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

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Abstract

Objective

Hepatitis 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.

Methods

Four 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).

Results

The 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.

Conclusions

This 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.

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Most cited references 23

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Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

A. Subramanian, P. Tamayo, V. K. Mootha … (2005)

Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.

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Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.

Richard Moreau, Rajiv Jalan, Pere Ginès … (2013)

Patients with cirrhosis hospitalized for an acute decompensation (AD) and organ failure are at risk for imminent death and considered to have acute-on-chronic liver failure (ACLF). However, there are no established diagnostic criteria for ACLF, so little is known about its development and progression. We aimed to identify diagnostic criteria of ACLF and describe the development of this syndrome in European patients with AD. We collected data from 1343 hospitalized patients with cirrhosis and AD from February to September 2011 at 29 liver units in 8 European countries. We used the organ failure and mortality data to define ACLF grades, assess mortality, and identify differences between ACLF and AD. We established diagnostic criteria for ACLF based on analyses of patients with organ failure (defined by the chronic liver failure-sequential organ failure assessment [CLIF-SOFA] score) and high 28-day mortality rate (>15%). Of the patients assessed, 303 had ACLF when the study began, 112 developed ACLF, and 928 did not have ACLF. The 28-day mortality rate among patients who had ACLF when the study began was 33.9%, among those who developed ACLF was 29.7%, and among those who did not have ACLF was 1.9%. Patients with ACLF were younger and more frequently alcoholic, had more associated bacterial infections, and had higher numbers of leukocytes and higher plasma levels of C-reactive protein than patients without ACLF (P < .001). Higher CLIF-SOFA scores and leukocyte counts were independent predictors of mortality in patients with ACLF. In patients without a prior history of AD, ACLF was unexpectedly characterized by higher numbers of organ failures, leukocyte count, and mortality compared with ACLF in patients with a prior history of AD. We analyzed data from patients with cirrhosis and AD to establish diagnostic criteria for ACLF and showed that it is distinct from AD, based not only on the presence of organ failure(s) and high mortality rate but also on age, precipitating events, and systemic inflammation. ACLF mortality is associated with loss of organ function and high leukocyte counts. ACLF is especially severe in patients with no prior history of AD. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

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Apoptosis and necroptosis in the liver: a matter of life and death

Robert Schwabe, Tom Luedde (2018)

Cell death represents a basic biological paradigm that governs outcomes and long-term sequelae in almost every hepatic disease condition. Acute liver failure is characterized by massive loss of parenchymal cells but is usually followed by restitution ad integrum . By contrast, cell death in chronic liver diseases often occurs at lesser extents but leads to long-term alterations in organ architecture and function, contributing to chronic hepatocyte turnover, the recruitment of immune cells and activation of hepatic stellate cells, and thereby to the development of liver fibrosis, cirrhosis and cancer. It has become evident that besides apoptosis, necroptosis represents a highly relevant form of programmed cell death (PCD) in the liver. Differential activation of specific forms of PCD might not only affect outcomes in liver diseases, but also offer novel opportunities for therapeutic intervention. Here, we will summarize the underlying molecular mechanisms and open questions about disease-specific activation and roles of PCD forms, their contribution to response signatures as well as their detection. We will focus on the role of apoptosis and necroptosis in acute liver injury, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and liver cancer, and possible translation into clinical applications.

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Author and article information

Journal

Journal ID (nlm-ta): Gut

Journal ID (iso-abbrev): Gut

Journal ID (hwp): gutjnl

Journal ID (publisher-id): gut

Title: Gut

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Print): 0017-5749

ISSN (Electronic): 1468-3288

Publication date (Print): January 2022

Publication date (Electronic): 11 January 2021

Volume: 71

Issue: 1

Pages: 163-175

Affiliations

[1 ] departmentState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases , The First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, China

[2 ] departmentPrecision Medicine Center , Taizhou Central Hospital (Taizhou University Hospital) , Taizhou, China

[3 ] departmentInstitute of Pharmaceutical Biotechnology , Zhejiang University School of Medicine , Hangzhou, China

[4 ] departmentKey Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine , Tongde Hospital of Zhejiang Province , Hangzhou, China

[5 ] departmentDepartment of Pathology , The First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, China

[6 ] departmentThe State Key Laboratory of Ophthalmology , Zhongshan Ophthalmic Center, Sun Yat-Sen University , Guangzhou, China

[7 ] departmentThe Liver Disease Department , The Ninth Hospital of Nanchang , Nanchang, China

[8 ] departmentDepartment of Liver and Infectious Diseases , The Fifth Medical Center of PLA General Hospital , Beijing, China

[9 ] departmentInstitute of Immunology , Zhejiang University School of Medicine , Hangzhou, China

[10 ] departmentTranslational Hepatology, Department of Internal Medicine I , University Clinic Frankfurt , Frankfurt, Germany

[11 ] departmentEF Clif , European Foundation for the Study of Chronic Liver Failure , Barcelona, Spain

[12 ] departmentInstitute of Pharmaceutical Biotechnology and the First Affiliated Hospital Department of Radiation Oncology , Zhejiang University School of Medicine , Hangzhou, 310058, China

[13 ] departmentJoint Institute for Genetics and Genome Medicine between Zhejiang University and University of Toronto , Zhejiang University , Hangzhou, China

Author notes

[Correspondence to ] Professor Jun Li, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine First Affiliated Hospital, Hangzhou, Zhejiang, China; lijun2009@ 123456zju.edu.cn ; Professor Xin Chen; xinchen@ 123456zju.edu.cn ; Professor Jonel Trebicka; jonel.trebicka@ 123456efclif.com ; Professor Di Wang; diwang@ 123456zju.edu.cn

Author information

Jun Li http://orcid.org/0000-0002-7236-8088

Article

Publisher ID: gutjnl-2020-323395

DOI: 10.1136/gutjnl-2020-323395

PMC ID: 8666828

PubMed ID: 33431576

SO-VID: d433b278-b147-4a00-85ca-e48ac70e285d

License:

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 17 October 2020

Date revision received : 25 December 2020

Date accepted : 26 December 2020

Funding

Funded by: the National S&T Major Project of China;

Award ID: 2017ZX10203201

Funded by: the National Natural Science Foundation of China;

Award ID: 81830073

Funded by: the State’s Key Project of Research and Development Plan of China;

Award ID: 2017C01026

Funded by: the National special support program for high-level personnel recruitment;

Award ID: Ten-thousand Talents Program

Funded by: the Zhejiang Provincial Key Project of Research and Development Plan of China;

Award ID: 2016YFC1101303/4

Funded by: the Zhejiang Provincial special support program for high-level personnel recruitment;

Award ID: Ten-thousand Talents Program

Custom metadata

special-feature unlocked

ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: liver failure,hepatitis b,cirrhosis

Data availability:

ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: liver failure, hepatitis b, cirrhosis

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

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Abstract

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Methods

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Conclusions

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Karger: Gastroenterology

Most cited references 23

Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.

Apoptosis and necroptosis in the liver: a matter of life and death

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Cited by 42

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