Hepatology Communications最新文献

Background: Hepatocellular carcinoma (HCC) is a serious complication of Fontan-associated liver disease (FALD). However, data on its incidence, risk factors, and outcomes in this rare population are limited. We aimed to assess the incidence and predictors of HCC and evaluate the utility of surveillance in patients with FALD.

Methods: We conducted a retrospective cohort study on patients with FALD who were referred to our gastroenterology department. The cumulative incidence of HCC after FALD diagnosis was calculated, and multivariate analysis was used to identify independent risk factors. Overall survival after FALD diagnosis was compared between patients who developed HCC and those who did not.

Results: A total of 120 patients with FALD were followed up for a median period of 50.0 months. The cumulative incidence rates of HCC at 1, 2, and 3 years after FALD diagnosis were 0.9%, 2.7%, and 3.9%, respectively. Elevated alpha-fetoprotein (AFP) at FALD diagnosis was independently associated with HCC development (hazard ratio, 1.29; 95% confidence interval, 1.04-1.60; p=0.01). There was no significant difference in overall survival between patients with and without HCC in this cohort (log-rank test, p=0.50).

Conclusions: Patients with FALD face a non-negligible risk of developing HCC, thus supporting the need for surveillance. Elevated AFP levels at the time of FALD diagnosis may aid in risk stratification, which enables the targeted monitoring and early detection of HCC. Furthermore, routine surveillance contributes to the excellent prognosis of patients with FALD who develop HCC, thus making their prognosis comparable to that of patients without HCC.

Background: Anti-Mullerian hormone (AMH) is produced by ovarian follicles and is clinically reflective of reproductive aging. AMH has been associated with the severity of steatohepatitis in those with known metabolic dysfunction-associated steatotic liver disease (MASLD), although its association with prevalent MASLD is not known.

Methods: Using the multicenter longitudinal Coronary Artery Risk Development in Young Adults cohort, we evaluated the association of low AMH levels in healthy young women with subsequent MASLD in midlife, assessed by CT scan 10 years later. Alternate causes of steatosis were excluded, and multivariable logistic regression was adjusted for confounding metabolic risk factors.

Results: Among 585 eligible participants, 50 (8.5%) had MASLD. MASLD was more common among participants with low AMH (14% vs. 7%, p=0.03). Adjusted for baseline covariates, low AMH was associated with 2.50-fold higher odds of prevalent MASLD (95% CI: 1.18-5.28, p=0.02). The findings persisted after adjusting for both baseline and change in metabolic profiles (OR: 2.36, 95% CI: 1.05-5.27, p=0.04). The relationship between low AMH and MASLD was not mediated by body mass index (p=0.82) or visceral adipose tissue volume (p=0.14).

Conclusions: Low AMH levels in reproductive-aged women conferred a more than 2-fold higher odds of prevalent MASLD in midlife, independent of metabolic comorbidities. AMH levels may therefore serve as a valuable marker of MASLD risk in young women.

Cholangiocarcinoma (CCA), a subset of biliary tract cancers, remains a therapeutically challenging malignancy with poor long-term survival despite recent advances in targeted therapies. Recent data suggest that IDH1-mutated CCA exhibits unique mitochondrial vulnerabilities. In this report, we discuss the emerging role of mitochondrial metabolism as a target in IDH1-mutated CCA, including preclinical evidence supporting the inhibition of the tricarboxylic acid (TCA) cycle, glutamine metabolism, and potential combination approaches. We aim to highlight the growing need to integrate mitochondrial-targeted strategies into future clinical investigations.

Background: Hepatocellular carcinoma (HCC) develops from chronic inflammatory conditions to malignancy, with the immune microenvironment playing a significant role in this progression. However, the changes in the dynamic immune microenvironment during the transition from hepatitis to HCC remain poorly understood. Systematic analysis of stage-specific immune microenvironment alterations is essential for identifying therapeutic targets and creating precision strategies for HCC.

Methods: Using single-cell RNA sequencing (scRNA-seq), we created dynamic transcriptome maps of the immune microenvironment across healthy liver, hepatitis, cirrhosis, and HCC stages. Cell-cell communication, trajectory, and enrichment analyses were utilized to characterize relationships between clusters. TCGA-LIHC data were used to validate gene expression and its prognosis. The spatial distribution of ligand-receptor complexes in HCC was confirmed by spatial transcriptomics and multiplexed immunofluorescence. The effects of the tumor microenvironment on cancer cell behavior were examined using co-immunoprecipitation and cell co-culture assays. Finally, the impact of the immune microenvironment on in vivo tumor progression was evaluated using a mouse transplantation model.

Results: We identified specific immune cell clusters across HCC progression and revealed significant correlations between the abundance of immune cells (macrophages, B cells)and fibroblasts with disease severity. Crosstalk between SPP1+ macrophages and ITGA5+ fibroblasts was observed explicitly in HCC. In vitro and in vivo data demonstrated that the SPP1-ITGA5 interaction triggered the secretion of MMP2 by fibroblasts, thereby promoting malignant progression in HCC.

Conclusions: We present a dynamic transcriptional profile of immune microenvironment evolution during HCC development, aiding in the refinement of diagnostics and the optimization of therapy strategies.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with chronic hepatitis B (CHB) accounting for more than half of the cases. Regular surveillance, including abdominal ultrasonography with alpha-fetoprotein testing every 6 months, enables early tumor detection and curative treatment; however, current guideline recommendations based mainly on age, sex, and race/ethnicity insufficiently capture individual risk variation, particularly among patients with CHB who do not have cirrhosis. In addition, real-world adherence to HCC surveillance is suboptimal-fewer than 40% of eligible patients receive surveillance at the recommended 6-month intervals. To improve both efficiency and impact, surveillance resources should be reallocated to patients whose estimated risk exceeds the cost-effective surveillance threshold. Recent studies support biomarker-based risk stratification as a more precise approach. For example, in untreated CHB, HBeAg-negative patients meeting inactive disease criteria with HBsAg <100 IU/mL have an annual HCC incidence below the 0.2% cost-effectiveness threshold, suggesting that routine surveillance may be unnecessary. In antiviral-treated CHB, models such as PAGE-B and its derivatives can accurately identify low-risk patients who may safely forgo HCC surveillance. Conversely, for patients at extremely high risk, including those with cirrhosis, intensified strategies-such as abbreviated MRI or combined biomarker algorithms-may enhance early detection. Collectively, these findings support a transition from a categorical, one-size-fits-all approach toward a precision surveillance paradigm that tailors the need for and intensity of HCC surveillance to biomarker-defined risk, thereby optimizing resource use, improving adherence, and maximizing clinical benefit. Nevertheless, further large-scale, prospective studies across diverse populations are needed to validate biomarker thresholds and confirm the long-term safety of exempting very-low-risk patients with CHB from HCC surveillance.

Background: Resmetirom is approved for MASH F2-F3 fibrosis. Health-related quality of life (HRQL) was assessed in patients with MASH treated with resmetirom.

Methods: Patients with MASH enrolled in MAESTRO-NAFLD-1 (NCT04197479) and the 52-week open-label extension study (year 2). HRQL was assessed using LDQoL and CLDQ-NAFLD. Magnetic resonance imaging-proton density fat fraction (MRI-PDFF) response definition for early MASH: a decrease ≥30% from baseline; MASH cirrhosis ≥20% decrease (if baseline MRI-PDFF >5%).

Results: MAESTRO-NAFLD-1 included 180 patients with MASH cirrhosis and 1143 with early MASH [baseline MRI-PDFF ≥8%, vibration-controlled transient elastography (VCTE) ≥5.5 kPa <8.5 kPa] treated with 80 mg or 100 mg resmetirom or placebo or 100 mg open-label resmetirom. Baseline HRQL for MASH cirrhosis was significantly lower (up to -15% of score range) for all 6 domains of CLDQ-NAFLD and 13/17 domains of LDQoL (p<0.05). MASH cirrhosis, by week 24 of resmetirom treatment year 1, had improvements in Worry (CLDQ-NAFLD) and Health Distress (LDQoL) up to +4% of score range, sustained through week 52 and throughout year 2 (day 1, week 12, week 28) (p<0.05). Cirrhotic patients with MRI-PDFF response by year 1 week 52, improved in Stigma score (LDQoL): mean change (+3.9 vs. -4.2, p=0.042). Early MASH receiving resmetirom experienced improvement in: Abdominal and Worry (CLDQ-NAFLD) and Health Distress (LDQoL) (up to +5% of score range size); no similar improvements observed in placebo (all p>0.05). Early MASH patients with MRI-PDFF response experienced Abdominal and Worry score (up to +6%) improvements-greater than placebo or nonresponders.

Conclusions: Early MASH and MASH cirrhosis treated with resmetirom experience improvement in some disease-specific HRQL scores.

Background: Despite major advances in surgical and medical management, only one-third of pediatric liver transplant (LT) recipients remain morbidity-free at 10 years. The Society of Pediatric Liver Transplantation (SPLIT) published a research agenda over 10 years ago, and much progress has been made since then. An updated consensus-driven SPLIT research agenda could guide future research and funding priorities. We aimed to identify and prioritize key research needs across the continuum of pediatric LT care using a modified Delphi consensus approach.

Methods: We conducted a three-round modified Delphi process among SPLIT members. In round 1, participants submitted open-ended research priorities. In round 2, the Steering Committee synthesized these into 156 unique statements for rating. The third and final round included revision and rerating of 42 statements. Consensus was defined as a median importance rating ≥7 on a 9-point Likert scale.

Results: Sixty-nine multidisciplinary experts participated in round 1, with <30% attrition across rounds. The panel identified 46 high-priority research topics, organized into 7 domains: (1) end-stage disease and waitlist management; (2) transplant access, allocation, and organ utilization; (3) perioperative management; (4) immunosuppression management; (5) transplant complications; (6) long-term health and transition to adulthood; and (7) special populations. Highest-ranked research priorities included (1) developing an updated LT waitlist allocation scoring tool, (2) identifying novel biomarkers to guide immunosuppression minimization/withdrawal, and (3) developing new organ preservation strategies to increase the availability of high-quality organs for pediatric LT candidates.

Conclusions: SPLIT members identified 46 consensus research priorities that define the next frontier of pediatric LT research and provide a roadmap for investigators, funders, and health systems to improve survival and lifelong health in children after LT.

Background: Myosin 5b (Myo5b) is a motor protein critical for trafficking proteins to the apical surface of intestinal epithelial cells. Inactivating mutations in MYO5B cause microvillus inclusion disease (MVID), a congenital diarrhea disorder that often leads to liver cholestasis. While Myo5b's role in the intestine is well characterized, its function in the liver remains unclear.

Methods and results: To define the hepatic consequences of Myo5b loss, we analyzed germline Myo5b knockout (KO) mice. Bulk RNAseq of KO livers revealed significant transcriptomic alterations, notably downregulation of genes linked to cell proliferation. Immunostaining confirmed reduced Ki67, phospho-histone H3, and cyclin D1 expression, along with impaired growth of liver organoids in Myo5b-deficient mice. Histology and lipid staining showed steatosis and enlarged lipid droplets, with gene signatures favoring lipogenesis and ketogenesis in mice lacking Myo5b. Myo5b KO livers also displayed disrupted zonated gene expression and loss of zone 1 and zone 3 markers. Bile acid profiling revealed reduced hepatic bile acid levels, decreased expression of classical pathway genes (Cyp7a1, Cyp7b1), and compensatory upregulation of Cyp27a1. In the ileum, we observed mislocalization of the apical bile acid transporter ASBT and decreased levels of basolateral OSTβ, leading to impaired enterohepatic recycling and increased luminal bile acids.

Conclusions: These findings reveal a previously unrecognized role for Myo5b in liver proliferation, metabolic zonation, and bile acid homeostasis, highlighting its importance in maintaining hepatobiliary function.

Background: Predicting liver-related events (LREs) in stable cirrhosis is crucial; however, traditional scoring methods perform poorly. Ammonia, due to its pathophysiological integration, may prognosticate LRE. This study tests the hypothesis that hyperammonemia can predict LRE and evaluates the AMMON-OHE score in a prospective cohort.

Methods: A total of 280 patients with cirrhosis were prospectively enrolled and followed until LRE, liver transplant, or death. Ammonia was measured at enrollment and periodically, along with other parameters. LRE at 1 year was defined as hospitalization for ascites, variceal bleeding, hepatic encephalopathy, or bacterial infection. AMN ≥ULN was calculated by adjusting ammonia to the lab's upper normal limit. Cox regression and time-dependent analyses were performed. AMMON-OHE was validated using TRIPOD+AI and decision curve analysis.

Results: Most patients were male (60.7%), with a mean age of 66.1±10.3 years. MASLD was the commonest etiology (43.7%). Median CTP and MELD scores were 6 (IQR: 5-7) and 8 (IQR: 6-11). Overall, 60 (21.4%) developed LRE at 1 year, and 23 (8.2%) died. In multivariable analysis, AMN ≥ULN was an independent predictor of LRE (HR: 4.92; 95% CI: 2.80-8.64). The AMMON-OHE score predicted LRE with a time-dependent AUROC of 0.859 (CI: 0.810-0.907), outperforming MELD (p=0.014) but similar to CTP (p=NS). The AMMON-OHE score underestimated the risk of LRE in our cohort.

Conclusions: AMN ≥ULN in stable outpatients with cirrhosis can predict LRE. Although the AMMON-OHE score has a high AUROC, it underestimates the risk of LRE in this cohort.