PBMC transcriptomics identifies immune-metabolism disorder during the development of HBV-ACLF

Abstract

ObjectiveHepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) pathophysiology remains unclear. This study aims to characterise the molecular basis of HBV-ACLF using transcriptomics.MethodsFour hundred subjects with HBV-ACLF, acute-on-chronic hepatic dysfunction (ACHD), liver cirrhosis (LC) or chronic hepatitis B (CHB) and normal controls (NC) from a prospective multicentre cohort were studied, and 65 subjects (ACLF, 20; ACHD, 10; LC, 10; CHB, 10; NC, 15) among them underwent mRNA sequencing using peripheral blood mononuclear cells (PBMCs).ResultsThe functional synergy analysis focusing on seven bioprocesses related to the PBMC response and the top 500 differentially expressed genes (DEGs) showed that viral processes were associated with all disease stages. Immune dysregulation, as the most prominent change and disorder triggered by HBV exacerbation, drove CHB or LC to ACHD and ACLF. Metabolic disruption was significant in ACHD and severe in ACLF. The analysis of 62 overlapping DEGs further linked the HBV-based immune-metabolism disorder to ACLF progression. The signatures of interferon-related, neutrophil-related and monocyte-related pathways related to the innate immune response were significantly upregulated. Signatures linked to the adaptive immune response were downregulated. Disruptions of lipid and fatty acid metabolism were observed during ACLF development. External validation of four DEGs underlying the aforementioned molecular mechanism in patients and experimental rats confirmed their specificity and potential as biomarkers for HBV-ACLF pathogenesis.ConclusionsThis study highlights immune-metabolism disorder triggered by HBV exacerbation as a potential mechanism of HBV-ACLF and may indicate a novel diagnostic and treatment target to reduce HBV-ACLF-related mortality.

Development and validation of a new prognostic score for hepatitis B virus-related acute-on-chronic liver failure

“…The early prognosis of patients with HBV-ACLF is very important to decrease the high short-term mortality rate. 3,4 Any prognostic score should use objective and accessible clinical indicators to simply and accurately predict the disease outcome for clinical application. 19 In this study, the clinical data and laboratory indicators from the multicentre and prospective open cohort of the COSSH study were used to identify the clinical characteristics of patients with HBV-ACLF and develop a new simplified score, the COSSH-ACLF IIs, which can be used to accurately predict the 28-day and 90-day mortality of these patients.…”

“…[1][2][3] Early diagnosis and prognosis for the effective treatment of ACLF is very important to decrease the high mortality rate. 4 The Model for End-stage Liver Disease score (MELDs) and the Model for End-stage Liver Disease-sodium score (MELD-Nas) have been widely used for predicting the outcome of end-stage liver disease or for organ allocation of liver transplantation. [5][6][7][8] Recently, two large prospective multicentre cohorts of ACLF, the Chronic Liver Failure (CLIF) Consortium Acute-On-Chronic Liver Failure in Cirrhosis (CANONIC) study and the Chinese Group on the Study of Severe Hepatitis B (COSSH) study, indicated that ACLF has regional phenotypic specificities due to the disease aetiology and precipitants.…”

“…2 Our recently proposed definition based on the COSSH study for hepatitis B virus-related ACLF (HBV-ACLF) describes that different clinical characteristics, such as total bilirubin (TB) and international normalized ratio (INR), were significantly worse in HBV-ACLF populations than in non-HBV-ACLF populations, liver failure was the most frequent type of organ failure, and HBV relapse was the most frequent potential precipitant. 3,4 These two well-accepted definitions have been used to develop prognostic scores, the CLIF-C ACLF score (CLIF-C ACLFs) and the COSSH-ACLF score (COSSH-ACLFs), for the early prognostication and identification of patients who are likely to have poor outcomes from ACLF for whom early intensive treatments including prior J o u r n a l P r e -p r o o f organ allocation from limited liver donors should be considered. 3,9,10 However, based on the complicated assessment of organ failure, the CLIF-C ACLFs and COSSH-ACLFs still should be further simplified and more accurate.…”

The Short-Term Efficacy of Tenofovir Alafenamide (TAF) in Acute-On-Chronic Liver Failure: A Single Center Experience

“…Mireia Casulleras group reported that a systemic hyperin ammatory state is the main driver of widespread tissue and organ injury in patients with ACLF. The massive release of in ammatory mediators leads to severe tissue damage [22].Jiang Li [23] group con rmed that HBV exacerbate immune-metabolism disorder in HBV-ACLF patients. Therefore, we thought that although received 12 weeks antiviral therapy making HBV DNA load decrease to lower level, immune and metabolic disorder process still drive the development and progression of HBV-ACLF in the followed time, which was the reason of why these two groups achieved similar survival rate after 12 weeks treatment.…”

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

“…The occurrence of drug resistance to nucleos(t)ide analogs (NAs) and NAs withdrawal without authorization are the main causes of HBV reactivation ( 9 ). Li et al found that the immune metabolic disorder caused by HBV was the core axis of the occurrence and progression of HBV-ACLF ( 10 ). Bacterial infection is another common inducement of HBV-ACLF.…”