Hepatology最新文献

Background and aims: The human leukocyte antigen (HLA) locus is implicated in HCC among chronic HBV carriers. We investigated associations of HLA variants, amino acid polymorphisms, zygosity, and evolutionary divergence with HBV-related HCC in Han Chinese and explored biological mechanisms.

Approach and results: We examined the associations of HLA variants (imputed 4-digit classical alleles and amino acid polymorphisms), zygosity, and evolutionary divergence with HBV-related HCC in a discovery set (706 HBV-related HCC cases, 6197 chronic HBV carriers in Taiwan). Significant signals were validated in an independent set (636 cases, 560 controls in Qidong, Mainland China). We used logistic regression adjusted for sex, age, and top 10 genetic principal components, with a Bonferroni correction for multiple testing ( p <1.6×10 -4 ). We evaluated predicted peptide-binding affinities and control of viral load, viral population diversity, and inflammatory markers for significant signals. HLA-DQB1*03:01 was most significantly associated with HBV-related HCC in discovery and validation sets (OR meta-analysis =1.33, pmeta-analysis =2.6×10 -8 ). Three amino acids within the DQβ1 peptide-binding region, HLA-DQβ1Ala13, HLA-DQβ1Tyr26, and HLA-DQβ1Glu45, were positively associated with HCC. HLA-DQB1*03:01 was associated with lower binding affinity of HBV nucleocapsid antigen and higher HBV DNA load and serum soluble programmed cell death 1 (sPD-1) ( p <0.05). HLA-DQB1 heterozygosity was inversely associated with HCC independent of HLA-DQB1*03:01 ( pmeta-analysis =3.3×10 -3 ).

Conclusions: HLA-DQB1*03:01 and its 3 key amino acids are associated with an increased HBV-related HCC risk. This association may be explained by the low binding affinity to HBV antigen, resulting in poor control of viral load and increased inflammation, as evidenced by sPD-1 levels.

Background and aims: Metabolic dysfunction-associated steatohepatitis (MASH) and its related liver fibrosis represent a substantial public health burden with limited treatment options. Although MASH is associated with enhanced neutrophil infiltration in the liver, the mediators and mechanisms underlying neutrophil-driven progression of MASH and fibrosis remain largely unknown. This study aimed to investigate the role of neutrophil serine proteases neutrophil elastase (NE) and proteinase 3 (PR3) in the development of MASH and fibrosis.

Approach and results: Liver biopsies from 121 morbidly obese patients were recruited for analysis. NE -/- , PR3 -/- , microRNA-223 (miR-223) -/- mice and their wild-type controls were fed a choline-deficient, l -amino acid-defined, high-fat diet to induce MASH fibrosis. Bone marrow transplantation was performed to generate mice with miR-223 chimerism in bone marrow-derived cells. NE and PR3 content in the human liver with MASH and fibrosis was markedly increased in close association with histological features. Genetic ablation or adeno-associated virus-mediated inhibition of NE and PR3 substantially alleviated MASH and liver fibrosis in mice. A mechanistic study revealed that miR-223 suppressed neutrophilic NE and PR3 by targeting signal transducer and activator of transcription 3. MiR-223 deficiency augmented inflammation and fibrosis in mouse liver. Bone marrow transplantation-induced miR-223 chimerism significantly affected hepatic NE/PR3 content and the progression of MASH fibrosis in mice.

Conclusions: Our findings reveal that NE and PR3 are key factors triggering liver inflammation to potentiate the development of MASH and liver fibrosis, offering insight into the development of new therapeutic approaches that target NE and PR3.

Background and aims: This large-scale, population-based cohort study examined the associations between metabolic syndrome and cholangiocarcinoma risk, including its intrahepatic and extrahepatic forms.

Approach and results: A total of 4,932,211 adults aged ≥40 years participated in a government-initiated health checkup program (2012-2017), which collected lifestyle data, anthropometric measurements, and biochemical tests. Follow-up continued until 2021, with data linkage to National Cancer and Death Registries to ascertain the occurrence of cholangiocarcinoma and obtain vital status information. Fine and Gray models accounted for competing risks. During 35,879,371 person-years of follow-up, 6117 cholangiocarcinoma cases were identified, with an incidence rate of 17.05 (95% CI: 15.90-18.20) per 100,000 person-years. Individuals with metabolic syndrome had significantly higher incidences of both intrahepatic and extrahepatic cholangiocarcinoma ( p <0.0001). The multivariate-adjusted HR for cholangiocarcinoma among those with metabolic syndrome was 1.20 (1.14-1.27). Stratification analyses by age, sex, liver enzyme levels, and comorbidities consistently demonstrated an increased cholangiocarcinoma risk among individuals with metabolic syndrome. A dose-response relationship was observed, with a higher number of metabolic components correlating with an elevated cholangiocarcinoma risk, even after accounting for all-cause mortality as a competing risk. The adjusted subdistribution HRs ranged from 1.16 (95% CI: 1.02-1.32) for individuals with one metabolic component to 1.67 (95% CI: 1.45-1.94) for those with five ( p for trend <0.0001).

Conclusions: The positive association between metabolic syndrome and cholangiocarcinoma risk suggests that managing metabolic risk factors might reduce the occurrence of both intrahepatic and extrahepatic cholangiocarcinoma.

Background and aims: Immunotherapy has emerged as an effective treatment for advanced HCC. We aimed to investigate the real-world effectiveness of immunotherapy compared to lenvatinib in HCC.

Approach and results: From the TriNetX database, we used a target trial emulation framework and identified patients with HCC who received first-line treatment with immunotherapy (atezolizumab/bevacizumab or tremelimumab/durvalumab) or lenvatinib between or between August 2018 and December 2023. OS was compared using Kaplan-Meier analysis and Cox proportional hazards regression. After propensity score matching, 1203 patients were included in each group. Immunotherapy was associated with improved OS versus lenvatinib (median survival: 545 vs. 425 d; HR: 0.86, 95% CI: 0.76-0.97). Regarding treatment type, atezolizumab plus bevacizumab showed improved survival compared to lenvatinib (n=1070 in each group; HR: 0.87, 95% CI: 0.77-0.99), while the point estimate favored durvalumab plus tremelimumab versus lenvatinib (HR: 0.81, 95% CI: 0.59-1.12), though this difference was not statistically significant, likely due to small sample size. Regarding etiology, immunotherapy had improved OS compared to lenvatinib in viral hepatitis (n=510 in each group; HR: 0.74, 95% CI: 0.61-0.89) and alcohol-associated liver disease (n=190 in each group; HR: 0.65, 95% CI: 0.49-0.87), but not in metabolic dysfunction-associated steatotic liver diseases (n=156 in each group; HR: 0.96, 95% CI: 0.70-1.31).

Conclusions: In this real-world analysis, immunotherapy was associated with improved OS compared to lenvatinib in advanced HCC, with consistent benefit across most subgroups. These findings support the use of immunotherapy as a first-line treatment for advanced HCC.

Porto-sinusoidal vascular disorder (PSVD) is a rare liver disease. The pathophysiological mechanisms underlying the development of PSVD are unknown. Isolated cases of PSVD associated with gene mutations have been reported, but no overview is available. Therefore, we performed an extensive literature search to provide a comprehensive overview of gene mutations associated with PSVD. We identified 34 genes and 1 chromosomal abnormality associated with PSVD in the literature, and we describe here 1 additional gene mutation ( TBL1XR1 mutation, leading to Pierpont syndrome). These gene mutations are associated either with extrahepatic organ involvement as part of syndromes (Adams-Oliver, telomere biology disorders, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, immune deficiencies, cystic fibrosis, cystinosis, Williams-Beuren, Turner, Pierpont) or with isolated PSVD ( KCNN3 , DGUOK , FOPV , GIMAP5 , FCHSD1 , TRMT5 , HRG gene mutations). Most of the cases were revealed by signs or complications of portal hypertension. When analyzing the cell types in which these genes are expressed, we found that these genes are predominantly expressed in immune cells, suggesting that these cells may play a more important role in the development of PSVD than previously thought. In addition, pathway analyses suggested that there may be 2 types of PSVD associated with gene mutations: those resulting directly from morphogenetic abnormalities and those secondary to immune changes.

Background and aims: Frailty is strongly associated with mortality after liver transplantation. However, national guidelines discourage its use as a sole reason to decline a patient for liver transplantation, as some frail patients have acceptable outcomes. We aimed to develop a composite index, the Liver Transplant Comorbidity Index (LTCI), integrating frailty and other comorbidities, as a risk factor for longer-term (3-year) posttransplant mortality.

Approach and results: This 8-center prospective Functional Assessment in Liver Transplantation (FrAILT) Study included adult recipients of a primary deceased donor liver transplant from 2012 to 2022. Frailty was measured using the Liver Frailty Index (LFI ≥4.5=frail). Other candidate variables included demographics, laboratories, and comorbidities. Cox proportional hazards regression with best subset selection was used to identify risk factors of 3-year posttransplant death. The final model was selected based on Akaike Information Criterion and clinical pragmatism. Of 1472 liver transplant recipients, 290 (20%) were frail. Three-year posttransplant mortality was higher in frail versus non-frail patients (13% vs. 8%; p =0.03). The final LTCI included 5 variables: frailty, coronary artery disease, HCC, renal dysfunction, and diabetes. Three-year posttransplant mortality in low-risk, moderate-risk, and high-risk LTCI groups was 93%, 87%, and 80%, respectively. In multivariable analysis, after adjusting for donor factors (age and donation after circulatory death), both moderate-risk (HR: 2.23, 95% CI: 1.46-3.40; p <0.001) and high-risk (HR: 2.78, 95% CI: 1.67-4.64; p <0.001) status were associated with 3-year posttransplant mortality.

Conclusions: The LTCI, comprising 5 pretransplant clinical parameters, effectively identifies patients at increased risk of posttransplant mortality. By integrating frailty in the context of other comorbidities, the LTCI can help providers better weigh the relative transplant risks and benefits and standardize the selection of transplant candidates.

Background and aims: Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) prevent fibrosis progression in a preclinical model of steatotic liver disease. Our objective was to assess the impact of ACEi/ARB use on clinical outcomes in patients with metabolic dysfunction-associated steatotic liver diseases.

Approach and results: Using TriNetX, a nationwide database, we identified all patients with metabolic dysfunction-associated steatotic liver diseases from January 1, 2011, to December 31, 2019. Using a target trial emulation framework, ACEi/ARB users were matched with calcium channel blocker (CCB) users using propensity score matching (PSM). Patients were followed up to 10 years after the index date. Cox proportional hazards regression was used to determine the risk of mortality, major adverse liver outcomes, major adverse cardiac events, and incident cancers. Of the 35,988 eligible patients, 28,423 were ACEi/ARB users, and 7565 were CCB users. After PSM, 7238 pairs were well-balanced. ACEi/ARB use was associated with a significantly decreased mortality risk (HR: 0.59, 95% CI: 0.51-0.68). ACEi/ARB was associated with a significantly reduced risk of developing major adverse liver outcomes (HR: 0.70, 95% CI: 0.61-0.80), including ascites (HR: 0.78, 95% CI: 0.63-0.98) and HE (HR: 0.67, 95% CI: 0.57-0.78). ACEi/ARB use was also associated with a lower risk of major adverse cardiac events (HR: 0.82, 95% CI: 0.76-0.90) but not incident cancer (HR: 0.97, 95% CI: 0.86-1.10) compared with CCB.

Conclusions: ACEi/ARB use in patients with metabolic dysfunction-associated steatotic liver diseases was associated with a reduced risk of mortality, major adverse liver outcomes, and major adverse cardiac events compared with CCB use. A large prospective study is needed for external validation.