Heart failure (HF) is a major cause of morbidity and mortality worldwide and is frequently associated with dysfunction of other organs, including the liver. Hepatic congestion and impaired perfusion from cardiac dysfunction may lead to liver injury, described as cardiohepatic syndrome. Studies suggest that liver dysfunction markers, such as the Model for End-Stage Liver Disease (MELD) and MELD excluding international normalized ratio (MELD-XI) scores, may serve as prognostic indicators in HF patients. This systematic review and meta-analysis evaluated the relationship between liver dysfunction markers and mortality outcomes in HF patients. A systematic literature search was conducted. Studies evaluating the association between liver dysfunction markers (MELD or MELD-XI scores) and mortality outcomes in adult HF patients were included. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using the generic inverse variance method with a random-effects model in Review Manager (RevMan) version 5.4 (The Cochrane Collaboration, Copenhagen, Denmark). Subgroup analyses were performed by liver dysfunction marker type and HF phenotype. The primary outcome was all-cause mortality. Nine studies comprising over 32,000 HF patients were included. Elevated liver dysfunction markers were significantly associated with increased mortality risk (pooled HR = 1.12, 95% CI 1.06-1.18). Substantial heterogeneity was observed (I² = 91%). Subgroup analysis showed significant associations for both MELD-XI (HR = 1.09, 95% CI 1.04-1.14) and MELD scores (HR = 1.10, 95% CI 1.06-1.14). Analysis by HF type revealed significant associations in acute HF (HR = 1.07), chronic HF (HR = 1.23), and advanced HF (HR = 1.05). Sensitivity analyses confirmed the findings, with no substantial publication bias observed. Elevated liver dysfunction markers significantly correlate with increased mortality in HF patients. Both MELD and MELD-XI scores provide prognostic information across HF populations. These findings emphasize the importance of considering hepatic dysfunction in HF assessment and suggest liver dysfunction markers may aid risk stratification. Further prospective studies are needed to determine the role of these markers in clinical decision-making.

The heterogeneity in ACLF definitions proposed by different expert associations worldwide has led to variations in clinical phenotypes and prognosis. This study proposes a new approach for a unified definition based on the type of organ failure within the first week of disease onset.This prospective cohort study collected clinical data from hospitalized ACLF patients presenting with liver failure (total bilirubin ≥ 5 mg/dL, INR ≥ 1.5) across four liver centers in China. Patients with liver failure within the first week of onset were classified as Type I ACLF, while those with concurrent extrahepatic organ failure were categorized as Type II ACLF. We compared the clinical characteristics and prognosis of Type I and Type II ACLF patients, as well as the inclusivity of these classifications within existing mainstream ACLF definitions.A total of 846 patients were included in the analysis population. Type I ACLF occurred in 86.9% of cases, primarily in patients with non-cirrhotic chronic liver disease (34.3%) or compensated cirrhosis (48.6%), while Type II ACLF, observed in 13.1% of cases, predominantly developed in patients with cirrhosis (73%) (P < 0.001). Mortality rates at 28 and 90 days were significantly higher in Type II ACLF patients (43.2% and 52.3%) compared to those with Type I ACLF (15.8% and 24.9%) (P < 0.001). Patients with Type I ACLF met the APASL criteria more frequently (82.9%), whereas those with Type II ACLF more often met the EASL criteria (69.4%). For predicting the 90-day prognosis in Type I ACLF, the COSSH-ACLF II score achieved the highest AUROC at 0.788 (95% CI: 0.749-0.828). In Type II ACLF, the CLIF-C OF score provided the highest AUROC for predicting 90-day mortality, at 0.902 (95% CI: 0.840-0.964), outperforming the MELD, MELD-Na, and COSSH-ACLF II scores (P < 0.05) and showing no significant difference when compared to the CLIF-C ACLF score (0.872 [95% CI: 0.791-0.953], P = 0.426).This new clinical classification approach takes into account the characteristics defined by both Eastern and Western ACLF, and is expected to improve the comparability and interpretability of data in global studies, enhancing global understanding and management of ACLF.

Disseminated intravascular coagulation (DIC) is a critical complication of systemic illness, and its diagnosis can be especially challenging in patients with cirrhosis, where baseline liver-related coagulopathy may mask the development of superimposed consumptive coagulopathy. In the setting of sepsis and liver dysfunction, DIC may progress to purpura fulminans (PF), a rare, life-threatening condition characterized by dermal necrosis and microvascular thrombosis. We present the case of a 54-year-old man with alcoholic cirrhosis and untreated hepatitis C who developed DIC and PF following methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia and toxic shock syndrome (TSS). Despite treatment with antibiotics, transfusions, intravenous immunoglobulin (IVIG), and hemodialysis, he developed multiorgan failure. This case highlights that in patients with sepsis and cirrhosis, acutely worsening coagulation parameters, falling fibrinogen, and evolving purpuric or necrotic skin lesions should not be attributed to liver disease alone but should instead prompt urgent evaluation for DIC and PF. The early recognition of this distinction is essential to guide timely multidisciplinary intervention in this rare but devastating complication.

GIM/FP/GP:[Formula: see text] Gastroenterology:[Formula: see text] Critical Care:[Formula: see text].

Drug-induced liver injury (DILI) can lead to potentially fatal complications, such as acute liver failure and even death. In clinical practice, glucocorticoids have been considered in some cases of DILI, especially those with hyperbilirubinemia. However, the available evidence remains controversial and its quality is also very limited.

Acute-on-chronic liver failure (ACLF) is a highly lethal clinical syndrome with limited effective therapeutic options. Urine-derived stem cells (USCs) represent a non-invasive and readily accessible cell source, but whether USCs obtained from patients with severe liver dysfunction retain therapeutic and immunomodulatory potential remains unclear.

Liver transplantation remains the definitive treatment for end-stage liver disease and acute liver failure, yet a critical and persistent shortage of donor organs results in thousands of preventable deaths annually worldwide. Xenotransplantation has emerged as a potential solution to this structural deficit. This narrative review traces the evolution of liver xenotransplantation, from early non-human primate trials in the 1960s through the application of CRISPR/Cas9-driven multi-gene editing platforms in contemporary porcine donors. The immunological barriers that drove the transition from primate to porcine donors are examined, including hyperacute rejection mediated by anti-α-Gal antibodies, coagulation dysregulation and xenograft thrombotic microangiopathy. The genetic engineering strategies underlying current triple-knockout, ten-gene-edited donor pigs are reviewed alongside the preclinical non-human primate evidence establishing biological feasibility. The three pig-to-human liver xenotransplantation studies published between 2025 and 2026 are then analyzed, encompassing heterotopic auxiliary transplantation in a brain-dead decedent, extracorporeal liver cross-circulation and the first auxiliary liver xenotransplantation in a living recipient with a documented 171-day survival. These cases collectively provide preliminary evidence supporting proof-of-concept for porcine hepatic bridging therapy, with current evidence supporting a role for xenogeneic liver support as a temporary bridge to recovery or allotransplantation rather than definitive organ replacement. Xenograft thrombotic microangiopathy is identified as the principal remaining biological barrier, and the substantial translational challenges, including reproducibility, scalability and regulatory readiness that must be resolved before broader clinical application can be considered.

Background/Objectives: Acute-on-chronic liver failure (ACLF) is a severe syndrome in chronic liver disease (CLD) patients, characterized by multi-organ failure and high mortality. Living donor liver transplantation (LDLT) is vital in donor-scarce areas. This study compares baseline characteristics, perioperative complications, and long-term survival between ACLF and non-ACLF patients, emphasizing etiology, ACLF grading, and graft factors. Methods: Data from a prospective registry of 591 adult LDLT recipients (2019-2023) were analyzed. ACLF was defined by EASL-CLIF (multi-organ failure, grades 1-3) and APASL (jaundice/coagulopathy with complications) criteria, evaluated at initial assessment and within 24 h pre-LDLT. Results: ACLF patients (n = 101, 17.1%) showed higher MELD-Na (27 vs. 20, p < 0.001), bilirubin (6.84 vs. 1.75 mg/dL, p < 0.001), creatinine (108 vs. 70.5 μmol/L, p < 0.001), metabolic/genetic etiologies (9.9% vs. 2.8%, p = 0.001), and chronic kidney disease (23.7% vs. 8.1%, p < 0.001), and lower HCC rates (11.8% vs. 29.6%, p < 0.001). GRWR was marginally lower in ACLF patients (0.59 vs. 0.66, p = 0.10). The ACLF group had elevated infection (27.7% vs. 10.4%, p < 0.001), bleeding (14.9% vs. 6.3%, p = 0.004), and biliary complications (15.8% vs. 7.8%, p = 0.010), with longer ICU (5 vs. 3 days, p < 0.001) and hospital stays (33.66 vs. 20.7 days, p = 0.036). Five-year overall survival was reduced in ACLF patients (log-rank p = 0.001), worsening with grade (EASL-CLIF grade 3: 55% vs. 81% for no ACLF, p = 0.002). Graft survival was also lower (75% vs. 85%, p = 0.02). Multivariable analysis identified chronic kidney disease as an independent mortality predictor (HR 2.09, 95% CI 1.11-3.95, p = 0.023). Conclusions: LDLT for ACLF involves higher perioperative risks and poorer long-term survival than non-ACLF patients, with outcomes deteriorating by ACLF grade. Chronic kidney disease independently predicts mortality. Timely LDLT is essential in donor-limited regions.

Acute liver failure is often accompanied by neurological disturbances collectively referred to as hepatic encephalopathy (HE), characterized by neuroinflammation and subsequent cognitive decline. Insulin-like growth factor 1 (IGF1) is a neuroprotective peptide with anti-inflammatory properties in the brain. The role of IGF1 in cognitive deficits and neuroinflammation during HE remains largely unexplored. In C57Bl/6 mice, HE was established through an intraperitoneal injection of azoxymethane (AOM), and tissues were collected at defined time points during disease development. IGF1 expression in the cortex was downregulated following AOM administration. Central infusion of recombinant mouse IGF1 (rmIGF1) before AOM injection resulted in delayed neurological impairment, reduced microglial activation, and decreased proinflammatory cytokine and chemokine production in AOM mice. In vitro, rmIGF1 and conditioned media derived from rmIGF1-treated primary neurons attenuated phagocytic activity and C-C motif chemokine ligand 2 (CCL2) production in the microglial cell line EOC-20. Collectively, our results show that IGF1, whose levels decline during HE, alleviates neuroinflammation and improves the pathological state of AOM-treated mice through the suppression of microglial activation and the regulation of neuron-microglia paracrine communication.

Alcoholic liver disease (ALD), secondary to chronic alcohol abuse, encompasses a spectrum of liver disorders that progress from steatosis and hepatitis to fibrosis, cirrhosis, and acute-on-chronic liver failure. It poses a considerable global health burden due to its elevated rates of associated morbidity and mortality. The rising prevalence of ALD, coupled with the lack of approved pharmacotherapies, presents considerable unmet clinical needs. In this study, long-chain acyl-CoA synthetase 4 (ACSL4) was identified as a pathogenic driver in the context of chronic alcohol consumption. Hepatocyte Acsl4 ablation mitigated key pathological manifestations in Gao-Binge model mice, as evidenced by reduced inflammatory cell infiltration and attenuated lipid accumulation. Mechanistically, ACSL4 inhibition augmented cellular antioxidant defence through elevating gamma-glutamylcysteine (γ-GC) levels. In addition, γ-GC bound to and suppressed the expression of protein tyrosine phosphatase type IVA member 1 (PTP4A1). Both genetic silencing and pharmacological inhibition of PTP4A1 attenuated the activation of the downstream MAPK-NF-κB inflammatory cascade. Dronedarone, identified as a novel compound targeting ACSL4, demonstrated efficacy in ameliorating the progression of ALD. Overall, these findings elucidate a novel mechanism wherein ACSL4 modulates antioxidant responses via a small bioactive peptide, highlighting ACSL4 as a potential therapeutic target for ALD.

A major challenge in many liver diseases is the lack of highly sensitive, specific, and minimally invasive biomarkers. Cell-free DNA (cfDNA) methylation compensates for the limitations of existing biomarkers and exhibits substantial clinical application potential in a variety of liver diseases, notably hepatocellular carcinoma (HCC). A systematic literature search was conducted in the PubMed, Web of Science Core Collection, and Cochrane Library databases from 1 January 2000, to 31 December 2025.

Recent advances in xenotransplantation have gained substantial public and clinical attention as genetically modified porcine organs are now being transplanted into living human recipients. While only case reports have been published to date, the first clinical trials for kidney xenotransplantation are now ongoing. This transition to clinical practice presents multiple implementation challenges for establishing scalable transplant programs while ensuring patient safety. Machine perfusion is expected to play a critical role in addressing these challenges by serving as a central platform for organ preservation, assessment, transport, and therapeutic intervention. Given the limited number of designated pathogen-free (DPF) breeding facilities, regional and international organ transport depends on robust preservation strategies during transit. Additionally, perfusion devices enable essential pre-transplant screening for zoonotic pathogens, a crucial safety measure unique to xenotransplantation. Further, given recent developments that allow for multi-day perfusion of grafts, wild-type grafts could potentially be genetically modified while being perfused ex situ. Beyond these perfusion modalities of isolated whole organs, machine perfusion offers a new therapeutic approach for patients with acute liver failure. Here, cross-circulation between a perfused genetically modified porcine organ and the patient can provide temporary liver replacement therapy. This mini-review summarizes the transformative potential of machine perfusion technology in clinical xenotransplantation with a focus on livers.