RESUMO
The impact of the coronavirus disease 2019 (COVID-19) pandemic has been immense, and it continues to have lasting repercussions. While the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus primarily infects the respiratory system, other organ systems are affected, including the liver. Scientific knowledge on the role of SARS-CoV-2 infection and liver injury has evolved rapidly, with recent data suggesting specific hepatotropism of SARS-CoV-2. Moreover, additional concerns have been raised in regard to long-term liver damage, related to emerging cases of post-COVID-19 cholangiopathy and chronic cholestasis. Great effort has also been focused on studying how specific subpopulations with chronic medical conditions might be disproportionately impacted by COVID-19. One such population includes individuals with chronic liver disease (CLD) and cirrhosis, with an expanding body of research indicating these patients being particularly susceptible to adverse outcomes. In this review, we provide an updated summary on the current pathogenesis and mechanism of liver injury in the setting of SARS-CoV-2 infection, the association between health outcomes and SARS-CoV-2 infection in patients with CLD, and the unique consequences of the COVID-19 pandemic on the routine care of patients with CLD.
RESUMO
Prevention of SARS-CoV-2 entry in cells through the modulation of viral host receptors, such as ACE2, could represent a new therapeutic approach complementing vaccination. However, the mechanisms controlling ACE2 expression remain elusive. Here, we identify the farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple COVID19-affected tissues, including the gastrointestinal and respiratory systems. We demonstrate that FXR antagonists, including the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA), downregulate ACE2 levels, and reduce susceptibility to SARS-CoV-2 infection in lung, cholangiocyte and gut organoids. We then show that therapeutic levels of UDCA downregulate ACE2 in human organs perfused ex situ and reduce SARS-CoV-2 infection ex vivo. Finally, we perform a retrospective study using registry data and identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 infection, including hospitalisation, ICU admission and death. In conclusion, we identify a novel function of FXR in controlling ACE2 expression and provide evidence that this approach could be beneficial for reducing SARS-CoV-2 infection, thereby paving the road for future clinical trials.
RESUMO
Background: COVID-19, the clinical syndrome caused by infection with SARS-CoV-2, has been associated with deranged liver biochemistry in studies from China, Italy and the USA. However, the clinical utility of liver biochemistry as a prognostic marker of outcome for COVID-19 is currently debated. Methods: We extracted routinely collected clinical data from a large teaching hospital in the UK, matching 585 hospitalised SARS-CoV-2 RT-PCR-positive patients to 1165 hospitalised SARS-CoV-2 RT-PCR-negative patients for age, gender, ethnicity and pre-existing comorbidities. Liver biochemistry was compared between groups over time to determine whether derangement was associated with outcome. Results: 26.8% (157/585) of COVID-19 patients died, compared to 11.9% (139/1165) in the non-COVID-19 group (p<0.001). At presentation, a significantly higher proportion of the COVID-19 group had elevated alanine aminotransferase (20.7% vs. 14.6%, p=0.004) and hypoalbuminaemia (58.7% vs. 35.0%, p<0.001), compared to the non-COVID-19 group. Within the COVID-19 group, those with hypoalbuminaemia at presentation had 1.83-fold increased hazards of death compared to those with normal albumin (adjusted hazard ratio [HR] 1.83, 95% CI 1.25-2.67), whilst the hazard of death was ~4-fold higher in those aged [≥]75 years (adjusted HR 3.96, 95% CI 2.59-6.04) and ~3-fold higher in those with pre-existing liver disease (adjusted HR 3.37, 95% CI 1.58-7.16). In the COVID-19 group, alkaline phosphatase increased (R=0.192, p<0.0001) and albumin declined (R=-0.123, p=0.0004) over time in patients who died. We did not find a significant association between other liver biochemistry and death. Conclusion: In this UK population, liver biochemistry is commonly deranged in patients with COVID-19 but only baseline low albumin and a rising alkaline phosphatase over time are prognostic markers for death.
