Hepatology Research最新文献

Aim: Fontan surgery improves outcomes in univentricular heart disease; however, some patients develop severe Fontan-associated liver disease (FALD). Even during adolescence, hepatocellular carcinoma occurs in some patients with FALD, although the mechanism remains unclear. In this study, we conducted proteomic analyses of liver tissues obtained using laser capture microdissection (LCM) and serum samples to investigate FALD-related peripheral liver oncogenic factors and explore potential biomarkers.

Methods: Ten-week-old mice underwent sham surgery, and age-matched mice underwent partial ligation of the suprahepatic inferior vena cava as a congestive hepatopathy (CH) model. Control liver (CL) and serum were collected from the control models, whereas peripheral congestive liver (PCL) and serum were obtained from the CH models. LCM-isolated liver and serum samples were subjected to qualitative and quantitative proteomic analyses. Differentially expressed proteins (DEPs) were identified by mass spectrometry.

Results: We identified 3904 hepatic proteins and 2947 serum proteins. Cancer-related proteins were upregulated in PCL, whereas hepatoprotective proteins were reduced compared with those in CL. Enrichment analysis revealed the upregulation of oncogenic signaling pathways in PCL. Twenty DEPs (e.g., transforming growth factor-beta-induced protein ig-h3, complement C1q subcomponent subunit A, and Dickkopf-related protein 3) were concurrently increased in PCL and serum of the CH models.

Conclusions: PCL upregulated oncogenic proteins and activated oncogenic signaling pathways. DEPs detectable in the liver and serum indicate potential FALD biomarkers. These findings offer insights into the pathophysiology of FALD and hepatocarcinogenesis and support the development of novel diagnostic and therapeutic strategies.

Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by the presence of hepatic steatosis and at least one of five cardiometabolic risk factors, leading to the development of cardiovascular-kidney-metabolic syndrome including chronic kidney disease (CKD). However, the impact of heterogeneity of MASLD on new onset of CKD remains unclear. We explored the relationship between subgroups of MASLD divided by using a machine learning (ML) model called supervised clustering and the development of CKD during a 10-year follow-up period.

Methods: A total of 12,168 Japanese subjects (men/women: 7927/4,241 and mean age: 48 years) who received annual health examinations including abdominal ultrasonography were recruited.

Results: Using the supervised clustering by SHapley Additive exPlanations (SHAP) and uniform manifold approximation and projection (UMAP) for steatotic liver diseases, 10 subclusters including 3 distinctive subgroups of MASLD were detected by a Gaussian mixture model. Kaplan-Meier survival curve analysis showed a significant difference in the cumulative incidence for new onset of CKD among the 3 subgroups of MASLD. Among the MASLD subclusters, an obese subgroup with an atherogenic profile of serum lipids as well as high levels of fatty liver index and uric acid was the worst subcluster for the development of CKD in individuals with MASLD.

Conclusions: The supervised clustering of MASLD using a SHAP-converted matrix and UMAP reveals phenotypically distinct subpopulations that improved risk stratification for new onset of CKD. An obese subgroup with atherogenic lipid profiles and hyperuricemia in MASLD is associated with an increased risk for the development of CKD.

Background and aim: Anti-vascular endothelial growth factor (VEGF) agents are widely used for hepatocellular carcinoma (HCC); inhibition of VEGF-mediated liver regeneration may compromise hepatic reserve. We investigated the impact of anti-VEGF therapy on liver function and risk factors for deterioration of albumin-bilirubin (ALBI) score during the treatment.

Methods: We retrospectively analyzed 223 patients with HCC who received systemic therapy for more than 10 weeks at Kindai University Hospital between November 2013 and May 2024 with lenvatinib (n = 94), atezolizumab plus bevacizumab (n = 87), or pure immunotherapy without anti-VEGF agents (n = 42). Liver function was monitored for ≥ 24 weeks using ALBI score and percentage changes from baseline in serum albumin, bilirubin, and ammonia levels (ΔALB, ΔBil, and ΔNH3). Multivariable logistic regression identified risk factors for the worsening of ALBI ≥ 0.4.

Results: ALBI scores worsened significantly from week 2 with lenvatinib and from week 8 with atezolizumab plus bevacizumab, whereas pure immunotherapy showed no significant change. Ammonia elevations were also significant with lenvatinib. In multivariable analyses, older age among lenvatinib cohort and higher baseline alanine aminotransferase (ALT) among atezolizumab plus bevacizumab cohort were independently associated with ALBI deterioration at 24 weeks (p = 0.0187 and p = 0.0307, respectively).

Conclusion: Treatment that include anti-VEGF agents can substantially worsen ALBI scores and lenvatinib additionally increases ammonia levels. Older age (lenvatinib) and elevated baseline ALT (atezolizumab plus bevacizumab) are risk factors for hepatic functional decline. Careful patient selection and management tailored to age and baseline inflammatory markers is required to minimize adverse liver outcomes and preserve treatment continuity.

Aim: At-risk metabolic dysfunction-associated steatohepatitis (MASH), characterized by significant activity and fibrosis, increases the risk of liver complications. Liver stiffness measurement (LSM), commonly used to detect significant fibrosis, has limitations in terms of accessibility and performance in certain populations. We aimed to develop a simple-to-use machine learning (ML) model to identify at-risk MASH without LSM.

Methods: We analyzed 884 patients with histologically confirmed metabolic dysfunction-associated steatotic liver disease from a nationwide multicenter cohort, divided into derivation (80%) and validation (20%) sets. Multiple ML algorithms (random forest [RF], logistic regression [LR], gradient boosting [GB], support vector machine [SVM], and deep learning [DL]) were trained using variables including age, sex, body mass index, hematological/biochemical parameters, and comorbidities.

Results: In the validation cohort, the RF model showed superior discriminatory ability for predicting at-risk MASH (AUROC: 0.8405) compared to LR (0.7729), GB (0.8252), SVM (0.7816), and DL (0.7422). Using only seven routine clinical parameters, the RF model outperformed the fibrosis-4 index (AUROC: 0.7329; p < 0.001) and LSM (AUROC: 0.7428; p = 0.01) and showed comparable performance to the FibroScan-aspartate aminotransferase score (AUROC: 0.7914; p = 0.09) in the validation cohort. This RF model, termed the STEALTH-ARMS model, was implemented as an online application to enable patient-based individual risk assessment.

Conclusions: The RF-based ML model demonstrated high accuracy in identifying at-risk MASH using only seven routine clinical data, offering a highly accurate, noninvasive, and cost-effective alternative to LSM-based methods. This approach holds promise for broader clinical applications, particularly in resource-limited settings.

Trial registration: UMIN-CTR 000049068.

Liver transplantation for patients with hemophilia and HIV/HCV coinfection presents unique challenges due to the complexity of perioperative management, including coagulation disorders, drug interactions, and potential complications such as pulmonary hypertension. We report a successful case of brain-dead donor liver transplantation in a patient with hemophilia B and HIV/HCV coinfection, complicated by pulmonary hypertension. The patient, a man in his 50s, acquired multidrug-resistant HIV and HCV in childhood from contaminated blood products. Despite successful HCV eradication, liver function declined, and he was listed for transplantation. Preoperative evaluation revealed pulmonary arterial hypertension, which improved with sildenafil citrate, macitentan, and home oxygen therapy. Intraoperatively, coagulation was managed with factor IX supplementation, and circulation remained stable following reperfusion. Postoperatively, immunosuppression, antiretroviral therapy, and treatment for pulmonary hypertension were carefully coordinated to avoid drug interactions. Nitric oxide therapy was utilized to improve oxygenation. The patient was discharged on postoperative day 51 with normal liver function and good overall condition. This case underscores the importance of multidisciplinary collaboration and careful perioperative planning in achieving successful outcomes in liver transplantation for patients with complex comorbidities such as hemophilia, HIV/HCV coinfection, and pulmonary hypertension.

Aim: Reports on the effects of hepatitis C virus (HCV) clearance through direct-acting antiviral (DAA) administration after hepatocellular carcinoma (HCC) treatment on survival and recurrence rates in older patients remain limited. We examined the effects of DAA administration after HCC treatment in patients aged ≥ 75 years on survival and recurrence rates.

Methods: This present retrospective multicenter study included patients aged ≥ 75 years with HCV-related HCC who received DAA within 12 months after HCC treatment (DAA group) and patients without DAA for HCV-related HCC (non-DAA group). Cases were classified as Barcelona Clinic Liver Cancer stage A or 0, limiting treatment method to liver resection and radiofrequency ablation. Propensity score matching was carried out, and patient's prognoses were examined.

Results: After matching, each group included 43 patients. In the DAA and non-DAA groups, respectively, the 5-year overall survival rates were 76.3% and 49.1% (p = 0.024) whereas 5-year cumulative recurrence rates were 61.7% and 92.4% (p < 0.001). Cox proportional hazards model (reporting hazard ratio and 95% confidence interval) showed DAA use as significantly associated with overall survival (p = 0.03; 0.47; and 0.23-0.93) and recurrence (p = 0.002; 0.45; and 0.27-0.74). The 5-year median albumin-bilirubin score was -2.77 (DAA group, n = 16) and -2.36 (non-DAA group, n = 12) (p = 0.002). DAA group had fewer deaths due to liver disease than non-DAA group; however, the number of deaths due to nonliver diseases was almost same.

Conclusions: DAA improved hepatic reserve function and improved survival and recurrence rates after HCC treatment in patients aged ≥ 75 years and should be administered after assessing the status of comorbidities.