Published online Jun 7, 2021. doi: 10.3748/wjg.v27.i21.2850
Peer-review started: February 6, 2021
First decision: March 14, 2021
Revised: March 30, 2021
Accepted: May 10, 2021
Article in press: May 10, 2021
Published online: June 7, 2021
The coronavirus disease 2019 (COVID-19), a pandemic contributing to more than 105 million cases and more than 2.3 million deaths worldwide is associated with extrapulmonary manifestations, including liver dysfunction. Liver dysfunction and elevated liver enzymes were observed in about 53% of COVID-19 patients. However, the molecular mechanistic aspect of this is not clear but can be of importance in understanding how the virus infects the hepatocytes and the infection leads to liver dysfunction. Understanding this can help in the diagnosis and treatment of liver dysfunction caused by COVID-19.
Liver is an important organ in human health as it is involved in the detoxification of many compounds accumulated through pollution or using the wrong diet. Liver dysfunction can lead to many systemic diseases in the body. One of the organs affected by SARS-CoV-2 infection is the liver and therefore understanding the mechanism of infection and the cause of liver dysfunction can help COVID-19 patients whose liver is affected but also the results can shed light on the molecular mechanism of liver dysfunction that may results from other liver diseases including cirrhosis, fibrosis, non-alcoholic fatty liver disease (NAFLD), and hepatitis A/B/C.
The main objectives of this research are: (1) Obtain genetic data from COVID-19 patients who had hepatic dysfunction; (2) Compare the genetic signature of COVID-19 patients with hepatic failure with that of other liver diseases including cirrhosis, fibrosis, NAFLD, and hepatitis A/B/C; and (3) Carry out in vitro validation of the biomarkers identified using blood samples from severe COVID-19 patients with liver dysfunction.
The transcriptome of liver autopsy samples from severe COVID-19 patients against those of non-COVID donors was analyzed. Differentially expressed genes were identified from normalized RNA-seq data and analyzed for the enrichment of functional clusters and pathways. The differentially expressed genes were then compared against the genetic signatures of liver diseases including cirrhosis, fibrosis, NAFLD, and hepatitis A/B/C. Gene expression of some differentially expressed genes was assessed in the blood samples of severe COVID-19 patients with liver dysfunction using qRT-PCR.
Analysis of the differential transcriptome of the liver tissue of severe COVID-19 patients revealed a significant upregulation of transcripts implicated in tissue remodeling including GPCRs, DNAJB1, IGF2, EGFR, and HDGF. Concordantly, the differential transcriptome of severe COVID-19 liver tissues substantially overlapped with the disease signature of liver diseases characterized with pathological tissue remodeling (liver cirrhosis, Fibrosis, NAFLD, and hepatitis A/B/C). Moreover, we observed a significant suppression of transcripts implicated in metabolic pathways as well as mitochondrial function, including cytochrome P450 family members, ACAD11, CIDEB, GNMT, and GPAM. Consequently, drug and xenobiotics metabolism pathways are significantly suppressed suggesting a decrease in liver detoxification capacity. In correspondence with the RNA-seq data analysis, we observed a significant upregulation of DNAJB1 and HSP90AB1 as well as significant downregulation of CYP39A1 in the blood plasma of severe COVID-19 patients with liver dysfunction.
Some insights into the molecular mechanisms underlying liver dysfunction in severe COVID-19 patients was obtained using RNA-seq data of severe COVID-19 liver autopsy samples. Through systems biology analysis, we observed a significant upregulation in transcripts implicated in GPCRs signaling, tissue remodeling, and intracellular/transmembrane transport (e.g., DNAJB1, IGF2, EGFR, and HDGF). On the other hand, we observed a significant downregulation in transcripts implicated in metabolic pathways and mitochondrial function (e.g., ACAD11, CIDEB, GNMT, and GPAM). Moreover, we observed a significant suppression of cytochrome P450 family members, which play central roles in the metabolism of drugs and xenobiotics metabolism suggesting a compromised hepatic detoxification capacity. Moreover, the dysregulation of some genes (e.g., DNAJB1, HSP90AB1, and CYP39A1) in the tissue autopsies correlated with their dysregulation in the blood plasma of severe COVID-19 patients with hepatic dysfunction suggesting their potential as putative biomarkers of liver dysfunction.
This study identified key cellular pathways involved in liver dysfunction in general but also liver dysfunction linked to COVID-19 patients. The analysis identified key molecular biomarkers which can be used in future to general a biomarker panel that can assess the degree of hepatic dysfunction in patients from a blood test since the biomarkers identified in this study was shown to follow the same trend when compared with blood samples from COVID-19 patients with hepatic dysfunction. Mechanistically, the study showed that severe COVID-19 patients appear to experience significant transcriptional shift that may ensue tissue remodeling, mitochondrial dysfunction and apparent hepatic toxification resulting in the clinically observed liver dysfunction. The finding from this study can be used in future to assess the degree of hepatic dysfunction but also to differentiate patients with COVID-19 related hepatic dysfunction from hepatic dysfunction caused by other liver diseases. This can be of importance in the management of COVID-19 patients including those with long COVID who have experienced hepatic dysfunction.