aimed to determine the impact of the COVID-19 pandemic on people with liver disease in the US using a national death dataset. They compared observed vs. predicted mortality for 2020-2021 based on trends from 2010-2019 with joinpoint and prediction modelling analyses. Age standardised mortality rates (ASMRs) for alcohol-related liver disease (ALD) dramatically increased between 2010-2019 and 2020-2021 (5 times higher annual percentage change), leading to a higher observed ASMR than predicted for 2020 and 2021. The ASMR rise for ALD was higher in certain ethnic groups and particularly for the 25–44-year age group. The ASMR for non-alcoholic fatty liver disease (NAFLD) also increased during the pandemic while the rates for hepatitis B and C decreased. The increased trend in mortality was also higher in females than in males. Therefore, during the COVID-19 pandemic, the impact of viral hepatitis has slowed down, while the increasing mortality trend for ALD and NAFLD has accelerated. The gut and liver form a closely interlinked functional unit (“gut-liver axis”), but also share a common cellular origin, as these organs develop from the definitive endoderm forming the foregut. now demonstrate that submucosal glands in the human duodenum contain cells with stem/progenitor markers and genetic similarities to biliary epithelial cells. Intriguingly, these human duodenal submucosal gland cells form organoids in vitro, acquire hepatobiliary markers and engraft into the livers of immunocompromised mice. In this experimental setting of cell transplantation, the duodenal gland-derived “hepatocytes” protect the hosts from liver injury and promote liver regeneration. This work sheds new light on cellular plasticity in the gut-liver axis and may provide important avenues for regenerative medicine in liver diseases. A single nucleotide polymorphism in PNPLA3 is strongly associated with NAFLD and advanced disease. tried to understand the mechanistic link between this PNPLA3 mutation and the development of NAFLD. They used a multicellular liver culture system that utilises human pluripotent stem cell (hPSC)-derived hepatocytes, stellate cells and macrophages expressing either wild-type or mutated PNPLA3 in a lipotoxic milieu reflecting the circulating levels of disease risk factors in individuals with NAFLD. Under these conditions the PNPLA3-mutated hPSCs recapitulated many key aspects of NAFLD including lipid accumulation, oxidative stress, inflammatory response, and stellate cell activation. This was associated with elevated levels of IL6/STAT3 activity, which is consistent with transcriptomics from patient liver biopsies. Moreover, dampening IL6/STAT3 activity alleviated the I148M-mediated susceptibility to NAFLD, while boosting it in wild-type liver cultures enhanced NAFLD development. Selective inhibition of trans signalling by IL6 (achievable pharmacologically) produced the same inhibitory results on NAFLD development. The preclinical model developed here is suitable for mechanistic dissection of genetic variants and the manipulation of the IL6 pathway opens new therapeutic prospects akin to those existing in inflammatory bowel disease. HEV genotype 3 infections display a wide spectrum of clinical presentations. Host – but not viral – factors are reported to be associated with worse clinical outcomes. analysed the role of viral and host factors on disease presentation using clinical, biochemical, virological, chemokine and histological data from infected individuals in Belgium, with disease signs collected retrospectively over an 8-year timeframe. Subtype assignment was possible for 179/218 viraemic cases, confirming genotype 3 as dominant with an almost equal representation of clades abchijklm and efg. An increased hospitalisation rate and higher peak serum levels of alanine aminotransferase, bilirubin and alkaline phosphatase were found in individuals with clade efg infections on univariate and multivariable analyses. In addition, acute clade efg infections were characterised by higher serum CXCL10 levels and more pronounced liver necro-inflammatory activity. Data on the long-term persistence of HCV resistance-associated substitutions (RASs) after treatment with direct-acting antivirals are limited. evaluated the persistence of NS3, NS5A and NS5B RASs for up to 5 years after the end of treatment (EOT). After protease inhibitor failure, the frequencies of NS3 RASs were 40-90% at EOT and RASs disappeared rapidly in GT1b and GT3 after follow-up month 3, while RASs were stable (≥60%) in GT1a due to Q80 K. The SOF-resistant NS5B RAS S282T was only found in GT3a patients. NS5A RASs were very common in all GTs after NS5A inhibitor failure (88-95%), and even after 24 weeks follow-up their frequency was ≥65%. However, while RASs in GT1b had a stable course, RASs in GT1a and GT3 declined slightly during follow-up. RIG-I-like receptors, including RIG-I, MDA5 and LGP2, sense viral RNA to induce the antiviral interferon response. LGP2, unable to activate the IFN response itself, modulates RIG-I and MDA5 signalling. HDV is sensed by MDA5. show that LGP2 is essential for the MDA5-mediated IFN response induced upon HDV infection. This induction requires both RNA binding and ATPase activities of LGP2. The IFN response only moderately reduced HDV replication in resting cells but profoundly suppressed cell division-mediated HDV spread. An LGP2 variant (Q425R), predominating in Africans who develop less severe chronic hepatitis D, mediated detectably higher basal and faster HDV-induced IFN responses, as well as stronger HDV suppression. Thus, the natural Q425R LGP2 is a gain-of-function variant and may contribute to an attenuated course of hepatitis D. Not all sequelae of chronic hepatitis C appear to be completely reversible after sustained virologic response (SVR). aimed to investigate whether chronic HCV infection is associated with epigenetic changes and biological age acceleration and whether this is reversible after SVR. The authors show that individuals with HCV had an overall significant epigenetic age acceleration (EAA) of 3.12 years at baseline compared with 2.61 years in the age-and sex-matched reference group. HCV elimination resulted in a significant long-term increase in DNA methylation, EAA decreased to 1.37 years at long-term follow-up. Interestingly, eight individuals who developed hepatocellular carcinoma after SVR had the highest EAA and showed no evidence of reversal after SVR. In alcohol-related hepatitis (AH) neutrophil count increases and is associated with poor clinical outcomes; however, the mechanisms of neutrophil-mediated liver damage remain unclear. have shown that neutrophil depletion significantly ameliorates liver damage in a mouse model of AH. There are several neutrophil subpopulations and by studying serum samples from individuals with AH, the authors showed that high density neutrophils (HDNs) were activated and produce neutrophil extracellular traps (NETs), which contribute to liver damage. They also identified low density neutrophils (LDNs) that have opposing transcriptomic profiles and exhibit exhausted/defective phenotypes. Moreover, alcohol can induce NET release by HDNs, which then switch to an LDN phenotype. Thus, these results provide a mechanistic explanation for the paradox of previously observed neutrophil activation and dysfunction in AH. Since LDNs remain in the circulation and the liver for longer, they could be associated with the high susceptibility to infections observed in those with AH. Further, the authors tested two therapeutic approaches in mice: the first involved antibody-mediated neutrophil depletion, which resulted in the elimination of both NET-producing HDNs and defective LDNs. The other involved G-CSF administration, which prevented NET formation and reduced alcohol-related liver damage. These results are important as they provide new insights into neutrophil-mediated inflammation and liver damage in AH. Some studies have associated NAFLD with mild cerebral dysfunction and cognitive decline. used a high-fat diet-induced steatosis model and demonstrated anxiety and depression-mediated behaviour in the mice. They also showed low-grade brain tissue hypoxia, likely attributed to the low-grade brain inflammation, and decreased cerebral blood volume, accompanied by morphological and metabolic alterations (higher oxygen consumption) in the microglia and astrocytes, suggesting the early stages of an obesogenic diet-induced encephalopathy. The authors then used the same NAFLD model but in Mct1 haploinsufficient mice and showed that, despite fat accumulation in adipose tissue, these mice were protected from NAFLD and associated cerebral alterations. MCT-1 is a carrier of short-chain fatty acids, ketone bodies, and lactate in several tissues, playing an important role in energy homeostasis. It could therefore be a potential new therapeutic target. Secretin/secretin receptor (SCT/SR) signalling is a major regulator of biliary homeostasis as it modulates the “bicarbonate umbrella”, a protective mechanism whereby cholangiocytes release bicarbonate to reduce damage from toxic bile acids. used transgenic mice expressing a dominant-negative form of human transforming growth factor-beta receptor II, which can be used as a model of late-stage primary biliary cholangitis (PBC), as well as serum, bile and liver samples from individuals with stage III/IV PBC. They observed a reduction in SCT and SR expression, in particular in primary PBC cholangiocytes, suggesting a blunted biliary SCT/SR axis in late-stage PBC. The authors demonstrated that, in late-stage PBC, impairment of SCT/SR downregulates the “bicarbonate umbrella”, induces loss of mature cholangiocyte differentiation and mucin secretion and leads to enhanced ductular reaction, triggering liver fibrosis and inflammation. They then studied the effects of SCT administration. SCT reduced hepatic bile acid content, cholangitis activity, immune cell infiltration and collagen deposition. It restored the loss of ductulo-canalicular junction connections, and mucin secretion, and restored bile duct loss, supporting bile flow and bile duct system integrity. Through these choleretic effects and the restoration of the bicarbonate umbrella, secretin could be of therapeutic value for late-stage PBC. aimed to assess the feasibility and potential clinical benefits of remote management of individuals with acute decompensation (AD) of cirrhosis. Twenty individuals with cirrhosis and AD (mean age 59±10 years, 14 male, 80 % with alcohol-related aetiology, mean MELD-Na score 16.1±4.2) and 20 controls with no statistically different demographic and clinical variables were enrolled. Heart rate, blood pressure, weight, %body water, cognitive function, self-reported well-being and intake of food, fluid and alcohol were recorded daily with the use of commercially available monitoring devices linked to a smartphone (CirrhoCare® app). Independent external adjudicators assessed appropriateness of CirrhoCare®-based decisions. The length of the follow-up was 10.1±2.4 weeks. Fifteen patients showed good engagement (≥4 readings/week), 2 moderate (2-4/week), and 3 poor (<2/week). Five CirrhoCare®-managed patients had 8 readmissions, and none required hospitalization for >14 days. Sixteen other CirrhoCare®-guided patient contacts were made, leading to clinical interventions that prevented further progression. Appropriateness was confirmed by adjudicators. Controls had 13 readmissions in 8 patients, lasting a median of 7 days with 4 admissions of >14 days. They had 6 unplanned paracenteses compared to 1 in the CirrhoCare® group. Thus, the authors concluded that CirrhoCare® is feasible for community-management of individuals with decompensated cirrhosis and alerts clinicians to new decompensating events. Long-term anticoagulation is not recommended by CPGs in non-cirrhotic portal vein thrombosis (NC-PVT) without underlying thrombophilia due to a very low risk of recurrent thrombosis (RT). In this multicentre retrospective observational study, aimed to describe the incidence of RT in patients with NC-PVT without an indication for long-term anticoagulation. The second aim was to identify RT risk factors and then verify them in a validation cohort. Risk factors for RT in 64 individuals with NC-PVT of idiopathic/local aetiology were evaluated. In a subgroup of 48, the potential value of additional thrombophilic parameters was analysed. Findings were validated in 70 independent individuals with idiopathic/local NC-PVT. Of the 64 individuals in the original cohort, 17 presented splanchnic and/or extra-splanchnic RT (overall-RT) during follow-up. Splanchnic RT was asymptomatic in 53% of the cases. No clinical or biochemical parameters predicted overall-RT. However, in the 48 individuals with additional comprehensive thrombophilic study, factor VIII ≥150% was the only independent factor predicting overall-RT. In the validation cohort, 19 individuals presented overall-RT, and the predictive value of factor VIII was confirmed. Thus, individuals with idiopathic/local NC-PVT appear to be at risk of overall-RT. Splanchnic RT can be asymptomatic and requires screening for its detection. Values of factor VIII ≥150% may help select patients at high risk of overall-RT who could benefit from long-term anticoagulation. The possibility to use objective tumour response as a predictor of overall survival (OS) is important for the clinical development of new drugs for hepatocellular carcinoma (HCC). REFLECT is a phase III randomised clinical trial that compared lenvatinib with sorafenib. analysed the potential association between OS and objective response assessed by investigators (INV) and independent radiologists (IR) using ordinary (RECIST 1.1) and modified RECIST (mRECIST) criteria. OS was significantly better in responders than in non-responders using IR-RECIST 1.1 (0.50), IR-mRECIST (HR 0.61), and INV-mRECIST (HR 0.61). Similarly, survival rates at 2, 4, and 6 months after randomization were also better for responders using the 3 criteria. An exploratory multivariate Cox regression analysis showed that objective response by IR-RECIST 1.1 (HR 0.49) and INV-mRECIST (HR 0.55) were independent predictors of OS. Additional studies are nevertheless needed to confirm surrogacy. YAP is a transcriptional co-activator and the effector protein of the Hippo signalling pathway, which regulates a number of cell functions linked to cell proliferation and prevention of apoptosis. Notably, YAP is aberrantly activated in many cancers, including cholangiocarcinoma (CCA). On the other hand, LCK is a protein tyrosine kinase that activates YAP and NTRC 0652 is a novel tyrosine kinase inhibitor with relative selectivity for LCK. studied the effects of LCK inhibition in vitro and in vivo. NTRC 0652-0 resulted in apoptotic cell death in CCA cell lines and in a subset of patient-derived organoids. In particular, CCA with FGFR2 fusions were identified as a clinically relevant genetic subset. In PDX models of FGFR2 fusion-positive CCA, treatment with NTRC 0652-0 showed acceptable toxicity, decreased YAP tyrosine phosphorylation, and significant antitumor activity. These findings warrant clinical testing of this strategy in patients with CCA and FGFR2 fusions. CD4+CD25+Foxp3+ regulatory T cells (Tregs) are essential to maintain immunological tolerance and have been shown to promote liver allograft tolerance both in rodents and humans. Low dose interleukin-2 (LDIL-2) can expand human endogenous circulating Tregs in vivo, but its role in promoting Treg trafficking to the sites of inflammation is unknown. conducted a clinical trial in stable liver recipients 2-6 years post-transplant to determine the capacity of LDIL-2 to suppress allospecific immune responses and allow for the complete discontinuation of maintenance immunosuppression. One month after initiating LDIL-2, patients exhibiting at least a 2-fold increase in circulating Tregs gradually discontinued immunosuppression over a 4-month period while continuing LDIL-2. All patients achieved a marked and sustained increase in circulating Tregs, but this was not associated with the preferential expansion of donor-reactive Tregs nor the accumulation of intrahepatic Tregs. The trial was terminated after the first six participants failed to reach the primary endpoint due to rejection requiring immunosuppression reinstitution. The authors concluded that the expansion of circulating Tregs in response to LDIL-2 is not sufficient to control alloimmunity and to promote liver allograft tolerance. Patrizia Burra∗ at Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy. Frank Tacke at Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany. Vlad Ratziu at Insitute for Cardiometabolism and Nutrition, Sorbonne Université and Hospital Pitié Salpêtrière, Paris, France. Stefan Zeuzem at Department of Medicine I, Goethe University Hospital, Frankfurt, Germany. Bruno Sangro at Liver Unit, Clinica Universidad Navarra and CIBEREHD, Pamplona, Spain. Paolo Angeli at Unit of Internal Medicine and Hepatology, University of Padua, Padua, Italy.