Steatotic liver disease is prevalent among people with hepatitis C virus (HCV). The new definition of metabolic dysfunction-associated steatotic liver disease (MASLD) emphasises the metabolic drivers of steatosis and recognises its frequent coexistence with other chronic liver diseases, including HCV. We aimed to evaluate the association of coexisting MASLD and HCV with liver fibrosis. Individuals with HCV who underwent transient elastography (TE) with associated controlled attenuation parameter (CAP) were included from two clinical centres. MASLD and significant liver fibrosis were defined as the presence of steatosis (CAP ≥ 275 dB/m) with at least one cardiometabolic risk factor, and liver stiffness measurement (LSM) ≥ 7.1 kPa measured by TE, respectively. Associated cofactors of significant liver fibrosis were determined using stepwise regression and cross-validation by LASSO models to select confounders. Among 590 participants, 31% were diagnosed with MASLD. The prevalence of significant liver fibrosis was the highest among people with MASLD (58%) followed by HCV-related steatosis (45%) and the non-steatosis group (39%). After adjusting for potential confounders, MASLD was associated with significant liver fibrosis (adjusted odds ratio [aOR] 2.29, 95% confidence interval [CI] 1.07-4.87). Furthermore, specific MASLD phenotypes including diabetes, hypertension and overweight were associated with significant liver fibrosis, with aORs of 4.76 (95% CI 2.16-10.49), 3.44 (95% CI 1.77-6.68) and 2.54 (95% CI 1.27-5.07), respectively. In conclusion, MASLD is associated with liver fibrosis in people with HCV, specifically the diabetes, overweight and hypertensive phenotypes. Beyond pursuing a virological cure, healthcare providers should prioritise managing metabolic conditions, particularly diabetes, hypertension and obesity.

Direct-acting antivirals (DAA) improve sustained virological response (SVR) rates with normalization of liver enzymes in patients with hepatitis C. However, liver inflammation may persist despite virus eradication. We aimed to investigate the rate and risk factors for persistent elevated aminotransferase levels in patients with advanced fibrosis after DAA-induced SVR.

From January 2017 to April 2018, chronic hepatitis C patients with advanced fibrosis and SVR after DAA treatment at the Taipei Veterans General Hospital were prospectively enrolled. Persistent liver inflammation after SVR was defined as an increase in levels of alanine aminotransferase (ALT) (>40 U/L) at SVR12.

A total of 461 patients were included (57.9% females, mean age 64 years, 69.6% genotype 1b, 46.4% cirrhosis). At SVR12, there was a decline in ALT levels (90.5 ± 80.8 U/L to 25.3 ± 26.5 U/L) from baseline levels. Persistent liver inflammation at SVR12 was detected in 45 patients (9.8%). The presence of cirrhosis, markers of impaired liver functions, history of interferon-based therapy, steatosis, and elevated ALT levels at baseline was associated with persistent liver inflammation after SVR12. Results of multivariate analysis indicated that levels of baseline serum total bilirubin (odds ratio [OR]: 2.605, 95% CI: 1.158-5.858), international normalized ratio (OR: 14.389, 95% CI: 1.754-118.049), ALT (OR: 1.006, 95% CI: 1.003-1.009), and the presence of steatosis (OR: 3.635, 95% CI: 1.716-7.698) were independent predictors of persistent liver inflammation at SVR12.

Persistent liver inflammation is not uncommon in chronic hepatitis C patients with advanced fibrosis after DAA-induced SVR. It is associated with impaired baseline liver function and steatosis. Long-term follow-up is required to assess the implication of liver inflammation on disease progression.

DNA and RNA based antiviral strategies using nonviral vectors have shown better potential over the viral pathway due to the fewer chances of gene recombination and immunogenicity. In this work a mesoporous silica nanoparticle (MSN) based carrier system has been used for targeted delivery of shDNA molecule against the conserved 5'-untranslated region (UTR) in the RNA of a hepatitis C virus to inhibit its replication. The MSNs coated with amine and galactose could specifically target liver cells. Significant reduction (about 94%) of viral RNA level was achieved in HCV-JFH1 infectious cell culture compared to the control RNA levels directed the successful delivery and action of the shDNA. This study showed that Gal-AMSN can be used as a synthetic delivery vector to deliver the shDNA effectively for the treatment of HCV infection.

Oxidative/nitrosative stress is proposed to be a critical factor in various diseases, including liver pathologies. Antioxidants derived from medicinal plants have been studied extensively and are relevant to many illnesses, including liver diseases. Several hepatic disorders, such as viral hepatitis and alcoholic or nonalcoholic steatohepatitis, involve free radicals/oxidative stress as agents that cause or at least exacerbate liver injury, which can result in chronic liver diseases, such as liver fibrosis, cirrhosis and end-stage hepatocellular carcinoma. In this scenario, nuclear factor-E2-related factor-2 (Nrf2) appears to be an essential factor to counteract or attenuate oxidative or nitrosative stress in hepatic cells. In fact, a growing body of evidence indicates that Nrf2 plays complex and multicellular roles in hepatic inflammation, fibrosis, hepatocarcinogenesis and regeneration via the induction of its target genes. Inflammation is the most common feature of chronic liver diseases, triggering fibrosis, cirrhosis and hepatocellular carcinoma. Increasing evidence indicates that Nrf2 counteracts the proinflammatory process by modulating the recruitment of inflammatory cells and inducing the endogenous antioxidant response of the cell. In this review, the interactions between antioxidant and inflammatory molecular pathways are analyzed.

Chronic hepatitis C virus (HCV) infection can result in steatosis, a condition displaying aberrant accumulation of neutral lipid vesicles, the component of lipid droplets (LDs), which are essential for HCV assembly. However, the interplay between HCV infection and steatosis remains unclear. Here, we show that HCV-infected cells have higher levels of CD2-associated protein (CD2AP), which plays two distinct, yet tightly linked, roles in HCV pathogenesis: Elevated CD2AP binds to nonstructural protein 5A (NS5A) and participates in the transport of NS5A to LDs to facilitate viral assembly; Up-regulated CD2AP also interacts with casitas B-lineage lymphoma (b) (Cbl/Cbl-b) E3 ligases to degrade insulin receptor substrate 1 (IRS1), which, in turn, disrupts insulin signaling and increases LD accumulation through the IRS1/protein kinase B (Akt)/adenosine monophosphate-activated protein kinase (AMPK)/hormone-sensitive lipase (HSL) signaling axis to accommodate viral assembly. In the HCV-infected mouse model, CD2AP expression is up-regulated during the chronic infection stage and this up-regulation correlates well with liver steatosis. Importantly, CD2AP up-regulation was also detected in HCV-infected human liver biopsies showing steatosis compared to non-HCV-infected controls. Conclusion: CD2AP is indicated as a protein up-regulated by HCV infection, which, in turn, stimulates HCV propagation and steatosis by disrupting insulin signaling; targeting CD2AP may offer an opportunity for alleviating HCV infection and its associated liver pathology. (Hepatology 2018;XX:XXX-XXX.).

To determine the accuracy of shear-wave elastography (SWE) to differentiate low from advanced degrees of liver fibrosis in hepatitis C patients.

Consented native/transplant hepatitis C patients underwent SWE using a C1-6 MHz transducer before ultrasound (US)-guided liver biopsy. Five interpretable SWE samples were obtained from the right lobe of the liver immediately before US-guided random biopsy of the right lobe. Average kilopascal (kPa) values were compared to the meta-analysis of histological data in viral hepatitis (METAVIR) fibrosis grading. SWE values were correlated with the degree of inflammation and fatty infiltration.

Study population consisted of 115 patients (63 with transplant, and 52 with native liver) including 29 women and 86 men, with a mean ± SD age of 56 ± 8.7 years. Mean ± SD SWE values were 7.9 ± 3 kPa in 83 patients with METAVIR scores of 0-2 and 13.2 ± 5.9 kPa in 32 patients with METAVIR scores of 3 or 4 (P < .001). Area under curve (AUC) of a Receiver Operating Characteristics curve for advanced degrees of fibrosis was 0.81 (95% CI: 0.71, 0.90) (P < .001). AUCs of transplant versus native livers (0.78 [CI:0.62, 0.94] versus 0.85 [CI: 0.73, 0.96]), degree of inflammation (0.81 [CI: 0.65, 0.97] versus 0.72 [0.56, 0.88]), or degree of fat deposition (0.81 [CI:0.70, 0.92] versus 0.80 [CI:0.61, 1]) were not statistically different (P > .05). for kPa threshold of SWE value of 10.67 kPa to differentiate advanced from low degree of fibrosis had a sensitivity of 59% (CI: 41%-76%) and specificity of 90% (CI: 82%-96%).

Liver stiffness evaluated by SWE can differentiate low from advanced liver fibrosis.

Intracellular lipid droplets (LDs) are remarkably dynamic and complex organelles that enact regulated storage and release of lipids to fulfil their fundamental roles in energy metabolism, membrane synthesis and provision of lipid-derived signaling molecules. The recent finding that LDs can be selectively degraded by the lysosomal pathway of autophagy through a process termed lipophagy has opened up a new understanding of how lipid metabolism regulates cellular physiology and pathophysiology. Many new functions for autophagic lipid metabolism have now been defined in various diseases including liver disease. Lipophagy was originally described in hepatocytes, where it is critical for maintaining cellular energy homeostasis in obesity and metabolic syndrome. In vitro and in vivo studies have demonstrated the selective uptake of LDs by autophagosomes, and inhibition of autophagy has been shown to reduce the β-oxidation of free fatty acids due to the increased accumulation of lipids and LDs. The identification of lipophagy as a new process dedicated to cellular lipid removal has mapped autophagy as an emerging player in cellular lipid metabolism. Pharmacological or genetic modulation of lipophagy might point to possible therapeutic strategies for combating a broad range of liver diseases. This review summarizes recent work focusing on lipophagy and liver disease as well as highlighting challenges and future directions of research. On the other hand, it also offers a glimpse into different strategies that have been used in experimental models to counteract excessive pathological lipophagy in the prevention and treatment of liver disease.

Hepatitis C virus (HCV) infection induces steatosis and is accompanied by multiple metabolic alterations including hyperuricemia, reversible hypocholesterolemia and insulin resistance. Total cholesterol, low-density lipoprotein-cholesterol and triglyceride levels are increased by peginterferon and ribavirin combination therapy when a sustained virologic response (SVR) is achieved in patients with HCV. Steatosis is significantly more common in patients with HCV genotype 3 but interferon-free regimens are not always effective for treating HCV genotype 3 infections. HCV infection increases fatty acid synthase levels, resulting in the accumulation of fatty acids in hepatocytes. Of note, low-density lipoprotein receptor, scavenger receptor class B type I and Niemann-Pick C1-like 1 proteins are candidate receptors that may be involved in HCV. They are also required for the uptake of cholesterol from the external environment of hepatocytes. Among HCV-infected patients with or without human immunodeficiency virus infection, changes in serum lipid profiles are observed during interferon-free treatment and after the achievement of an SVR. It is evident that HCV affects cholesterol metabolism during interferon-free regimens. Although higher SVR rates were achieved with interferon-free treatment of HCV, special attention must also be paid to unexpected adverse events based on host metabolic changes including hyperlipidemia.

The aim of the study was to detect the expression level of thymosin β4 (Tβ4) in serum and tissues of patients with chronic hepatitis B (CHB) combined nonalcoholic fatty liver disease (NAFLD). The effects of Tβ4 in hepatic steatosis, chronic inflammation, and fibrosis development in CHB combined NAFLD patients were also discussed. The study included 46 patients in the case group with CHB and NAFLD and 42 patients in the control group with CHB. ELISA was applied to detect serum Tβ4 and TNF-α level. Furthermore, the correlation analysis of Tβ4 levels with biochemical index, pathological index, and TNF-α level was performed. The Tβ4 immunohistochemical levels of different inflammation fibrosis levels were compared, and the correlation analysis with TNF expression was performed. The Tβ4 levels in patients with CHB combined NAFLD showed no statistical difference when compared to the control group. In patients with CHB combined NAFLD group, the Tβ4 level had no correlation with ALT, AST, TG, FGP, hepatitis B virus (HBV)-DNA levels, and fat grading, but had negative correlation with inflammation score and fibrosis score (P <0.01). The immunohistochemical results of hepatic tissues showed that the expression intensity of severe inflammation fibrosis group had statistical significance compared with that of slight group, and the Tβ4 expression both in serum and in liver tissue negatively correlated with TNF-α expression. Tβ4 could be involved in the regulation of chronic inflammation and fibrosis and plays a defense role in the disease progression of CHB combined NAFLD patients.

Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) is globally increasing and has become a world-wide health problem. Chronic infection with hepatitis B virus or hepatitis C virus (HCV) is associated with hepatic steatosis. Viral hepatitis-associated hepatic steatosis is often caused by metabolic syndrome including obesity, type 2 diabetes mellitus and/or dyslipidemia. It has been reported that HCV genotype 3 exerts direct metabolic effects that lead to hepatic steatosis. In this review, the differences between NAFLD/NASH and viral hepatitis-associated steatosis are discussed.