With data from one large academic center in the United States, the current study demonstrated that the incidence of CLD in COVID-19 (3.3%) was low and within the range of previous studies4,5,9,13,14. CLD was a very uncommon comorbidity for COVID-19 patients compared to other comorbidities and it also did not appear to be associated with critical outcomes. The incidence of CLD (3.3%) was even lower than the prevalence of hepatitis B infection in the US adult population (4.3%)15. The incidence of alcoholic hepatitis was also lower in our patients (< 1%) than in the general US population (8%)16. These findings concurred with the observation that no evidence of CLD was found in eight postmortem liver autopsies, while liver injury was common in critical patients due to variable severity of central vein out flow obstruction and mild portal lymphocytic triaditis. Central vein outflow associated pathology is likely due to right heart failure commonly seen in these fatal cases while the significance and biology of lymphocytic triaditis is unknown.
Similar to other studies, older age, and comorbidities like diabetes, hypertension, acute liver injury and cardiovascular diseases were associated with critical outcomes. The incidence of liver injury was higher in critically ill patients than in non-critically ill patients. However, liver injury was not associated with a history of CLD in hospitalized COVID-19 patients. The time distribution of liver injury also suggested that acute liver injury generally occurred earlier and was not affected by the side effects of treatment. The main results in the present study are consistent with a previous study, which demonstrated that outcomes were not worse in 47 patients with CLD and COVID-19 than those without CLD and COVID-19 using data from seven Chinese studies8. Another study from China by Guan et al. showed that only one out of 23 COVID-19 patients (2.1%) with Hepatitis B infection had a severe outcome5. Fan et al. also showed that there was no statistical difference in the proportion of chronic hepatitis B/C between an abnormal liver function group and a normal liver function group17. Interestingly, a limited number of studies and a recent meta-analysis reported findings contradictory to those herein. Singh et al. compared the outcomes of patients with and without a preexisting liver disease by using the TriNetX (Cambridge, MA) Research Network, and found that patients with a preexisting liver disease were at increased risk for mortality compared to patients without liver disease7. Ji et al. demonstrated that patients with NAFLD had a higher risk of liver injury and disease progression6. A meta-analysis conducted by Kovalic et al. used data from 73 pooled clinical studies to conclude that CLD is associated with more severe COVID-19 infection and higher mortality in COVID-19 patients18.
The most likely explanation for the high prevalence of positive associations found in the literature between CLD and COVID-19 severity is that patients with CLD in the meta-analysis probably have other comorbidities that contributed to the higher severity and mortality. This was not investigated in the meta-analysis because multivariate analyses were not performed. Publication bias could also be in favor of these positive findings. Another possible reason for contradictory results in the literature could be the different composition of CLD types in COVID-19 patients. Kovalic et al. mentioned that most of the studies included in their meta-analysis did not categorize their CLD patients based on specific disease etiologies of CLD nor did they come with a set definition for CLD18, which makes it more difficult to pinpoint if the positive association they found between CLD and COVID-19 severity is driven by one type of CLD or various types or CLD at all. It is known that the majority (77%, 36/47) of our patients from the United States had chronic hepatitis B/C, while patients with chronic hepatitis B/C in the study by Singh et al. only accounted for 21% of the COVID-19 cohort7—the worse outcomes observed in CLD patients with COVID-19 from their study could have been due to etiologies of CLD other than hepatitis B/C. We speculate that the comorbid mechanism of liver injury by various hepatitis viruses in COVID-19 patients is different from that of other types of CLD. Another possible explanation is altered immune status of unknown etiology in some patients with CLD. This is supported by the observation of lymphocytic triaditis during postmortem evaluation of critical COVID-19 patients. Although the liver injury in these 8 patients did not seem to contribute significantly to their demise, the potential long-term effect of this possible viral related liver injury in COVID-19 patients remains unknown. These observations may support a possible protective role of some CLD diseases in COVID-19 through alternating the host innate immunity against the virus19.
Several limitations in the present study are worth noting. First, this is a retrospective study from a single academic center in the United States. Second, all patients enrolled in the study were inpatient and possible selection bias cannot be eliminated because outpatients can also suffer from CLD. Since the incidence of CLD in outpatients tends to be similar if not lower than that in inpatients and outpatients tend to less ill20, it is likely that adding outpatients may further support our findings. To better define the impact of CLD on COVID-19, future studies will focus on subgroup analysis of CLD with different etiologies and severities in a larger, prospective cohort.
In conclusion, patients with CLD were not associated with higher risk of liver injury or critical outcomes. In hospitalized COVID-19 patients, CLD did not appear to be a premorbid or comorbid condition to COVID-19. These findings can inform healthcare providers’ determination of risk factors for critical outcomes and their subsequent allocation of healthcare resources during the current COVID-19 pandemic. Further studies with a large cohort size and subgroup analysis are needed to validate these findings.