Yoshihito Uchida

Background and Aims: Although the widespread use of direct‐acting antivirals (DAAs) has reduced the proportion of hepatitis C virus (HCV) antibody‐positive patients eligible for antiviral treatment, the current proportion requiring referral for DAA therapy in ophthalmology departments, which have both high testing volumes and high HCV antibody‐positive rates, remains unclear. Methods: This nationwide multicenter retrospective cohort study included HCV antibody‐positive patients identified through testing in ophthalmology departments at 20 institutions in Japan between 2019 and 2023. The proportions of patients requiring referral for DAA therapy were assessed by electronic medical record (EMR) review across all 20 institutions and by a combination of EMR review and HCV antibody titer determination across nine institutions where antibody titers could be measured. Results: A total of 2792 HCV antibody‐positive patients were identified across 20 institutions. Based on EMR review, the proportions requiring referral for DAA therapy were 44.4%, 38.7%, 34.2%, 38.9%, and 42.5% in 2019, 2020, 2021, 2022, and 2023, respectively. Among 1255 HCV antibody‐positive patients from 9 institutions where HCV antibody titers could be determined, the corresponding proportions assessed by combined EMR review and antibody titer determination were 28.4%, 23.7%, 20.8%, 22.4%, and 25.9%, respectively. Despite a decline in HCV antibody‐positive rates over time, the proportion requiring referral remained high. Conclusions: Although the number of HCV antibody‐positive patients in ophthalmology departments has decreased, a considerable proportion could still be considered for DAA therapy. Combining HCV antibody titer determination with EMR review improves the efficiency of identifying patients requiring referral.

Background: The Baveno endoscopy avoidance criteria are widely used to reduce unnecessary screening endoscopy in patients with chronic liver disease. However, evidence regarding their performance in Japanese populations remains limited, and detection‐oriented strategies for high‐risk varices (HRV) may also be clinically relevant in settings with broad endoscopic availability. Methods: We retrospectively analyzed 1675 Japanese patients with chronic liver disease who underwent liver stiffness measurement (LSM) and upper gastrointestinal endoscopy at a single center. The performance and safety of the Baveno criteria were evaluated overall and by etiology. Patients were temporally divided into derivation and validation cohorts. Based on independent predictors of HRV, a simple high‐risk varices detection score (HRV‐DS) incorporating LSM, platelet count, and alcohol‐related etiology was developed. Results: The Baveno criteria classified 79.4% of patients as suitable for endoscopy avoidance, with an overall HRV miss rate of 0.39%. However, safety was modestly reduced in patients with alcohol‐related liver disease. The HRV‐DS achieved 100% sensitivity for HRV detection at the lowest threshold (score ≥ 1), while recommending endoscopy to 27.0% of patients. At a higher threshold (score ≥ 2), sensitivity remained approximately 87% with improved positive predictive value. These findings were consistently reproduced in both derivation and validation cohorts. Conclusions: In this large real‐world Japanese cohort, the Baveno endoscopy avoidance criteria demonstrated excellent safety for excluding HRV. The exploratory HRV‐DS also showed high sensitivity for identifying HRV and may provide a complementary detection‐oriented approach in clinical practice.

Background and Aim: Immune checkpoint inhibitor (ICI)‐induced liver injury is a clinically important adverse event that may lead to interruption of anticancer therapy. Although systemic corticosteroids are recommended for severe cases, the optimal corticosteroid tapering strategy for relapse prevention and subsequent ICI rechallenge has not been established. We evaluated the clinical outcomes of an empirical institutional gradual corticosteroid tapering strategy developed with reference to Japanese AIH management. Methods: We retrospectively analyzed 36 consecutive patients with grade ≥ 3 ICI‐induced liver injury. Prednisolone (PSL) was generally initiated at 0.8 mg/kg/day and tapered gradually at a rate of 5 mg every 2 weeks. Steroid pulse therapy was selectively administered in patients with severe liver injury with signs of liver failure. The primary endpoint was relapse during corticosteroid tapering. Results: Liver injury improved in 35 of 36 patients (97%). The median duration required to taper PSL to ≤ 10 mg/day was 73 (range, 50–168) days. Relapse during corticosteroid tapering occurred in only 1 patient (3%), and no patients required additional immunosuppressive therapy, including mycophenolate mofetil. ICI rechallenge was performed in 13 patients, including 6 with prior CTCAE grade 4 liver injury, and recurrence after rechallenge occurred in only 1 patient (8%). Histopathological findings were characterized predominantly by lobular inflammation with CD8‐positive T‐cell infiltration, whereas classical autoimmune hepatitis‐associated features were relatively limited. Conclusions: An empirical gradual corticosteroid tapering strategy developed with reference to Japanese AIH management may contribute to relapse prevention and facilitate ICI rechallenge in patients with ICI‐induced liver injury.

Background: Spontaneous bacterial peritonitis (SBP) remains a life‐threatening complication in cirrhotic patients with refractory ascites. Evidence for rifaximin (RFX) in SBP prevention and prognosis is lacking in Japan. We investigated the effect of RFX on prognosis and recurrence of SBP and evaluated the prognostic role of oral health within the oral–gut–hepatic axis. Methods: This single‐center, retrospective study included 142 patients with a first SBP episode. Patients were stratified into an RFX‐treated group and a non‐RFX group. Outcomes included 90‐day survival, SBP recurrence, and cirrhosis‐related complications. Oral health status and acid‐suppressive therapy were also evaluated. Results: Forty‐seven patients received RFX. Ascitic culture positivity was comparable between groups, but RFX‐treated patients had fewer enteric bacteria and more oral flora ( p = 0.0033). Ninety‐day survival was significantly higher with RFX (85.1% vs. 60.0%, p = 0.0023). The 12‐month recurrence rate was markedly lower in the RFX‐treated group (10.4% vs. 63.2%; HR 0.19, 95% CI 0.09–0.40). Oral contamination independently predicted overt hepatic encephalopathy (HR 2.56) and variceal rupture (HR 6.72). Denture use was an independent predictor of mortality (HR 2.04, 95% CI 1.23–3.38). Conclusion: Rifaximin use was associated with higher short‐term survival and lower SBP recurrence in cirrhotic patients with refractory ascites. Oral contamination and denture use were associated with adverse outcomes, providing novel clinical evidence for the oral–gut–hepatic axis. Integration of RFX therapy with oral hygiene interventions may offer a comprehensive strategy to improve prognosis in cirrhosis.

Aim: The prognostic value of serum C‐X‐C motif chemokine ligand 10 (CXCL10) levels for liver function was investigated in hepatitis C virus (HCV)–infected patients with compensated or decompensated cirrhosis (cLC and dLC, respectively) following treatment with direct‐acting antivirals (DAAs). Methods: In this nationwide study involving multiple centers, 164 HCV‐related liver cirrhosis patients (95 with cLC and 69 with dLC), who underwent treatment with DAAs, were analyzed. Serum levels of CXCL10 were assessed at the baseline (pre‐CXCL10) and at 12 or 24 weeks after the end of therapy (post‐CXCL10). Associations between CXCL10 levels and liver function after DAA therapy were evaluated. Results: Of the 164 study patients, the albumin–bilirubin (ALBI) grade was reduced to Grade 1 in 85 patients at one year after end of therapy (EOT1Y). Serum CXCL10 ratios (post‐CXCL10/pre‐CXCL10 levels) were significantly lower in ALBI Grade 1 patients than the others ( p = 0.014) at EOT1Y. Receiver operating curve analysis for distinguishing ALBI Grade 1 at EOT1Y demonstrated that the area under the curve was 0.611, with an optimal cutoff value of 0.504. Multivariate analysis revealed that body mass index (BMI; odds ratio [OR] 0.816; p < 0.001), absence of ascites (OR 3.340; p = 0.003), FIB‐4 index (OR 0.872; p = 0.026), and serum CXCL10 ratios < 0.504 (OR 2.630; p = 0.010) were independently correlated to ALBI Grade 1 at EOT1Y. Conclusions: The post‐to pretreatment serum CXCL10 ratio was independently associated with short‐term liver function outcome following HCV eradication in cirrhotic patients. Registry and registration Nos: This study was registered to the University Hospital Medical Information Network (36,150).

Background and Aims: Although direct‐acting antivirals (DAAs) achieve high sustained virologic response (SVR) rates, the long‐term outcomes of patients with hepatitis C virus (HCV)‐related cirrhosis remain variable. Growth differentiation factor 15 (GDF15), a stress‐induced cytokine, has emerged as a potential biomarker for liver disease progression. This study aimed to evaluate the prognostic value of serum GDF15 levels in predicting hepatocellular carcinoma (HCC), hepatic decompensation, and mortality in patients with HCV‐related cirrhosis. Methods: We retrospectively analyzed 196 patients with HCV‐related cirrhosis who achieved SVR at 18 Japanese institutions. Serum GDF15 levels were measured at baseline (BL) and 24 weeks posttreatment (p24w). A previously validated cutoff of 1.75 ng/mL was applied. The clinical outcomes included HCC occurrence, hepatic decompensation, and all‐cause mortality. Results: During a median follow‐up of 46.2 months, 75 patients developed HCC, 28 experienced hepatic decompensation, and 25 died. Hepatic decompensation occurred significantly less frequently in the BL GDF15‐low group. Importantly, no deaths occurred in the GDF15‐low group, whereas the 5‐year survival rate in the GDF15‐high group was 71.7%. Similar trends were observed for GDF15 levels at p24w. In the overall cohort, GDF15 was not significantly associated with incident HCC; among HCC‐naïve patients, a nonsignificant trend toward lower 3‐year HCC incidence was observed in the GDF15‐low group. Conclusions: Serum GDF15 is a promising prognostic biomarker for post‐SVR outcomes in patients with HCV‐related cirrhosis. Its ability to predict decompensation and mortality through a validated cutoff supports its use for risk stratification and long‐term management in patients with chronic liver disease.

Aim: A nationwide survey was conducted to clarify the recent status of patients with acute liver failure (ALF) and late‐onset fulminant hepatitis (LOHF) in Japan.Methods: Two‐step surveys were performed annually targeting 782 hospitals, focusing on patients meeting the Japanese diagnostic criteria.Results: A total of 1404 patients seen between 2016 and 2021 were enrolled, including 1373 patients with ALF (824 non‐comatose, 320 acute type, and 229 subacute type) and 31 patients with LOHF. Of these, 1117 patients (79.6%) had hepatitis, and 287 patients (20.4%) did not have hepatitis. Compared to patients seen from 2010 to 2015, those from 2016 to 2021 showed a decrease in the proportion of viral cases across all types compared to those up to 2009, whereas the proportion of drug‐induced, autoimmune, and indeterminate cases increased. Among the patients, 32 had HBV reactivation due to immunosuppressive and/or antineoplastic therapies (17 HBsAg positive and 15 HBsAg negative). The frequency of complications and various treatment methods did not show significant changes compared to previous surveys. Excluding non‐comatose cases, the survival rate with medical treatment for patients with and without hepatitis remained low. Liver transplantation was performed in 144 patients with hepatitis (12.9%) and in 19 patients without hepatitis (6.6%). Multivariate analysis identified disease types, patient age, etiology, liver atrophy, and complications as factors associated with the outcome.Conclusion: Although the clinical features and etiologies of patients with ALF and LOHF have evolved, patient outcomes have not improved in recent years.

Primary sclerosing cholangitis (PSC) is a progressive autoimmune hepatobiliary disease characterized by fibrotic strictures in the bile ducts, leading to chronic cholestasis and cirrhosis. Magnetic resonance cholangiopancreatography (MRCP) is a noninvasive method for evaluating the condition of the bile ducts, and has high sensitivity and specificity, making it the first‐line diagnostic tool for PSC. However, the importance of endoscopic retrograde cholangiopancreatography (ERCP) remains unchanged. ERCP is particularly useful in differentiating PSC from cholangiocarcinoma. It allows for tissue sampling from strictures and offers superior spatial resolution to detect subtle changes in the bile ducts. Endoscopic ultrasonography (EUS) is a minimally invasive endoscopic modality with growing importance in the management of pancreato‐biliary diseases. Although the role of EUS in PSC patients has not been established, future research in this area is warranted. ERCP is particularly important for patients who are not eligible for liver transplantation, as it allows bile drainage from the dominant or high‐grade strictures through balloon dilation and stenting, alleviating symptoms and extending survival. Balloon dilation is currently considered superior to biliary stenting, due to its lower risk of bacterial cholangitis. However, refractory complications, such as bacterial cholangitis and pancreatitis, can still occur in some cases. Therefore, careful patient selection and involvement of highly skilled specialists are essential. In the diagnosis and treatment of PSC, it is crucial to perform endoscopic procedures tailored to its unique pathophysiology. Further research is needed to optimize treatment protocols and improve outcomes. This review presents the latest insights on these topics.

Background/Objectives: Rifaximin is a therapeutic agent for patients with hepatic encephalopathy (HE); however, there is little data on the effects of its long-term (>1 year) administration in Japanese patients with cirrhosis. The effects and safety of 3-year rifaximin treatment on HE was investigated in Japan. Methods: A total of 190 Japanese patients with cirrhosis who were continuously administered rifaximin for more than 1 year suffered overt or covert HE, which was diagnosed by a physician. Laboratory data were collected at baseline, 3, 6, 12, 18, 24, 30, and 36 months following rifaximin administration. We examined the cumulative overt HE incidences, overall survival rates, and hepatic functional reserves following rifaximin treatment. The occurrence of adverse events was also assessed. Results: The levels of ammonia improved significantly after 3 months of rifaximin administration, which continued for 3 years. Serum albumin and prothrombin activity also significantly improved 3 years after initiation of rifaximin treatment. Cumulative overt HE incidences were 12.1%, 19.7%, and 24.9% at 1, 2, and 3 years, respectively. The survival rates following rifaximin treatment were 100%, 88.9%, and 77.8% at 1, 2, and 3 years, respectively. In contrast, renal function and electrolytes did not change following rifaximin administration. Only three (1.6%) patients discontinued rifaximin therapy because of severe diarrhea after 1 year of rifaximin administration. No other serious adverse events were observed. Conclusions: Three years of continuous rifaximin (RFX) treatment was both effective and safe for patients with hepatic encephalopathy. Liver function improved and did not worsen during treatment.