Liver Sinusoidal Endothelial Cells Contribute to Portal Hypertension Through Collagen Type IV-Driven Sinusoidal Remodeling.

Portal hypertension (PHTN) is a severe complication of liver cirrhosis and is associated with intrahepatic sinusoidal remodeling induced by sinusoidal resistance and angiogenesis. Collagen type IV (COL4), a major component of basement membrane, forms in liver sinusoids upon chronic liver injury. However, the role, the cellular source and expression regulation of COL4 in liver diseases is unknown. Here, we examined how COL4 is produced and how it regulates sinusoidal remodeling in fibrosis and PHTN. Human cirrhotic liver sample RNA-sequencing showed increased COL4 expression, which was further confirmed via immunofluorescence staining. scRNA-sequencing identified liver sinusoidal endothelial cells (LSECs) as the predominant source of COL4 upregulation in mouse fibrotic liver. In addition, COL4 was upregulated in a tumor necrosis factor α-nuclear factor-κB dependent manner through an epigenetic mechanism in liver sinusoidal endothelial cells in vitro. Indeed, by utilizing a CRISPRi-dCas9-KRAB-mediated epigenome editing approach, epigenetic repression of the enhancer-promoter interaction showed silencing of COL4 gene expression. LSEC-specific COL4 gene mutation or repression in vivo abrogated sinusoidal resistance and angiogenesis, which thereby alleviated sinusoidal remodeling and PHTN. Our findings reveal that LSECs promote sinusoidal remodeling and PHTN during liver fibrosis through COL4 deposition.

Effectiveness of Hepatitis B Vaccination for Patients With Inflammatory Bowel and Celiac Disease.

BACKGROUND & AIMS: Guidelines recommend measuring antibody (Ab) titers to hepatitis B virus (HBV) after vaccination for patients with inflammatory bowel disease (IBD) or celiac disease (CD) ("patients with IBD/CD") and revaccinating when titers are low. Few data, however, support this recommendation. We aimed to compare effectiveness of HBV vaccination (immunity and infection rates) for patients with IBD/CD vs matched referents. METHODS: Using the Rochester Epidemiology Project, we performed a retrospective cohort study of patients first diagnosed with IBD/CD (index date) while residing in Olmsted County, Minnesota, from January 1, 2000, through December 31, 2019. HBV screening results were obtained from health records. RESULTS: In 1264 incident cases of IBD/CD, only 6 HBV infections were diagnosed before the index date. A total of 351 IBD/CD cases had documented receipt of 2 or more HBV vaccines before their index date and had hepatitis B surface antigen Ab (anti-HBs) titers measured after their index date. The proportion of patients with HBV-protective titers (≥10 mIU/mL) decreased with time before plateauing, with protective titer rates of 45% at 5 up to 10 years and 41% at 15 up to 20 years after the last HBV vaccination. The proportion of referents with protective titers also decreased with time and was consistently higher than the levels of patients with IBD/CD within 15 years after the last HBV vaccination. However, no new HBV infection developed in any of 1258 patients with IBD/CD during a median follow-up of 9.4 years (interquartile range, 5.0-14.1 years). CONCLUSIONS: Routine testing of anti-HBs titers may not be indicated for fully vaccinated patients with IBD/CD. Additional studies are needed to confirm these findings in other settings and populations.

Epigenetics of alcohol-related liver diseases.

Alcohol-related liver disease (ARLD) is a primary cause of chronic liver disease in the United States. Despite advances in the diagnosis and management of ARLD, it remains a major public health problem associated with significant morbidity and mortality, emphasising the need to adopt novel approaches to the study of ARLD and its complications. Epigenetic changes are increasingly being recognised as contributing to the pathogenesis of multiple disease states. Harnessing the power of innovative technologies for the study of epigenetics (e.g., next-generation sequencing, DNA methylation assays, histone modification profiling and computational techniques like machine learning) has resulted in a seismic shift in our understanding of the pathophysiology of ARLD. Knowledge of these techniques and advances is of paramount importance for the practicing hepatologist and researchers alike. Accordingly, in this review article we will summarise the current knowledge about alcohol-induced epigenetic alterations in the context of ARLD, including but not limited to, DNA hyper/hypo methylation, histone modifications, changes in non-coding RNA, 3D chromatin architecture and enhancer-promoter interactions. Additionally, we will discuss the state-of-the-art techniques used in the study of ARLD (e.g. single-cell sequencing). We will also highlight the epigenetic regulation of chemokines and their proinflammatory role in the context of ARLD. Lastly, we will examine the clinical applications of epigenetics in the diagnosis and management of ARLD.

Accuracy of noninvasive fibrosis scores in predicting advanced fibrosis in pediatric patients after liver transplantation.

BACKGROUND: Liver biopsy is the gold standard to stage fibrosis in liver disease. Several scoring systems have been studied to predict advanced fibrosis in liver disease. Those scores have not been validated in pediatric liver transplant patients. AIM: Evaluate the performance of three fibrosis scores (FSc) in assessing the presence of advanced fibrosis (AF) in children after orthotopic liver transplantation (OLT). METHODS: Patients < 20 years of age who underwent liver biopsy post-OLT with laboratory values within 1 month of the biopsy were included. Fibrosis was determined by an experienced pathologist (F0-4). We defined AF as F3-4. The following FSc were calculated: AST/ALT ratio, APRI, and FIB-4 index. Receiver operating characteristic curve analysis was done to assess the FSc performance in predicting AF. RESULTS: A total of 232 biopsies were analyzed, of those 42 (18.1%) showed AF (F3-4). FIB-4 was significantly higher in patients with AF compared to those without AF [median value of 1.1 [0.7, 3.0] and 0.6 [0.2, 1.4], respectively (p = .02)]; however, FIB-4 had satisfactory accuracy to diagnose AF with significant overlap and AUC of 0.68 (CI 0.56-0.81). Cutoff points of 0.2 and 3.03 were used to rule in and rule out AF, respectively. AST/ALT and APRI were not significantly different between patients with and without AF. CONCLUSION: Even though FIB-4 had satisfactory accuracy in detecting AF in pediatric transplant patients, noninvasive hepatic FSc developed in adults still performed poorly. Our results highlight the need to develop a reliable pediatric FSc.

Celiac Disease: Risk of Hepatitis B Infection.

OBJECTIVE: The aim of our study was to assess the response to hepatitis B virus (HBV) vaccination and the risk of HBV infection in patients with celiac disease (CD). PATIENTS AND METHODS: We performed a cross-sectional study using the National Health and Nutrition Examination Survey (NHANES) database (2009-2014) to assess the rate of HBV vaccination, immune response, and HBV infection risk in patients with and without CD. We also determined the rate of HBV infection via retrospective analysis of two cohorts: patients seen at Mayo Clinic (1998-2021), and a stable longitudinally observed cohort, the Rochester Epidemiology Project (REP; 2010-2020). RESULTS: Based on the NHANES data, the rate of HBV infection in the United States was 0.33% (95% confidence interval 0.25-0.41). Of 93 patients with CD, 46 (49%) were vaccinated for HBV and of the remaining 19,422 without CD, 10,228 (53%) were vaccinated. Twenty-two (48%) vaccinated patients with CD had HBV immunity and 4405 (43.07%) vaccinated patients without CD had HBV immunity, which was not statistically different. In NHANES data, there were no cases of HBV infection in patients with CD. During the study period, 3568 patients with CD were seen at Mayo Clinic and 3918 patients with CD were identified using the REP database. Of those patients with CD, only four (0.11%) at Mayo Clinic and nine (0.23%) of the REP patients had HBV infection. CONCLUSION: The rate of HBV vaccination and immunity was similar in individuals with and without CD. Predictably, no increased risk of HBV infection was detected in CD patients. These results do not support screening and revaccination practice for HBV immunity in patients with CD within the United States.

An Adolescent with Chanarin-Dorfman Syndrome Presenting with Ichthyosis and Hepatic Steatosis.

Chanarin-Dorfman syndrome also known as neutral lipid storage disease is a rare multisystemic autosomal recessive disorder. It is mostly encountered in patients of Mediterranean and Middle Eastern origin. Most patients are brought to medical attention secondary to dermatological manifestations namely ichthyosis. Here, we report a 10-year-old Kurdish male patient with ichthyosis, who was referred to pediatric liver clinic for transaminase elevation of unknown etiology despite elaborate workup. Histological findings on liver biopsy were consistent with nonalcoholic steatohepatitis. Genetic testing identified homozygous mutation C.776G>A (p.G259D) in the Abhydrolase domain containing 5 gene on chromosome 3 described in patients with Chanarin-Dorfman syndrome. After the initiation of a diet with high medium chain triglycerides/long chain triglycerides ratio, aerobic exercise, and vitamin E, the patient liver enzymes improved. Due to debilitating ichthyosis, he was started on acitretin therapy that was discontinued due to transaminases elevation. Patient is currently stable and doing well.