COVID-19 and Liver Injury: A Systematic Review and Meta-Analysis

Abstract

Background and Aims The prevalence and extent of liver damage in coronavirus disease 2019 (COVID-19) patients remain poorly understood, primarily due to small-sized epidemiological studies with varying definitions of "liver injury". We conducted a meta-analysis to derive generalizable, well-powered estimates of liver injury prevalence in COVID-19 patients. We also aimed to assess whether liver injury prevalence is significantly greater than the baseline prevalence of chronic liver disease (CLD). Our secondary aim was to study whether the degree of liver injury was associated with the severity of COVID-19. Materials and Methods Electronic databases (PubMed and Scopus) were systematically searched in June 2020 for studies reporting the prevalence of baseline CLD and current liver injury in hospitalized COVID-19 patients. Liver injury was defined as an elevation in transaminases >3 times above the upper limit of normal. For the secondary analysis, all studies reporting mean liver enzyme levels in severe versus non-severe COVID-19 patients were included. A random-effects model was used for meta-analysis. Proportions were subjected to arcsine transformation and pooled to derive pooled proportions and corresponding 95% confidence intervals (CIs). Subgroup differences were tested for using the chi-square test and associated p-value. Means and their standard errors were pooled to derive weighted mean differences (WMDs) and corresponding 95% CIs. Results Electronic search yielded a total of 521 articles. After removal of duplicates and reviewing the full-texts of potential studies, a total of 27 studies met the inclusion criteria. Among a cohort of 8,817 patients, the prevalence of current liver injury was 15.7% (9.5%-23.0%), and this was significantly higher than the proportion of patients with a history of CLD (4.9% [2.2%-8.6%]; p < 0.001). A total of 2,900 patients in our population had severe COVID-19, and 7,184 patients had non-severe COVID-19. Serum ALT (WMD: 7.19 [4.90, 9.48]; p < 0.001; I² = 69%), AST (WMD: 9.02 [6.89, 11.15]; p < 0.001; I² = 73%) and bilirubin levels (WMD: 1.78 [0.86, 2.70]; p < 0.001; I² = 82%) were significantly higher in patients with severe COVID-19 when compared to patients with non-severe disease. Albumin levels were significantly lower in patients with severe COVID-19 (WMD: -4.16 [-5.97, -2.35]; p < 0.001; I² = 95%). Conclusions Patients with COVID-19 have a higher than expected prevalence of liver injury, and the extent of the injury is associated with the severity of the disease. Further studies are required to assess whether hepatic damage is caused by the virus, medications, or both.

Keywords: coronavirus disease 2019; covid-19; hepatic injury; liver abnormalities; liver enzymes; liver injury; liver injury biomarkers; sars-cov-2.

Figure 1. PRISMA flow chart summarizing the literature search

PRISMA, Preferred Reporting Items for Systemic Reviews and Meta-Analyses

Figure 2. Funnel plot for publication bias

The funnel plot is based on serum ALT levels. SE, standard error; MD, mean difference; ALT, alanine transaminase

Figure 3. Pooled prevalence of (A) patients with a history of chronic liver disease and (B) patients with liver injury

CI, confidence interval; Ev/Trt, events/total; I², heterogeneity

Figure 4. Forest plot showing the association between serum ALT levels and severity of disease in COVID-19 patients

SD, standard deviation; IV, inverse variance; CI, confidence interval; ALT, alanine transaminase; COVID-19, coronavirus disease 2019

Figure 5. Forest plot showing the association between serum AST levels and severity of disease in COVID-19 patients

SD, standard deviation; IV, inverse variance; CI, confidence interval; AST, aspartate transaminase; COVID-19, coronavirus disease 2019

Figure 6. Forest plot showing the association between serum total bilirubin levels and severity of disease in COVID-19 patients

SD, standard deviation; IV, inverse variance; CI, confidence interval; COVID-19, coronavirus disease 2019

Figure 7. Forest plot showing the association between serum albumin levels and severity of disease in COVID-19 patients

SD, standard deviation; IV, inverse variance; CI, confidence interval; COVID-19, coronavirus disease 2019