COVID-19 Severity and Mortality Among Chronic Liver Disease Patients

A Systematic Review and Meta-Analysis

Ramya Nagarajan, MD; Yuvaraj Krishnamoorthy, MD; Sathish Rajaa, MD; Vishnu Shankar Hariharan, MD


Prev Chronic Dis. 2022;19(8):e53 

In This Article


We found that the risk of COVID-19 severity and death was twice as high among CLD patients than among non-CLD patients. Similar results were observed in a review conducted by Wu and Yang in which COVID-19 patients with CLD had more than 4 times the chance of developing severe disease and almost twice the chance of dying compared with non-CLD COVID-19 patients.[53] Reviews conducted by Sharma et al and Yadav et al also found higher chances of developing severe disease and death among COVID-19 hospitalized patients with pre-existing liver diseases. Patients with elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were also reported to have higher chances of severe illness and death.[54,55] However, a review conducted by Lippi et al states otherwise; no significant changes between liver disease and non–liver disease groups were found with respect to COVID-19 outcomes. However, the studies included in that analysis were limited, so its results should be interpreted cautiously.[56]

Subgroup analysis based on the type of CLD showed that patients with NAFLD had the highest risk of severe disease, followed by those with MAFLD and cirrhosis. The estimates were also similar compared with the previous review findings.[57–59] A similar analysis could not be done for mortality outcomes because of limitations in the number of studies. Still, research based on cirrhosis showed a higher effect size than the overall pooled estimate. Understanding the mechanism behind this finding is essential because it will help explain the reason for the association obtained in all the existing evidence. Subgroup analysis was also performed based on the study design adapted to conduct the study. We found higher odds of severity and mortality among studies adapting a cohort design. Though the estimates obtained from a cohort design are considered to be more powerful compared with a case-control or cross-sectional design, we are unclear about how the study design influences the severity and mortality outcome in our review.[60] We recommend conducting further studies to evaluate the influence of study design in the outcome of severity and mortality studies.

The possible reason for the higher risk of severity among NAFLD patients could be the complex interplay of chronic active inflammatory pathways between the COVID-19–associated cytokine storm and NAFLD.[59] Injury caused by the accumulation of fat in the liver could exacerbate the cytokine storm and worsen the prognosis of patients.[61] In addition, liver fibrosis has been linked with a higher risk of severity among COVID-19 patients.[62] Hence, liver fat accumulation and subsequent fibrosis may be the reasons for NAFLD patients' more deficient outcomes. A similar mechanism was also observed for MAFLD because it was found to exacerbate the virus-induced inflammatory cytokine storm by increased reactive oxygen production and hepatic release of the proinflammatory cytokines in the COVID-19 patients.[57,63] Finally, the possible pathogenesis behind the cirrhosis patients having a higher rate of severity and death following COVID-19 infection could be the excess systemic inflammation, intestinal dysbiosis, cirrhosis-induced immune dysfunction, and coagulopathies.[59] Despite all these reasonings and mechanisms, determining the reason for such differential risk associated with different CLD patients is necessary. This determination can be achieved by performing proper longitudinal research in such patients and developing a deeper understanding of this issue.

The major strength of our review was the rigorous literature search and methodology followed to provide reliable estimates. In addition, this review adds to the limited evidence available on the prognostic importance of CLD among COVID-19 patients. We also performed additional subgroup analyses to stratify the risk of adverse outcomes based on the type of CLD and study design, meta-regression to explore the source of heterogeneity, and sensitivity analysis to check the robustness of our results.

Our study had limitations and findings should be interpreted cautiously, considering the difference in methods and quality across the included studies. Although the review by Mauvais-Jarvis et al stated the influence of gender over disease profile globally and the importance of having gender representation in medical research, our search found that data relevant to evaluating the severity of disease and mortality caused by COVID-19 in CLD patients by gender was lacking in the included studies, which is a limitation in our review.[64] Our analysis also found significant between-study variability (significant χ 2 test for heterogeneity and I 2 statistics) for both outcomes. Such high heterogeneity can be attributed to the methodologic differences between the included studies, such as analysis by type of CLD, setting, sample size, and mean age. Meta-regression analysis did not indicate a significant source of heterogeneity for severity outcome and found only mean age as an essential source of heterogeneity for mortality outcome. In addition, we found substantial publication bias for the mortality outcome and found that most of the studies included in our review were of lower quality, which might further limit the generalizability of our study findings.

Although our results provide crucial information for better understanding the association of CLD and adverse COVID-19 outcomes, a need exists to perform longitudinal studies to establish the temporality of association and causal link between CLD and adverse clinical effects in the COVID-19 patients. Understanding this link will break a crucial barrier in managing COVID-19 patients and help prevent many deaths worldwide.

Our findings have implications for clinical management. Although patients with any liver pathology have some adverse outcomes, the magnitude almost doubles if the patients have CLD. Results of our meta-analysis should encourage clinicians worldwide to provide extra attention and intensive care for patients with CLD, who should be provided with advanced management to prevent adverse clinical outcomes.