Search Results (69)

Acute-on-chronic liver failure (ACLF) is a rapidly progressing and highly lethal clinical syndrome characterized by multiorgan failure, driven primarily by a severe systemic inflammatory response. The pathophysiological cascade, triggered by a “cytokine storm,” subsequently evolves into profound immune paralysis. This phenomenon is driven by the dysfunction of monocytes, neutrophils, and other immune cells, compounded by their impaired cellular energetics resulting from a metabolic shift toward less efficient energy-yielding mechanisms, mainly aerobic glycolysis, with the pentose phosphate pathway contributing NADPH and biosynthetic precursors rather than ATP. This process is further exacerbated by disruptions within the gut–liver axis, wherein severe dysbiosis and impaired intestinal barrier integrity promote pathogen translocation. Beyond the gut, the liver–spleen axis constitutes a second amplification loop: the congested and immunologically remodeled spleen is proposed to sustain portal hypertension, to contribute to the circulating cytokine pool and to relay profibrogenic signals back to the liver. Coupled with generalized endothelial dysfunction, this is thought to contribute to the failure of peripheral organs. This cascade is presented as a synthesizing model of partially overlapping mechanistic hypotheses and heterogeneous evidence—much of it derived from studies in cirrhosis or animal models and still requiring deeper, ACLF-specific investigation rather than a fully established, strictly linear sequence. To date, no specific targeted therapies are available, and liver transplantation remains the sole intervention capable of substantially improving patient prognosis. Experimental immunomodulatory approaches including granulocyte colony-stimulating factor (G-CSF), intravenous albumin supplementation, therapeutic plasma exchange, mesenchymal stem cell therapy, and anti-cytokine agents represent promising therapeutic avenues. Nevertheless, appropriately tailoring these interventions to the evolving pathophysiological phases of the disease remains a significant clinical challenge, underscoring the critical need for developing precision therapies targeted at specific molecular pathways. Full article

Background: Acute-on-chronic liver failure (ACLF) carries high short-term mortality, and liver transplantation remains the only definitive treatment for selected patients. Whether ACLF continues to confer a survival disadvantage after transplantation remains clinically relevant for graft allocation, candidate selection, and prognostic counselling. Methods: This systematic review and meta-analysis evaluated one-year survival after liver transplantation in patients with ACLF compared with non-ACLF transplant recipients. PubMed was searched for eligible studies reporting post-transplant survival outcomes. Data were extracted on study design, population, ACLF definition, comparator group, and one-year survival. Pooled survival proportions were calculated separately for ACLF and non-ACLF groups using random-effects models. Comparative survival was assessed using pooled risk ratios. Heterogeneity and publication bias were evaluated using I², τ², funnel plot inspection, and Egger’s test. Results: Ten studies including 59,686 liver transplant recipients were included, of whom 25,016 had ACLF and 34,670 did not. The pooled one-year survival after liver transplantation in ACLF patients was 78.8% (95% CI: 70.1–85.4), with substantial heterogeneity (I² = 93.1%). In non-ACLF recipients, pooled one-year survival was 86.9% (95% CI: 75.3–93.5), also with high heterogeneity (I² = 97.8%). Direct comparison showed lower one-year survival in ACLF recipients than in non-ACLF recipients, with a pooled risk ratio of 0.93 (95% CI: 0.92–0.94; p < 0.0001). Egger’s test did not suggest significant publication bias. Conclusions: ACLF does still matter after liver transplantation. Transplanted ACLF patients achieve clinically meaningful one-year survival, supporting transplantation as a valid treatment in selected candidates, but their survival remains lower than that of non-ACLF recipients. The implication is not that ACLF should exclude transplantation, but that ACLF severity, organ failure burden, infection status, and perioperative risk must be integrated more explicitly into selection and allocation decisions. Full article

Background/Objectives: Acute-on-chronic liver failure (ACLF) is characterized by multiple organ failure and short-term mortality, and hepatic encephalopathy (HE) is its frequent complication. We investigated whether the severity of HE upon admission in patients with alcohol-related ACLF at the intensive care unit (ICU) was associated with short-term mortality. Methods: In total, 100 patients with alcohol-related ACLF and HE admitted in ICU were enrolled in the study. Laboratory biomarkers, total hospital length of stay (LOS), ICU length of stay, acute kidney injury (AKI), Acute Physiology and Chronic Health Evaluation II score, CLIF-C organ failure and Sequential Organ Failure Assessment score were tested in relation to the mortality risk. HE was assessed and divided into groups using the West Haven criteria. Results: Total hospital LOS, 7-day and 28-day mortality were significantly higher in the higher-grade HE group (p = 0.035, p = 0.031, p = 0.002, respectively). CLIF-C OF, SOFA, and APACHE II scores were significantly higher in the higher-grade HE group (p < 0.001). Kaplan–Meier survival analysis demonstrated reduced survival in patients with higher-grade HE (log-rank p < 0.001). In Cox regression analyses, AKI was associated with short-term mortality in both HE groups. Total hospital LOS and ICU length of stay were also associated with mortality, but were interpreted as post-baseline markers of clinical trajectory rather than baseline prognostic predictors. Conclusions: In patients with alcohol-related ACLF and HE, higher-grade HE was associated with poorer short-term survival. AKI and higher CLIF-C OF, SOFA and APACHE II scores were associated with poor outcomes, supporting their clinical relevance for mortality risk stratification in this population. LOS-related findings should be interpreted as markers of clinical trajectory rather than baseline prognostic predictors. Full article

Acute-on-chronic liver failure (ACLF) is the point at which cirrhosis stops behaving as a chronic liver disease and becomes a rapidly destabilising systemic illness. It is the real tipping point in advanced liver disease: the moment when limited hepatic reserve is no longer the only issue, and the clinical picture is instead defined by systemic inflammation, extrahepatic organ dysfunction, and a high risk of short-term death. This has changed how we understand the natural history of cirrhosis. Rather than a simple linear progression toward liver failure, advanced chronic liver disease is now better seen as a dynamic continuum that may lead to first decompensation, recurrent decompensation, ACLF, end-stage disease, or, in selected cases, recompensation if the underlying driver is effectively controlled. This shift matters because patients with ACLF are not simply “sicker cirrhotics”. They are in a distinct pathophysiological state, marked by inflammation, circulatory dysfunction, immune dysregulation, and organ cross-talk that extends beyond the liver. In this setting, the boundaries between liver failure, sepsis, renal dysfunction, and critical illness become blurred, which is why ACLF remains such a difficult syndrome to manage. At the same time, recent guidance has improved the approach to decompensated cirrhosis, HRS-AKI, infection, transplantation, and palliative care, while newer consensus efforts have tried to reduce differences between ACLF definitions. In practice, management still depends on simple but disciplined principles: early recognition, rapid identification of precipitants, parallel organ support, prompt treatment of infection and HRS-AKI, repeated reassessment, and urgent transplant evaluation when appropriate. This review examines ACLF and end-stage liver disease as interconnected stages of advanced cirrhosis and discusses how care can be both aggressive when recovery is possible and humane when recovery is not. Full article

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. Full article

Background/Aims: Sepsis as an acute cause of liver dysfunction is associated with high mortality. Routine infection/inflammation markers—C-reactive-protein (CRP), procalcitonin (PCT), and leukocyte count (LeuC)—are frequently used for risk stratification in septic patients. This study aimed to evaluate these markers as predictors of short-term and 12-month mortality in septic patients with distinct liver dysfunction phenotypes. Methods: This single-center retrospective pilot analysis involved adults with sepsis and varying degrees of liver dysfunction—acute liver failure (ALF), acute-on-chronic liver failure (ACLF), or acute-on-cirrhosis (ACOC)—treated in intermediate or intensive care units between 2016 and 2017. At sepsis onset, patients were categorized into ACOC, ACLF, and ALF groups. Only patients with recorded CRP, PCT, and LeuC measurements 24 h before, on the day of, and 24/48 h after sepsis onset were included in the analysis. Associations with in-hospital and 12-month mortality were analyzed using Firth bias-reduced logistic regression, ROC analysis, and internal validation by bootstrapping and cross-validation. Results: 49 patients were included (ACOC n = 21; ACLF n = 20; ALF n = 8). In-hospital and 12-month mortality rates were 34.7% and 61.2%, respectively, with the highest long-term mortality observed in the ACOC group (76.2%). In the ACOC group, PCT 24 h before sepsis onset independently predicted in-hospital mortality (OR ~5 per PCT doubling; AUC 0.94), with an optimal rule-in cut-off of 1.0 ng/mL (specificity 1.00, PPV 1.00). PCT was not predictive in ACLF/ALF, and CRP/LeuC offered limited prognostic value. Conclusions: In this hypothesis-generating analysis, PCT 24 h before sepsis onset shows a phenotype-specific association with early mortality in ACOC. Larger, prospective multicenter studies are needed to validate PCT-guided risk stratification. Full article

Background: The prognosis of acute-on-chronic liver failure (ACLF) is impaired by etiology heterogeneity across regions. Currently, prognostic models incorporating nutrient anabolism–related indicators for patients with hepatitis B virus (HBV)–associated ACLF are lacking. Objectives: This study aimed to construct a nomogram that incorporates nutrition-related indexes alongside traditional predictors to estimate 12-week mortality in HBV-ACLF. Methods: We retrospectively analyzed adult patients with HBV-ACLF treated at our department between May 2020 and December 2021. A total of 242 HBV-ACLF patients were enrolled and categorized into survivor (n = 174) and progression (n = 68) groups. Independent prognostic factors were identified using logistic regression analysis and incorporated into a nomogram. Nomogram performance was evaluated in terms of discrimination, calibration, and clinical utility, with internal validation using bootstrap resampling. Results: Patients in the progression group were older, more prone to hepatorenal syndrome and spontaneous peritonitis, and had lower levels of prothrombin activity, L3 skeletal muscle index and ceruloplasmin (all p < 0.05). These six independent predictors were incorporated into the nomogram, which demonstrated superior discrimination ability, with an area under the receiver operating characteristic curve of 0.95, enabling accurate identification of patients at high risk of short-term mortality. The Hosmer–Lemeshow test confirmed excellent calibration, decision curve analysis confirmed the clinical benefit, and bootstrap validation confirmed the robustness. Conclusions: The developed nomogram, incorporating nutritional status, may provide complementary information to support short-term risk stratification and clinical decision-making in patients with HBV-ACLF awaiting liver transplantation. Full article

Background/Objectives: Acute-on-chronic liver failure (ACLF) is a life-threatening complication of cirrhosis, characterized by organ failures and high short-term mortality. Alcohol-related cirrhosis is one of the most frequent underlying etiologies of ACLF in Europe. Infections, particularly those leading to sepsis are recognized triggers; however, their relative contribution, clinical features, and prognostic impact in critically ill patients with alcohol-related cirrhosis remain incompletely defined. This study aimed to systematically identify and characterize precipitating events of ACLF in this population and to compare outcomes between sepsis- and non-sepsis-related cases. Methods: We conducted a retrospective cohort study including 188 ICU patients with alcohol-related cirrhosis who were treated for ACLF at a tertiary university medical center. ACLF was defined and graded according to the European Association for the Study of the Liver—Chronic Liver Failure Consortium (EASL-CLIF) criteria, and sepsis was diagnosed according to Sepsis-3 definitions. Clinical data, precipitating events, microbiological evidence, organ support requirements, and in-hospital outcomes were systematically analyzed. Results: Sepsis was the most frequent precipitating event, identified in 118 patients (62.8%), while 70 patients (37.2%) developed ACLF due to non-septic triggers such as gastrointestinal bleeding. Patients with sepsis-associated ACLF presented with more advanced disease (ACLF grade 2–3 in 80.5% vs. 57.1%, p = 0.004), higher Chronic Liver Failure Consortium—Acute-on-Chronic Liver Failure Score (CLIF-C ACLF) scores (median 55 vs. 50, p = 0.04), longer ICU stays (median 11 vs. 4.5 days, p < 0.001), and markedly higher in-hospital mortality (60.2% vs. 20.0%, p < 0.001) compared to patients without sepsis. Pneumonia (48.3%), urinary infections (17.8%) and spontaneous bacterial peritonitis (16.1%) were the leading infectious foci triggering sepsis. Microbiological evidence was obtained in 82.2% of sepsis cases, with frequent polymicrobial infections and opportunistic pathogens including Enterococcus faecium and Candida albicans. Conclusions: In critically ill patients with alcohol-related cirrhosis, infections leading to sepsis are the predominant precipitating event of ACLF and the strongest determinant of short-term prognosis. Compared with non-sepsis triggers, sepsis-associated ACLF is characterized by more severe disease, greater need for organ support, longer ICU stays, and substantially higher mortality. These findings highlight the urgent need for early recognition, rapid diagnostic strategies, and optimized infection management to improve outcomes in this high-risk population. Full article

Acute-on-chronic liver failure (ACLF) is a distinct clinical syndrome characterized by an acute decompensation of chronic liver disease in association with extrahepatic organ failure(s) and a high short-term mortality. Despite its increasing clinical relevance, there is no internationally standardized definition of ACLF to date. This review provides a comprehensive overview of current ACLF definitions, underlying pathogenic mechanisms, frequent precipitating events, and current treatment strategies. While liver transplantation remains the only curative treatment option, its role in the setting of ACLF is controversially debated, and patient selection remains complex due to high perioperative risk. Thus, the review article describes the current role of liver transplantation in patients with ACLF and describes novel prognostic scoring systems (e.g., TAM core, SALT-M model) that may be helpful in selecting suitable transplant candidates. Further emerging treatment options for ACLF include extracorporeal liver support systems, therapeutic plasma exchange, and immune-modulating approaches targeting toll-like receptor signaling that offer promising adjunctive strategies, though clinical evidence remains limited. Given the high burden and complexity of ACLF, harmonized definitions and evidence-based therapeutic frameworks are urgently needed to improve patient care and optimize transplant prioritization. Full article

Hepatitis A virus (HAV) infection sometimes results in the occurrence of acute liver failure and acute-on-chronic liver failure (ACLF), which is often fatal, especially in patients with diabetes mellitus or elderly individuals. ACLF is observed in patients with cirrhosis who occasionally have zinc deficiency. However, effective drugs for hepatitis A are currently unavailable. Glucose-regulated protein 78 (GRP78) is an antiviral agent that has been reported to prevent HAV replication. The effects of zinc acetate on HAV HA11-1299 genotype IIIA replication and changes in GRP78 levels in human hepatocytes with or without HAV infection were examined. Zinc acetate inhibited HAV HA11-1299 genotype IIIA replication in both Huh7 and GL37 cells. Zinc acetate also inhibited HAV replication in both low- and high-glucose media. Zinc acetate increased the expression of GRP78, in response to HAV replication. The combination of zinc acetate with ribavirin led to greater suppression of both HAV HA11-1299 genotype IIIA and HAV HM175/18f genotype IB replication in Huh7 cells than that of ribavirin alone. In conclusion, zinc acetate inhibits HAV replication in accompany with the elevation of GRP78 expression without causing cellular toxicity. Zinc compounds may be useful for the treatment of ACLF caused by HAV infection. Full article

Background/Objectives: The prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is significantly affected by inflammatory state and immune dysregulation. The systemic inflammatory response index (SIRI), which reflects neutrophil, monocyte, and lymphocyte dynamics, has emerged as a potential marker of immune-inflammatory status. However, its role in predicting HBV-ACLF outcomes remains unclear. This research aims to elucidate the prognostic value of SIRI and its dynamic changes combined with disease severity scores in predicting the outcomes of HBV-ACLF. Methods: The study included HBV-ACLF patients enrolled in a multicenter clinical study between July 2019 and April 2024. Based on 90-day outcomes, the participants were categorized into survival and death groups. Clinical data and SIRI values were collected on days 0 (baseline), 3, 7, and 14. Independent prognostic factors were identified using Cox regression and least absolute shrinkage and selection operator (LASSO) analysis. The predictive value of dynamic SIRI changes combined with disease severity scores was evaluated using receiver operating characteristic (ROC) curves. Results: A total of 153 patients with HBV-ACLF were analyzed, including 104 in the survival group and 49 in the death group. SIRI values were significantly lower in the survival group than in the death group across all time points. Multivariate Cox regression analysis identified that an increased ΔSIRI at day 3 (ΔSIRI3), a higher MELD score, and a lower albumin level were independently associated with increased 90-day mortality. The combination of SIRI on day three (SIRI3) and MELD-Na score on day three (MELD-Na3) demonstrated the highest predictive performance, with an AUC of 0.817 (95% CI: 0.750–0.883). Conclusions: The combination of the SIRI and MELD-Na score on day three provides a strong predictive value for the short-term prognosis of HBV-ACLF, highlighting its potential utility in early prognostic evaluation. Full article

Liver failure, both acute and chronic, represents a complex, life-threatening condition frequently requiring intensive care unit (ICU) admission. Nutritional management is a crucial component of supportive therapy, aiming to mitigate catabolism, preserve lean body mass, and support immune and organ function. In acute liver failure (ALF), early nutritional intervention within 24–48 h and individualized energy–protein prescriptions are essential, even in the presence of hepatic encephalopathy. Chronic liver failure (CLF) and acute-on-chronic liver failure (ACLF) are often associated with severe malnutrition, sarcopenia, and systemic inflammation, necessitating tailored nutritional strategies. Subjective Global Assessment (SGA) and Royal Free Hospital Global Assessment (RFH-GA) tools are instrumental in identifying nutritional risk. Enteral nutrition (EN) is preferred across all stages, with parenteral nutrition (PN) reserved for contraindications. Special considerations include micronutrient repletion, prevention of refeeding syndrome, and perioperative nutritional support in transplant candidates and recipients. This clinical overview summarizes current evidence and guidelines on ICU nutrition in liver failure, emphasizing a multidisciplinary approach to improve outcomes. Full article

Acute-on-chronic liver failure (ACLF) is a complex and severe condition marked by multiple organ failure and high short-term mortality. Coagulopathy, a key component of ACLF, is characterized by rebalanced hemostasis with both hypo- and hypercoagulable features, increasing the risk of bleeding and thrombosis. Conventional coagulation tests, including prothrombin time (PT) and platelet count, fail to fully capture the complexity of coagulation dysfunction in ACLF. Advanced diagnostic tools, like viscoelastic tests (VETs), offer a more comprehensive assessment, yet they remain limited in evaluating endothelial dysfunction and fail to account for reduced levels of anticoagulant factors. Emerging therapeutic strategies targeting coagulopathies in ACLF hold promise, but their clinical efficacy remains unclear. A more nuanced approach to diagnosing and managing coagulopathy in ACLF is needed, incorporating advanced hemostatic profiling to better inform prognosis and guide treatment decisions. Full article

ACLF is a severe stage of liver cirrhosis, characterized by multiple organ failure, systemic inflammation, and high short-term mortality. The intestinal microbiota (IM) influences its pathophysiology; however, there are currently no studies in Latin American populations. Therefore, we analyzed IM and its relationships with sepsis, organ failure, and mortality. In parallel, we quantified serum lipopolysaccharides as a marker of bacterial translocation. Fecal samples from 33 patients and 20 healthy controls (HCs) were obtained. The IMs were characterized by 16S-rRNA amplicon sequencing, the metagenomic functional predictive profiles were analyzed by PICRUSt2, and LPS quantification was performed by ELISA. Patients with ACLF showed significant alterations in alpha and beta diversity compared to the HCs. A strong dominance index accurately predicted 28-day and 90-day mortalities. The IMs showed a polarization toward Proteobacteria associated with increased LPS. The LPS correlated with clinical severity, organ dysfunction, and higher pathogenic taxa. The Klebsiella/Faecalibacterium ratio showed good performance in identifying sepsis (AUROC = 0.83). Furthermore, Morganella, Proteus, and Klebsiella were enriched in patients with multiorgan failure. Lactobacillus, Escherichia/Shigella, Veillonella, and Ruminococcus gnavus exhibited potential in predicting 28- and 90-day mortalities. The IM alterations in ACLF may be useful as clinical biomarkers of poor prognosis, primarily for mortality and sepsis. These findings are representative of western Mexico. Full article

Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome characterized by high morbidity and mortality rates. Bacterial infection is a frequent precipitating factor and complication in ACLF patients, significantly worsening patient outcomes. Elucidating the mechanisms underlying bacterial infections and their impact on ACLF pathophysiology is crucial for developing effective therapies to reduce infection rates and mortality. Current research highlights that immune suppression in ACLF increases susceptibility to bacterial infections, which in turn exacerbate immune dysfunction. However, a comprehensive review summarizing the emerging mechanisms underlying this immunosuppression is currently lacking. This review aims to provide an overview of the latest research, focusing on alterations in the immune responses of innate immune cells—including monocytes, macrophages, and neutrophils—as well as adaptive immune cells such as T and B lymphocytes during the onset and progression of bacterial infections in ACLF. In addition, recent advances in immunomodulatory therapies, including stem cell-based interventions, will also be discussed. Full article