Clinical and Molecular Hepatology最新文献

Background: Plasma pregenomic hepatitis B virus RNA (pgRNA) is a novel biomarker in chronic hepatitis B infection (CHB). We aimed to describe the longitudinal profile of pgRNA and factors influencing its levels in CHB patients on nucleoside analogue (NUC).

Methods: Serial plasma samples from 1354 CHB patients started on first-line NUC were evaluated. Time of NUC initiation was taken as baseline (year 0), followed by 1-year, 3-year and 5-year of NUC therapy. pgRNA was measured by Research Use Only RealTime HBV RNA v2.0 (0.2 mL) (Abbott Diagnostics) with lower limit of detection of 0.8 log U/mL (~20 copies/mL).

Results: Among 1354 subjects (median age at baseline 49.8 (interquartile range [IQR] 40.2-57.3) years, 65.2% male, 16.1% HBeAg-positive, 28.6% cirrhotic), baseline median HBV RNA was 3.68 (IQR 2.42-5.19) log U/mL. Upon NUC therapy, median pgRNA levels were 2.45 (IQR 1.82-3.62), 2.23 (IQR 1.67-3.05) and 2.14 (IQR 1.48-2.86) log U/mL at 1, 3 and 5 years respectively, with the corresponding log U/mL reductions of 0.82, 1.20 and 1.54. Undetectable/ unquantifiable pgRNA was achieved in 13.5%, 15.9% and 20.1% of patients at 1, 3 and 5 years respectively. Older age, male sex, HBeAg-negativity and high PAGE-B score were associated with lower pgRNA.

Conclusion: Plasma pgRNA declines are modest under NUC therapy, with only 16.3% achieving RNA undetectability after 5 years of first-line NUC indicating cccDNA silencing has not been achieved in the majority of patients. Clinical characteristics should be taken into consideration when interpreting the plasma pgRNA level.

Hepatocellular carcinoma (HCC) is a major global burden, ranking as the third leading cause of cancer-related mortality. HCC due to chronic hepatitis B virus (HBV) or C virus (HCV) infection has decreased due to universal vaccination for HBV and effective antiviral therapy for both HBV and HCV, but HCC related to metabolic dysfunction associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) is increasing. Biannual liver ultrasonography and serum α-fetoprotein are the primary surveillance tools for early HCC detection among high-risk patients (e.g., cirrhosis, chronic HBV). Alternative surveillance tools such as blood-based biomarker panels and abbreviated MRIs are being investigated. Multiphasic CT or MRI is the standard for HCC diagnosis, but histological confirmation should be considered, especially when inconclusive findings are seen on cross-sectional imaging. Staging and treatment decisions are complex and should be made in multidisciplinary settings, incorporating multiple factors including tumor burden, degree of liver dysfunction, patient performance status, available expertise, and patient preferences. Early-stage HCC is best treated with curative options such as resection, ablation, or transplantation. For intermediate-stage disease, locoregional therapies are primarily recommended although systemic therapies may be preferred for patients with large intrahepatic tumor burden. In advanced-stage disease immune checkpoint inhibitor (ICI)-based therapy is the preferred treatment regimen. In this review article, we discuss the recent global epidemiology, risk factors, and HCC care continuum encompassing surveillance, diagnosis, staging, and treatments.

The creation of self-organizing liver organoids represents a significant, although modest, step toward addressing the ongoing organ shortage crisis in allogeneic liver transplantation. However, researchers have recognized that achieving a fully functional whole liver remains a distant goal, and the original ambition of organoid-based liver generation has been temporarily put on hold. Instead, liver organoids have revolutionized the field of hepatology, extending their influence into various domains of precision and molecular medicine. These 3D cultures, capable of replicating key features of human liver function and pathology, have opened new avenues for human-relevant disease modeling, CRISPR gene editing, and high-throughput drug screening that animal models cannot accomplish. Moreover, advancements in creating more complex systems have led to the development of multicellular assembloids, dynamic organoid-on-chip systems, and 3D bioprinting technologies. These innovations enable detailed modeling of liver microenvironments and complex tissue interactions. Progress in regenerative medicine and transplantation applications continues to evolve and strives to overcome the obstacles of biocompatibility and tumorigenecity. In this review, we examine the current state of liver organoid research by offering insights into where the field currently stands, and the pivotal developments that are driving its shaping its future.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global epidemic. MASLD has a strong genetic component, and a common missense variant (rs2642438) in the mitochondrial amidoxime-reducing component 1 (MARC1) gene confers protection against its onset and severity. However, there are contrasting results regarding the mechanisms entangling this protection.

Methods: We downregulated MARC1 in primary human hepatocytes (PHH) using short interfering RNA (siRNA). Neutral lipid content was measured by Oil-Red O staining and fatty acid oxidation measured using radiolabeled tracers. RNA-seq and proteomic analysis using LC-MS were also performed. Additionally, we analyzed data from 239,075 participants from the UK Biobank.

Results: Downregulation of MARC1 reduced neutral lipid content in PHH homozygous for the wild type (p.A165, risk) but not for the mutant (p.T165, protective) protein. Experimental results demonstrated that this reduction was mediated by an increased fatty acid utilization by beta-oxidation. Consistently, 3-hydroxybutyrate levels, a by-product of β-oxidation, were higher in carriers of the rs2642438 minor allele from the UK Biobank indicating higher β-oxidation in these individuals. Moreover, downregulation of MARC1 p.A165 variant resulted in a more favorable phenotype by reducing ferroptosis and reactive oxygen species levels.

Conclusions: MARC1 downregulation in carriers of the risk allele results in lower hepatocyte neutral lipids content due to higher β-oxidation, and upregulates beneficial pathways for cell survival.