Hepatology Research最新文献

Background: There is a paucity of data regarding the efficacy and safety of lenvatinib as a second-line treatment following first-line combination immunotherapy with durvalumab and tremelimumab (Dur + Tre).

Methods: This retrospective multicenter study included 14 patients with unresectable hepatocellular carcinoma who received lenvatinib after progression on Dur + Tre therapy, conducted at five institutions, including Hiroshima University. In cases where the multidisciplinary team determined that concurrent transcatheter arterial chemoembolization (TACE) would be beneficial, on-demand TACE was administered concomitantly with lenvatinib. The therapeutic response and safety profile of lenvatinib were evaluated in all enrolled patients, including those who underwent TACE.

Results: The objective response rate (ORR), disease control rate (DCR), and median progression-free survival (PFS) for Dur + Tre and subsequent lenvatinib treatment were 14.3%/30.7%, 57.1%/61.5%, and 2.4/2.3 months, respectively. Five patients (35.7%) received combined lenvatinib and TACE therapy. Among these, one patient each with stable disease (SD) and progressive disease (PD) on Dur + Tre improved to partial response (PR) during lenvatinib therapy. Two patients (14.3%) remained on lenvatinib at the time of analysis. Six patients (42.9%) transitioned to subsequent lines of systemic therapy, all receiving atezolizumab combined with bevacizumab. Overall, five patients (35.7%) had died at the data cutoff, with a median overall survival (OS) of 18.4 months. Grade 3 or higher adverse events (AEs) were observed in 7 patients (50%) across both Dur + Tre and lenvatinib treatment phases.

Conclusions: Lenvatinib administered after progression on Dur + Tre demonstrates promising efficacy and an acceptable safety profile in patients who tolerate the therapy. The integration of TACE in suitable candidates warrants further exploration, and timely transition to subsequent systemic therapies should be considered when adverse events or intolerance are encountered.

Aim: Hepatic edema indicates a poor prognosis and impaired quality of life in patients with cirrhosis. Tolvaptan is used in Japan to treat patients who do not respond to conventional diuretics. However, the long-term prognostic effect of tolvaptan has not yet been fully determined in large-scale, real-world cohorts.

Methods: We conducted a retrospective multicenter study of patients with cirrhosis and hepatic edema who were treated with tolvaptan at 17 centers to identify the clinical predictors of treatment response and long-term survival. An early response was defined as a ≥ 1.5-kg weight reduction within 7 days.

Results: Of 1165 patients, 58.8% showed an early response. In a multivariate analysis, blood urea nitrogen concentrations (BUN; per 1.0-mg/dL decrease), serum sodium concentrations (per 10-mEq/L increase), and the absence of hepatocellular carcinoma were independently associated with an early response. Early responders had longer overall survival than non-responders (median, 15.3 vs. 7.7 months; p = 2.70 × 10^-6). An early response remained an independent factor associated with 5-year survival (hazard ratio: 0.83; p = 2.60 × 10^-2) after adjustment for age, hepatic functional reserve, hepatocellular carcinoma, serum sodium concentrations, and BUN concentrations. Subgroup analyses of liver-related mortality were consistent with the primary survival analysis.

Conclusions: An early response to tolvaptan, which is more likely to occur in patients without elevated BUN concentrations or hyponatremia, is independently associated with improved long-term survival in patients with cirrhosis and hepatic edema. Our findings indicate the importance of initiating tolvaptan treatment before renal impairment or hyponatremia develops.

Aim: Portal hypertension (pH) is a major determinant of complications associated with chronic liver disease, and high-risk varices (HRV) require prophylactic intervention. Hepatic venous pressure gradient (HVPG) measurement is the gold standard for assessment. However, it is invasive. This study examined the most reliable noninvasive biomarker for evaluating HVPG and diagnosing HRV.

Methods: Seventy-eight patients with chronic liver disease (including 44 with cirrhosis) underwent HVPG measurement. Noninvasive markers including 7S domain of type IV collagen (4COL7S), Mac-2-binding protein glycosylation isomer (M2BPGi), liver stiffness, enhanced liver fibrosis (ELF) score, hyaluronic acid and type III procollagen peptide levels, aspartate aminotransferase-to-platelet ratio index, fibrosis-4 index, platelet count, von Willebrand factor (vWF), a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) activity, vWF-to-ADAMTS13 ratio, and vWF antigen-to-platelet ratio score were evaluated.

Results: In the receiver operating characteristic analyses, 4COL7S had the highest diagnostic accuracy for both clinically significant HRV, with a superior area under the receiver operating characteristic curve compared with the other markers. 4COL7S showed the strongest correlation with HVPG (r = 0.713 and 95% confident interval: 0.617-0.84), outperforming M2BPGi and the ELF score. Vascular markers, such as the vWF antigen-to-platelet ratio and vWF-to-ADAMTS13 ratio, had additional but weaker predictive ability. However, 4COL7S remained the most consistent predictor across both variceal outcomes and HVPG.

Conclusions: 4COL7S is the most reliable noninvasive biomarker for predicting HRV. Its superior diagnostic accuracy supports its use as a practical surrogate for HVPG and as a valuable tool in clinical risk stratification for variceal bleeding.

Aim: Liver and spleen stiffness (LS and SS) measurements in predicting high risk varices (HRVs) are reported useful in biliary atresia (BA). In children, inability to temporarily hold their breath may pose challenges in obtaining accurate measurements. This cross-sectional prospective study aimed to evaluate the diagnostic accuracy of LS and SS measurements obtained under general anesthesia during brief pauses in ventilation compared with those obtained in the awake state, in predicting HRVs.

Methods: Among patients with BA aged 15 years or younger who underwent esophagogastroduodenoscopy under general anesthesia for evaluation of varices, 43 patients with LS and SS measured both in the awake and anaesthetized states were enrolled. HRVs were defined as large esophagogastric varices or esophagogastric varices of any size with red color signs.

Results: The median age was 4 years. Nineteen patients had HRVs. In the HRVs group compared with the non-HRVs group, awake-LS, awake-SS, anesthesia-LS, and anesthesia-SS were significantly higher: 2.23 versus 1.71, 4.40 versus 3.45, 2.56 versus 1.73, and 4.13 versus 3.62 m/s, respectively. The area under the curve for awake-LS, awake-SS, anesthesia-LS, and anesthesia-SS were 0.784, 0.794, 0.814, and 0.698, respectively. Awake-LS and anesthesia-LS showed a strong positive correlation (ρ = 0.894), whereas awake-SS and anesthesia-SS showed a weak correlation (ρ = 0.468).

Conclusions: As anesthetics and mechanical ventilation affect abdominal hemodynamics, SS measurements obtained under general anesthesia deviated from those obtained during the awake state. Further research is needed to determine whether mild sedation could help optimize measurement conditions.

Trial registration: This study was registered on the University Hospital Medical Information Network (UMIN000033123).

In April 2023, the Japan Society of Hepatology published its official guidelines on liver rehabilitation for chronic liver disease. In this article, we summarize the current evidence on the role of liver rehabilitation in slowing the progression of chronic liver disease, particularly metabolic dysfunction-associated steatotic liver disease (MASLD), liver cirrhosis, and hepatocellular carcinoma (HCC). Specifically, we outline the following: (1) the definition of liver rehabilitation and its target population; (2) exercise therapy in liver rehabilitation according to disease state; (3) considerations for patients with complications; (4) nutritional therapy in liver rehabilitation; and (5) potential economic benefits. Liver rehabilitation represents a novel therapeutic approach for patients with chronic liver disease, and this guidance aims to promote high-quality clinical research and strengthen the evidence base for its application.

Background and aims: Glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/ledipasvir (SOF/LDV) are widely used as first-line direct-acting antiviral (DAA) regimens for chronic hepatitis C, achieving high virus eradication rates. However, a small proportion of patients experience treatment failure, and the optimal retreatment strategies for such cases remain unclear. This nationwide, multicenter, prospective study aimed to evaluate the efficacy of retreatment regimens in patients who failed initial DAA therapy.

Methods: A total of 330 patients were enrolled, including 117 with prior GLE/PIB failure and 213 with prior SOF/LDV failure. The primary outcome was sustained virologic response at 12 weeks after retreatment (SVR12). Retreatment regimens included 12 weeks of GLE/PIB, sofosbuvir/velpatasvir (SOF/VEL) plus ribavirin (RBV), or SOF/LDV.

Results: Among patients retreated after GLE/PIB failure, SVR12 rates were 99.0% (98/99) with SOF/VEL + RBV, 92.3% (12/13) with GLE/PIB 12 weeks, and 100% (5/5) with SOF/LDV, with no significant differences among regimens. Among patients retreated after SOF/LDV failure, SVR12 rates were 100% (12/12) with SOF/VEL + RBV, 99.5% (197/198) with GLE/PIB 12 weeks, and 66.7% (2/3) with SOF/LDV. Retreatment of SOF/VEL + RBV or GLE/PIB demonstrated high therapeutic efficacy in patients with prior SOF/LDV failure. One patient who relapsed after GLE/PIB 8-week therapy and harbored a P32del mutation achieved SVR12 with SOF/VEL + RBV retreatment.

Conclusions: Retreatment with SOF/VEL + RBV, GLE/PIB for 12 weeks, or SOF/LDV achieved high SVR12 rates, indicating that effective viral eradication is feasible using currently available DAA regimens even after prior treatment failure.

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.