Search Results and Included Studies
The search yielded a total of 6053 citations and additional 28 papers were identified from other sources like bibliography search. After removal of 2206 duplicates, 3875 papers were screened for title and abstract. After removal of 3559 papers for various reasons (Figure 1), a total of 316 papers were eligible for full text screening. Eventually a total of 128 papers were included in at least one of the different analyses which were conducted as part of the meta-analysis (Supplementary Table 2).
Overall frequency of various abnormalities in liver function in COVID-19
The pooled prevalence of hyperbilirubinemia reported in various studies was 10.98% (95% CI: 6.87 - 17.08; I2: 94%) (Figure 2A) . The pooled prevalence of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation reported in various studies were 23.28% (19.92 - 27.01; 90%) and 23.41% (18.84 - 28.70; 95%) respectively (Figures 3A and 4A). The pooled prevalence of ALP and GGT elevation among overall reported studies were 7.48% (3.91 - 13.83; 75%) and 27.94% (18.22 - 40.27; 93%) respectively (Supplementary Figure 1 and Figure 5A) . The pooled prevalence of hypoalbuminemia among overall reported studies was 61.27% (48.24 - 72.87; 91%) (Figure 6A). The overall pooled frequency of increased globulin levels reported was 20.17% (4.73 - 56.25; 95%) respectively (Supplementary Figure 2). The pooled frequency of acute hepatic injury as reported in various studies is shown in Supplementary Figure 3. The pooled prevalence of hepatitis B, fatty liver, total liver disease and chronic liver disease as a comorbidity are shown in Supplementary Figure 4-7. The pooled prevalence of chronic liver disease as a comorbidity in various studies was 2.49% (1.79-3.46, 84%) (Supplementary Figure 7). The pooled frequency of hepatitis B, nonalcoholic fatty liver disease and total frequency of any liver disease is shown in Supplementary Figures 4, 5 and 6.
Comparison between severe and nonsevere COVID-19
The pooled prevalence of bilirubin abnormality among the studies which reported the finding on the basis of underlying severity of COVID-19 was 13.71% (95% CI: 7.53 - 23.69; I2: 95%). The pooled frequency of hyperbilirubinemia in severe COVID disease was 18.80% (9.55 - 33.67; 91%) while in non-severe disease it was 9.24% (3.15 - 24.17; 97%) (Figure 2B). The risk ratio (RR) of deranged bilirubin concentration in severe as compared to non-severe subgroups was 1.82 (95% CI: 1.22-2.73; I2: 66%) (Figure 2C).The SMD for bilirubin concentration between the severe and non-severe group was 0.43 (95% CI: 0.26 - 0.61; I2: 66% ) (Figure 2D).
The pooled prevalence of ALT and AST abnormality among the studies reporting severity were 31.31% (25.82 - 37.37; 87%) (Figure 3B) and 33.95% (26.90 - 41.79; 91%) (Figure 4B). The pooled frequency of ALT elevation was 39.58% (30.92 - 48.94; 80%) for severe & 24.15% (17.98 - 31.63; 90%) for nonsevere disease (Figure 3C). The pooled frequency of AST elevation was 49.68% (41.90 - 57.49; 73%) & 19.40% (13.27 - 27.45; 91%) respectively for severe and non-severe disease (Figure 4C). The RR of SGPT and SGOT abnormality in the severe as compared to non-severe subgroups were 1.76(1.44 - 2.15; 65%) and 2.30 (1.82 - 2.90, 67%) respectively (Figures 3D and 4D). The SMD for SGPT and SGOT concentration between the severe and non-severe group were 0.42 (0.27 - 0.56; 70%) and 0.69 (0.52 - 0.86; 76%) respectively (Figures 3E and 4E).
The pooled prevalence of ALP and GGT abnormality among the studies reporting severity were 6.99% (4.08 - 11.72; 59%) (Supplementary Figure 1B) and 30.62% (18.13 - 46.79; 94%) (Figure 5B) with subdivision for ALP being 11.33% (5.89 - 20.69; 42%) for severe & 4% (1.68 - 9.26; 64%) for nonsevere and for GGT being 46.90% (25.13 - 69.92; 89%) & 18.66% (9.20 - 34.18; 93%). The RR of ALP and GGT abnormality in severe as compared to non-severe subgroups were 1.99 (0.85 - 4.68; 22%) (Supplementary Figure 1C) and 2.31 (1.6 - 3.33; 55%) (Figure 5C) respectively. The SMD for ALP and GGT concentration between the severe and non-severe group were 0.24 (-0.12 - 0.60; 83%) (Supplementary Figure 1D) and 0.76 (0.40 - 1.12; 82%) (Figure 5D) respectively.
The pooled prevalence of albumin abnormality among the studies reporting severity was 61.57% (42.73 - 77.48; 90%) with subdivision of 75.91% (67.02 - 83.02; 35%) for severe and 31.04% (13.72 - 56.02; 84%) for nonsevere (Figure 6B). The RR of albumin abnormality in severe as compared to non-severe subgroup was 2.65 (1.38 - 5.07; 79%) (Figure 6C). The SMD for albumin concentration between the severe and non-severe group was -1.05 (-1.27 - -0.83; 77%) (Figure 6D). The SMD for globulin concentration between severe and nonsevere group was 2.46 (0.24 - 4.69, 99%) (Supplementary Figure 2B)
The pooled prevalence of chronic liver disease (CLD) among studies reporting severity was 2.64% (1.73- 4; 72%) with 3.03 (1.97 - 4.64; 21%) among severe and 2.20% (1.16 - 4.15; 83%) among nonsevere (Supplementary Figure 7B). The RR of CLD in severe as compared to non-severe subgroup was 1.69 (1.05-2.73; 0%) (Supplementary Figure 7C)
Presence of Acute Hepatic injury (Supplementary Figure 3)
The pooled prevalence of acute hepatic injury among overall reported studies was 23.70% (95% CI: 16.31 - 33.11; I2: 97%) (Supplementary Figure 3A). Among the studies reporting severity the total frequency of acute hepatic injury was 31.66% (22.66 - 42.27; 91%), whereas in severe disease it was 44.63% (30.13 - 60.11; 88%) and in nonsevere disease it was 20.02% (12.74 - 30.02; 88%) (Supplementary Figure 3B). The RR of acute hepatic injury in severe as compared to nonsevere were: LD 2.18 (1.49 - 3.18, 67%) (Supplementary Figure 3C).
Comparison between COVID and non-COVID disease
The RR of ALT and AST abnormality in the COVID as compared to non-COVID subgroups were 1.09 (95% CI: 0.55 - 2.15; I2: 21%) and 1.02 (0.45 - 2.30; 48%), both statistically non-significant (Figure 2E and 3E). The SMD for SGPT and SGOT concentration between the COVID and non-COVID group were 0.18 (0.05-0.32; 0%) and 0.02 (-0.47 - 0.52; 91%) (Figure 2F and 3F). The SMD of bilirubin, GGT and albumin concentration between COVID and non-COVID subgroup were -0.27 (-0.49 - -0.05, 28%), 0.12 (-0.24 - 0.48; 58%) and 0.82 (0.30 - 1.33; 82%) respectively (Figure 2E, Figure 5E, Figure 6E).
Hepatic histological findings in COVID-19
Only limited cases have reported findings on liver histology using either post-mortem histology or liver biopsy in patients with COVID-19 and are tabulated in Supplementary Table 3. The findings reported are non-specific and include sinusoidal dilatation, mild activity in portal area and lobules and occasional necrosis. It is unclear if these are a manifestation of virus mediated liver injury or due to other factors like drugs or immune injury.
COVID-19 in Liver transplant recipients
Some case reports and studies have reported the outcomes of COVID-19 in patients with liver transplant and are shown in Supplementary Table 4.