Reply to: 'No evidence for an increased liver uptake of SARS-CoV-2 in metabolic-associated fatty liver disease'.

To the Editor:

We read with interest the letter by Biquard et al. In their study, mRNA expression of SARS-CoV-2 infection critical genes, such as angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), phosphatidylinositol 3-phosphate 5-kinase (PIKFYVE) and cathepsin L were found not to be enhanced in patients with metabolic-associated fatty liver disease (MAFLD, previously called non-alcoholic fatty liver disease [NAFLD]) or obesity. This finding is of potential added value to our observation that patients with COVID-19 had worse outcomes if they had underlying MAFLD. Firstly, persistent liver injury observed in our patients was unlikely to be related to the direct cytopathic effects of the virus. Though ideally, one should compare hepatocyte expression of these 4 genes in patients with/without MAFLD that do not have COVID-19. Secondly, this is in keeping with our hypothesis that dysregulated hepatic innate immunity in patients with MAFLD contributes to the pathogenesis of COVID-19. Apart from lung alveolar epithelial cells, the enterocytes of the small intestine also have abundant expression of ACE2 receptors and thus could be another portal of entry for SARS-CoV-2. In keeping with this, gastrointestinal manifestations, such as diarrhoea and abdominal pain occurred in up to one-quarter of patients with COVID-19, without cough. Overall about half of the patients with COVID-19 tested positive for SARS-CoV-2 RNA in faecal and respiratory specimens concomitantly. The liver is enriched with innate immune cells (such as macrophages, natural killer, natural killer T, and γδ T cells) and due to its rich blood supply from the small bowel, circulation of the virus via the hepatic reticular system is expected. Hepatic innate immunity populations are potent cytokine producers and there are reports that obesity and NAFLD were associated with increased production of pro-inflammatory cytokines like tumour necrosis factor-α by adipose cells and Kupffer cells. , This may lead to an increased likelihood of symptomatic SARS-CoV-2 infections and the high prevalence of NAFLD in our study populations. Further studies are required to enhance our understanding of the link between the dysregulated hepatic innate immunity and COVID-19. This could be the missing link between the well-recognized risk factors of diabetes mellitus, obesity, chronic liver diseases and age and the outcome of COVID-19 in humans.

Financial support

This work is funded by the Capital Characteristic Clinic Project of (Z181100001718034) and Key Project of Jumei Special Fund for Hepatobiliary Disease Prevention and Treatment (2018JM12603003).

Authors' contributions

DJ, EQ, JX, and DZ treated the patients. DJ, GC, YW and GL processed statistical data and drafted the manuscript. DJ and GL had the idea for and designed the study.

Conflict of interest

We declare no competing interests.

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