Hepatology Communications最新文献

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: HCC is a notably immunosuppressive malignancy with limited therapeutic options and poor prognosis. Macrophages, as major immune cell populations within the tumor microenvironment, significantly influence disease progression and therapy efficacy. We aim to identify pivotal macrophage subsets associated with HCC progression and resistance to immunotherapy.

Methods: Immunotherapy-associated macrophage-specific marker genes were identified by single-cell RNA-sequencing analysis and transcriptome analysis. The clinical relevance of macrophages with heme oxygenase 1 (HMOX1) positive was assessed in HCC patients by immunofluorescence. The immune microenvironment of HCC and the functional phenotype of HMOX1+ macrophages were explored using cytometry by time-of-flight (CyTOF).

Results: Single-cell RNA-sequencing analyses revealed that HMOX1 was predominantly expressed in intratumoral macrophages within the HCC microenvironment. Intratumoral HMOX1+ macrophages abundance was associated with worse prognosis and immunotherapy efficacy in patients with HCC. CyTOF analysis showed that the HCC microenvironment with high infiltration of HMOX1+ macrophages was characterized by high infiltration of CD4+ regulatory T cells (Tregs) and high expression of programmed death-1 (PD-1) in CD8+ T cells. Besides, HMOX1+ macrophages exhibited an immunosuppressive functional state. Pharmacological inhibition of HMOX1 by Znpp enhanced the therapeutic efficacy of anti-PD-1 antibody in the HCC mouse model.

Conclusions: Macrophage-specific HMOX1 serves as a novel biomarker for predicting the efficacy of immunotherapy, and targeting HMOX1 has the potential to enhance the efficacy of anti-PD-1 therapy in HCC patients.

Background: Addiction commonly co-occurs with liver disease; however, few patients receive addiction treatment. Although integrated models are emerging, hepatology clinician perspectives on the implementation of alcohol (AUD), opioid (OUD), and tobacco (TUD) use disorder treatment within hepatology clinics are rarely evaluated. We assessed readiness and associated barriers and facilitators to providing treatment of AUD, OUD, and TUD in hepatology clinics.

Methods: A mixed-methods formative evaluation, including a survey and in-depth semi-structured interviews of hepatology clinicians grounded within the Promoting Action on Research Implementation in Health Services implementation science framework, was conducted at a large urban academic medical center from July to September 2022. Practice patterns, attitudes, readiness, barriers, and facilitators toward treating AUD, OUD, and TUD were evaluated.

Results: Among 50 survey respondents (94% response rate; median age 41, 56% female), 35 completed interviews. Overall, 84%, 38%, and 49% routinely asked patients about alcohol, opioid, and tobacco use, respectively. Furthermore, 86%, 52%, and 42% considered it very important to provide AUD, OUD, and TUD treatment within hepatology clinics, respectively. Among prescribers, 41%, 11%, and 34% felt ready to provide medications for AUD, OUD, and TUD, respectively. In addition, 50% preferred hepatology clinicians directly provide AUD treatment, compared with 26% and 38% for OUD and TUD, respectively. Themes emerging from interviews included knowledge gaps regarding addiction treatments, practical concerns such as time constraints, and the need for flexible care models, new clinical tools, multidisciplinary resources, and training to facilitate addiction treatment.

Conclusions: Hepatology clinicians prioritize providing AUD treatment; however, less than half of prescribers feel ready to provide medications. Initiatives to incorporate addiction treatments within hepatology clinics will require tailored approaches that address knowledge gaps and contextual issues.

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: 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.

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.