[The predictive value of dynamic changes of neutrophil/lymphocyte ratio (NLR) combined with the model of end-stage liver disease (MELD) score in patients with acute-on-chronic hepatitis B liver failure].

Objective: To determine the predictive value of dynamic changes of neutrophil/lymphocyte ratio (NLR) combined with the model of end-stage liver disease (MELD) score in patients with acute-on-chronic hepatitis B liver failure. Methods: Patients with acute-on-chronic hepatitis B liver failure who were hospitalized in the Department of Hepatology of Qilu Hospital of Shandong University from January 2010 to July 2023 were retrospectively enrolled. According to the clinical outcomes of patients within 30 days of admission, they were divided into the survival group and the death group. The dynamic changes in NLR and initial values on day 3, 5, 8, and 12 in two groups were analyzed for the diagnostic value of 30-day prognosis in patients with acute-on-chronic hepatitis B liver failure. Logistic regression analysis and machine learning XGBoost algorithm were used to evaluate the risk factors influencing the prognosis of patients at 30 days. Receiver operating characteristic(ROC) curve was used to evaluate the diagnostic value of NLR and initial value change combined with MELD score on day 12 of admission in patients with chronic acute hepatitis B liver failure. Results: A total of 243 patients were enrolled in the study, including 145 patients in the survival group [115 males, 30 females, aged 25-74 (47±11)] and 98 patients in the death group [80 males, 18 females, aged 22-80 (49±13) ]. The median initial NLR of survival group and death group were 3.5 (2.1, 5.3) and 4.9 (2.9, 8.3), respectively, and the difference was statistically significant (P=0.003). The variation of NLR from the initial value on day 3, 5, 8, and 12 in the survival group [1.6 (0, 4.3), 1.9 (-0.2, 4.1), 2.0 (-0.1, 4.3) and 2.9 (0.3, 7.0), respectively] were lower than that in the death group [3.2 (0.9, 7.5), 5.1 (1.8, 7.6), 5.8 (2.0, 10.6) and 9.6 (3.5, 16.4), respectively] (all P<0.001). Logistic regression multivariate analysis showed that the changes in NLR on the 12th day and initial value (OR=1.07,95%CI:1.01-1.14, P=0.014), the changes in NLR on the 3rd day and initial value (OR=2.71, 95%CI: 1.32-5.55, P=0.007), the initial value of NLR (OR=1.18,95%CI:1.01-1.37,P=0.035) and fibrinogen (OR=0.21,95%CI:0.05-0.96,P=0.044) were related factors for death within 30 days. Machine learning XGBoost algorithm showed that the weight of the change between the NLR on the 12th day and the initial value was the highest. The area under the ROC curve of the combined MELD score was 0.812 (95%CI: 0.728-0.895), the specificity was 67.78%, and the sensitivity was 82.35%. Conclusion: Dynamic change of NLR combined with MELD score has high predictive value for the short-term prognosis of patients with acute-on-chronic hepatitis B liver failure.

[Prognostic nutritional index application value for acute-on-chronic liver failure co-infection].

Objective: To explore the predictive value of the prognostic nutritional index (PNI) in concurrently infected patients with acute-on-chronic liver failure (ACLF). Methods: 220 cases with ACLF diagnosed and treated at the First Affiliated Hospital of Xi'an Jiaotong University from January 2011 to December 2016 were selected. Patients were divided into an infection and non-infection group according to whether they had co-infections during the course of the disease. Clinical data differences were compared between the two groups of patients. Binary logistic regression analysis was used to screen out influencing factors related to co-infection. The receiver operating characteristic curve was used to evaluate the predictive value of PNI for ACLF co-infection. The measurement data between groups were compared using the independent sample t-test and the Mann-Whitney U rank sum test. The enumeration data were analyzed using the Fisher exact probability test or the Pearson χ(2) test. The Pearson method was performed for correlation analysis. The independent risk factors for liver failure associated with co-infection were analyzed by multivariate logistic analysis. Results: There were statistically significant differences in ascites, hepatorenal syndrome, PNI score, and albumin between the infection and the non-infection group (P < 0.05). Among the 220 ACLF cases, 158 (71.82%) were infected with the hepatitis B virus (HBV). The incidence rate of infection during hospitalization was 69.09% (152/220). The common sites of infection were intraabdominal (57.07%) and pulmonary infection (29.29%). Pearson correlation analysis showed that PNI and MELD-Na were negatively correlated (r = -0.150, P < 0.05). Multivariate logistic analysis results showed that low PNI score (OR=0.916, 95%CI: 0.865~0.970), ascites (OR=4.243, 95%CI: 2.237~8.047), and hepatorenal syndrome (OR=4.082, 95%CI : 1.106~15.067) were risk factors for ACLF co-infection (P < 0.05). The ROC results showed that the PNI curve area (0.648) was higher than the MELD-Na score curve area (0.610, P < 0.05). The effectiveness of predicting infection risk when PNI was combined with ascites and hepatorenal syndrome complications was raised. Patients with co-infections had a good predictive effect when PNI ≤ 40.625. The sensitivity and specificity were 84.2% and 41.2%, respectively. Conclusion: Low PNI score and ACLF co-infection have a close correlation. Therefore, PNI has a certain appraisal value for ACLF co-infection.

Guidelines for the management of coagulation disorders in patients with cirrhosis.

Coagulation management in the patient with cirrhosis has undergone a significant transformation since the beginning of this century, with the concept of a rebalancing between procoagulant and anticoagulant factors. The paradigm that patients with cirrhosis have a greater bleeding tendency has changed, as a result of this rebalancing. In addition, it has brought to light the presence of complications related to thrombotic events in this group of patients. These guidelines detail aspects related to pathophysiologic mechanisms that intervene in the maintenance of hemostasis in the patient with cirrhosis, the relevance of portal hypertension, mechanical factors for the development of bleeding, modifications in the hepatic synthesis of coagulation factors, and the changes in the reticuloendothelial system in acute hepatic decompensation and acute-on-chronic liver failure. They address new aspects related to the hemorrhagic complications in patients with cirrhosis, considering the risk for bleeding during diagnostic or therapeutic procedures, as well as the usefulness of different tools for diagnosing coagulation and recommendations on the pharmacologic treatment and blood-product transfusion in the context of hemorrhage. These guidelines also update the knowledge regarding hypercoagulability in the patient with cirrhosis, as well as the efficacy and safety of treatment with the different anticoagulation regimens. Lastly, they provide recommendations on coagulation management in the context of acute-on-chronic liver failure, acute liver decompensation, and specific aspects related to the patient undergoing liver transplantation.

sTREM-1 as promising prognostic biomarker for acute-on-chronic liver failure and mortality in patients with acute decompensation of cirrhosis.

BACKGROUND: Acute decompensation (AD) of cirrhosis is associated with high short-term mortality, mainly due to the development of acute-on-chronic liver failure (ACLF). Thus, there is a need for biomarkers for early and accurate identification of AD patients with high risk of development of ACLF and mortality. Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is released from activated innate immune cells and correlated with various inflammatory processes. AIM: To explore the prognostic value of sTREM-1 in patients with AD of cirrhosis. METHODS: A multicenter prospective cohort of 442 patients with cirrhosis hospitalized for AD was divided into a study cohort (n = 309) and validation cohort (n = 133). Demographic and clinical data were collected, and serum sTREM-1 was measured at admission. All enrolled patients were followed-up for at least 1 year. RESULTS: In patients with AD and cirrhosis, serum sTREM-1 was an independent prognosis predictor for 1-year survival and correlated with liver, coagulation, cerebral and kidney failure. A new prognostic model of AD (P-AD) incorporating sTREM-1, blood urea nitrogen (BUN), total bilirubin (TBil), international normalized ratio (INR) and hepatic encephalopathy grades was established and performed better than the model for end-stage liver disease (MELD), MELD-sodium (MELD-Na), chronic liver failure-consortium (CLIF-C) ACLF and CLIF-C AD scores. Additionally, sTREM-1 was increased in ACLF and predicted the development of ACLF during first 28-d follow-up. The ACLF risk score incorporating serum sTREM-1, BUN, INR, TBil and aspartate aminotransferase levels was established and significantly superior to MELD, MELD-Na, CLIF-C ACLF, CLIF-C AD and P-AD in predicting risk of ACLF development. CONCLUSION: Serum sTREM-1 is a promising prognostic biomarker for ACLF development and mortality in patients with AD of cirrhosis.

Outcome of individuals with alcoholic cirrhosis hospitalized with first decompensation and their predictors.

BACKGROUND OBJECTIVES: Alcohol is one of most common aetiologies of cirrhosis and decompensated cirrhosis is linked to higher morbidity and death rates. This study looked at the outcomes and mortality associated risk variables of individuals with alcoholic cirrhosis who had hospitalization with their first episode of decompensation. METHODS: Individuals with alcoholic cirrhosis who were hospitalized with the first episode of decompensation [acute decompensation (AD) or acute-on-chronic liver failure (ACLF)] were included in the study and were prospectively followed up until death or 90 days, whichever was earlier. RESULTS: Of the 227 study participants analyzed, 167 (73.56%) and 60 (26.43%) participants presented as AD and ACLF, respectively. In the ACLF group, the mortality rate at 90 days was higher than in the AD group (48.3 vs 32.3%, P=0.02). In the AD group, participants who initially presented with ascites as opposed to variceal haemorrhage had a greater mortality rate at 90 days (36.4 vs 17.1%, P=0.041). The chronic liver failure-consortium AD score and the lactate-free Asian Pacific Association for the study of the Liver-ACLF research consortium score best-predicted mortality in individuals with AD and ACLF. INTERPRETATION CONCLUSIONS: There is significant heterogeneity in the type of decompensation in individuals with alcoholic cirrhosis. We observed significantly high mortality rate among alcoholic participants hospitalized with initial decompensation; deaths occurring in more than one-third of study participants within 90 days.

Postoperative outcomes of acute-on-chronic liver failure in infants and children with biliary atresia.

INTRODUCTION: Acute-on-chronic liver failure (ACLF) is associated with increased mortality and morbidity in patients with biliary atresia (BA). Data on impact of ACLF on postoperative outcomes, however, are sparse. METHOD: We performed a retrospective analysis of patients with BA aged <18 years who underwent LT between 2011 and 2021 at our institution. ACLF was defined using the pediatric ACLF criteria: ≥1 extra-hepatic organ failure in children with decompensated cirrhosis. RESULTS: Of 107 patients (65% female; median age 14 [9-31] months) who received a LT, 13 (12%) had ACLF during the index admission prior to LT. Two (15%) had Grade 1; 4 (30%) had Grade 2; and 7 (55%) had Grade ≥3 ACLF. ACLF cohort was younger at time of listing (5 [4-8] vs. 9 [6-24] months; p < .001) and at LT (8 [8-11] vs. 16 [10-40] months, p < .001) compared to no-ACLF group. Intraoperatively, ACLF patients had higher blood loss (40 [20-53] vs. 10 [6-19] mL/kg; p < .001) and blood transfusion requirements (33 [21-69] vs. 18 [7-25] mL/kg; p = .004). Postoperatively, they needed higher vasopressor support (31% vs. 10.6%; p = .04) and had higher total hospital length of stay (106 [45-151] vs. 13 [7-30] days; p = .023). Rate of return to the operating room, hospital readmission rates, and 1-year post-LT survival rates were comparable between the groups. CONCLUSION: Despite higher perioperative complications, survival outcomes for ACLF in BA after LT are favorable and comparable to those without ACLF. These encouraging data reiterate prioritization during organ allocation of these critically ill children for LT.

Herpes Simplex Virus Bronchopneumonitis in Critically Ill Patients with Acute on Chronic Liver Failure: A Retrospective Analysis.

(1) Background: Critically ill patients are frequently diagnosed with pulmonary Herpes simplex virus-1 (HSV) reactivation, which then can lead to HSV bronchopneumonitis and is associated with higher mortality and longer mechanical ventilation. For the particular subgroup of critically ill patients with acute on chronic liver failure (ACLF), however, the impact of HSV reactivation is unknown. We investigated the impact of HSV reactivation in these patients. (2) Methods: We conducted a retrospective analysis, evaluating data from 136 mechanically ventilated patients with ACLF between January 2016 and August 2023. Clinical parameters were compared between patients with and without HSV bronchopneumonitis. (3) Results: 10.3% were diagnosed with HSV bronchopneumonitis (HSV group). Mortality did not differ between the HSV and non-HSV group (85.7% vs. 75.4%, p = 0.52). However, the clinical course in the HSV group was more complicated as patients required significantly longer mechanical ventilation (14 vs. 21 days, p = 0.04). Furthermore, fungal superinfections were significantly more frequent in the HSV group (28.6% vs. 6.6%, p = 0.006). (4) Conclusions: Mortality of critically ill patients with ACLF with HSV bronchopneumonitis was not increased in spite of the cirrhosis-associated immune dysfunction. Their clinical course, however, was more complicated with significantly longer mechanical ventilation.

Chishao - Fuzi herbal pair restore the macrophage M1/M2 balance in acute-on-chronic liver failure.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional herbal pair Paeoniae Radix Rubra (roots of Paeonia lactiflora Pall., Chishao in Chinese) and Aconiti Lateralis Radix Praeparata (lateral roots of Aconitum carmichaelii Debeaux, Fuzi in Chinese) are widely used for the treatment of liver diseases, demonstrating clinical efficacy against acute-on-chronic liver failure (ACLF). As the core drug pair representing the "clearing method" and "warming method" in traditional Chinese medicine (TCM), they align with the TCM syndromic characteristics of ACLF, characterized by a mixture of deficiencies and realities. However, the molecular mechanisms underlying the anti-ACLF effects of Chishao - Fuzi herbal pair remain unclear. AIM OF THE STUDY: To reveal the immunoinflammatory status of patients with hepatitis B virus-related ACLF (HBV-ACLF) based on macrophage polarization and to explore the mechanism of action of Chishao - Fuzi herbal pair in regulating macrophage polarization against ACLF. MATERIALS AND METHODS: Peripheral blood samples were prospectively obtained from patients with HBV-ACLF, patients with chronic hepatitis B (CHB) in the immunoactive phase and healthy individuals. Flow cytometry, qRT-qPCR, and ELISA were used to reveal the activation status of monocyte-macrophages and the expression differences in related cytokines in the peripheral blood of patients with HBV-ACLF. Then, an ACLF rat model and a macrophage inflammation model in vitro were established. Hematoxylin-eosin staining, immunohistochemical staining, transmission electron microscopy, flow cytometry, western blotting, RT-qPCR, and ELISA were used to observe changes in the expression of M1/M2 macrophage markers and related inflammatory factors after Chishao - Fuzi herbal pair intervention, both in vivo and in vitro. RESULTS: Patients with HBV-ACLF exhibited an imbalance in M1/M2 macrophage polarization, showing a tendency to activate M1 macrophages with high expression of CD86 and iNOS. This imbalance led to an increase in relevant pro-inflammatory factors (IL-1ß, IL-6, TNF-α) and a decrease in anti-inflammatory factors (IL-10, TGF-ß, VEGF), exacerbating the uncontrolled immune-inflammatory response. Chishao - Fuzi herbal pair intervention improved liver function, coagulation function, and histopathological injury in ACLF rats. It also partially ameliorated endotoxemia and inflammatory injury in ACLF. The mechanism was to restore the immune-inflammatory imbalance and prevent the exacerbation of inflammatory response to liver failure by promoting macrophage polarization toward M2 anti-inflammatory direction, inhibiting M1 macrophage activation, and increasing the levels of anti-inflammatory factors and decreasing pro-inflammatory factors. CONCLUSION: Chishao - Fuzi herbal pair can reduce the systemic inflammatory burden of liver failure by modulating macrophage polarization and restoring ACLF immune-inflammatory imbalance. This study provides new perspectives and strategies for studying HBV-ACLF immune reconstitution and inflammatory response control.

Prognostic value of genome-wide methylation in acute-on-chronic hepatitis B liver failure.

AIM: Methylation status of genome varies between pre-acute-on-chronic hepatitis B liver failure (pre-ACHBLF), acute-on-chronic hepatitis B liver failure (ACHBLF), and chronic hepatitis B patients. This study aimed to find better prognostic indicators for acute-on-chronic liver failure. METHODS: The level of global genome methylation in peripheral blood mononuclear cells (PBMCs) was detected. The overall genome methylation rate was determined using MethylFlash™ Methylated DNA Quantification Kit(Colorimetric). DNMT activity were measured using DNA Methyltransferase Activity/Inhibition Assay Kit. Gene expression of DNA methyltransferases (DNMT)，methyl-CpG-binding domain (MBD) were detected by qRT-PCR. RESULTS: The global genome methylation level in ACHBLF group was significantly higher than that in chronic hepatitis B group (P<0.001). There was also obvious difference of the global genome methylation level between pre-ACHBLF group and CHB group (P<0.001). Meanwhile, the activity of DNMT in ACHBLF group was significantly higher than that in chronic hepatitis B group (P<0.001). The mRNA expression level of DNMT1 was higher than that in pre-ACHBLF group (P<0.01) and CHB group (PP<0.001). The mRNA expression level of MBD1 in ACHBLF group was also higher than that in CHB group (P<0.001) and healthy controls (HCs) (P<0.01). And the mRNA expression level of MBD3 and MBD4 in ACHBLF, pre-ACHBLF and CHB group were lower than that in HCs (P<0.001). Meanwhile we observed an opposite change in the mRNA expression level of MECP2. The ROC curve suggested that global genome methylation level was a better prognostic predictor than MELD score in ACHBLF (AUC 0.950, SE 0.0237, 95%CI 0.874-0.986 VS AUC 0.863, SE 0.0439, 95%CI 0.765-0.931, P=0.0429). CONCLUSIONS: Genome methylation level can be a good biomarker in predicting the severity and prognosis of ACHBLF.

Mitochondrial dysfunction affects hepatic immune and metabolic remodeling in patients with hepatitis B virus-related acute-on-chronic liver failure.

BACKGROUND: Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). However, the mechanisms underlying immune and metabolic derangement in patients with advanced HBV-ACLF are unclear. AIM: To identify the bioenergetic alterations in the liver of patients with HBV-ACLF causing hepatic immune dysregulation and metabolic disorders. METHODS: Liver samples were collected from 16 healthy donors (HDs) and 17 advanced HBV-ACLF patients who were eligible for liver transplantation. The mitochondrial ultrastructure, metabolic characteristics, and immune microenvironment of the liver were assessed. More focus was given to organic acid metabolism as well as the function and subpopulations of macrophages in patients with HBV-ACLF. RESULTS: Compared with HDs, there was extensive hepatocyte necrosis, immune cell infiltration, and ductular reaction in patients with ACLF. In patients, the liver suffered severe hypoxia, as evidenced by increased expression of hypoxia-inducible factor-1α. Swollen mitochondria and cristae were observed in the liver of patients. The number, length, width, and area of mitochondria were adaptively increased in hepatocytes. Targeted metabolomics analysis revealed that mitochondrial oxidative phosphorylation decreased, while anaerobic glycolysis was enhanced in patients with HBV-ACLF. These findings suggested that, to a greater extent, hepa-tocytes used the extra-mitochondrial glycolytic pathway as an energy source. Patients with HBV-ACLF had elevated levels of chemokine C-C motif ligand 2 in the liver homogenate, which stimulates peripheral monocyte infiltration into the liver. Characterization and functional analysis of macrophage subsets revealed that patients with ACLF had a high abundance of CD68+ HLA-DR+ macrophages and elevated levels of both interleukin-1ß and transforming growth factor-ß1 in their livers. The abundance of CD206+ CD163+ macrophages and expression of interleukin-10 decreased. The correlation analysis revealed that hepatic organic acid metabolites were closely associated with macrophage-derived cytokines/chemokines. CONCLUSION: The results indicated that bioenergetic alteration driven by hypoxia and mitochondrial dysfunction affects hepatic immune and metabolic remodeling, leading to advanced HBV-ACLF. These findings highlight a new therapeutic target for improving the treatment of HBV-ACLF.

Thrombospondin 1 enhances systemic inflammation and disease severity in acute-on-chronic liver failure.

BACKGROUND: The key role of thrombospondin 1 (THBS1) in the pathogenesis of acute-on-chronic liver failure (ACLF) is unclear. Here, we present a transcriptome approach to evaluate THBS1 as a potential biomarker in ACLF disease pathogenesis. METHODS: Biobanked peripheral blood mononuclear cells (PBMCs) from 330 subjects with hepatitis B virus (HBV)-related etiologies, including HBV-ACLF, liver cirrhosis (LC), and chronic hepatitis B (CHB), and normal controls (NC) randomly selected from the Chinese Group on the Study of Severe Hepatitis B (COSSH) prospective multicenter cohort underwent transcriptome analyses (ACLF = 20; LC = 10; CHB = 10; NC = 15); the findings were externally validated in participants from COSSH cohort, an ACLF rat model and hepatocyte-specific THBS1 knockout mice. RESULTS: THBS1 was the top significantly differentially expressed gene in the PBMC transcriptome, with the most significant upregulation in ACLF, and quantitative polymerase chain reaction (ACLF = 110; LC = 60; CHB = 60; NC = 45) was used to verify that THBS1 expression corresponded to ACLF disease severity outcome, including inflammation and hepatocellular apoptosis. THBS1 showed good predictive ability for ACLF short-term mortality, with an area under the receiver operating characteristic curve (AUROC) of 0.8438 and 0.7778 at 28 and 90 days, respectively. Enzyme-linked immunosorbent assay validation of the plasma THBS1 using an expanded COSSH cohort subjects (ACLF = 198; LC = 50; CHB = 50; NC = 50) showed significant correlation between THBS1 with ALT and γ-GT (P = 0.01), and offered a similarly good prognostication predictive ability (AUROC = 0.7445 and 0.7175) at 28 and 90 days, respectively. ACLF patients with high-risk short-term mortality were identified based on plasma THBS1 optimal cut-off value (< 28 µg/ml). External validation in ACLF rat serum and livers confirmed the functional association between THBS1, the immune response and hepatocellular apoptosis. Hepatocyte-specific THBS1 knockout improved mouse survival, significantly repressed major inflammatory cytokines, enhanced the expression of several anti-inflammatory mediators and impeded hepatocellular apoptosis. CONCLUSIONS: THBS1 might be an ACLF disease development-related biomarker, promoting inflammatory responses and hepatocellular apoptosis, that could provide clinicians with a new molecular target for improving diagnostic and therapeutic strategies.

From hepatitis B virus infection to acute-on-chronic liver failure: The dynamic role of hepatic macrophages.

Acute-on-chronic liver failure (ACLF) is a progressive disease that is associated with rapid worsening of clinical symptoms and high mortality. A multicentre prospective study from China demonstrated that patients with hepatitis B virus-related ACLF (HBV-ACLF) exhibited worse clinical characteristics and higher mortality rates compared to non-HBV-ACLF patients. Immune dysregulation is closely linked to the potential mechanisms of initiation and progression of ACLF. Innate immune response, which is represented by monocytes/macrophages, is up-regulated across ACLF development. This suggests that monocytes/macrophages play an essential role in maintaining the immune homeostasis of ACLF. Information that has been published in recent years shows that the immune status and function of monocytes/macrophages vary in ACLF precipitated by different chronic liver diseases. Monocytes/macrophages have an immune activation effect in hepatitis B-precipitated-ACLF, but they exhibit an immune suppression in cirrhosis-precipitated-ACLF. Therefore, this review aims to explain whether this difference affects the clinical outcome in HBV-ACLF patients as well as the mechanisms involved. We summarize the novel findings that highlight the dynamic polarization phenotype and functional status of hepatic macrophages from the stage of HBV infection to ACLF development. Moreover, we discuss how different HBV-related liver disease tissue microenvironments affect the phenotype and function of hepatic macrophages. In summary, increasing developments in understanding the differences in immune phenotype and functional status of hepatic macrophages in ACLF patients will provide new perspectives towards the effective restoration of ACLF immune homeostasis.

Ammonia is associated with liver-related complications and predicts mortality in acute-on-chronic liver failure patients.

The relationship between ammonia and liver-related complications (LRCs) in acute-on-chronic liver failure (ACLF) patients is not clearly established. This study aimed to evaluate the association between ammonia levels and LRCs in patients with ACLF. The study also evaluated the ability of ammonia in predicting mortality and progression of LRCs. The study prospectively recruited ACLF patients based on the APASL definition from the ACLF Research Consortium (AARC) from 2009 to 2019. LRCs were a composite endpoint of bacterial infection, overt hepatic encephalopathy (HE), and ascites. A total of 3871 cases were screened. Of these, 701 ACLF patients were enrolled. Patients with LRCs had significantly higher ammonia levels than those without. Ammonia was significantly higher in patients with overt HE and ascites, but not in those with bacterial infection. Multivariate analysis found that ammonia was associated with LRCs. Additionally, baseline arterial ammonia was an independent predictor of 30-day mortality, but it was not associated with the development of new LRCs within 30 days. In summary, baseline arterial ammonia levels are associated with 30-day mortality and LRCs, mainly overt HE and ascites in ACLF patients.

Acute decompensation of cirrhosis versus acute-on-chronic liver failure: What are the clinical implications?

It is essential to identify the subgroup of patients who experience poorer outcomes in order to adapt clinical management effectively. In the context of liver disease, the earlier the identification occurs, the greater the range of therapeutic options that can be offered to patients. In the past, patients with acute decompensation (AD) of chronic liver disease were treated as a homogeneous group, with emphasis on identifying those at the highest risk of death. In the last 15 years, a differentiation has emerged between acute-on-chronic liver failure syndrome (ACLF) and AD, primarily due to indications that the latter is linked to a less favorable short-term prognosis. Nevertheless, the definition of ACLF varies among the different knowledge societies, making it challenging to assess its true impact compared with AD. Therefore, the purpose of this review is to provide a detailed analysis emphasizing the critical importance of identifying ACLF in the field of advanced liver disease. We will discuss the differences between Eastern and Western approaches, particularly in relation to the occurrence of liver failure and disease onset. Common characteristics, such as the dynamic nature of the disease course, will be highlighted. Finally, we will focus on two key clinical implications arising from these considerations: the prevention of ACLF before its onset and the clinical management strategies once it develops, including liver transplantation and withdrawal of care.

The Immunoregulatory and Regenerative Potential of Activated Human Stem Cell Secretome Mitigates Acute-on-Chronic Liver Failure in a Rat Model.

Acute-on-chronic liver failure (ACLF) is a syndrome marked by sudden liver function decline and multiorgan failure, predominantly acute kidney injury (AKY), in patients with chronic liver disease. Unregulated inflammation is a hallmark of ACLF; however, the key drivers of ACLF are not fully understood. This study explores the therapeutic properties of human mesenchymal stem cell (MSC) secretome, particularly focusing on its enhanced anti-inflammatory and pro-regenerative properties after the in vitro preconditioning of the cells. We evaluated the efficacy of the systemic administration of MSC secretome in preventing liver failure and AKI in a rat ACLF model where chronic liver disease was induced using by the administration of porcine serum, followed by D-galN/LPS administration to induce acute failure. After ACLF induction, animals were treated with saline (ACLF group) or MSC-derived secretome (ACLF-secretome group). The study revealed that MSC-secretome administration strongly reduced liver histological damage in the ACLF group, which was correlated with higher hepatocyte proliferation, increased hepatic and systemic anti-inflammatory molecule levels, and reduced neutrophil and macrophage infiltration. Additionally, renal examination revealed that MSC-secretome treatment mitigated tubular injuries, reduced apoptosis, and downregulated injury markers. These improvements were linked to increased survival rates in the ACLF-secretome group, endorsing MSC secretomes as a promising therapy for multiorgan failure in ACLF.

Comparative metabolome analysis reveals higher potential of haemoperfusion adsorption in providing favourable outcome in ACLF patients.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a serious illness associated with altered metabolome, organ failure and high mortality. Need for therapies to improve the metabolic milieu and support liver regeneration are urgently needed. METHODS: We investigated the ability of haemoperfusion adsorption (HA) and therapeutic plasma exchange (TPE) in improving the metabolic profile and survival in ACLF patients. Altogether, 45 ACLF patients were randomized into three groups: standard medical therapy (SMT), HA and TPE groups. Plasma metabolomics was performed at baseline, post-HA and TPE sessions on days 7 and 14 using high-resolution mass spectrometry. RESULTS: The baseline clinical/metabolic profiles of study groups were comparable. We identified 477 metabolites. Of these, 256 metabolites were significantly altered post 7 days of HA therapy (p < .05, FC > 1.5) and significantly reduced metabolites linked to purine (12 metabolites), tryptophan (7 metabolites), primary bile acid (6 metabolites) and arginine-proline metabolism (6 metabolites) and microbial metabolism respectively (p < .05). Metabolites linked to taurine-hypotaurine and histidine metabolism were reduced and temporal increase in metabolites linked to phenylalanine and tryptophan metabolism was observed post-TPE therapy (p < .05). Finally, weighted metabolite correlation network analysis (WMCNA) along with inter/intragroup analysis confirmed significant reduction in inflammatory (tryptophan, arachidonic acid and bile acid metabolism) and secondary energy metabolic pathways post-HA therapy compared to TPE and SMT (p < .05). Higher baseline plasma level of 11-deoxycorticosterone (C03205; AUROC > 0.90, HR > 3.2) correlated with severity (r2 > 0.5, p < .05) and mortality (log-rank-p < .05). Notably, 51 of the 64 metabolite signatures (ACLF non-survivor) were reversed post-HA treatment compared to TPE and SMT(p < .05). CONCLUSION: HA more potentially (~80%) improves plasma milieu compared to TPE and SMT. High baseline plasma 11-deoxycorticosterone level correlates with early mortality in ACLF patients.

[Epidemiological characteristics of inpatients with liver failure at the Beijing You'an Hospital from 2012 to 2021].

Objective: To elucidate the epidemiological characteristics and changing trends of liver failure in order to provide evidence-based strategies for prevention and treatment. Methods: The epidemiological information of inpatients with liver failure admitted and treated at Beijing You'an Hospital from 2012 to 2021 was retrospectively collected. The trend test was used to analyze age, gender, as well as the year-by-year changes in the underlying acute and chronic etiology of acute liver failure (ALF), sub-acute liver failure (SALF), acute-on-chronic liver failure (ACLF), and chronic liver failure (CLF). Results: During the study period, information on a total of 8512 inpatients, aged 51.3±13.5 years and mainly male (71.9%) with liver failure, was collected. The highest to lowest proportions of liver failure types were ACLF 4 023 (47.3%), CLF 3 571(42.0%), SALF 670 (7.9%), and ALF 248 (2.9%). The top five causes of liver failure in the overall population, accounting for 87.6% of the total, were hepatitis B 3 199 (37.58%), alcoholic liver disease 2 237 (26.28%), cryptogenic liver disease 906(10.61%), hepatitis B + alcoholic liver disease 603 (7.08%), drugs 488 (5.73%), The top three etiologies of patients with different types of liver failure were acute etiologies for acute liver failure (ALF), followed by drugs 107 (43.1%), hepatitis B 47(19.0%), and unknown etiology 36 (14.5%); sub-acute liver failure (SALF), followed by drugs 381(56.9%), unknown etiology 106 (15.8%), and sepsis 56 (8.4%); and acute-on-chronic liver failure (ACLF), followed by drugs 2 092(52.0%), alcoholic liver disease 813(20.2%), and cryptogenic liver disease 398(9.9%); and chronic etiologies for chronic liver failure (CLF), followed by alcoholic liver disease 1 410(39.5%), hepatitis B 1 028(28.8%), and cryptogenic liver disease 364(10.2%). Longitudinal analysis showed that the average age of patients with liver failure increased year by year, but the sex ratio trend did not change significantly, with male patients predominating throughout. The proportion of drug-induced liver failure in patients with ALF and SALF increased year by year, and the difference in the trend test was statistically significant (P < 0.05). The proportion of patients with chronic etiologies of ACLF and CLF decreased year by year among hepatitis B, while the proportion of alcoholic liver disease, autoimmune liver disease, and cryptogenic liver disease increased year by year (the difference was statistically significant, P < 0.05). Conclusion: The etiological spectrum of liver failure is changing in our country. Although hepatitis B is still the main cause of liver failure, its proportion shows a decreasing trend year by year, with the exception of ACLF, which is no longer the primary etiology of other types of liver failure, while drug-induced liver disease, alcoholic liver disease, autoimmune liver disease, and cryptogenic liver disease are increasing year by year and will become the focus of liver disease prevention and treatment in the future.

Histological characteristics in patients admitted to the hospital with alcoholic hepatitis complicated by acute-on-chronic liver failure.

OBJECTIVES: Alcoholic hepatitis (AH) is a frequent precipitating event for the development of acute-on-chronic liver failure (ACLF), a syndrome characterised by organ failures due to immune dysfunction. The histological features of this complication are not well characterized. We investigated whether ACLF has specific histological characteristics. METHODS: Prospective cohort study in consecutive adult patients admitted between 03-2008 and 04-2021 to a tertiary referral centre with suspected AH. Diagnosis of AH was based on clinical presentation and confirmed by transjugular liver biopsy. All biopsies were assessed by a dedicated liver pathologist, blinded for clinical data and outcome. Diagnosis of ACLF was based on EASL-CLIF criteria. Histological and clinical characteristics of patients with and without ACLF at baseline were compared. RESULTS: 184 patients with biopsy-proven AH were enrolled. Median time from hospital admission to transjugular biopsy was 4.5 days (IQR 2-8). At baseline, ACLF was present in 73 patients (39.7%). Out of the 110 patients without ACLF at baseline, 30 (27.3%) developed ACLF within 28 days (median 7.5 days (IQR 2-20)). At baseline, ductular bilirubinostasis (DB) was the only histological feature significantly more frequently present in patients with ACLF compared to patients without ACLF (50.7% vs. 30.6%, p = 0.003). No clear association between histological features and the development of ACLF later on could be demonstrated. CONCLUSIONS: In this well-defined cohort of patients with biopsy-proven AH, DB was associated with the presence of ACLF. This finding fits with the pathophysiology of this syndrome, which is characterized by systemic inflammation and an increased risk of infections.

The 90-Day Survival Threshold: A Pivotal Determinant of Long-Term Prognosis in HBV-ACLF Patients - Insights from a Prospective Longitudinal Cohort Study.

This work aims to explore the long-term prognosis of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). In this prospective study, eligible inpatients with HBV-ACLF are enrolled and followed up from December 2012 to February 2023, for clinical events, laboratory tests at least every 6 months. Overall, the survival rates at 28 days, 90 days, 1 year, 5 years, and 8 years are 64.7%, 48.8%, 46.1%, 43.8%, and 42.2%, respectively. Among the 8-year mortality and liver transplant cases, ACLF survivors (who survived over 90 days) accounted for 7.8% (9/115). Among 101 patients who survived for more than 90 days, 97.9% of patients achieve virologic response at 1 year. For HBeAg-positive patients, the HBeAg seroconversion are 25.5%, 63.6%, and 76.9% at 1, 5, and 8 years, respectively. Alanine aminotransferase, aspartate aminotransferase, total bilirubin, INR, white blood cell count, and albumin levels gradually improve within the first year. Fibrosis biomarkers APRI, FIB-4 and Chitinase-3-like protein 1 (CHI3L1) levels decreases within the first 5 years. The Cox proportional hazards regression reveal that high total bilirubin (HR = 1.008, p = 0.021) is the independent risk factor for 8-year survival of ALCF survivors. The 90-day period following of HBV-ACLF represented a critical juncture for long-term prognosis, revealing favorable outcomes beyond this timeframe.

A novel prognostic model to predict mortality in patients with acute-on-chronic liver failure in intensive care unit.

Acute-on-chronic liver failure (ACLF) implies high short-term mortality rates and usually requires intensive care unit (ICU) admission. Proper prognosis for these patients is crucial for early referral for liver transplantation. The superiority of CLIF-C ACLF score in Asian patients with ACLF admitted to an ICU remains inconclusive when compared to other scoring systems. The purpose of the study is (i) to compare the predictive performance of original MELD, MELD-Lactate, CLIF-C ACLF, CLIF-C ACLF-Lactate, and APACHE-II scores for short-term mortality assessment. (ii) to build and validate a novel scoring system and to compare its predictive performance to that of the original five scores. Two hundred sixty-five consecutive cirrhotic patients with ACLF who were admitted to our ICU were enrolled. The prognostic values for mortality were assessed by ROC analysis. A novel model was developed and internally validated using fivefold cross-validation. Alcohol abuse was identified as the primary etiology of cirrhosis. The AUROC of the five prognostic scores were not significantly superior to each other in predicting 1-month and 3-month mortality. The newly developed prognostic model, incorporating age, alveolar-arterial gradient (A-a gradient), BUN, total bilirubin level, INR, and HE grades, exhibited significantly improved performance in predicting 1-month and 3-month mortality with AUROC of 0.863 and 0.829, respectively, as compared to the original five prognostic scores. The novel ACLF model seems to be superior to the original five scores in predicting short-term mortality in ACLF patients admitted to an ICU. Further rigorous validation is required.