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The acute‐on‐chronic liver failure (ACLF) development is highly dynamic. Currently, no satisfactory algorithm identifies patients with HBV at risk of this complication. The aim of the study was to characterize ACLF development in hospitalized HBV‐related patients without previous decompensation and to test the performance of traditional prognostic models in ruling out ACLF development within 28 days on admission we conducted a cohort study. Two multi‐center cohorts with hospitalized HBV‐related previous compensated patients were analyzed. Performances of MELD, MELD‐Na, CLIF‐C AD, and CLIF‐C ACLF‐D in ruling out ACLF development within 28 days were compared and further validated by ROC analyses. In the derivation cohort (n = 892), there were 102 patients developed ACLF within 28 days, with profound systemic inflammatory levels and higher 28‐day mortality rate (31.4% vs. 1.0%) than those without ACLF development. The MELD score (cut‐off = 18) achieved acceptable missing rate (missed/total ACLF development) at 2.9%. In the validation cohort (n = 1656), the MELD score (<18) was able to rule out ACLF development within 28 days with missing rate at 3.0%. ACLF development within 28 days were both lower than 1% (0.6%, derivation cohort; 0.5%, validation cohort) in patients with MELD < 18. While in patients with MELD ≥ 18, 26.6% (99/372, derivation cohort) and 17.8% (130/732, validation cohort) developed into ACLF within 28 days, respectively. While MELD‐Na score cut‐off at 20 and CLIF‐AD score cut‐off at 42 did not have consistent performance in our two cohorts. MELD < 18 was able to safely rule out patients with ACLF development within 28 days in HBV‐related patients without previous decompensation, which had a high 28‐day mortality. [ABSTRACT FROM AUTHOR]

Introduction: Acute-on-chronic liver failure (ACLF) patients are susceptible to invasive fungal infections. We evaluated the prognosis and antifungal options in ACLF patients with invasive pulmonary aspergillosis (IPA). Methods: ACLF patients with IPA from 15 hospitals were retrospectively screened from 2011 to 2018, and 383 ACLF patients without lung infections were included from a prospective cohort (NCT02457637). Demographic, laboratory, clinical data, and 28-day outcomes were documented in the two cohorts. Results: ACLF patients with probable IPA (n = 145) had greater 28-day mortality (33.6% vs. 15.7%, p < 0.001) than those without (n = 383). The respiratory failure-associated 28-day mortality was greater in ACLF patients with IPA than in those without before (17.1% vs. 0.3%, p < 0.001) and after (16.0% vs. 0.0%, p < 0.001) propensity score matching in 116 pairs. IPA patients with lung injury had greater 28-day all-cause mortality (66.5% vs. 24.2%, p < 0.001) and IPA-associated mortality (45.8% vs. 8.1%, p < 0.001) than patients without lung injury (PaO2/FiO2 ≥ 400 mmHg). Antifungal therapy was prescribed to 139 of 145 patients, and 102 patients were treated with voriconazole alone (n = 59) or sequential/combined therapy (n = 43) with varying loading doses (100–800 mg) and daily maintenance doses (0–800 mg). A proposed optimal voriconazole regimen (loading dose, 200 mg twice daily; daily maintenance dose, 100 mg) achieved comparable short-term survival and optimal trough drug concentrations (1–5 μg/mL) on therapeutic drug monitoring in 26 patients. Conclusion: Presence of IPA increases the short-term mortality of ACLF patients mainly due to respiratory failure. An optimal voriconazole regimen is needed for such critical patients. [ABSTRACT FROM AUTHOR]

Background. Acute-on-chronic liver failure (ACLF) is a clinical syndrome characterized by acute deterioration of liver function and high short-term mortality. Clusterin, with biological functions similar to small heat shock proteins, can protect cells from apoptosis induced by various stressors. The aim of this study was to detect the level of serum clusterin in hepatitis B virus- (HBV-) related ACLF and to assess the predictive value of clusterin for the short-term prognosis of HBV-ACLF. Methods. We detected serum clusterin by ELISA in 108 HBV-ACLF patients, 63 HBV-non-ACLF patients, and 44 normal controls. Results. Serum clusterin was markedly lower in HBV-ACLF patients (median, 51.09 μg/mL) than in HBV-non-ACLF patients (median, 188.56 μg/mL) and normal controls (median, 213.45 μg/mL; all P < 0.05). Nonsurviving HBV-ACLF patients who died within 90 days had much lower clusterin levels than did surviving patients, especially those who died within 28 days (nonsurvival group vs. survival group: 39.82 ± 19.34 vs. 72.26 ± 43.52 , P < 0.001 ; survival time ≤ 28 vs. survival time > 28 : median 28.39 vs. 43.22, P = 0.013). The results showed that for identifying HBV-ACLF, the sensitivity of clusterin (93.7%) was similar to the sensitivities of the international normalized ratio (INR; 94.4%) and total bilirubin (TBIL; 94.8%), but its specificity (90.7%) was higher than that of prothrombin activity (PTA; 65.8%) and TBIL (69.8%) and was similar to INR (88.9%). As the concentration of clusterin increased, the mortality of HBV-ACLF patients decreased significantly from 59.3% to 7.0%. Clusterin had better ability for predicting the prognosis of HBV-ACLF patients than did the model for end-stage liver disease (MELD) score and the chronic liver failure consortium (CLIF-C) ACLF score (MELD vs. clusterin: P = 0.012 ; CLIF-C ACLF vs. clusterin: P = 0.031). Conclusion. Serum clusterin is a potential biomarker for HBV-ACLF which can be used to assess clinical severity and the short-term prognosis of patients with this disease and may help clinicians identify HBV-ACLF with greater specificity and improved prognostic accuracy than existing prognostic markers. [ABSTRACT FROM AUTHOR]

Background & Aims: Current guidelines on the management of bacterascites are limited. This multicentre, retrospective study investigated the clinical features and outcomes of cirrhosis patients with bacterascites. Methods: Two series of cirrhosis patients were evaluated. The first included 418 patients with ascites‐positive cultures at 11 hospitals during 2012‐2018. Clinical characteristics and outcomes were recorded. The second included 208 patients with sterile ascites from a prospective cohort (NCT02457637). Clinical features and outcomes of cirrhotic patients with or without bacterascites were investigated. Results: In the first series, bacterascites was diagnosed in 254/418 (60.8%) patients, and culture‐positive spontaneous bacterial peritonitis (SBP) in 164/418 (39.2%) patients. Gram‐positive bacteria were more prevalent in bacterascites patients than in culture‐positive SBP patients (59.1% vs 22.0%; P <.001). For patients with acute‐on‐chronic liver failure (ACLF) in bacterascites and culture‐positive SBP groups, the 28‐day transplant‐free mortality (41.3% vs 65.5%; P =.015) and the prevalence of in‐hospital acute kidney injury (AKI) (84.8% vs 75%; P =.224). For patients without ACLF in the bacterascites (n = 208) and culture‐positive SBP groups (n = 108), the 28‐day transplant‐free mortalities were 13% vs 13.9% (P =.822), the probabilities of progression to ACLF within 28 days were 10.1% vs 14.8% (P =.216) and the prevalences of in‐hospital AKI were 14.4% vs 30.6% (P =.001). Bacterascites patients had higher 28‐day mortality than those patients with sterile ascites, after propensity score matching (18.4% vs 8.6%; P =.010). Conclusion: Bacterascites patients had non‐negligible poor clinical outcomes, including in‐hospital AKI, progression to ACLF and 28‐day mortality. Future studies are warranted to expedite the diagnosis of bacterascites and optimize antibiotic treatment. [ABSTRACT FROM AUTHOR]

Background: This study aimed to develop prognostic models for predicting 28- and 90-day mortality rates of hepatitis B virus (HBV)-associated acute-on-chronic liver failure (HBV-ACLF) through artificial neural network (ANN) systems.Methods: Six hundred and eight-four cases of consecutive HBV-ACLF patients were retrospectively reviewed. Four hundred and twenty-three cases were used for training and constructing ANN models, and the remaining 261 cases were for validating the established models. Predictors associated with mortality were determined by univariate analysis and were then included in ANN models for predicting prognosis of mortality. The receiver operating characteristic curve analysis was used to evaluate the predictive performance of the ANN models in comparison with various current prognostic models.Results: Variables with statistically significant difference or important clinical characteristics were input in the ANN training process, and eight independent risk factors, including age, hepatic encephalopathy, serum sodium, prothrombin activity, γ-glutamyltransferase, hepatitis B e antigen, alkaline phosphatase and total bilirubin, were eventually used to establish ANN models. For 28-day mortality in the training cohort, the model's predictive accuracy (AUR 0.948, 95% CI 0.925-0.970) was significantly higher than that of the Model for End-stage Liver Disease (MELD), MELD-sodium (MELD-Na), Chronic Liver Failure-ACLF (CLIF-ACLF), and Child-Turcotte-Pugh (CTP) (all p < 0.001). In the validation cohorts the predictive accuracy of ANN model (AUR 0.748, 95% CI: 0.673-0.822) was significantly higher than that of MELD (p = 0.0099) and insignificantly higher than that of MELD-Na, CTP and CLIF-ACLF (p > 0.05). For 90-day mortality in the training cohort, the model's predictive accuracy (AUR 0.913, 95% CI 0.887-0.938) was significantly higher than that of MELD, MELD-Na, CTP and CLIF-ACLF (all p < 0.001). In the validation cohorts, the prediction accuracy of the ANN model (AUR 0.754, 95% CI: 0.697-0.812 was significantly higher than that of MELD (p = 0.019) and insignificantly higher than MELD-Na, CTP and CLIF-ACLF (p > 0.05).Conclusions: The established ANN models can more accurately predict short-term mortality risk in patients with HBV- ACLF. The main content has been postered as an abstract at the AASLD Hepatology Conference (https://doi.org/10.1002/hep.30257). [ABSTRACT FROM AUTHOR]

Acute-on-chronic liver failure (ACLF) is a clinical syndrome associated with high short-term mortality in patients with chronic liver disease. Chronic hepatitis B is the main cause of ACLF (HBV-ACLF) in China and other Asian countries. To improve disease management and survival for patients with ACLF, we aimed to discover novel biomarkers to enhance HBV-ACLF diagnosis and prognostication. We performed a metabolomics profiling of 1,024 plasma samples collected from patients with HBV-related chronic liver disease with acute exacerbation at hospital admission in a multi-year and multi-center prospective study (367 ACLF and 657 non-ACLF). The samples were randomly separated into equal halves as a discovery set and a validation set. We identified metabolites associated with 90-day mortality in the ACLF group and the progression to ACLF within 28 days in the non-ACLF group (pre-ACLF) using statistical analysis and machine learning. We developed diagnostic algorithms in the discovery set and used these to assess the findings in the validation set. ACLF significantly altered the plasma metabolome, particularly in membrane lipid metabolism, steroid hormones, oxidative stress pathways, and energy metabolism. Numerous metabolites were significantly associated with 90-day mortality in the ACLF group and/or pre-ACLF in the non-ACLF group. We developed algorithms for the prediction of 90-day mortality in patients with ACLF (area under the curve 0.87 and 0.83 for the discovery set and validation set, respectively) and the diagnosis of pre-ACLF (area under the curve 0.94 and 0.88 for the discovery set and validation set, respectively). To translate our discoveries into practical clinical tests, we developed targeted assays using liquid chromatography-mass spectrometry. Based on novel metabolite biomarkers, we established tests for HBV-related ACLF with higher accuracy than existing methods. NCT02457637 and NCT03641872. Acute-on-chronic liver failure (ACLF) is a clinical syndrome associated with high short-term mortality affecting 25% of patients hospitalized with cirrhosis. Chronic hepatitis B is the main etiology of ACLF in China and other Asian counties. There is currently no effective therapy. Early diagnosis and accurate prognostication are critical for improving clinical outcomes in patients with ACLF. Based on novel metabolite biomarkers, we developed liquid chromatography-mass spectrometry tests with improved accuracy for the early diagnosis and prognostication of HBV-related ACLF. The liquid chromatography-mass spectrometry tests can be implemented in clinical labs and used by physicians to triage patients with HBV-related ACLF to ensure optimized clinical management. [Display omitted] • Metabolomics uncovered profound metabolic perturbations associated with HBV-related ACLF in patient plasma. • We identified novel metabolite biomarkers that can be used to enhance ACLF prognostication and early diagnosis. • We developed and validated LCMS-based clinical tests with improved accuracy for ACLF prognostication and early diagnosis. [ABSTRACT FROM AUTHOR]

Recent studies have found that endotoxin not only activates immune response, exacerbates liver injury, and induces liver failure, but also plays an important role in the development of hepatic encephalopathy, hepatorenal syndrome, spontaneous bacterial peritonitis, and other fatal complications. T e recent progress in research on the pathogenesis of intestinal endotoxemia (IETM) and its impact on the development and progression of liver failure is reviewed and summarized. It is suggested that seeking effective methods to prevent and control IETM holds promise as the key to treating severe liver disease and liver failure successfully [ABSTRACT FROM AUTHOR]

Background & Aims The important pathophysiological role of immune dysfunction, especially innate immune dysfunction in patients with acute-on-chronic liver failure ( ACLF), has been investigated in recent years, but dysregulation of adaptive immunity remains poorly elucidated. The aim of this study was to (i) determine the CD3+ T-lymphocyte count and the balance between CD4+ regulatory T (Tregs) and conventional T cells (Tconv) in hepatitis B virus ( HBV)-related ACLF patients; (ii) analyse the frequencies of Tregs subpopulations; and (iii) assess the suppressive potency of CD4+ Tregs and each fraction. Methods We enrolled 20 HBV- ACLF patients, 10 septic shock subjects, 20 chronic hepatitis B ( CHB) patients and 20 healthy volunteers ( HC). Based on flow cytometry, we performed the absolute counting of circulating T lymphocytes and phenotyping of CD4+ Tregs and quantified the effects of Tregs and each subpopulation on Tconv proliferation by CFSE staining. Results Compared with CHB patients and HC, we observed an equal reduction in peripheral T subsets in HBV- ACLF and septic shock subjects; the number of CD4+ Tregs remained unchanged and the Tconv count declined, promoting elevation of the Treg-to-Tconv ratio. The frequencies of Treg-II and -III were elevated in HBV- ACLF. Functional studies showed that the suppressive capacity of Tregs was preserved in the HBV- ACLF group and Treg-II came first. Conclusions Similar to septic shock subjects, in HBV- ACLF patients there exists a reduction in CD4+ T lymphocytes, predominantly CD4+ Tconv, and the development of suppressive CD4+ Tregs greatly prevails over Tconv, constituting important characteristics of adaptive immune dysfunction of HBV- ACLF. [ABSTRACT FROM AUTHOR]