Liver injury with autoimmune features after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is increasingly reported. We investigated a large international cohort of individuals with acute hepatitis arising after SARS-CoV-2 vaccination, focusing on histological and serological features. Individuals without known pre-existing liver diseases and transaminase levels ≥5x the upper limit of normal within 3 months after any anti-SARS-CoV-2 vaccine, and available liver biopsy were included. Fifty-nine patients were recruited; 35 females; median age 54 years. They were exposed to various combinations of mRNA, vectorial, inactivated and protein-based vaccines. Liver histology showed predominantly lobular hepatitis in 45 (76%), predominantly portal hepatitis in 10 (17%), and other patterns in four (7%) cases; seven had fibrosis Ishak stage ≥3, associated with more severe interface hepatitis. Autoimmune serology, centrally tested in 31 cases, showed anti-antinuclear antibody in 23 (74%), anti-smooth muscle antibody in 19 (61%), anti-gastric parietal cells in eight (26%), anti-liver kidney microsomal antibody in four (13%), and anti-mitochondrial antibody in four (13%) cases. Ninety-one percent were treated with steroids ± azathioprine. Serum transaminase levels improved in all cases and were normal in 24/58 (41%) after 3 months, and in 30/46 (65%) after 6 months. One patient required liver transplantation. Of 15 patients re-exposed to SARS-CoV-2 vaccines, three relapsed. Acute liver injury arising after SARS-CoV-2 vaccination is frequently associated with lobular hepatitis and positive autoantibodies. Whether there is a causal relationship between liver damage and SARS-CoV-2 vaccines remains to be established. A close follow-up is warranted to assess the long-term outcomes of this condition. Cases of liver injury after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) have been published. We investigated a large international cohort of individuals with acute hepatitis after SARS-CoV-2 vaccination, focusing on liver biopsy findings and autoantibodies: liver biopsy frequently shows inflammation of the lobule, which is typical of recent injury, and autoantibodies are frequently positive. Whether there is a causal relationship between liver damage and SARS-CoV-2 vaccines remains to be established. Close follow-up is warranted to assess the long-term outcome of this condition.

Background: Although atezolizumab plus bevacizumab (Atezo/Bev) therapy has been used as the preferred first-line treatment for advanced hepatocellular carcinoma (HCC), up to 26% of patients do not achieve disease control, suggesting alternative treatments might be more beneficial for such patients. We investigated key predictors for refractoriness to Atezo/Bev therapy, particularly in the first-line setting. Methods: We retrospectively analyzed 302 patients with HCC who received Atezo/Bev therapy between October 2020 and September 2022 across nine hospitals in Japan. Refractoriness was defined as best overall response (BOR) of progressive disease or stable disease and a progression-free survival (PFS) of < 180 days (RECIST v1.1). Clinical benefit was defined as BOR of partial/complete response or stable disease with PFS of ≥ 180 days. Baseline characteristics and potential predictors, identified through literature review, were compared between these groups. Stratifications of overall survival (OS), and PFS were also assessed. Results: Refractoriness was observed in 126 (41.7%) patients, while 154 (51.0%) achieved clinical benefit. Due to a significant association between the treatment line and refractory rate, the subsequent analysis focused on the first-line cohort ( n = 214; 72 [33.6%] patients showed refractoriness). Among 13 potential predictors, the CRP and AFP in immunotherapy (CRAFITY) score had the best predictive performance, with refractory rates of 24.6%, 44.6%, and 57.9% in CRAFITY-0, 1, and 2 patients, respectively ( p < 0.001). OS and PFS were also well-stratified by this scoring system. Conclusions: Approximately one-third of patients were refractory to first-line Atezo/Bev therapy. The CRAFITY score demonstrated superior performance in predicting refractoriness.

Stereotactic body radiation therapy versus radiofrequency ablation for single small hepatocellular carcinoma: a propensity-score matching analysis of their impact on liver function and clinical outcomes Masayuki Ueno, Hiroyuki Takabatake, Satoshi Itasaka, Takahisa Kayahara, Youichi Morimoto, Hiroshi Yamamoto, Motowo Mizuno

Background: Immune checkpoint inhibitors (ICIs) sometimes cause immune‐related liver injury, which can lead to cessation of treatment, hospitalization, and even mortality. Although high‐dose corticosteroids are usually effective in treatment of ICI‐related liver injury, one fifth of affected patients require additional immunosuppressive therapy. It remains uncertain how best to treat ICI‐related liver injury that relapses under corticosteroid therapy after temporary remission.Case: Here we report two cases of ICI‐related liver injury successfully treated with mycophenolate mofetil (MMF). In the first case, a 74‐year‐old man with stage IIIA lung cancer underwent curative chemoradiotherapy. After the second infusion of durvalumab, grade 3 ICI‐related liver injury (mixed pattern) developed. In the second case, a 46‐year‐old man with stage IVB lung cancer received pembrolizumab‐containing chemotherapy. After the first cycle, grade 2 ICI‐related hepatitis developed. In the both cases, liver injury improved with high‐dose prednisolone but relapsed during tapering of the drug. After liver biopsy was performed to confirm the diagnosis of ICI‐related liver injury, MMF (2000 mg/day) was added. MMF was effective for both patients and permitted discontinuation or reduction of prednisolone.Conclusion: MMF appears to be an appropriate treatment option for ICI‐related liver injury that respond to high‐dose corticosteroids but relapse during steroid tapering.

A few decades ago, antibiotic prophylaxis for patients with acute variceal bleeding was reported beneficial. However, endoscopic and systemic therapy for variceal bleeding has dramatically improved since then, so the necessity of prophylactic antibiotics can be questioned. In this study, we reevaluated the efficacy of antibiotic prophylaxis in acute variceal bleeding, using the most recent data in our hospital. We retrospectively analyzed the medical records of 150 patients with acute variceal bleeding who were admitted to Kurashiki Central Hospital between January 2012 and December 2016. We compared the rates of bacterial infection, in-hospital mortality, 5-day rebleeding rate, and 30-day emergency readmission between patients treated or not treated with antibiotic prophylaxis. Forty-six patients (30.7%) received antibiotic prophylaxis; 104 (69.3%) did not. The rates of the outcomes in patients with antibiotic prophylaxis were 6.5% (bacterial infection), 4.3% (in-hospital mortality), 2.2% (5-day rebleeding), and 10.9% (30-day emergency readmission) and were not significantly different form the corresponding figures in those without antibiotic prophylaxis (1.9%, 7.7%, 1.9%, and 10.6%, respectively). Moreover, these rates in our patients, even without antibiotic prophylaxis, were much lower than rates reported in past years, perhaps because of improvements in care of patients with variceal hemorrhage. Antibiotic prophylaxis was not associated with significantly better outcomes of bacterial infection, mortality, rebleeding or readmission rate in patients with acute variceal bleeding. Universal antibiotic prophylaxis for patients with acute variceal bleeding should be reconsidered.

Telomerase reverse transcriptase (TERT) gene aberration is detectable in >80% of cases with hepatocellular carcinoma (HCC). TERT reactivation is essential for cellular immortalization because it stabilizes telomere length, although the role of TERT in hepatocarcinogenesis remains unelucidated. To elucidate the significance of aberrant TERT expression in hepatocytes in inflammation‐associated hepatocarcinogenesis, we generated Alb‐Cre;TertTg mice, which overexpress TERT in the liver and examined their phenotype during chronic inflammation. Based on transcriptome data from the liver tissue of Alb‐Cre;TertTg mice, we examined the role of TERT in hepatocarcinogenesis in vitro. We also evaluated the relationship between TERT and cell‐cycle‐related molecules, including p21, in HCC samples. The liver tumor development rate was increased by TERT overexpression during chronic inflammation, especially in the absence of p53 function. Gene set enrichment analysis of liver tissues revealed that gene sets related to TNF‐NFκB signaling, cell cycle, and apoptosis were upregulated in Alb‐Cre;TertTg liver. A luciferase reporter assay and immunoprecipitation revealed that TERT interacted with NFκB p65 and enhanced NFκB promoter activity. On the other hand, TERT formed protein complexes with p21, cyclin A2, and cyclin E and promoted ubiquitin‐mediated degradation of p21, specifically in the G1 phase. In the clinical HCC samples, TERT was highly expressed but p21 was conversely downregulated, and TERT expression was associated with the upregulation of molecules related to the cell cycle. Taken together, the aberrant upregulation of TERT increased NFκB promoter activity and promoted cell cycle progression via p21 ubiquitination, leading to hepatocarcinogenesis. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.