Hepatology Communications最新文献

Background: Dietary interventions are key for managing metabolic dysfunction-associated steatotic liver disease (MASLD), yet optimal diets and the role of PNPLA3 in modulating response to diet remain unclear. We evaluated the efficacy of a Mediterranean diet (MD) versus a low-fat diet (LFD) on hepatic fat and fibrosis, assessing interactions with PNPLA3 genotype.

Methods: Two hundred fifty adults with MASLD with BMI ≥25 kg/m2 were randomized to a 12-week moderately hypocaloric MD or LFD intervention. Individuals with excess alcohol intake and other etiologies of steatosis were excluded. Subjects were genotyped for PNLPA3 single-nucleotide polymorphism. Anthropometric measures, blood tests, and liver assessments [controlled attenuation parameter (CAP) and liver stiffness measurement (LSM)] were conducted at baseline and follow-up. Essential food items were provided, and adherence was tracked using validated questionnaires. The primary outcome was CAP, analyzed using linear mixed models adjusted for age and metabolic syndrome.

Results: Both diets significantly reduced CAP, LSM, and body weight at follow-up, with no significant differences between groups. The mean difference between MD and LFD was -0.13 dB/m for CAP (p=0.976, 95% CI: -8.54, 8.28), -0.19 kPa for LSM (p=0.355, 95% CI: -0.58, 0.21), and 3.01 kg for weight (p=0.159, 95% CI: -7.21, 1.19). PNPLA3 genotype did not significantly interact with diet for CAP, LSM, or weight (p=0.286, p=0.464, p=0.622, respectively).

Conclusions: Weight reduction achieved by MD and LFD is similarly efficient in steatosis and fibrosis reduction, while PNPLA3 genotype does not affect the response to diet. Further studies investigating the impact of diet and nutrigenetics on liver-related outcomes are warranted.

Background: Group-based, telehealth behavioral interventions may be efficient, effective, and acceptable treatment modalities for patients with chronic liver diseases; however, pilot feasibility and patient satisfaction data are needed to justify efficacy trials. Given the poor quality of life, symptoms, and health risk factors, patients with chronic hepatitis C-associated liver disease (HCV-LD) may benefit from psychosocial interventions. A pilot feasibility study of a videoconferencing-delivered cognitive behavioral coping skills intervention ("VC-CBCS") was conducted to evaluate multiple indicators of feasibility, levels of patient satisfaction, and changes in patient-reported outcomes (PROs).

Methods: We pilot tested a 14-week, 90-minute VC-CBCS intervention by conducting a small randomized controlled trial. Thirty-two adults with HCV-LD and high stress/symptom levels were randomized to the protocolized VC-CBCS intervention (n=24) or standard of care (n=8), in 4 waves of 7-9 participants in 2020-2021.

Results: Based upon rates of approach to enrollment (60%), retention (84%), PRO data collection (99.4%), and session attendance (91%), a future efficacy trial appears highly feasible. Levels of participant satisfaction were encouraging for VC delivery, intervention content and structure, and group processes. Technological and behavioral issues were minor. Collection of in-home saliva testing was not feasible. Moderate to large pre-post-intervention effect sizes were observed for some mediators (perceived stress, coping, relaxation, self-efficacy, sleep hygiene), with some of these changes correlating with small to moderate improvements in mental health and symptoms (eg, depression, fatigue; effect size range: 0.23-0.47). No consistent patterns were evident between changes in eating and exercise behaviors and PROs.

Conclusions: A group-based VC-CBCS intervention appears feasible and may address unmet psychosocial needs in patients living with chronic liver disease.

Background: Hepatoblastoma is the most prevalent liver cancer in children. Immunotherapy targeting immune checkpoint molecules has become pivotal in various cancer treatments. However, the clinical significance of immune checkpoint ligands in hepatoblastoma remains largely unclear due to various challenges. This study sought to first characterize the expression profile of the immune checkpoint ligand CD276 in hepatoblastoma and assess its potential as a predictor of malignant characteristics and regulator of neutrophil infiltration.

Methods: Univariable and multivariable logistic regression analyses were performed to evaluate the clinical significance of immune checkpoint ligands in the bulk RNA-seq dataset and develop a novel predictive model for malignancy. Furthermore, single-cell RNA sequencing (scRNA-seq), immunohistochemistry (IHC), deconvolution analysis, and correlation analysis were employed to characterize the expression pattern of CD276 and explore its influence on the tumor immune microenvironment.

Results: The bulk RNA-seq analysis revealed CD276 transcript levels were significantly elevated in hepatoblastoma tissues, especially in patients with more aggressive malignant phenotypes. Furthermore, we developed a predictive model based on a risk score and constructed a user-friendly nomogram to predict patient metastasis by integrating CD276 levels with clinical features. Both scRNA-seq and multiplex immunohistochemistry (mIHC) analyses confirmed that CD276 is highly expressed, predominantly in cancer-associated fibroblasts. Our results also demonstrated that CD276 levels correlate with immune infiltration in hepatoblastoma, and that CD276 regulates CXCL2 to modulate neutrophil infiltration, suggesting a potential mechanism underlying the role of CD276 in hepatoblastoma malignancy. In addition, we validated that CD276 in cancer-associated fibroblasts promotes hepatoblastoma growth in mice.

Conclusions: Our findings highlight the critical role of CD276 in hepatoblastoma malignancy, potentially providing novel insights and therapeutic targets for the development of combinatorial immunotherapy strategies for this disease.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and a leading cause of cancer-related deaths globally. Chronic liver disease (CLD), primarily due to viral hepatitis, alcohol use, and metabolic dysfunction-associated steatotic liver disease with steatohepatitis (MASLD/MASH), remains the major risk factor for HCC development. Chemoprevention, the use of medications or supplements to prevent or delay cancer, offers a compelling strategy to reduce HCC incidence, especially during the extended latency period between CLD onset and HCC progression. This review evaluates the current evidence for chemopreventive strategies for HCC, including immunizations, pharmacologic therapies, and dietary supplements.

Background: Large epidemiologic studies of autoimmune hepatitis (AIH) in the United States are limited. None have reported prevalence trends over time. This contemporary study examines AIH prevalence and demographic trends over 10 years in a community-based integrated healthcare system in Northern California. We further assessed whether prevalence trends differed by AIH ascertainment approach.

Methods: This retrospective study used data from adults aged ≥18 years in Kaiser Permanente Northern California (2010-2019). AIH was identified by coded diagnosis and confirmed with diagnostic testing (laboratory and/or liver biopsy) and treatment response. Annual AIH prevalence was estimated and stratified by age, sex, and race/ethnicity.

Results: Among 1129 patients with confirmed AIH, 80% were female, 44% non-Hispanic White, 26% Hispanic, 16% Asian/Pacific Islander, and 9% Black. In all, 76% of patients on AIH treatment demonstrated treatment response at 6 months. AIH prevalence (per 100,000 adults) increased from 9.1 in 2010 to 18.8 in 2019 (p<0.0001). Prevalence among older adults (≥75 years) quadrupled from 10.1 to 43.7 per 100,000. Prevalence rose among all ethnicities and in 2019 was highest for Black (28.9) and Hispanic populations (25.2) per 100,000.

Conclusions: AIH prevalence doubled over 10 years in a large healthcare system, with pronounced increases among older populations. Prevalence was highest among Black and Hispanic adults. Further studies should examine demographic differences in the clinical course of AIH, including response to therapy, adverse events, and outcomes.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in the United States and worldwide. HCC screening among patients at elevated risk is associated with improved early detection and overall survival, but current ultrasound-based screening strategies are challenged by low adherence and suboptimal sensitivity. Blood-based screening tests have the potential to enhance adherence and improve early-stage HCC detection if they can demonstrate favorable performance compared with ultrasound-based screening. Here we present the design and rationale for ALTUS (Alternative to Ultrasound), a prospective, longitudinal, multicenter study in the United States to investigate the performance of the multi-target HCC blood test (mt-HBT) for the detection of HCC in a screening population.

Methods: Adults with liver cirrhosis or chronic hepatitis B infection will be enrolled to undergo standard-of-care screening imaging and concurrent blood collection for the mt-HBT. All participants will undergo contrast-enhanced CT or MRI imaging with central radiology LI-RADS assessment as the reference method to determine HCC status. Participants without an identified malignancy will undergo a second screening visit and blood collection, and longitudinal clinical and imaging data will be collected up to 18 months from enrollment. The primary study objectives are to demonstrate that the mt-HBT is non-inferior to ultrasound for early-stage HCC sensitivity and to assess mt-HBT HCC specificity. The secondary objective is to assess mt-HBT overall sensitivity.

Results: ALTUS is in progress with readout of the primary analysis expected in 2025.

Conclusions: This prospective head-to-head comparison of the mt-HBT versus ultrasound will provide novel data regarding the performance and utility of the mt-HBT for HCC screening.

Background: The liver plays a critical role in metabolism and immune function, yet the contributions of its heterogeneous cell types to these processes remain unclear. While most liver studies focus on adults, pediatric liver diseases often present differently, underscoring the need for age-specific research.

Methods: To better understand cellular drivers of childhood liver diseases, we generated single-cell RNA-sequencing maps of the normal pediatric liver and used this map to examine disease-related populations in biopsies from pediatric patients with intestinal failure-associated liver disease (IFALD).

Results: The normal pediatric liver map consists of 42,660 cells from 9 donors under 17 years of age. Compared with normal adult liver (26,372 cells; 7 donors, age 26-69), pediatric livers exhibited differences in myeloid populations. Specifically, pediatric Kupffer-like cells (MARCO+C1QA+VSIG4+) exhibited higher expression of immune activation genes, including CCL4, CCL3, and IL1B. In vitro stimulation confirmed more IL-1β-secreting myeloid cells in pediatric versus adult livers, supporting these findings. Using the pediatric atlas as a reference, we analyzed 3 IFALD biopsies (11,969 cells; 3 donors, under 9 y of age) and identified increased expression of fibrosis-associated genes (eg, LY96) in Kupffer-like cells. In addition, mesenchymal cells in IFALD showed fibrotic gene modules resembling adult liver cells more than healthy pediatric cells. These signatures, undetectable when comparing IFALD to adult liver alone, highlight the value of a pediatric map.

Conclusion: Taken together, our healthy pediatric liver atlas reveals distinct age-related signatures and provides a background against which to interpret pediatric liver disease data.

Background: Primary hepatocytes are commonly used in vitro to model liver metabolism, but prolonged culturing results in dedifferentiation and potentially limits the applicability of this model.

Methods: We characterized the transcriptome and proteome of full liver and primary hepatocytes as either freshly isolated cells or after 24 hours of 2D-culturing.

Results: We found that 2D-culturing for 24 hours changes more than 10,000 genes and 3000 proteins compared with freshly isolated cells, accompanied by a decrease in transcriptional heterogeneity and a loss of zonal markers. Moreover, there were changes in proteins associated with the extracellular matrix, in mitochondrial and ribosomal protein abundances, as well as an increase in the abundance of acute-phase response proteins.

Conclusion: Collectively, primary mouse hepatocytes in culture rewire the transcriptome and proteome, which may affect the utility of this model to study physiological and molecular mechanisms related to the liver. We developed the Shiny app "Hepamorphosis" (https://cbmr.ku.dk/research/resources/shiny-apps/), which allows users to explore RNA/protein correlations, zonation profiles, and cell-type-specific transcription in full liver and cultured hepatocytes.

Background: Osteoporosis is a common complication in patients with primary biliary cholangitis (PBC). This study aimed to compare the efficacy and safety of denosumab and zoledronic acid (ZOL) in treating osteoporosis in PBC patients.

Methods: This multicenter, randomized, open-label trial enrolled Japanese patients with PBC and osteoporosis. Patients were randomized to receive either subcutaneous denosumab 60 mg every 6 months (denosumab group) or i.v. zoledronic acid 5 mg yearly (ZOL group). The primary endpoint was the mean percent change in bone mineral density (BMD) at the lumbar spine and total hip from baseline to 12 months.

Results: Of 47 enrolled patients, 41 (87.2%) completed the study (denosumab: n=21; ZOL: n=20). At 12 months, lumbar spine BMD increased by 7.5% in the denosumab group and 6.4% in the ZOL group, demonstrating the non-inferiority of denosumab (95% CI: -1.6% to 3.8%). Although the total hip BMD increased more in the denosumab group than in the ZOL group (5.0% vs. 2.6%, p<0.01), the difference did not meet the predefined non-inferiority margin (95% CI: -1.3% to 6.2%). Serum ALP to upper limit of normal ratio and bone turnover markers significantly decreased in both groups; however, the rates of change were not significantly different between them. The incidence of adverse events was significantly lower in the denosumab group compared with the ZOL group (14.3% vs. 50.0%, p=0.013).

Conclusions: Denosumab is a safe and effective treatment option for osteoporosis in patients with PBC.