Cyclophilin D knockout significantly prevents HCC development in a streptozotocin-induced mouse model of diabetes-linked NASH.

A family of Peptidyl-prolyl isomerases (PPIases), called Cyclophilins, localize to numerous intracellular and extracellular locations where they contribute to a variety of essential functions. We previously reported that non-immunosuppressive pan-cyclophilin inhibitor drugs like reconfilstat (CRV431) or NV556 decreased multiple aspects of non-alcoholic fatty liver disease (NAFLD) in mice under two different non-alcoholic steatohepatitis (NASH) mouse models. Both CRV431 and NV556 inhibit several cyclophilin isoforms, among which cyclophilin D (CypD) has not been previously investigated in this context. It is unknown whether it is necessary to simultaneously inhibit multiple cyclophilin family members to achieve therapeutic benefits or if loss-of-function of one is sufficient. Furthermore, narrowing down the isoform most responsible for a particular aspect of NAFLD/NASH, such as hepatocellular carcinoma (HCC), would allow for more precise future therapies. Features of human diabetes-linked NAFLD/NASH can be reliably replicated in mice by administering a single high dose of streptozotocin to disrupt pancreatic beta cells, in conjunction with a high sugar, high fat, high cholesterol western diet over the course of 30 weeks. Here we show that while both wild-type (WT) and Ppif-/- CypD KO mice develop multipe severe NASH disease features under this model, the formation of HCC nodules was significantly blunted only in the CypD KO mice. Furthermore, of differentially expressed transcripts in a qPCR panel of select HCC-related genes, nearly all were downregulated in the CypD KO background. Cyclophilin inhibition is a promising and novel avenue of treatment for diet-induced NAFLD/NASH. This study highlights the impact of CypD loss-of-function on the development of HCC, one of the most severe disease outcomes.

Potential utility of l-carnitine for preventing liver tumors derived from metabolic dysfunction-associated steatohepatitis.

BACKGROUND: Recent reports have unveiled the potential utility of l-carnitine to alleviate metabolic dysfunction-associated steatohepatitis (MASH) by enhancing mitochondrial metabolic function. However, its efficacy at preventing the development of HCC has not been assessed fully. METHODS: l-carnitine (2 g/d) was administered to 11 patients with MASH for 10 weeks, and blood liver function tests were performed. Five patients received a serial liver biopsy, and liver histology and hepatic gene expression were evaluated using this tissue. An atherogenic plus high-fat diet MASH mouse model received long-term l-carnitine administration, and liver histology and liver tumor development were evaluated. RESULTS: Ten-week l-carnitine administration significantly improved serum alanine transaminase and aspartate transaminase levels along with a histological improvement in the NAFLD activity score, while steatosis and fibrosis were not improved. Gene expression profiling revealed a significant improvement in the inflammation and profibrotic gene signature as well as the recovery of lipid metabolism. Long-term l-carnitine administration to atherogenic plus high-fat diet MASH mice substantially improved liver histology (inflammation, steatosis, and fibrosis) and significantly reduced the incidence of liver tumors. l-carnitine directly reduced the expression of the MASH-associated and stress-induced transcriptional factor early growth response 1. Early growth response 1 activated the promoter activity of neural precursor cell expressed, developmentally downregulated protein 9 (NEDD9), an oncogenic protein. Thus, l-carnitine reduced the activation of the NEDD9, focal adhesion kinase 1, and AKT oncogenic signaling pathway. CONCLUSIONS: Short-term l-carnitine administration ameliorated MASH through its anti-inflammatory effects. Long-term l-carnitine administration potentially improved the steatosis and fibrosis of MASH and may eventually reduce the risk of HCC.

Aspirin for Metabolic Dysfunction-Associated Steatotic Liver Disease Without Cirrhosis: A Randomized Clinical Trial.

Importance: Aspirin may reduce severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and lower the incidence of end-stage liver disease and hepatocellular carcinoma, in patients with MASLD. However, the effect of aspirin on MASLD is unknown. Objective: To test whether low-dose aspirin reduces liver fat content, compared with placebo, in adults with MASLD. Design, Setting, and Participants: This 6-month, phase 2, randomized, double-blind, placebo-controlled clinical trial was conducted at a single hospital in Boston, Massachusetts. Participants were aged 18 to 70 years with established MASLD without cirrhosis. Enrollment occurred between August 20, 2019, and July 19, 2022, with final follow-up on February 23, 2023. Interventions: Participants were randomized (1:1) to receive either once-daily aspirin, 81 mg (n = 40) or identical placebo pills (n = 40) for 6 months. Main Outcomes and Measures: The primary end point was mean absolute change in hepatic fat content, measured by proton magnetic resonance spectroscopy (MRS) at 6-month follow-up. The 4 key secondary outcomes included mean percentage change in hepatic fat content by MRS, the proportion achieving at least 30% reduction in hepatic fat, and the mean absolute and relative reductions in hepatic fat content, measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Analyses adjusted for the baseline value of the corresponding outcome. Minimal clinically important differences for study outcomes were not prespecified. Results: Among 80 randomized participants (mean age, 48 years; 44 [55%] women; mean hepatic fat content, 35% [indicating moderate steatosis]), 71 (89%) completed 6-month follow-up. The mean absolute change in hepatic fat content by MRS was -6.6% with aspirin vs 3.6% with placebo (difference, -10.2% [95% CI, -27.7% to -2.6%]; P = .009). Compared with placebo, aspirin treatment significantly reduced relative hepatic fat content (-8.8 vs 30.0 percentage points; mean difference, -38.8 percentage points [95% CI, -66.7 to -10.8]; P = .007), increased the proportion of patients with 30% or greater relative reduction in hepatic fat (42.5% vs 12.5%; mean difference, 30.0% [95% CI, 11.6% to 48.4%]; P = .006), reduced absolute hepatic fat content by MRI-PDFF (-2.7% vs 0.9%; mean difference, -3.7% [95% CI, -6.1% to -1.2%]; P = .004]), and reduced relative hepatic fat content by MRI-PDFF (-11.7 vs 15.7 percentage points; mean difference, -27.3 percentage points [95% CI, -45.2 to -9.4]; P = .003). Thirteen participants (32.5%) in each group experienced an adverse event, most commonly upper respiratory tract infections (10.0% in each group) or arthralgias (5.0% for aspirin vs 7.5% for placebo). One participant randomized to aspirin (2.5%) experienced drug-related heartburn. Conclusions and Relevance: In this preliminary randomized clinical trial of patients with MASLD, 6 months of daily low-dose aspirin significantly reduced hepatic fat quantity compared with placebo. Further study in a larger sample size is necessary to confirm these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT04031729.

From prediction to prevention: Machine learning revolutionizes hepatocellular carcinoma recurrence monitoring.

In this editorial, we comment on the article by Zhang et al entitled Development of a machine learning-based model for predicting the risk of early postoperative recurrence of hepatocellular carcinoma. Hepatocellular carcinoma (HCC), which is characterized by high incidence and mortality rates, remains a major global health challenge primarily due to the critical issue of postoperative recurrence. Early recurrence, defined as recurrence that occurs within 2 years posttreatment, is linked to the hidden spread of the primary tumor and significantly impacts patient survival. Traditional predictive factors, including both patient- and treatment-related factors, have limited predictive ability with respect to HCC recurrence. The integration of machine learning algorithms is fueled by the exponential growth of computational power and has revolutionized HCC research. The study by Zhang et al demonstrated the use of a groundbreaking preoperative prediction model for early postoperative HCC recurrence. Chall-enges persist, including sample size constraints, issues with handling data, and the need for further validation and interpretability. This study emphasizes the need for collaborative efforts, multicenter studies and comparative analyses to validate and refine the model. Overcoming these challenges and exploring innovative approaches, such as multi-omics integration, will enhance personalized oncology care. This study marks a significant stride toward precise, effi-cient, and personalized oncology practices, thus offering hope for improved patient outcomes in the field of HCC treatment.

Berberine prevents NAFLD and HCC by modulating metabolic disorders.

Non-alcoholic fatty liver disease (NAFLD) is a global metabolic disease with high prevalence in both adults and children. Importantly, NAFLD is becoming the main cause of hepatocellular carcinoma (HCC). Berberine (BBR), a naturally occurring plant component, has been demonstrated to have advantageous effects on a number of metabolic pathways as well as the ability to kill liver tumor cells by causing cell death and other routes. This permits us to speculate and make assumptions about the value of BBR in the prevention and defense against NAFLD and HCC by a global modulation of metabolic disorders. Herein, we briefly describe the etiology of NAFLD and NAFLD-related HCC, with a particular emphasis on analyzing the potential mechanisms of BBR in the treatment of NAFLD from aspects including increasing insulin sensitivity, controlling the intestinal milieu, and controlling lipid metabolism. We also elucidate the mechanism of BBR in the treatment of HCC. More significantly, we provided a list of clinical studies for BBR in NAFLD. Taking into account our conclusions and perspectives, we can make further progress in the treatment of BBR in NAFLD and NAFLD-related HCC.

Entecavir versus tenofovir for prevention of hepatitis B virus-associated hepatocellular carcinoma after curative resection: study protocol for a randomized, open-label trial.

BACKGROUND: Entecavir and tenofovir disoproxil fumarate (TDF) are standard first-line treatments to prevent viral reactivation and hepatocellular carcinoma (HCC) in individuals chronically infected with the hepatitis B virus (HBV), but the long-term efficacy of the two drugs remains controversial. Also unclear is whether the drugs are effective at preventing viral reactivation or HCC recurrence after hepatectomy to treat HBV-associated HCC. This trial will compare recurrence-free survival, overall survival, viral indicators and adverse events in the long term between patients with HBV-associated HCC who receive entecavir or TDF after curative resection. METHODS: This study is a randomized, open-label trial. A total of 240 participants will be randomized 1:1 into groups receiving TDF or entecavir monotherapy. The two groups will be compared in terms of recurrence-free and overall survival at 1, 3, and 5 years after surgery; adverse events; virological response; rate of alanine transaminase normalization; and seroreactivity at 24 and 48 weeks after surgery. DISCUSSION: This study will compare long-term survival between patients with HBV-associated HCC who receive TDF or entecavir monotherapy. Numerous outcomes related to prognosis will be analyzed and compared in this study. TRIAL REGISTRATION: ClinicalTrials.gov NCT02650271. Registered on January 7, 2016.

Virological, serological and clinical outcomes in chronic hepatitis B virus infection: development and validation of the HEPA-B simulation model.

OBJECTIVES: Detailed simulation models are needed to assess strategies for prevention and treatment of hepatitis B virus (HBV) infection, the world's leading cause of liver disease. We sought to develop and validate a simulation model of chronic HBV that incorporates virological, serological and clinical outcomes. METHODS: We developed a novel Monte Carlo simulation model (the HEPA-B Model) detailing the natural history of chronic HBV. We parameterised the model with epidemiological data from the Western Pacific and sub-Saharan Africa. We simulated the evolution of HBV DNA, 'e' antigen (HBeAg) and surface antigen (HBsAg). We projected incidence of HBeAg loss, HBsAg loss, cirrhosis, hepatocellular carcinoma (HCC) and death over 10-year and lifetime horizons. We stratified outcomes by five HBV DNA categories at the time of HBeAg loss, ranging from HBV DNA<300 copies/mL to >106 copies/mL. We tested goodness of fit using intraclass coefficients (ICC). RESULTS: Model-projected incidence of HBeAg loss was 5.18% per year over lifetime (ICC, 0.969 (95% CI: 0.728 to 0.990)). For people in HBeAg-negative phases of infection, model-projected HBsAg loss ranged from 0.78% to 3.34% per year depending on HBV DNA level (ICC, 0.889 (95% CI: 0.542 to 0.959)). Model-projected incidence of cirrhosis was 0.29-2.09% per year (ICC, 0.965 (95% CI: 0.942 to 0.979)) and HCC incidence was 0.06-1.65% per year (ICC, 0.977 (95% CI: 0.962 to 0.986)). Over a lifetime simulation of HBV disease, mortality rates were higher for people with older age, higher HBV DNA level and liver-related complications, consistent with observational studies. CONCLUSIONS: We simulated HBV DNA-stratified clinical outcomes with the novel HEPA-B Model and validated them to observational data. This model can be used to examine strategies of HBV prevention and management.

Inhibition of IL-33 signaling ameliorate hepatic fibrosis with decreasing MCP-1 in a mouse model of diabetes and non-alcoholic steatohepatitis; comparison for luseogliflozin, an SGLT2 inhibitor.

Non-alcoholic fatty liver disease (NAFLD) is increasing globally, and seeking therapeutic molecule targets is urgent. Several studies have demonstrated that IL-33 plays an important role in the progression of Non-alcoholic steatohepatitis (NASH) with fibrosis and the proliferation of hepatocellular carcinoma (HCC). However, whether the inhibition of IL-33 signaling prevents NAFLD from progressing to NASH and HCC has not been clarified. We investigated the effects of a novel antibody, IL-33RAb, and luseogliflozin, a SGLT2 inhibitor, when administered to a model mouse for NASH and HCC, and their effects were compared to investigate the mechanisms of how IL-33 is involved in the pathogenesis of NASH progression. Compared with the positive control of luseogliflozin, inhibition of IL-33 signaling ameliorated decreasing hepatic fibrosis via decreasingαSMA and MCP-1, and also partially suppressed the progression of the HCC cell line in in vitro experiments. These findings suggest that inhibition of IL-33 possibly prevents progression from NASH to HCC, and their effect may be a newly arrived therapeutic agent.

Metformin and Hepatocellular Carcinoma Risk Reduction in Diabetic Patients with Chronic Hepatitis C: Fact or Fiction?

BACKGROUND: Patients with chronic hepatitis C (CHC) and concomitant type 2 diabetes mellitus (DM) show a higher risk of developing hepatocellular carcinoma (HCC). Successful antiviral therapy has reduced the incidence of post-therapy HCC, but the presence of DM still represents an unfavourable predictive factor even in cured patients. Metformin (MET) is recommended as a first-line therapy for DM, and its use is associated with a significant reduction in HCC among diabetic patients with chronic liver disease of different etiology, but very few studies specifically address this issue in patients with CHC. AIM: the aim of this review is to evaluate whether the use of MET induces a significant decrease in HCC in diabetic patients with CHC, treated or untreated with antiviral therapy. METHODS: A search of PubMed, Medline, Web of Sciences and Embase was conducted for publications evaluating the role of MET in reducing the risk of HCC in patients with DM and CHC, with no language and study type restrictions up to 30 June 2023. Only studies fulfilling the following inclusion criteria were considered: (1) data on the incidence of HCC in the follow-up of diabetic patients with CHC only; (2) follow-up ≥24 months; (3) sufficient data to establish the rate of diabetic patients with CHC treated with metformin or other antidiabetic medications; and (4) data on the type of antiviral treatment and the clinical outcome. RESULTS: Three studies met the inclusion criteria. A prospective cohort study considering only patients with DM and untreated advanced CHC, or non-responders to interferon (IFN) therapy, showed that the use of MET was associated with a significant decrease in HCC incidence, liver-related death and liver transplants. A recent retrospective study focusing on a large-scale nationwide cohort of patients with CHC in Taiwan successfully treated with IFN-based therapy stratified patients into 3 groups: non-MET users, MET users and non-diabetic patients, with 5-year cumulative rates of HCC of 10.9%, 2.6% and 3.0%, respectively, showing a significantly higher HCC risk in non-MET users compared with MET users and with non-diabetic patients, while it was not significantly different between MET users and non-diabetic patients. In a recent Italian cohort study focusing on 7007 patients with CHC treated and cured with direct-acting antiviral agents (DAAs), a combined effect of DM and MET therapy was found, showing a higher incidence of HCC in diabetic patients not taking MET compared with those without DM and those with DM taking MET. CONCLUSION: according to the current evidence, the use of MET should be encouraged in diabetic patients with CHC in order to reduce the risk of HCC; however, a well-designed randomized controlled trial is needed to establish the generalizability of the beneficial effects of MET in this particular subset of patients.

Hepatitis D: A Review.

Importance: Hepatitis D virus (HDV) infection occurs in association with hepatitis B virus (HBV) infection and affects approximately 12 million to 72 million people worldwide. HDV causes more rapid progression to cirrhosis and higher rates of hepatocellular carcinoma than HBV alone or hepatitis C virus. Observations: HDV requires HBV to enter hepatocytes and to assemble and secrete new virions. Acute HDV-HBV coinfection is followed by clearance of both viruses in approximately 95% of people, whereas HDV superinfection in an HBV-infected person results in chronic HDV-HBV infection in more than 90% of infected patients. Chronic hepatitis D causes more rapidly progressive liver disease than HBV alone. Approximately 30% to 70% of patients with chronic hepatitis D have cirrhosis at diagnosis and more than 50% die of liver disease within 10 years of diagnosis. However, recent studies suggested that progression is variable and that more than 50% of people may have an indolent course. Only approximately 20% to 50% of people infected by hepatitis D have been diagnosed due to lack of awareness and limited access to reliable diagnostic tests for the HDV antibody and HDV RNA. The HBV vaccine prevents HDV infection by preventing HBV infection, but no vaccines are available to protect those with established HBV infection against HDV. Interferon alfa inhibits HDV replication and reduces the incidence of liver-related events such as liver decompensation, hepatocellular carcinoma, liver transplant, or mortality from 8.5% per year to 3.3% per year. Adverse effects from interferon alfa such as fatigue, depression, and bone marrow suppression are common. HBV nucleos(t)ide analogues, such as entecavir or tenofovir, are ineffective against HDV. Phase 3 randomized clinical trials of bulevirtide, which blocks entry of HDV into hepatocytes, and lonafarnib, which interferes with HDV assembly, showed that compared with placebo or observation, these therapies attained virological and biochemical response in up to 56% of patients after 96 weeks of bulevirtide monotherapy and 19% after 48 weeks of lonafarnib, ritonavir, and pegylated interferon alfa treatment. Conclusions and Relevance: HDV infection affects approximately 12 million to 72 million people worldwide and is associated with more rapid progression to cirrhosis and liver failure and higher rates of hepatocellular carcinoma than infection with HBV alone. Bulevirtide was recently approved for HDV in Europe, whereas pegylated interferon alfa is the only treatment available in most countries.

Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy.

Hepatocellular carcinoma (HCC) mortality rates are increasing globally, and particularly in the Western world. Cirrhosis remains the predominant risk factor for HCC. However, epidemiological shifts in the incidence of HCC from patients with virus-related liver disease to those with non-viral aetiologies, including alcohol-associated and metabolic dysfunction-associated steatotic liver disease, have important implications for prevention, surveillance and treatment. Hepatitis B vaccination and antiviral therapy for hepatitis B and C are effective for primary prevention of virus-related HCCs, but chemoprevention strategies for non-viral liver disease remain an unmet need. Emerging data suggest associations between aspirin, statins, metformin and coffee and reduced HCC incidence, although none has been proved to be causally related. Secondary prevention of HCC via semi-annual surveillance is associated with improvements in early detection and thus reduced mortality; however, current tools, including abdominal ultrasonography, have suboptimal sensitivity for the detection of early stage HCC, particularly in patients with obesity and/or non-viral liver disease. Promising blood-based or imaging-based surveillance strategies are emerging, although these approaches require further validation before adoption in clinical practice. In the interim, efforts should be focused on maximizing use of the existing surveillance tools given their prevalent underuse globally. Remarkable advances have been made in the treatment of HCC, including expanded eligibility for surgical therapies, improved patient selection for locoregional treatments and increased systemic treatment options, including immune-checkpoint inhibitors. In this Review, we discuss trends in the epidemiology of HCC and their implications for screening, prevention and therapy.

Statin use and the risk of hepatocellular carcinoma among patients with chronic hepatitis B: an emulated target trial using longitudinal nationwide population cohort data.

BACKGROUND: No randomized controlled trials have been completed to see whether statin can decrease hepatocellular carcinoma (HCC) risk in chronic hepatitis B (CHB) patients. We used large-scale, population-based, observational data to emulate a target trial with two groups, statin user and statin non-user. METHODS: Among 1,379,708 nonunique individuals from the Korean National Health Insurance Service data, 2,915 CHB patients with serum cholesterol level of 200 mg/dL or higher who started statin therapy and 8,525 propensity-score matched CHB patients with serum cholesterol level of 200 mg/dL or higher who did not start statin therapy were analyzed for the development of HCC. In addition, liver cancer or liver-related mortality and all-cause mortality were assessed. RESULTS: During follow-up, 207 participants developed HCC. Incidence rate of HCC was 0.2 per 1,000 person-years in the statin user group and 0.3 per 1,000 person-years in the statin non-user group. Fully adjusted hazard ratio (HR) for incident HCC comparing statin user group to statin nonuser group was 0.56 (95% confidence interval [CI]: 0.39 to 0.80). The association between statin use and decreased HCC risk was consistent in all subgroups analyzed. Fully adjusted HR comparing statin user to statin nonuser was 0.59 (95% CI: 0.35 to 0.99) for liver cancer or liver-related mortality and 0.93 (95% CI: 0.78 to 1.11) for all-cause mortality. CONCLUSIONS: Statin might have a benefit for preventing HCC in CHB patients with elevated cholesterol levels. Statin should be actively considered for CHB patients with dyslipidemia.

Chronic Hepatitis B: Treat all Who Are Viremic?

The main aim of antiviral therapy in patients with chronic hepatitis B (CHB) is to prevent disease progression and reduce the risk of hepatocellular carcinoma (HCC). In general, treatment is recommended for select patient groups viewed as being at higher risk of developing adverse outcomes from CHB. However, patients who do not meet treatment criteria under current international guidelines may still benefit from antiviral therapy to reduce CHB-related complications. Moreover, well-tolerated antiviral drugs that are highly effective at suppressing viral replication are now widely available, and withholding therapy from patients with viremia is increasingly controversial. In this article, we review traditional treatment paradigms and argue the merits of expanding treatment eligibility to patients with CHB who do not meet current treatment criteria.

Unmet Needs in the Post-Direct-Acting Antiviral Era: Hepatocarcinogenesis After Hepatitis C Virus Eradication.

Infection with chronic hepatitis C virus (HCV) is an important risk factor for hepatocellular carcinoma (HCC). Direct-acting antiviral therapy has transformed care for patients with HCV and reduces the risk of HCC. Despite HCV cure, a residual HCC risk remains in patients with advanced fibrosis and cirrhosis, with multiple mechanisms underlying subsequent hepatocarcinogenesis. Transcriptomic and proteomic signatures demonstrate the capacity for HCC risk stratification, and chemoprevention strategies are emerging. For now, pending more precise stratification, HCC surveillance of patients with cured HCV and advanced fibrosis or cirrhosis should continue.

Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC.

The incidence of hepatocellular carcinoma (HCC) is rapidly rising largely because of increased obesity leading to nonalcoholic steatohepatitis (NASH), a known HCC risk factor. There are no approved treatments to treat NASH. Here, we first used single-nucleus RNA sequencing to characterize a mouse model that mimics human NASH-driven HCC, the MUP-uPA mouse fed a high-fat diet. Activation of endoplasmic reticulum (ER) stress and inflammation was observed in a subset of hepatocytes that was enriched in mice that progress to HCC. We next treated MUP-uPA mice with the ER stress inhibitor BGP-15 and soluble gp130Fc, a drug that blocks inflammation by preventing interleukin-6 trans-signaling. Both drugs have progressed to phase 2/3 human clinical trials for other indications. We show that this combined therapy reversed NASH and reduced NASH-driven HCC. Our data suggest that these drugs could provide a potential therapy for NASH progression to HCC.

Hepatocellular Carcinoma Prevention in the Era of Hepatitis C Elimination.

The hepatitis C virus (HCV), a single-stranded RNA virus belonging to the Flaviviridae family, is a major cause of hepatocellular carcinoma (HCC) worldwide. Tumors caused by HCC have an increased mortality rate globally, which is more accentuated in Western countries. The carcinogenic potential of this virus is mediated through a wide range of mechanisms, spanning from the induction of chronic inflammation to oxidative stress and deregulation of cellular pathways by viral proteins. As the number of new infections continues unabated, HCC-related mortality should be prioritized through early detection, continued prevention of HCV transmission, and treatment of HCV with safe and efficacious direct antiviral agents (DAAs). People who inject drugs (PWID) are a significant reservoir of new HCV infections globally, and in order to eliminate hepatitis C as a global health threat, as set out by the World Health Organization, an integrated approach based on the optimization of care delivery and increased access to harm reduction and treatment for PWID is needed. Thanks to the development of safe and effective antiviral agents, eradication of the infection is now possible in almost all treated patients, leading to a significant reduction but not the elimination of the risk for HCC in cured patients. This is particularly relevant among aged populations who have cofactors of morbidity known to accelerate HCC progression, such as diabetes, obesity, and excessive alcohol consumption. Given the restless accumulation of individuals with cured HCV infection, the implementation of risk-stratified surveillance programs becomes impellent from a cost-effectiveness perspective, whereas the availability of a performant biomarker to predict HCC in cured patients remains an unmet clinical need.

Bifidobacterium pseudolongum-generated acetate suppresses non-alcoholic fatty liver disease-associated hepatocellular carcinoma.

BACKGROUND & AIMS: Recent studies have highlighted the role of the gut microbiota and their metabolites in non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC). We aimed to identify specific beneficial bacterial species that could be used prophylactically to prevent NAFLD-HCC. METHODS: The role of Bifidobacterium pseudolongum was assessed in two mouse models of NAFLD-HCC: diethylnitrosamine + a high-fat/high-cholesterol diet or + a choline-deficient/high-fat diet. Germ-free mice were used for the metabolic study of B. pseudolongum. Stool, portal vein and liver tissues were collected from mice for non-targeted and targeted metabolomic profiles. Two human NAFLD-HCC cell lines (HKCI2 and HKCI10) were co-cultured with B. pseudolongum-conditioned media (B.p CM) or candidate metabolites. RESULTS: B. pseudolongum was the top depleted bacterium in mice with NAFLD-HCC. Oral gavage of B. pseudolongum significantly suppressed NAFLD-HCC formation in two mouse models (p < 0.01). Incubation of NAFLD-HCC cells with B.p CM significantly suppressed cell proliferation, inhibited the G1/S phase transition and induced apoptosis. Acetate was identified as the critical metabolite generated from B. pseudolongum in B.p CM, an observation that was confirmed in germ-free mice. Acetate inhibited cell proliferation and induced cell apoptosis in NAFLD-HCC cell lines and suppressed NAFLD-HCC tumor formation in vivo. B. pseudolongum restored heathy gut microbiome composition and improved gut barrier function. Mechanistically, B. pseudolongum-generated acetate reached the liver via the portal vein and bound to GPR43 (G coupled-protein receptor 43) on hepatocytes. GPR43 activation suppressed the IL-6/JAK1/STAT3 signaling pathway, thereby preventing NAFLD-HCC progression. CONCLUSIONS: B. pseudolongum protected against NAFLD-HCC by secreting the anti-tumor metabolite acetate, which reached the liver via the portal vein. B. pseudolongum holds potential as a probiotic for the prevention of NAFLD-HCC. IMPACT AND IMPLICATIONS: Non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC) is an increasing healthcare burden worldwide. There is an urgent need to develop effective agents to prevent NAFLD-HCC progression. Herein, we show that the probiotic Bifidobacterium pseudolongum significantly suppressed NAFLD-HCC progression by secreting acetate, which bound to hepatic GPR43 (G coupled-protein receptor 43) via the gut-liver axis and suppressed the oncogenic IL-6/JAK1/STAT3 signaling pathway. Bifidobacterium pseudolongum holds potential as a novel probiotic for NAFLD-HCC prevention.

Association between daily aspirin therapy and risk of hepatocellular carcinoma according to metabolic risk factor burden in non-cirrhotic patients with chronic hepatitis B.

BACKGROUND: Several studies have demonstrated chemopreventive effects of aspirin against hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). AIMS: To investigate the associations of aspirin use with risks of HCC, liver-related mortality, and major bleeding according to metabolic risk factor burden among non-cirrhotic patients with CHB METHODS: Using the Korean National Health Insurance Service database, we identified 282,611 non-cirrhotic adults with CHB. Data on obesity, diabetes, high blood pressure, and hypercholesterolemia were collected. Subjects were stratified into lower and higher metabolic risk groups (≤2 and ≥3 risk factors, respectively). Propensity score-matched cohorts of aspirin users and non-users were generated. Risks of HCC, liver-related death and major bleeding were analyzed. RESULTS: During the median follow-up of 7.4 years, positive associations between metabolic risk factor burden and outcomes were verified (all ptrend < 0.001). In the lower metabolic risk group (13,104 pairs), the association between aspirin use and HCC risk was not significant after multivariable adjustment (adjusted subdistribution hazard ratio [aSHR]: 0.93; 95% CI: 0.84-1.03); however, aspirin use was associated with elevated major bleeding risk (aSHR: 1.22; 95% CI: 1.08-1.39). In the higher metabolic risk group (2984 pairs), aspirin use was associated with reduced risks of HCC (aSHR: 0.72; 95% CI: 0.57-0.91) and liver-related mortality (aSHR: 0.69; 95% CI: 0.50-0.96) without an increase in risk of major bleeding (aSHR: 1.02; 95% CI: 0.79-1.32). CONCLUSIONS: Aspirin therapy was associated with reduced risks of HCC and liver-related death without excess risk of major bleeding, in non-cirrhotic patients with CHB who had a higher metabolic risk factor burden.

Dynamic risk assessment for hepatocellular carcinoma in patients with chronic hepatitis C.

Chronic hepatitis C (HCV) is a primary cause of hepatocellular carcinoma (HCC). Although antiviral treatment reduces risk of HCC, few studies quantify the impact of treatment on long-term risk in the era of direct-acting antivirals (DAA). Using data from the Chronic Hepatitis Cohort Study, we evaluated the impact of treatment type (DAA, interferon-based [IFN], or none) and outcome (sustained virological response [SVR] or treatment failure [TF]) on risk of HCC. We then developed and validated a predictive risk model. 17186 HCV patients were followed until HCC, death or last follow-up. We used extended landmark modelling, with time-varying covariates and propensity score justification and generalized estimating equations with a link function for discrete time-to-event data. Death was considered a competing risk. We observed 586 HCC cases across 104,000 interval-years of follow-up. SVR from DAA or IFN-based treatment reduced risk of HCC (aHR 0.13, 95% CI 0.08-0.20; and aHR 0.45, 95% CI 0.31-0.65); DAA SVR reduced risk more than IFN SVR (aHR 0.29, 95% CI 0.17-0.48). Independent of treatment, cirrhosis was the strongest risk factor for HCC (aHR 3.94, 95% CI 3.17-4.89 vs. no cirrhosis). Other risk factors included male sex, White race and genotype 3. Our six-variable predictive model had 'excellent' accuracy (AUROC 0.94) in independent validation. Our novel landmark interval-based model identified HCC risk factors across antiviral treatment status and interactions with cirrhosis. This model demonstrated excellent predictive accuracy in a large, racially diverse cohort of patients and could be adapted for 'real world' HCC monitoring.

Past, present, and future of long-term treatment for hepatitis B virus.

The estimated world prevalence of hepatitis B virus (HBV) infection is 316 million. HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma (HCC) despite universal vaccination programs, and effective antiviral therapy. Long-term administration of nucleos(t)ide analogues (NA) has been the treatment of choice for chronic hepatitis B during the last decades. The NA has shown a good safety profile and high efficacy in controlling viral replication, improving histology, and decreasing the HCC incidence, decompensation, and mortality. However, the low probability of HBV surface antigen seroclearance made necessary an indefinite treatment. The knowledge, in recent years, about the different phases of the viral cycle, and the new insights into the role of the immune system have yielded an increase in new therapeutic approaches. Consequently, several clinical trials evaluating combinations of new drugs with different mechanisms of action are ongoing with promising results. This integrative literature review aims to assess the knowledge and major advances from the past of hepatitis B, the present of NA treatment and withdrawal, and the future perspectives with combined molecules to achieve a functional cure.