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. 2022 Jul;10(14):775.
doi: 10.21037/atm-22-2742.

Identification of key genes and infiltrating immune cells among acetaminophen-induced acute liver failure and HBV-associated acute liver failure

Min Shi #  1   2 , Zhuyi Zhou #  1   2 , Zhongxia Zhou #  1   3 , Lijuan Shen  1   2 , Jianbo Shen  1   2 , Guoxiong Zhou  1 , Renfei Zhu  4
Affiliations

Identification of key genes and infiltrating immune cells among acetaminophen-induced acute liver failure and HBV-associated acute liver failure

Min Shi et al. Ann Transl Med. 2022 Jul.

Abstract

Background: Acute liver failure (ALF) is a life-threatening complication that is relatively uncommon. ALF causes severe hepatocyte damage and necrosis, which can lead to liver dysfunction and even multi-organ failure. A growing body of evidence suggests that immune cell infiltration and some abnormally expressed genes are associated with ALF development. However, in ALF, they have yet to be thoroughly investigated.

Methods: The Gene Expression Omnibus (GEO) database was used to obtain microarray datasets such as GSE74000, GSE120652, GSE38941, and GSE14668, which were then examined via GEO2R to determine differentially expressed genes (DEGs) associated with ALF. Metascape was employed to annotate the underlined genes using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The mechanism of IGF1 in 2 different kinds of ALF including acetaminophen-induced ALF and hepatitis B virus (HBV)-induced ALF was studied using gene set enrichment analysis (GSEA). Next, immune cell infiltration was investigated and differentiated in ALF using CIBERSORT.

Results: Six genes (HAO2, IGF1, PLA2G7, SC5D, GNE, SLC1A1) were found to be abnormally expressed in the 2 distinct types of ALF i.e., acetaminophen-induced ALF and HBV-induced ALF. IGF1 was identified as a hub gene in ALF and was found to be associated with several developmental cascades including immune responses, inflammatory responses, and intracellular calcium homeostasis. Additionally, the number of CD4 naive T cells, CD8 T cells, and follicular helper T cells was increased in acetaminophen-induced ALF, whereas the number of activated NK cells, resting NK cells, and plasma cells was increased in HBV-induced ALF.

Conclusions: The present study determined a potential molecular target, namely IGF1, in acetaminophen-induced ALF and HBV-induced ALF, which may provide novel insights into the pathophysiology and management of ALF. Concurrently, the putative immunological pathways have been found.

Keywords: HBV-associated acute liver failure; IGF1; acetaminophen-induced acute liver failure; immune cell infiltration.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-2742/coif). The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Volcano plot of DEGs (differentially expressed genes) in the mRNA expression profiling datasets. Volcano plots of DEGs in normal and acute liver failure samples in acetaminophen-induced ALF (A) and hepatitis B virus-induced ALF (B). Colors represent different genes: black nodes represent genes without significantly different expression, red nodes represent upregulated genes, blue nodes represent downregulated genes. ALF, acute liver failure; DEGs, differentially expressed genes.
Figure 2
Figure 2
Venn diagram of DEGs. GEO2R was used to reveal DEGs in ALF by Venn diagrams. (A) Genes with significant changes in acetaminophen-induced ALF (left) and hepatitis B virus-induced ALF (right). (B) IGF1 was identified as a hub gene in ALF and was to be further studied. DEGs, differentially expressed genes; ALF, acute liver failure.
Figure 3
Figure 3
GO and KEGG annotation analysis for the target genes of DEGs in terms of biological process, cellular component, and molecular function. (A) Related pathways in acetaminophen-induced ALF. (B) Related pathways in hepatitis B virus-induced ALF. GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; DEGs, differentially expressed genes; ALF, acute liver failure.
Figure 4
Figure 4
Significant pathways according to IGF1 obtained by GSEA in GEO datasets. (A) For the 2 types of acute liver failure, in the course of the disease, the immune response is activated, and intracellular calcium homeostasis is destroyed. (B) In acetaminophen induced acute liver failure, inflammatory response cytochrome P450 was activated, while cysteine and methionine metabolism was inhibited. (C) The immune response, MAPK and Ras signalling pathways were activated in HBV-associated ALF. GEO, Gene Expression Omnibus; HBV, hepatitis B virus; ALF, acute liver failure.
Figure 5
Figure 5
The fraction of 22 subsets of immune cells in acetaminophen-induced ALF. (A) GSE74000. (B) GSE120652. X axis: each GEO sample; Y axis: percentage of each kind of immune cell. GEO, Gene Expression Omnibus; ALF, acute liver failure.
Figure 6
Figure 6
The fraction of 22 subsets of immune cells in hepatitis B virus-induced ALF. (A) GSE38941. (B) GSE14668 . X axis: each GEO sample; Y axis: percentage of each kind of immune cell. GEO, Gene Expression Omnibus; ALF, acute liver failure.
Figure 7
Figure 7
The fraction of 22 subsets of immune cells in 2 types of acute liver failure. X axis: each GEO sample, red represents acetaminophen-induced ALF, yellow represents hepatitis B virus-induced ALF; Y axis: percentage of each kind of immune cell. GEO, Gene Expression Omnibus; ALF, acute liver failure.
Figure 8
Figure 8
The violin graph shows the difference in immune infiltration between acetaminophen-induced ALF and hepatitis B virus-induced ALF. ns, no sense, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. ALF, acute liver failure.
Figure 9
Figure 9
The co-expression patterns among fractions of immune cells. Red: positive correlation; purple: negative correlation (A). Principal component analyses performed on acute liver failure samples (B). PCA, principal components analysis.
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