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Alcoholic liver disease (ALD) caused by excessive drinking is a health and economic concern worldwide. Given the high morbidity, mortality, and the progressive nature of ALD, finding effective interventions is essential. Previous studies have confirmed that edible food plants and their bioactive compounds exert a protective effect against ALD. Dracocephalum tanguticum Maxim ( DTM ) is one of the important traditional Tibetan medicines in China with the effect of clearing away liver heat, used for the treatment of hepatitis. In this study, the DTM chloroform extract ( DtM-C ), ethyl acetate extract ( DtM-E ), and n-butanol extract ( DtM-B ) were obtained by ethanol extraction combined with fractional extraction. Acute ALD was induced in mice given intragastric ethanol. Serum and liver biochemical markers were detected by ELISA. Liver histological observation, Oil Red O, and Masson’s trichrome staining were performed. Liver injury cells were induced by ethanol. The cell vitality was detected by using MTT colorimetry. The expressions of Nrf2, NF-κB, STAT3, AP-1, CREB, HIF-1α, HO-1, NQO-1, GSTA1, IKB2, and Keap1 were detected by real-time polymerase chain reaction (PCR) to elucidate the mechanism of hepatoprotective effect, and the results were verified by using Western blot. The results of serum liver function indicators (ALT, AST, and ADH), serum hepatic lipid indicators (TC, TG, HDL-C, and LDL-C), and lipid peroxidation indicators (ADH, MDA, SOD, CAT, and GSH-Px) in liver tissue and liver histological observation showed that DtM-E could improve liver function, alleviate fatty degeneration, edema, cell necrosis, and liver fibrosis caused by alcohol. DtM-E also increased the vitality of EtOH-induced liver injury cells, upregulated the mRNA expression of Nrf2, HO-1, NQO-1, and GSTA1, while downregulated the expression of Keap-1, p65, and NF-κB. Western blot results were consistent with PCR. The results suggest that DtM-E has a protective effect against ALD in vitro and in vivo , and its mechanism of action may be related to the activation of Nrf2/Keap-1 and inhibition of the P65/NF-κB signaling pathways.

The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set up in 2004 on acute-on-chronic liver failure (ACLF) was published in 2009. With international groups volunteering to join, the “APASL ACLF Research Consortium (AARC)” was formed in 2012, which continued to collect prospective ACLF patient data. Based on the prospective data analysis of nearly 1400 patients, the AARC consensus was published in 2014. In the past nearly four-and-a-half years, the AARC database has been enriched to about 5200 cases by major hepatology centers across Asia. The data published during the interim period were carefully analyzed and areas of contention and new developments in the field of ACLF were prioritized in a systematic manner. The AARC database was also approached for answering some of the issues where published data were limited, such as liver failure grading, its impact on the ‘Golden Therapeutic Window’, extrahepatic organ dysfunction and failure, development of sepsis, distinctive features of acute decompensation from ACLF and pediatric ACLF and the issues were analyzed. These initiatives concluded in a two-day meeting in October 2018 at New Delhi with finalization of the new AARC consensus. Only those statements, which were based on evidence using the Grade System and were unanimously recommended, were accepted. Finalized statements were again circulated to all the experts and subsequently presented at the AARC investigators meeting at the AASLD in November 2018. The suggestions from the experts were used to revise and finalize the consensus. After detailed deliberations and data analysis, the original definition of ACLF was found to withstand the test of time and be able to identify a homogenous group of patients presenting with liver failure. New management options including the algorithms for the management of coagulation disorders, renal replacement therapy, sepsis, variceal bleed, antivirals and criteria for liver transplantation for ACLF patients were proposed. The final consensus statements along with the relevant background information and areas requiring future studies are presented here.Updated on the basis of AARC data of >3300 cases enrolled into AARC registry prospectivelyACLF is distinct form Acute Decompensation of cirrhosisNewer sections on DILI-ACLF, AIH-ACLF, PVT/HVOTO–ACLFReversibility of Chronic Liver Disease in ACLFPortal and systemic hemodynamics and their relevance in ACLFAcute Portal Hypertension and Variceal progression in ACLFAARC score as a guide for treatment strategies in ACLFACLF in Children-first consensus on pediatric ACLF

Macrophages are important immune cells in innate immunity, and have remarkable heterogeneity and polarization. Under pathological conditions, in addition to the resident macrophages, other macrophages are also recruited to the diseased tissues, and polarize to various phenotypes (mainly M1 and M2) under the stimulation of various factors in the microenvironment, thus playing different roles and functions. Liver diseases are hepatic pathological changes caused by a variety of pathogenic factors (viruses, alcohol, drugs, etc.), including acute liver injury, viral hepatitis, alcoholic liver disease, metabolic-associated fatty liver disease, liver fibrosis, and hepatocellular carcinoma. Recent studies have shown that macrophage polarization plays an important role in the initiation and development of liver diseases. However, because both macrophage polarization and the pathogenesis of liver diseases are complex, the role and mechanism of macrophage polarization in liver diseases need to be further clarified. Therefore, the origin of hepatic macrophages, and the phenotypes and mechanisms of macrophage polarization are reviewed first in this paper. It is found that macrophage polarization involves several molecular mechanisms, mainly including TLR4/NF-κB, JAK/STATs, TGF-β/Smads, PPARγ, Notch, and miRNA signaling pathways. In addition, this paper also expounds the role and mechanism of macrophage polarization in various liver diseases, which aims to provide references for further research of macrophage polarization in liver diseases, contributing to the therapeutic strategy of ameliorating liver diseases by modulating macrophage polarization.

Background‘Acute-on-chronic liver failure’ (ACLF) is characterised in a more advanced stage by liver failure associated with multiple other end-organ failure. The global clinical characteristics of this entity remain, however, ill-defined.ObjectiveTo characterise and evaluate the clinicopathological features of patients with ACLF compared with patients with chronic decompensated cirrhosis (CHD) in a prospective, homogeneous cohort of patients with histologically proven alcoholic cirrhosis from 2002 to 2007.ResultsIn total 250 patients were screened (ACLF (n=70, 28%) and CHD (n=180, 72%)). Alcoholic liver disease was observed in respectively 61/70 (87%) of patients with ACLF and 72/180 (40%) of patients with CHD. After exclusion of 31 patients, 102 patients were studied: 54 with ACLF (median age 51 years; Child–Pugh 12±2; in-hospital mortality 46% (25/54)) and 48 patients with CHD (median age 53 years; Child–Pugh 10±2; in-hospital mortality 10% (5/48)). In the patients with ACLF who survived the hospital stay, the difference in transplant-free survival compared with patients with CHD tended to attenuate with time. At admission the apparent infection of patient groups was comparable but during hospitalisation infection occurred more frequently in patients with ACLF (31/53 (58%)) than in those with CHD (12/47=26%) (p=0.007). Early signs of infection, positive systemic inflammatory response syndrome (SIRS) criteria at admission and ductular bilirubinostasis (p=0.04), were early features that predicted outcome in ACLF.ConclusionPatients with ACLF have a high short-term mortality but those who survived the acute exacerbation show a long-term outcome comparable to that of patients with CHD. Infection is the most common cause of mortality in these patients. Positive SIRS criteria and ductular bilirubinostasis are early markers of ACLF and might allow more rapid identification of high-risk patients.

Background Patients with a history of metabolic and bariatric surgery (MBS) are susceptible to developing alcohol use disorder, potentially resulting in end‐stage liver disease, with a paucity of data on the evolution of cirrhosis. Aims Our aim was to describe the demographics and mortality in hospitalizations over time in individuals diagnosed with cirrhosis due to alcohol‐associated liver disease (ALD) in relation to prior MBS. Methods We included patients hospitalized at the Ghent University Hospital between 1/1/2010 and 01/09/2023 with cirrhosis due to ALD. Data were retrieved retrospectively from all hospitalizations. Results 46/275 (16.7%) of individuals with cirrhosis admitted with ALD had a history of MBS; they were predominantly female (76.1%), in contrast to the non‐MBS population (29.7%) (p < 0.0001) and were significantly younger at the time of diagnosis (46 vs. 58 years, p < 0.0001). Liver disease evolved at a faster pace in the MBS group with a shorter time to first hospitalization (5 vs. 13 months, p = 0.036), and consecutive hospitalizations. The proportion with primary hospitalization due to acute‐on‐chronic liver failure (ACLF) was significantly larger in the MBS group (60.9% vs. 27.6%, p < 0.0001), and throughout the following hospitalizations, ACLF remained more prevalent in the MBS group. Modeled transplant‐free survival was lower in the MBS group (p = 0.004), with ACLF as the main cause of death. The weekly amount of alcohol consumed during drinking periods and duration of use were significantly lower in the MBS group. Conclusions MBS patients hospitalized with ALD develop acute decompensation at a faster pace, with more overall ACLF hospitalizations, and higher cumulative mortality, despite being 12 years younger on average. Clinical trial registration Not applicable. We examined the clinical significance of prior metabolic and prior bariatric surgery in patients hospitalized with alcohol‐associated liver disease in a single‐center retrospective study of 275 patients between 2000 and 2023. Patients with prior bariatric surgery were younger and predominantly female. Individuals with cirrhosis hospitalized with alcohol‐associated liver disease develop acute decompensations at a faster pace, resulting in a significantly higher mortality.

Background and AimCytokine storm has been reported in patients with coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. We examine the incidence of acute on chronic liver failure (ACLF) in COVID-19 patients with pre-existing compensated chronic liver disease (CLD).MethodsFrom 20 Jan 2020 to 7 Feb 2020, we studied 140 consecutive COVID-19 patients admitted to either Fuyang Second People’s Hospital (FYSPH), Anhui or the Fifth Medical Center of Chinese PLA General Hospital (PLAGH) in Beijing, China. Pre-existing CLD includes those with liver cirrhosis assessed by APRI/FIB-4 score and /or ultrasound; NAFLD as identified by either ultrasound or hepatic steatosis index with significant liver fibrosis and chronic hepatitis B (CHB) or hepatitis C (CHC) infection. The diagnosis, grading of severity and clinical management of COVID-19 patients complied to the guideline and clinical protocol issued by the China National Health Commission. All patients had liver function test at least twice weekly till discharge with full recovery or death.ResultsIn total, 3 had liver cirrhosis, 6 patients had CHB, 13 had NAFLD with significant liver fibrosis (one also had CHB). On admission, none had liver decompensation. COVID-19 disease progression was significantly less frequent in non-CLD patients (10/118 8.5%) than CLD patients (13/22 59.1%, p < 0.001). One patient with CLD had acute-on-chronic liver failure (ACLF).ConclusionDisease progression is significantly higher in those COVID-19 patients with CLD as compared to those with no CLD. ACLF can also occur in patient with pre-existing compensated CLD who had severe COVID-19.

Background Peroxisome proliferator-activated receptor (PPAR) agonists may have favorable outcomes on non-alcoholic fatty liver disease. This study serves as proof of concept to evaluate whether dual PPAR-α/γ agonists improve non-invasive tests of liver steatosis and fibrosis. Methods This is a post-hoc analysis of a randomized, double-blind, placebo-controlled, multi-center trial comprising 7226 patients with type 2 diabetes mellitus and recent coronary artery disease randomized to receive aleglitazar, a PPAR-α/γ agonists, or placebo for two years. Main outcomes were change in non-invasive tests for liver steatosis and fibrosis: Liver Fat Score (LFS), Liver Accumulation Product (LAP), Fibrosis-4 (FIB-4), and NAFLD Fibrosis Score (NFS). Results LFS, LAP and FIB-4 decreased upon treatment, whereas scores in the placebo group remained the same or increased (P<0.001). NFS responded differently but remained consistently lower than placebo. In the treatment group more participants shifted to a lower FIB-4 and NFS category, or improved in respect to the LAP cut-off values compared to the placebo group (P<0.001 for FIB-4 and LAP, P<0.004 for NFS). LFS had a low discriminative power in this study. Conclusion This post-hoc analysis showed improvement of non-invasive tests of liver steatosis and fibrosis after starting dual PPAR-α/γ agonist treatment, adding to the evidence that this pathway has potential in non-alcoholic fatty liver disease treatment.

Advancements in omics technologies and artificial intelligence (AI) methodologies are fuelling our progress towards personalised diagnosis, prognosis and treatment strategies in hepatology. This review provides a comprehensive overview of the current landscape of AI methods used for analysis of omics data in liver diseases. We present an overview of the prevalence of different omics levels across various liver diseases, as well as categorise the AI methodology used across the studies. Specifically, we highlight the predominance of transcriptomic and genomic profiling and the relatively sparse exploration of other levels such as the proteome and methylome, which represent untapped potential for novel insights. Publicly available database initiatives such as The Cancer Genome Atlas and The International Cancer Genome Consortium have paved the way for advancements in the diagnosis and treatment of hepatocellular carcinoma. However, the same availability of large omics datasets remains limited for other liver diseases. Furthermore, the application of sophisticated AI methods to handle the complexities of multiomics datasets requires substantial data to train and validate the models and faces challenges in achieving bias-free results with clinical utility. Strategies to address the paucity of data and capitalise on opportunities are discussed. Given the substantial global burden of chronic liver diseases, it is imperative that multicentre collaborations be established to generate large-scale omics data for early disease recognition and intervention. Exploring advanced AI methods is also necessary to maximise the potential of these datasets and improve early detection and personalised treatment strategies.

ObjectiveMonocyte chemoattractant protein-1 (MCP-1, CCL2), the primary ligand for chemokine receptor C–C chemokine receptor 2 (CCR2), is increased in livers of patients with non-alcoholic steatohepatitis (NASH) and murine models of steatohepatitis and fibrosis. It was recently shown that monocyte/macrophage infiltration into the liver upon injury is critically regulated by the CCL2/CCR2 axis and is functionally important for perpetuating hepatic inflammation and fibrogenesis. The structured L-enantiomeric RNA oligonucleotide mNOX-E36 (a so-called Spiegelmer) potently binds and inhibits murine MCP-1. Pharmacological inhibition of MCP-1 with mNOX-E36 was investigated in two murine models of chronic liver diseases.MethodsPharmacological inhibition of MCP-1 by thrice-weekly mNOX-E36 subcutaneously was tested in murine models of acute or chronic carbon tetrachloride (CCl4)- and methionine–choline-deficient (MCD) diet-induced chronic hepatic injury in vivo.ResultsAntagonising MCP-1 by mNOX-E36 efficiently inhibited murine monocyte chemotaxis in vitro as well as migration of Gr1+ (Ly6C+) blood monocytes into the liver upon acute toxic injury in vivo. In murine models of CCl4- and MCD diet-induced hepatic injury, the infiltration of macrophages into the liver was significantly decreased in anti-MCP-1-treated mice as found by fluorescence-activated cell sorting (FACS) analysis and immunohistochemistry. In line with lower levels of intrahepatic macrophages, proinflammatory cytokines (tumour necrosis factor α, interferon γ and interleukin 6) were significantly reduced in liver tissue. Overall fibrosis progression over 6 (CCl4) or 8 weeks (MCD diet) was not significantly altered by anti-MCP-1 treatment. However, upon MCD diet challenge a lower level of fatty liver degeneration (histology score, Oil red O staining, hepatic triglyceride content, lipogenesis genes) was detected in mNOX-E36-treated animals. mNOX-E36 also ameliorated hepatic steatosis upon therapeutic administration.ConclusionsThese results demonstrate the successful pharmacological inhibition of hepatic monocyte/macrophage infiltration by blocking MCP-1 during chronic liver damage in two in vivo models. The associated ameliorated steatosis development suggests that inhibition of MCP-1 is an interesting novel approach for pharmacological treatment in liver inflammation and steatohepatitis.

Lactate is a byproduct of glycolysis, and before the Warburg effect was revealed (in which glucose can be fermented in the presence of oxygen to produce lactate) it was considered a metabolic waste product. At present, lactate is not only recognized as a metabolic substrate that provides energy, but also as a signaling molecule that regulates cellular functions under pathophysiological conditions. Lactylation, a post-translational modification, is involved in the development of various diseases, including inflammation and tumors. Liver disease is a major health challenge worldwide. In normal liver, there is a net lactate uptake caused by gluconeogenesis, exhibiting a higher net lactate clearance rate compared with any other organ. Therefore, abnormalities of lactate and lactate metabolism lead to the development of liver disease, and lactate and lactate metabolism-related genes can be used for predicting the prognosis of liver disease. Targeting lactate production, regulating lactate transport and modulating lactylation may be potential treatment approaches for liver disease. However, currently there is not a systematic review that summarizes the role of lactate and lactate metabolism in liver diseases. In the present review, the role of lactate and lactate metabolism in liver diseases including liver fibrosis, non-alcoholic fatty liver disease, acute liver failure and hepatocellular carcinoma was summarized with the aim to provide insights for future research.