key: cord-0848711-4sxe7s03 authors: Xing, Q.-Q.; Dong, X.; Ren, Y.-D.; Chen, W.-M.; Zeng, D.-Y.; Cai, Y.-Y.; Hong, M.-Z.; Pan, J.-S. title: Liver Chemistries in COVID-19 Patients with Survival or Death: A Meta-Analysis date: 2020-05-01 journal: nan DOI: 10.1101/2020.04.26.20080580 sha: 20288540e0233f4a7fb120790f6a96ee9343b941 doc_id: 848711 cord_uid: 4sxe7s03 Background and Aims: Although abnormal liver chemistries are linked to higher risk of death related to coronavirus disease (COVID-19), liver manifestations may be diverse and even confused. Thus, we performed a meta-analysis of published liver manifestations and described the liver damage in COVID-19 patients with death or survival. Methods: We searched PubMed, Google Scholar, medRxiv, bioRxiv, Cochrane Library, Embase, and three Chinese electronic databases through April 22, 2020. We analyzed pooled data on liver chemistries stratified by the main clinical outcome of COVID-19 using a fixed or random-effects model. Results: In the meta-analysis of 18 studies, which included a total of 2,862 patients, the pooled mean alanine aminotransferase (ALT) was 30.9 IU/L in the COVID-19 patients with death and 26.3 IU/L in the COVID-19 patients discharged alive (p < 0.0001). The pooled mean aspartate aminotransferase (AST) level was 45.3 IU/L in the COVID-19 patients with death while 30.1 IU/L in the patients discharged alive (p < 0.0001). Compared with the discharged alive cases, the dead cases tended to have lower albumin levels but longer prothrombin time, and international standardized ratio. Conclusions: In this meta-analysis, according to the main clinical outcome of COVID-19, we comprehensively described three patterns of liver impairment related to COVID-19, hepatocellular injury, cholestasis, and hepatocellular disfunction. Patients died from COVID-19 tend to have different liver chemistries from those are discharged alive. Close monitoring of liver chemistries provides an early warning against COVID-19 related death. 5 Lay Summary 75 Abnormal liver chemistries are linked to higher risk of death related to coronavirus 76 disease (COVID-19). We performed a meta-analysis of 18 studies that included a total 77 of 2,862 patients with COVID-19. We noted that patients died from COVID-19 tend 78 to have different liver chemistries from those are discharged alive and close 79 monitoring of liver chemistries provides early warning against COVID-19 related 80 death. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 1, 2020. coronavirus disease (COVID-19) cases were confirmed globally with a fatality rate of 93 6.9% [1] . In response to the emerging threat, the WHO has declared a Public Health (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. COVID-19. Our meta-analysis also reveals the different patterns of abnormal liver 111 chemistries between patients with severe and non-severe COVID-19 [10] . (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. including PubMed, Google Scholar, medRxiv, bioRxiv, Embase, Cochrane Library, (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 1, 2020. . https://doi.org/10.1101/2020.04.26.20080580 doi: medRxiv preprint of dead cases were reported without data from survival cases, or only data of survival 150 cases were reported without data from dead cases) were also excluded. Data extraction 152 For the eligible articles, the following items: first author, study location, sample size, (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 1, 2020. Among the studies that reported death cases, death case accounted for 31.6% (range, 183 11.7-61.5%) of the cases. Figure 2B ). Significant heterogeneity was observed for the AST levels among the studies (I 2 = 194 74%, p < 0.01), which was significantly higher than that of the ALT levels (I 2 = 42%, (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 1, 2020. . https://doi.org/10.1101/2020.04.26.20080580 doi: medRxiv preprint tended to be higher than the mean ALT level in both the died and discharged alive 198 groups. Moreover, the gap between the AST and ALT levels (45.3 and 29.8 IU/L, 199 respectively) was even more significant in the group discharged alive (Figure 3 ). Evaluation of potential publication bias was also presented in Supplementary Figure 3 . in the group with death was slightly higher than that in the group discharged alive. Figure 5A ). High heterogeneity was observed among the studies (I 2 = 80%, p < 0.01). The mean ALB level in the patients with death was significantly lower than that in the 218 patients discharged alive. There were significant differences in the coagulation-related (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 1, 2020. The possible mechanisms of COVID-19 related liver injury include the direct damage 246 of SARS-CoV-2 to the liver, and the secondary liver injury caused by stress and 247 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 1, 2020. On the whole, the alteration of liver chemistries between the survival group and non-265 survival group is similar to that between the severe group and the non-severe group, 266 shown in our recent study [10] , although there are some differences. Similar to the age 267 difference between severe and non-severe group, our analysis also found that the 268 average age of the non-survival group was significantly higher than that of survival 269 group. The average ALT and AST in the dead group were also higher than those in 270 the non-survival group. Moreover, both in the non-survival group and survival group, 271 the average AST was higher than ALT, which was also similar to our previous study 272 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 14 [10] . GGT in the non-survival group was higher than that in the survival group. 273 However, there was no statistical significance. This may be due to the under-reported 274 on GGT. TBIL in the non-survival group was also higher than that in the survival 275 group whereas the average values of TBIL in both groups were all within the normal 276 range. ALB in the non-survival group was significantly lower than that in the survival 277 group, which was in accordance with our study between severe and non-severe group 278 [10] . In the non-survival group, PT and INR were significantly longer than those in 279 the survival group, which was even more remarkable than the difference we In this study, we found that the abnormalities of liver chemistries in the non-survival 288 group was worse than that in the survival group, which suggested that we should be Several substantial merits can be seen in this study. First, the literatures focused on 296 COVID-19 related abnormal liver chemistries are rapidly evolving and sometimes 297 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 1, 2020. AKP and GGT tended to be inadvertently ignored, which is even more significant 307 than that in our previous study [10] . We also compared hepatocellular dysfunction 308 between the survival and non-survival cases. The alarmingly high prevalence of 309 hypoalbuminemia and coagulation dysfunction in the non-survival group requires 310 vigilance. Third, we also covered the eligible studies preprinted in medRxiv, which 311 ensured that our meta-analysis has a clear leading position. However, our study has a However, this conversely helps to abate the heterogeneity caused by the physiological 317 differences. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 1, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 1, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 1, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 1, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 1, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 1, 2020. . https://doi.org/10.1101/2020.04.26.20080580 doi: medRxiv preprint World Health Organization. Coronavirus disease 2019 (COVID-19) Situation Report-96. 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The protocol for prevention, diagnosis 466 and treatment of liver injury in coronavirus disease 2019 Novel coronavirus pneumonia related liver injury: 469 etiological analysis and treatment strategy Inflammation and thrombosis: roles of neutrophils, platelets and 472 endothelial cells and their interactions in thrombus formation during sepsis Coagulation and sepsis (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint were reported without data from dead cases) were also excluded. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 1, 2020. . https://doi.org/10.1101/2020.04.26.20080580 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 1, 2020. . https://doi.org/10.1101/2020.04.26.20080580 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 1, 2020. . https://doi.org/10.1101/2020.04.26.20080580 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 1, 2020. . https://doi.org/10.1101/2020.04.26.20080580 doi: medRxiv preprint