Acquisition of epithelial plasticity in human chronic liver disease.

For many adult human organs, tissue regeneration during chronic disease remains a controversial subject. Regenerative processes are easily observed in animal models, and their underlying mechanisms are becoming well characterized, but technical challenges and ethical aspects are limiting the validation of these results in humans. We decided to address this difficulty with respect to the liver.

FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.

Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2), could represent a new chemoprophylactic approach for COVID-19 that complements vaccination. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems.

ABCB4 Mutations in Adults Cause a Spectrum Cholestatic Disorder Histologically Distinct from Other Biliary Disease.

Background: Mutations in the ABCB4 gene are associated with failure of bile acid emulsification leading to cholestatic liver disease. Presentations range from progressive familial intrahepatic cholestasis type 3 (PFIC3) in childhood, to milder forms seen in adulthood.

Aims: We sought to characterize adult disease with particular reference to histology which has been hitherto poorly defined.

Spleen Size Does Not Correlate With Histological Stage of Liver Disease in People With Nonalcoholic Fatty Liver Disease.

Splenomegaly in the context of liver disease is classically associated with advanced cirrhosis and portal hypertension. More recently, we observed an increasing number of patients with splenomegaly and nonalcoholic fatty liver disease (NAFLD), but in whom intensive work-up revealed no evidence of advanced liver disease or portal hypertension. In this study, we found no correlation between spleen size and histological stage of NAFLD, and a strong correlation between body weight, height and serum high density lipoprotein (HDL) levels.

Convergent somatic mutations in metabolism genes in chronic liver disease.

The progression of chronic liver disease to hepatocellular carcinoma is caused by the acquisition of somatic mutations that affect 20-30 cancer genes. Burdens of somatic mutations are higher and clonal expansions larger in chronic liver disease than in normal liver, which enables positive selection to shape the genomic landscape. Here we analysed somatic mutations from 1,590 genomes across 34 liver samples, including healthy controls, alcohol-related liver disease and non-alcoholic fatty liver disease.

Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression.

Objective: Non-alcoholic fatty liver disease (NAFLD) is a silent pandemic associated with obesity and the metabolic syndrome, and also increases cardiovascular- and cirrhosis-related morbidity and mortality. A complete understanding of adaptive compensatory metabolic programmes that modulate non-alcoholic steatohepatitis (NASH) progression is lacking.

Methods And Results: Transcriptomic analysis of liver biopsies in patients with NASH revealed that NASH progression is associated with rewiring of metabolic pathways, including upregulation of de novo lipid/cholesterol synthesis and fatty acid remodelling.

Cholangiocyte organoids can repair bile ducts after transplantation in the human liver.

Organoid technology holds great promise for regenerative medicine but has not yet been applied to humans. We address this challenge using cholangiocyte organoids in the context of cholangiopathies, which represent a key reason for liver transplantation. Using single-cell RNA sequencing, we show that primary human cholangiocytes display transcriptional diversity that is lost in organoid culture.

Pilot study of a noninvasive real-time optical backscatter probe in liver transplantation.

Transplantation of severely steatotic donor livers is associated with early allograft dysfunction and poorer graft survival. Histology remains the gold standard diagnostic of donor steatosis despite the lack of consensus definition and its subjective nature. In this prospective observational study of liver transplant patients, we demonstrate the feasibility of using a handheld optical backscatter probe to assess the degree of hepatic steatosis and correlate the backscatter readings with clinical outcomes.

The Alpha-1 Antitrypsin Polymer Load Correlates With Hepatocyte Senescence, Fibrosis Stage and Liver-Related Mortality.

Background: Alpha-1 antitrypsin deficiency (AATD) is an important, inherited cause of chronic liver disease. Marked variation in fibrosis stages in patients with homozygous deficiency and those factors that determine whether heterozygous carriers develop liver fibrosis, remain unexplained. Murine studies implicate polymerized alpha-1 antitrypsin (AAT) within hepatocytes as pathogenic.

Pervasive lesion segregation shapes cancer genome evolution.

Cancers arise through the acquisition of oncogenic mutations and grow by clonal expansion. Here we reveal that most mutagenic DNA lesions are not resolved into a mutated DNA base pair within a single cell cycle. Instead, DNA lesions segregate, unrepaired, into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations.

Somatic mutations and clonal dynamics in healthy and cirrhotic human liver.

The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes. Stem cells from normal livers have a low mutational burden and limited diversity of signatures, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation.

Severe steroid-resistant anti-PD1 T-cell checkpoint inhibitor-induced hepatotoxicity driven by biliary injury.

Introduction: Hepatotoxicity from T-cell checkpoint blockade is an increasingly common immune-related adverse event, but remains poorly characterised and can be challenging to manage. Such toxicity is generally considered to resemble autoimmune hepatitis, although this assumption is extrapolated from limited clinicopathological reports of anti-cytotoxic T-lymphocyte-associated protein 4-induced hepatotoxicity.

Methods: Here we report, with full clinicopathological correlation, three cases of T-cell checkpoint inhibitor-induced hepatotoxicity associated with anti-programmed cell death protein 1 agents.

Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids.

The treatment of common bile duct (CBD) disorders, such as biliary atresia or ischemic strictures, is restricted by the lack of biliary tissue from healthy donors suitable for surgical reconstruction. Here we report a new method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs) for regenerative medicine applications. The resulting ECOs closely resemble primary cholangiocytes in terms of their transcriptomic profile and functional properties.

Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease.

Unlabelled: Nonalcoholic fatty liver disease (NAFLD) can progress from simple steatosis (i.e., nonalcoholic fatty liver [NAFL]) to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer.

Any value in a specialist review of liver biopsies? Conclusions of a 4-year review.

Aims: Liver pathology is a challenging subspeciality, with histopathologists frequently seeking specialist opinions. This study aims to determine the impact of specialist reviews on the final diagnosis and patient management.

Methods And Results: Agreement with the initial reporting centre in the histopathological diagnosis of 1265 liver biopsies was determined.

Chronic Hepatitis B Virus Infection: The Relation between Hepatitis B Antigen Expression, Telomere Length, Senescence, Inflammation and Fibrosis.

Background: Chronic Hepatitis B virus (HBV) infection can lead to the development of chronic hepatitis, cirrhosis and hepatocellular carcinoma. We hypothesized that HBV might accelerate hepatocyte ageing and investigated the effect of HBV on hepatocyte cell cycle state and biological age. We also investigated the relation between inflammation, fibrosis and cell cycle phase.

Endoplasmic Reticulum Stress Is Implicated in Intestinal Failure-Associated Liver Disease.

Background: Intestinal failure-associated liver disease (IFALD) is the most serious consequence of long-term parenteral nutrition for intestinal failure. Little is known about the pathogenesis of IFALD, although many of the risk factors are also linked to endoplasmic reticulum stress (ERS). We propose that ERS may have a role in the development of IFALD.

Analysis of ischemia/reperfusion injury in time-zero biopsies predicts liver allograft outcomes.

Ischemia/reperfusion injury (IRI) that develops after liver implantation may prejudice long-term graft survival, but it remains poorly understood. Here we correlate the severity of IRIs that were determined by histological grading of time-zero biopsies sampled after graft revascularization with patient and graft outcomes. Time-zero biopsies of 476 liver transplants performed at our center between 2000 and 2010 were graded as follows: nil (10.

Pi*Z heterozygous alpha-1 antitrypsin states accelerate parenchymal but not biliary cirrhosis.

Objective: The degree to which heterozygous forms of alpha-1 antitrypsin (A1AT), principally MZ, causes liver disease is uncertain. If heterozygosity is a relevant cofactor, over-representation in patients with end-stage liver disease would be predicted. We therefore assessed the prevalence and disease-related distribution of A1AT heterozygosity in the largest cohort to date for this purpose.

Prevalence and risk factors for liver involvement in individuals with PiZZ-related lung disease.

Rationale: α1-Antitrypsin deficiency is one of the most common heritable human diseases, predisposing to liver and lung injury. Significant heterogeneity in phenotypic expression is well documented, but less is known of the prevalence, severity, and correlates of chronic liver disease among individuals presenting with lung disease.

Objectives: To determine the frequency of and risk factors for severe liver fibrosis and cirrhosis among individuals with PiZZ-related lung disease.

Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease.

Background & Aims: Models of non-alcohol-related fatty liver disease (NAFLD) reveal features of accelerated ageing, such as impaired regeneration, and an increased risk of hepatocellular carcinoma. The relation between accelerated ageing, disease progression and clinical outcome has not been previously investigated and is the subject of the current study.

Methods: Liver sections from 70 patients with NAFLD (105 biopsies) and 60 controls were studied for telomere length, nuclear area, DNA damage and cell cycle phase markers, using quantitative fluorescent in situ hybridization and immunohistochemistry.