observe a decrease in the ALBI score after TACE. Conclusion Rechallenge TACE after LEN is an effective treatment that may result in a favorable prognosis. We enrolled 63 consecutive patients with a history of TACE failure/refractoriness prior to LEN treatment as a first‐line systemic therapy, and of whom 25 patients underwent rechallenge TACE after LEN due to LEN‐refractoriness or intolerance. The survival rate of patients who underwent rechallenge TACE was significantly higher than that of patients who did not undergo rechallenge TACE(a), especially in BCLC‐A and B (b).

Background and Aim We assessed direct‐acting antiviral (DAA) treatment for patients with hepatitis C virus (HCV) and a history of injection drug use (IDU) in Japan. Method This retrospective observational study was based on clinical records. Overall, 804 DAA‐naïve HCV‐infected patients were enrolled, treated with a 12‐week regimen of DAAs, and had available information about a history of IDU. Anti‐HCV efficacy was defined as a sustained viral response 12 weeks post‐treatment (SVR12) only in patients who were assessed after 12 weeks [modified intention‐to‐treat (ITT) analyses]. We compared the antiviral effect between patients with (past‐IDU) and without a history of IDU (non‐IDU). We also evaluated the characteristics of each group, including the overall dropout rate and economic background. Results Overall, 78 (9.7%) patients had a history of IDU. Compared to the non‐IDU group at baseline, the past‐IDU group consisted of predominantly male and younger patients infected with HCV genotype 2. Overall, 3% (3/78) and 16% (116/726) of the patients had cirrhosis in the past‐IDU and non‐IDU group, respectively. There was a significantly higher rate of welfare recipients in the past‐IDU group. SVR rate was 97% (59/61) in the past‐IDU group and 99% (689/699) in the non‐IDU group. The cumulative rate of dropout from an aftercare program was high in the past‐IDU group (P < 0.01). Conclusions DAAs had a remarkable anti‐HCV effect in patients with past‐IDU who continued in an aftercare program. It is necessary to understand the characteristics of past‐IDU patients to establish a support system for aftercare programs. The cumulative dropout rates from the aftercare program of antihepatitis C therapy were significantly higher in the past‐IDU group compared to those in the non‐IDU group (P < .01).