HIV-Negative Case of Talaromyces marneffei Pulmonary Infection with Liver Cirrhosis in China: A Case Report and Literature Review.

Background: Talaromyces marneffei (TM) is the third most prevalent opportunistic infection in HIV-positive patients after tuberculosis and cryptococcosis. However, such infection of non-HIV individuals has rarely been reported. Case Presentation: We describe a very rare case of a 52-year-old male who presented with a single space-occupying lesion on the right lung and was eventually diagnosed with pulmonary TM infection. The patient was HIV-negative and had liver cirrhosis with portal vein thrombosis. Lung tissue next-generation sequencing (NGS) revealed TM infection. We successfully treated the patient with voriconazole for 8 weeks and observed lesion absorption via subsequent CT. The patient consumed wild bamboo rats two months before admission. Mutations related to congenital immune deficiency were not detected by whole-exome sequencing. Conclusion: Early and timely diagnosis is critical for improving patient prognosis. NGS plays a vital role in the diagnosis of pulmonary TM infection in patients. To our knowledge, this is the first published case of pulmonary TM infection in an HIV-negative patient with liver cirrhosis.

Association of AST/ALT ratio with 90-day outcomes in patients with acute exacerbation of chronic liver disease: a prospective multicenter cohort study in China.

Background and aim: A high aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio is associated with liver injury in liver disease; however, no data exist regarding its relationship with 90-day prognosis in patients with acute exacerbation of chronic liver disease. Methods: In this study, 3,758 participants (955 with advanced fibrosis and 2,803 with cirrhosis) from the CATCH-LIFE cohort in China were included. The relationships between different AST/ALT ratios and the risk of adverse 90-day outcomes (death or liver transplantation) were determined in patients with cirrhosis or hepatitis B virus (HBV)-associated advanced fibrosis, respectively. Results: In the patients with HBV-associated advanced fibrosis, the risk of 90-day adverse outcomes increased with AST/ALT ratio; after adjusting for all confounding factors, the risk of adverse 90-day outcomes was the highest when AST/ALT ratio was more than 1.08 (OR = 6.91 [95% CI = 1.789-26.721], p = 0.005), and the AST/ALT ratio of >1.9 accelerated the development of adverse outcomes. In patients with cirrhosis, an AST/ALT ratio > 1.38 increased the risk of adverse 90-day outcomes in all univariables (OR = 1.551 [95% CI = 1.216-1.983], p < 0.001) and multivariable-adjusted analyses (OR = 1.847 [95% CI = 1.361-2.514], p < 0.001), and an elevated AST/ALT ratio (<2.65) accelerated the incidence of 90-day adverse outcomes. An AST/ALT ratio of >1.38 corresponded with a more than 20% incidence of adverse outcomes in patients with cirrhosis. Conclusion: The AST/ALT ratio is an independent risk factor for adverse 90-day outcomes in patients with cirrhosis and HBV-associated advanced fibrosis. The cutoff values of the AST/ALT ratio could help clinicians monitor the condition of patients when making clinical decisions.

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.

The clinical courses of HBV-related acute-on-chronic liver failure and a multi-state model to predict disease evolution.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a highly dynamic syndrome. The objective of this study was to delineate the clinical course of patients with HBV-ACLF and to develop a model to estimate the temporal evolution of disease severity. METHODS: We enrolled eligible patients from 2 large, multicenter prospective cohorts. The ACLF grade, organ failures, and outcomes were assessed at multiple time points (days 1/4/7/14/21/28). Probabilities for ACLF transitions between these disease states and to death within 28 days were calculated using a multi-state model that used baseline information and updated ACLF status. The model was validated in independent patients. RESULTS: Among all the 445 patients with HBV-ACLF, 76 represented disease progression, 195 had a stable or fluctuating course, 8 with improvement, and the remaining 166 with resolution within 28-day follow-up. New coagulation (63.64%) or renal failure (45.45%) was frequently observed during early progression. Patients with disease progression had a higher incidence of new episodes of ascites [10 (13.16%) vs. 22 (5.96%), p = 0.027] and HE [13(17.11%) vs. 21 (5.69%), p = 0.001], and a significant increase in white blood cell count. The multi-state model represented dynamic areas under the receiver operating characteristic curves ranging from 0.71 to 0.84 for predicting all ACLF states and death at 4, 7, 14, 21, and 28 days post-enrollment and from 0.73 to 0.94 for predicting death alone, performing better than traditional prognostic scores. CONCLUSIONS: HBV-ACLF is a highly dynamic syndrome with reversibility. The multi-state model is a tool to estimate the temporal evolution of disease severity, which may inform clinical decisions on treatment.

Severe anemia is associated with increased short-term and long-term mortality in patients hospitalized with cirrhosis.

INTRODUCTION AND OBJECTIVES: The relationship between anemia and the outcome of patients with cirrhosis is not completely clear. Therefore, we performed this large-scale epidemiological study to investigate the prevalence and severity of anemia in patients with cirrhosis and acute decompensation or liver injury and how anemia impacts short-term and long-term outcomes. PATIENTS AND METHODS: Patients with cirrhosis and acute decompensation (AD) or acute liver injury (ALI) were enrolled in the Chinese AcuTe on CHronic LIver FailurE (CATCH-LIFE) studies, which consisted of two large, multicenter, prospective, observational cohorts between January 2015 and December 2016 and July 2018 and January 2019. We conducted data analysis on the prevalence of anemia and determined the relationship between anemia and prognosis. RESULTS: Among 1979 patients, 1389 (70.2%) had anemia, among whom 599 (41.3%) had mild anemia, 595 (15.8%) had moderate anemia and 195 (2.4%) had severe anemia. A linear association between hemoglobin level and 90-day or 1-year LT-free mortality was shown, and a 10 g/L decrease in hemoglobin level was associated with a 6.8% extra risk of 90-day death and a 5.7% extra risk of 1-year death. Severe anemia was an independent risk factor for 90-day [HR=1.649 (1.100, 2.473), p=0.016] and 1-year LT-free mortality [HR=1.610 (1.159, 2.238), p=0.005]. Multinomial logistic regression analysis further identified that severe anemia was significantly associated with post-28-day mortality but not within-28-day mortality. CONCLUSIONS: Anemia is common in patients with cirrhosis admitted for acute events. Severe anemia was associated with poor 90-day and 1-year prognoses in these patients.

Metabolic biomarkers significantly enhance the prediction of HBV-related ACLF occurrence and outcomes.

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Based on novel metabolite biomarkers, we established tests for HBV-related ACLF with higher accuracy than existing methods. CLINICAL TRIAL NUMBER: NCT02457637 and NCT03641872. IMPACT AND IMPLICATIONS: 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.

New Algorithm Rules Out Acute-on-chronic Liver Failure Development within 28 Days from Acute Decompensation of Cirrhosis.

Background and Aims: Approximately 10% of patients with acute decompensated (AD) cirrhosis develop acute-on-chronic liver failure (ACLF) within 28 days. Such cases have high mortality and are difficult to predict. Therefore, we aimed to establish and validate an algorithm to identify these patients on hospitalization. Methods: Hospitalized patients with AD who developed ACLF within 28 days were considered pre-ACLF. Organ dysfunction was defined according to the chronic liver failure-sequential organ failure assessment (CLIF-SOFA) criteria, and proven bacterial infection was taken to indicate immune system dysfunction. A retrospective multicenter cohort and prospective one were used to derive and to validate the potential algorithm, respectively. A miss rate of <5% was acceptable for the calculating algorithm to rule out pre-ACLF. Results: In the derivation cohort (n=673), 46 patients developed ACLF within 28 days. Serum total bilirubin, creatinine, international normalized ratio, and present proven bacterial infection at admission were associated with the development of ACLF. AD patients with ≥2 organ dysfunctions had a higher risk for pre-ACLF patients [odds ratio=16.581 95% confidence interval: (4.271-64.363), p<0.001]. In the derivation cohort, 67.5% of patients (454/673) had ≤1 organ dysfunction and two patients (0.4%) were pre-ACLF, with a miss rate of 4.3% (missed/total, 2/46). In the validation cohort, 65.9% of patients (914/1388) had ≤1 organ dysfunction, and four (0.3%) of them were pre-ACLF, with a miss rate of 3.4% (missed/total, 4/117). Conclusions: AD patients with ≤1 organ dysfunction had a significantly lower risk of developing ACLF within 28 days of admission and could be safely ruled out with a pre-ACLF miss rate of <5%.

High-Resolution Genomic Profiling of a Genotype 3b Hepatitis C Virus from a Flare of an Occult Hepatitis Patient with Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is defined as a syndrome of acutely decompensated cirrhosis in patients with chronic liver disease (CLD). Here we report an ACLF case caused by a flare of occult hepatitis C infection. This patient was infected with hepatitis C virus (HCV) more than a decade ago and hospitalized due to alcohol-associated CLD. Upon admission, the HCV RNA in the serum was negative and the anti-HCV antibody was positive, whereas the viral RNA in the plasma dramatically increased during hospitalization, which suggests an occult hepatitis C infection. Overlapped fragments encompassing the nearly whole HCV viral genome were amplified, cloned, and sequenced. Phylogenetic analysis indicated an HCV genotype 3b strain. Sanger sequencing to 10-fold coverage of the 9.4-kb nearly whole genome reveals high diversity of viral quasispecies, an indicator of chronic infection. Inherent resistance-associated substitutions (RASs) in the NS3 and NS5A but not in the NS5B regions were identified. The patient developed liver failure and accepted liver transplantation, followed by direct-acting antiviral (DAA) treatment. The hepatitis C was cured by the DAA treatment despite the existence of RASs. Thus, care should be taken for occult hepatitis C in patients with alcoholic cirrhosis. The analysis of viral genetic diversity may help to identify an occult hepatitis C virus infection and predict the efficacy of anti-viral treatment.

A novel prognostic nomogram for older patients with acute-on-chronic liver diseases (AoCLD): a nationwide, multicentre, prospective cohort study.

BACKGROUND: the incidence of acute-on-chronic liver disease (AoCLD) is increasing. OBJECTIVE: to investigate the clinical features and risk factors of AoCLD and construct an effective prognostic nomogram model for older patients with AoCLD. METHODS: data from 3,970 patients included in the CATCH-LIFE study were used, including 2,600 and 1,370 patients in the training and validation sets, respectively. Multivariate Cox regression analyses were performed to identify predictive risk factors in older individuals, and an easy-to-use nomogram was established. Performance was assessed using area under the curve, calibration plots and decision curve analysis (DCA). RESULTS: of the 3,949 patients with AoCLD, 809 were older with a higher proportion of autoimmune-related abnormalities, hepatitis C viral infection and schistosomiasis. In the older patient group, the incidence of cirrhosis, hepatic encephalopathy (HE), infection, ascites and gastrointestinal bleeding; neutrophil-to-lymphocyte ratio (NLR), aspartate-to-alanine transaminase ratio (AST/ALT), creatinine and blood urea nitrogen levels were higher, whereas incidence of acute-on-chronic liver failure, white blood cell, platelet and haemoglobin levels; albumin, total bilirubin (TB), AST and ALT levels; international normalised ratio (INR), estimated glomerular filtration rate and blood potassium levels were lower than in the younger group. The final nomogram was developed based on the multivariate Cox analysis in training cohort using six risk factors: ascites, HE grades, NLR, TB, INR and AST/ALT. Liver transplantation-free mortality predictions were comparable between the training and validation sets. DCA showed higher net benefit for the nomograph than the treat-all or treat-none strategies, with wider threshold probabilities ranges. CONCLUSIONS: our analysis will assist clinical predictions and prognoses in older patients with AoCLD.

Portal vein thrombosis compromises the performance of MELD and MELD-Na scores in patients with cirrhosis.

BACKGROUND AND AIMS: The accuracy of model for end-stage liver disease (MELD) and MELD with sodium (MELD-Na) scores in reflecting the clinical outcomes of patients with cirrhosis and portal vein thrombosis (PVT) remains unclear. This study aimed to evaluate the performance of scores in predicting 90-day mortality in patients with cirrhosis and PVT. METHODS: Post hoc analysis was performed in two prospective cohorts (NCT02457637 and NCT03641872). The correlation between the MELD/MELD-Na score and 90-day liver transplantation (LT)-free mortality was investigated in patients with cirrhosis with and without PVT. RESULTS: In this study, 2826 patients with cirrhosis were included, and 255 (9.02%) had PVT. The cumulative incidence of 90-day LT-free mortality did not significantly differ between patients with and without PVT (log-rank P = 0.0854). MELD [area under the receiver operating curve (AUROC), 0.649 vs. 0.842; P = 0.0036] and MELD-Na scores (AUROC, 0.691 vs. 0.851; P = 0.0108) were compared in patients with and without PVT, regarding the prediction of 90-day LT-free mortality. In MELD < 15 and MELD-Na < 20 subgroups, patients with PVT had a higher 90-day LT-free mortality than those without PVT (7.91% vs. 2.64%, log-rank P = 0.0011; 7.14% vs. 3.43%, log-rank P = 0.0223), whereas in MELD ≥ 15 and MELD-Na ≥ 20 subgroups, no significant difference was observed between patients with and without PVT. CONCLUSIONS: The performance of MELD and MELD-Na scores in predicting 90-day LT-free mortality of patients with cirrhosis was compromised by PVT. MELD < 15 or MELD-Na < 20 may underestimate the 90-day LT-free mortality in patients with PVT.

Prognosis prediction performs better in patients with non-cirrhosis hepatitis B virus-related acute-on-chronic liver failure than those with cirrhosis.

Background: The accurate prediction of the outcome of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is impeded by population heterogeneity. The study aimed to assess the impact of underlying cirrhosis on the performance of clinical prediction models (CPMs). Methods: Using data from two multicenter, prospective cohorts of patients with HBV-ACLF, the discrimination, calibration, and clinical benefit were assessed for CPMs predicting 28-day and 90-day outcomes in patients with cirrhosis and those without, respectively. Results: A total of 919 patients with HBV-ACLF were identified by Chinese Group on the Study of Severe Hepatitis B (COSSH) criteria, including 675 with cirrhosis and 244 without. COSSH-ACLF IIs, COSSH-ACLFs, Chronic Liver Failure-Consortium Acute-on-Chronic Liver Failure score (CLIF-C ACLFs), Tongji Prognostic Predictor Model score (TPPMs), Model for End-Stage Liver Disease score (MELDs), and MELD-Sodium score (MELD-Nas) were all strong predictors of short-term mortality in patients with HBV-ACLF. In contrast to a high model discriminative capacity in ACLF without cirrhosis, each prognostic model represents a marked decline of C-index, net reclassification index (NRI), and integrated discrimination improvement (IDI) in predicting either 28-day or 90-day prognosis of patients with cirrhosis. The hazard analysis identified largely overlapping risk factors of poor outcomes in both subgroups, while serum bilirubin was specifically associated with short-term mortality in patients with cirrhosis and blood urea nitrogen in patients without cirrhosis. A subgroup analysis in patients with cirrhosis showed a decline of discrimination of CPMS in those with ascites or infections compared to that in those without. Conclusion: Predicting the short-term outcome of HBV-ACLF by CPMs is optimal in patients without cirrhosis but limited in those with cirrhosis, at least partially due to the complicated ascites or infections.

Role of precipitants in transition of acute decompensation to acute-on-chronic liver failure in patients with HBV-related cirrhosis.

Background & Aims: Pre-acute-on-chronic liver failure (ACLF) is a distinct intermediate stage between acute decompensation (AD) and ACLF. However, identifying patients with pre-ACLF and predicting progression from AD to ACLF is difficult. This study aimed to identify pre-ACLF within 28 days, and to develop and validate a prediction model for ACLF in patients with HBV-related decompensated cirrhosis. Methods: In total, 1,736 patients with HBV-related cirrhosis and AD were enrolled from 2 large-scale, multicenter, prospective cohorts. ACLF occurrence within 28 days, readmission, and 3-month and 1-year outcomes were collected. Results: Among 970 patients with AD without ACLF in the derivation cohort, the 94 (9.6%) patients with pre-ACLF had the highest 3-month and 1-year LT-free mortality (61.6% and 70.9%, respectively), which was comparable to those with ACLF at enrollment (57.1% and 67.1%); the 251 (25.9%) patients with unstable decompensated cirrhosis had mortality rates of 22.4% and 32.1%, respectively; while the 507 (57.9%) patients with stable decompensated cirrhosis had the best outcomes (1-year mortality rate of 2.6%). Through Cox proportional hazard regression, specific precipitants, including hepatitis B flare with HBV reactivation, spontaneous hepatitis B flare with high viral load, superimposed infection on HBV, and bacterial infection, were identified to be significantly associated with ACLF occurrence in the derivation cohort. A model that incorporated precipitants, indicators of systemic inflammation and organ injuries reached a high C-index of 0.90 and 0.86 in derivation and validation cohorts, respectively. The optimal cut-off value (0.22) differentiated high-risk and low-risk patients, with a negative predictive value of 0.95. Conclusions: Three distinct clinical courses of patients with AD are validated in the HBV-etiology population. The precipitants significantly impact on AD-ACLF transition. A model developed by the precipitant-systemic inflammation-organ injury framework could be a useful tool for predicting ACLF occurrence. Clinical trial number: NCT02457637 and NCT03641872. Lay summary: It was previously shown that patients with decompensated cirrhosis could be stratified into 3 groups based on their short-term clinical prognoses. Herein, we showed that this stratification applies to patients who develop cirrhosis as a result of hepatitis B virus infection. We also developed a precipitant-based model (i.e. a model that incorporated information about the exact cause of decompensation) that could predict the likelihood of these patients developing a very severe liver disease called acute-on-chronic liver failure (or ACLF).

MELD score < 18 rule out 28-day ACLF development among inpatients with hepatitis B-related previous compensated liver disease.

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.

Prevalence and clinical characteristics of autoimmune liver disease in hospitalized patients with cirrhosis and acute decompensation in China.

BACKGROUND: Autoimmune liver disease (AILD) has been considered a relatively uncommon disease in China, epidemiological data for AILD in patients with cirrhosis and acute decompensation (AD) is sparse. AIM: To investigate the prevalence, outcome and risk factors for AILD in cirrhotic patients complicated with AD in China. METHODS: We collected data from patients with cirrhosis and AD from two prospective, multicenter cohorts in hepatitis B virus endemic areas. Patients were regularly followed up at the end of 28-d, 90-d and 365-d, or until death or liver transplantation (LT). The primary outcome in this study was 90-d LT-free mortality. Acute-on-chronic liver failure (ACLF) was assessed on admission and during 28-d hospitalization, according to the diagnostic criteria of the European Association for the Study of the Liver (EASL). Risk factors for death were analyzed with logistic regression model. RESULTS: In patients with cirrhosis and AD, the overall prevalence of AILD was 9.3% (242/2597). Prevalence of ACLF was significantly lower in AILD cases (14%) than those with all etiology groups with cirrhosis and AD (22.8%) (P < 0.001). Among 242 enrolled AILD patients, the prevalence rates of primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH) and PBC-AIH overlap syndrome (PBC/AIH) were 50.8%, 28.5% and 12.0%, respectively. In ACLF patients, the proportions of PBC, AIH and PBC/AIH were 41.2%, 29.4% and 20.6%. 28-d and 90-d mortality were 43.8% and 80.0% in AILD-related ACLF. The etiology of AILD had no significant impact on 28-d, 90-d or 365-d LT-free mortality in patients with cirrhosis and AD in both univariate and multivariate analysis. Total bilirubin (TB), hepatic encephalopathy (HE) and blood urea nitrogen (BUN) were independent risk factors for 90-d LT-free mortality in multivariate analysis. The development of ACLF during hospitalization only independently correlated to TB and international normalized ratio. CONCLUSION: AILD was not rare in hospitalized patients with cirrhosis and AD in China, among which PBC was the most common etiology. 90-d LT-free mortality were independently associated with TB, HE and BUN.

Hepatitis B Virus Reactivation Increased the Risk of Developing Hepatic Failure and Mortality in Cirrhosis With Acute Exacerbation.

Background and Aims: Hepatitis B virus (HBV) reactivation is a serious condition and has been extensively described in chemotherapeutic immunosuppressive population. However, little is known about HBV reactivation in immunocompetent patients with chronic hepatitis B (CHB). In this study, we evaluated the prevalence and the clinical significance of HBV reactivation in CHB patients with acute exacerbations. Method: Patients were screened from two prospective multicenter observational cohorts (CATCH-LIFE cohort). A total of 1,020 CHB patients with previous antiviral treatment history were included to assess the prevalence, risk factors, clinical characteristics of HBV reactivation, and its influence on the progression of chronic liver disease. Results: The prevalence of HBV reactivation was 51.9% in CHB patients with acute exacerbations who had antiviral treatment history in our study. Among the 529 patients with HBV reactivation, 70.9% of them were triggered by discontinued antiviral treatment and 5.9% by nucleos(t)ide analogs (NUCs) resistance. The prevalence of antiviral treatment disruption and NUCs resistance in patients with HBV reactivation is much higher than that in the patients without (70.9% vs. 0.2%, and 5.9% vs. 0, respectively, both p < 0.001). Stratified and interaction analysis showed that HBV reactivation was correlated with high short-term mortality in cirrhosis subgroup (HR = 2.1, p < 0.001). Cirrhotic patients with HBV reactivation had a significantly higher proportion of developing hepatic failure (45.0% vs. 20.3%, p < 0.001), acute-on-chronic liver failure (ACLF; 31.4% vs. 21.8%, p = 0.005), and short-term death (14.0% vs. 5.9% for 28-day, and 23.3% vs. 12.4% for 90-day, both p < 0.001) than those without. HBV reactivation is an independent risk factor of 90-day mortality for cirrhosis patients (OR = 1.70, p = 0.005), as well as hepatic encephalopathy, ascites, and bacterial infection. Conclusion: This study clearly demonstrated that there was a high prevalence of HBV reactivation in CHB patients, which was mainly triggered by discontinued antiviral treatment. The HBV reactivation strongly increased the risk of developing hepatic failure, ACLF and short-term death in HBV-related cirrhotic patients, which may suggest that HBV reactivation would be a new challenge in achieving the WHO target of 65% reduction in mortality from hepatitis B by 2030.

Prevalence and clinical significance of serum sodium variability in patients with acute-on-chronic liver diseases: a prospective multicenter study in China.

BACKGROUND: No reports exist regarding the prevalence of different Na levels and their relationship with 90-day prognosis in hospitalized patients with acute-on-chronic liver disease (AoCLD) in China. Therefore, the benefit of hyponatremia correction in AoCLD patients remains unclear. METHODS: We prospectively collected the data of 3970 patients with AoCLD from the CATCH-LIFE cohort in China. The prevalence of different Na levels (≤ 120; 120-135; 135-145; > 145) and their relationship with 90-day prognosis were analyzed. For hyponatremic patients, we measured Na levels on days 4 and 7 and compared their characteristics, based on whether hyponatremia was corrected. RESULTS: A total of 3880 patients were involved; 712 of those developed adverse outcomes within 90 days. There were 80 (2.06%) hypernatremic, 28 (0.72%) severe hyponatremic, and 813 (20.95%) mild hyponatremic patients at admission. After adjusting for all confounding factors, the risk of 90-day adverse outcomes decreased by 5% (odds ratio [OR] 0.95; 95% confidence interval [CI] 0.93-0.97; p < 0.001), 24% (OR 0.76; 95% CI 0.70-0.84; p < 0.001), and 42% (OR 0.58; 95% CI 0.49-0.70; p < 0.001) as Na level increased by 1, 5, and 10 mmol/L, respectively. Noncorrection of hyponatremia on days 4 and 7 was associated with 2.05-fold (hazard ratio [HR], 2.05; 95% CI, 1.50-2.79; p < 0.001) and 1.46-fold (HR 1.46; 95% CI 1.05-2.02; p = 0.028) higher risk of adverse outcomes. CONCLUSIONS: Hyponatremia was an independent risk factor for a poor 90-day prognosis in patients with AoCLD. Failure to correct hyponatremia in a week after admission was often associated with increased mortality. (ClinicalTrials.gov number: NCT02457637, NCT03641872). CLINICAL TRIAL NUMBERS: This study is registered at Shanghai www.clinicaltrials.org (NCT02457637 and NCT03641872).

Risk factors for myocardial injury at admission of 325 patients with coronavirus disease 2019 in Shanghai, China.

OBJECTIVE: Myocardial injury leads to higher mortality in COVID-19, but the causes and risk factors are variable. We evaluated the potential risk factors for myocardial injury in COVID-19 patients to improve treatment strategies and reduce mortality. METHODS: This retrospective analysis enrolled 325 COVID-19 patients in Shanghai, China. RESULTS: The median age in our cohort was 51 [range 15-88] years, 26 (8%) were critically ill, and 177 patients (19.7%) had myocardial injury. The myocardial injury group comprised older, more critically ill patients with hypertension, other comorbidities, history of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, lower peripheral blood lymphocyte count and higher D-dimer levels. Binary logistic regression analysis identified only age was an independent risk factor for myocardial injury (odds ratio 1.019; 95% confidence interval 1.003-1.036; age increase by 1 year = myocardial injury risk increase by 1.9%). CONCLUSIONS: Older age was associated with a higher incidence of myocardial injury for COVID-19 patients.

Determination of HMGB1 in hepatitis B virus-related acute-on-chronic liver failure patients with acute kidney injury: Early prediction and prognostic implications.

Background: Acute kidney injury (AKI) is a frequent complication in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) and is associated with high rates of mortality. We aimed to estimate serum high mobility group protein 1 (HMGB1) levels in hepatitis B virus-related acute-on-chronic liver failure patients and analyze their clinical value in the development and outcomes of Acute kidney injury. Methods: A total of 251 consecutive patients with hepatitis B virus-related acute-on-chronic liver failure were enrolled in this retrospective study. Using the International Club of Ascites staging criteria of Acute kidney injury, 153 patients developed Acute kidney injury. The clinical data of patients were collected and serum levels of high mobility group protein 1 were measured by ELISA. All patients were followed up until death or for a minimum of 3 months. Early prediction and prognostic implications of high mobility group protein 1 in Hepatitis B Virus-Related Acute-on-Chronic Liver Failure Patients with Acute Kidney Injury were investigated in different cohorts, including a propensity score-matched ACLF cohort. Results: Among all individuals with hepatitis B virus-related acute-on-chronic liver failure, the incidence of Acute kidney injury was 61.0% (153/251). The patients who developed stage 2/3 Acute kidney injury showed the highest high mobility group protein 1 levels, followed by those who developed stage 1 Acute kidney injury, and those without Acute kidney injury showed the lowest high mobility group protein 1 levels. Moreover, high mobility group protein 1 levels were significantly higher in non-survivors than in survivors among hepatitis B virus-related acute-on-chronic liver failure patients with Acute kidney injury. Furthermore, analysis of the area under the receiver operating characteristic curve (AUROC) indicated that serum high mobility group protein 1 levels (pre-matching: AUC = 0.740; post-matching: AUC = 0.661) may be a potential predictive factor for Acute kidney injury development and that high mobility group protein 1 (AUC = 0.727) might be a reliable biomarker for prognosis in patients with Acute kidney injury. Conclusion: In patients with hepatitis B virus-related acute-on-chronic liver failure, Acute kidney injury is universal. Acute kidney injury and its stages negatively influence the 90-day transplant-free mortality rate. Serum high mobility group protein 1 levels can serve as a positive predictor of Acute kidney injury development, and high mobility group protein 1 might also be a prognostic biomarker for Acute kidney injury among hepatitis B virus-related acute-on-chronic liver failure patients.

Increased INR Values Predict Accelerating Deterioration and High Short-Term Mortality Among Patients Hospitalized With Cirrhosis or Advanced Fibrosis.

Background and Objective: An increase in the international normalized ratio (INR) is associated with increased mortality in patients with cirrhosis and other chronic liver diseases, while little is known about the quantitative relationship. This study aimed to investigate the quantitative relationship between the INR and short-term prognosis among patients hospitalized with cirrhosis or advanced fibrosis and to evaluate the role of the INR as a risk factor for short-term liver transplant (LT)-free mortality in these patients. Patients and Methods: This study prospectively analyzed multicenter cohorts established by the Chinese Acute-on-Chronic Liver Failure (CATCH-LIFE) study. Cox regression was used to describe the relationship between the INR and independent risk factors for short-term LT-free mortality. Forest plots were used in the subgroup analysis. Generalized additive models (GAMs) and splines were used to illustrate the quantitative curve relationship between the INR and the outcome and inflection point on the curve. Results: A total of 2,567 patients with cirrhosis and 924 patients with advanced fibrosis were included in the study. The 90-day LT-free mortality of patients with cirrhosis and advanced fibrosis was 16.7% (428/2,567) and 7.5% (69/924), respectively. In the multivariable Cox regression analysis, the increase in the INR was independently associated with the risk of 90-day LT-free mortality both in patients with cirrhosis (HR, 1.06; 95% CI, 1.04-1.07, p < 0.001) and in patients with advanced fibrosis (HR, 1.09; 95% CI, 1.06-1.12, p < 0.001). An INR of 1.6/1.7 was found to be the starting point of coagulation dysfunction with a rapid increase in mortality in patients with cirrhosis or in patients with advanced fibrosis, respectively. A 28-day LT-free mortality of 15% was associated with an INR value of 2.1 in both cirrhosis and advanced fibrosis patients. Conclusions: This study was the first to quantitatively describe the relationship between the INR and short-term LT-free mortality in patients with cirrhosis or advanced fibrosis. The starting points of INR indicating the rapid increase in mortality and the unified cutoff value of coagulation failure in cirrhosis and advanced fibrosis, will help clinicians accurately recognize early disease deterioration.

Plasma Exchange-Based Non-bioartificial Liver Support System Improves the Short-Term Outcomes of Patients With Hepatitis B Virus-Associated Acute-on-Chronic Liver Failure: A Multicenter Prospective Cohort Study.

Background and aims: Hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) is a complicated syndrome with extremely high short-term mortality. Whether plasma exchange (PE) improves HBV-ACLF outcomes remains controversial. Here, PE-based non-bioartificial liver support system (NB-ALSS) effects on short-term HBV-ACLF patient outcomes were investigated. Materials and methods: HBV-ACLF patients from Chinese Acute-on-chronic Liver Failure (CATCH-LIFE) cohort receiving standard medical therapy (SMT) alone or PE-based NB-ALSS in addition to SMT were allocated to SMT and SMT+PE groups, respectively; propensity score matching (PSM) was used to eliminate confounding bias. Short-term (28/90-day and 1-year) survival rates were calculated (Kaplan-Meier). Results: In total, 524 patients with HBV-ACLF were enrolled in this study; 358 received SMT alone (SMT group), and the remaining 166 received PE-based NB-ALSS in addition to SMT (SMT+PE group). PSM generated 166 pairs of cases. In the SMT+PE group, 28-day, 90-day, and 1-year survival rates were 11.90, 8.00, and 10.90%, respectively, higher than those in the SMT group. Subgroup analysis revealed that PE-based NB-ALSS had the best efficacy in patients with ACLF grade 2 or MELD scores of 30-40 (MELD grade 3). In MELD grade 3 patients who received SMT+PE, 28-day, 90-day, and 1-year survival rates were improved by 18.60, 14.20, and 20.10%, respectively. According to multivariate Cox regression analysis, PE-based NB-ALSS was the only independent protective factor for HBV-ACLF patient prognosis at 28 days, 90 days, and 1 year (28 days, HR = 0.516, p = 0.001; 90 days, HR = 0.663, p = 0.010; 1 year, HR = 0.610, p = 0.051). For those who received SMT+PE therapy, PE-based NB-ALSS therapy frequency was the only independent protective factor for short-term prognosis (28-day, HR = 0.597, p = 0.001; 90-day, HR = 0.772, p = 0.018). Conclusions: This multicenter prospective study showed that the addition of PE-based NB-ALSS to SMT improves short-term (28/90 days and 1-year) outcomes in patients with HBV-ACLF, especially in MELD grade 3 patients. Optimization of PE-based NB-ALSS may improve prognosis or even save lives among HBV-ACLF patients.