key: cord-0950372-nkw4wqyb authors: Dong, Xuan; Zeng, Dan-Yi; Cai, Yan-Yan; Chen, Wei-Ming; Xing, Qing-Qing; Ren, Yan-Dan; Hong, Mei-Zhu; Pan, Jin-Shui title: Liver Chemistries in Patients with Severe or Non-Severe COVID-19: a Meta-Analysis date: 2020-04-29 journal: nan DOI: 10.1101/2020.04.24.20074179 sha: 00611e5391fc7ebadaf8cd0932b91a3abe98e231 doc_id: 950372 cord_uid: nkw4wqyb Background & Aims: Cumulating observations have indicated that COVID-19 patients undergo different patterns of abnormal liver chemistries. We performed a meta-analysis of published liver manifestations and tried to describe the liver damage. Methods: We searched PubMed, google scholar, Embase, Cochrane Library, medRxiv, bioRxiv, and three Chinese electronic databases through April 18, 2020 according to the Preferred Reporting Items for Meta-Analyses. We analyzed pooled data on liver chemistries stratified by the severity of COVID-19 using a fixed or random effects model. Results: In a meta-analysis of 37 studies, comprising 6,235 patients, the pooled mean of ALT was 36.4 IU/L in the severe cases of COVID-19 while 27.8 IU/L in the non-severe cases (95% CI: -9.4- -5.1, p<0.0001). Pooled average of AST was 46.8 IU/L in the severe cases while 30.4 IU/L in the non-severe cases (95% CI: -15.1- -10.4, p<0.0001). Compared with the non-severe cases, the severe cases tended to have higher γ-Glutamyltransferase while lower albumin. Conclusions: In this meta-analysis, we comprehensively described three patterns of liver impairment related to COVID-19, including hepatocellular injury, cholestasis, and synthetic disfunction, according to the severity of the COVID-19. Patients with abnormal liver tests are at higher risks of progressing to severe disease. Close monitoring on liver chemistries helps to early warn against disease progression. 4 Lay Summary 74 Data on abnormal liver chemistries related to coronavirus disease (COVID-19) are 75 cumulating but are potentially confusing. We performed a meta-analysis of 37 studies 76 that included a total of 6,235 patients with COVID-19. We noted that patients with 77 abnormal liver test results are at higher risk of progression to severe disease and close 78 monitoring of liver chemistries provides early warning against disease progression. 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 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.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 April 29, 2020. According to the situation report released by the World Health Organization (WHO), 82 as of April 18, 2020, 2,160,207 coronavirus disease (COVID-19) cases were 83 confirmed globally, of which 146,088 led to deaths [1] . Although effectively (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 April 29, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Studies that only reported the percentages of the indexes related to liver chemistries 148 rather than the mean or median values of the corresponding indexes were also 149 excluded. 150 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. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Characteristics of the studies included in the meta-analysis 174 The selection process of the potential studies is depicted in Figure 1 Figure 2B ). Significant heterogeneity was observed for the AST levels among the studies (I 2 = 193 68%, p < 0.01), which was slightly lower than that of the ALT levels (I 2 = 69%, p < 194 0.01). Potential publication bias was evaluated using a funnel plot (Supplementary 195 Figure 2 ). In the patients with COVID-19, the mean AST level tended to be higher 196 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 April 29, 2020. . https://doi.org/10.1101/2020.04.24.20074179 doi: medRxiv preprint than the mean ALT level in both the severe and non-severe groups. Moreover, the gap 197 between the AST and ALT levels (46.8 and 36.5 IU/L, respectively) was even more Sixteen studies compared the mean ALB levels according to COVID-19 severity, 218 between 713 and 1,772 severe and non-severe cases, respectively ( Figure 5A) . A 219 significant heterogeneity was observed among the studies (I 2 = 61%, p < 0.01). The 220 mean ALB level in the patients with severe disease was significantly lower than that 221 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 April 29, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. ALT/AST, AKP/GGT, and TBIL levels; higher INR; and prolonged PT. However, the 235 severe cases had lower ALB levels than the non-severe cases. The patients with 236 COVID-19 often had higher AST levels than ALT levels, especially in severe cases. 237 We also observed a tendency of the severe cases to arise in the elderly. Although the liver may act as the latent target of SARS-CoV-2, the actual prevalence 239 of abnormal liver chemistries could be underestimated because many studies did not (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 April 29, 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 April 29, 2020. China seem to have an adverse impact. On the contrary, this helps to abate the 303 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 April 29, 2020. . https://doi.org/10.1101/2020.04.24.20074179 doi: medRxiv preprint 15 heterogeneity caused by the disease grouping, as some potential discrepancies may 304 exist in the definition of severe and non-severe cases of COVID-19 between different 305 countries. 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. of liver chemistries provides an early warning against disease progression. 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 April 29, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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 (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 (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 April 29, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (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 April 29, 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 April 29, 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 April 29, 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 April 29, 2020. . https://doi.org/10.1101/2020.04.24.20074179 doi: medRxiv preprint World Health Organization. Coronavirus disease 2019 (COVID-19) Situation Report-89. World Health Organization Receptor Recognition by the Novel 373 Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of 374 SARS Coronavirus Gastrointestinal 376 Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples from the Hong Kong Cohort and Systematic Review and Meta-analysis High 380 Prevalence of Concurrent Gastrointestinal Manifestations in Patients with SARS CoV-2: Early Experience from California Epidemiological, clinical 383 and virological characteristics of 74 cases of coronavirus-infected disease 2019 384 (COVID-19) with gastrointestinal symptoms Gastrointestinal symptoms 386 of 95 cases with SARS-CoV-2 infection Evidence for Gastrointestinal 388 Infection of SARS-CoV-2 Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection Characteristics of Liver Tests in 393 COVID-19 Patients COVID-19 and the liver: little cause for concern Liver injury in COVID-19: management and challenges Clinical characteristics of Non-ICU 399 hospitalized patients with coronavirus disease 2019 and liver injuryA Retrospective 400 study Liver impairment in COVID-19 402 patients: a retrospective analysis of 115 cases from a single center in Wuhan city ACG Clinical Guideline: Evaluation of Abnormal 405 Liver Chemistries The 407 PRISMA statement for reporting systematic reviews and meta-analyses of studies that 408 evaluate healthcare interventions: explanation and elaboration How to estimate the sample mean and standard 410 deviation from the sample size, median, extremes or quartiles Quantifying heterogeneity in a meta-analysis Clinical Features of Patients 415 Infected with the 2019 Novel Coronavirus (COVID-19 Clinical features and laboratory inspection of novel coronavirus pneumonia 418 (COVID-19) in Xiangyang Clinical and immunological 420 features of severe and moderate coronavirus disease 2019 Epidemiological and clinical 422 features of 291 cases with coronavirus disease 2019 in areas adjacent to Hubei, China: 423 a double-center observational study Acute liver injury and its 425 association with death risk of patients with COVID-19: a hospital-based prospective 426 case-cohort study Diagnostic utility of clinical laboratory 428 data determinations for patients with the severe COVID-19 Lactate dehydrogenase, a Risk 430 Factor of Severe COVID-19 Patients Clinical features of patients 432 infected with 2019 novel coronavirus in Wuhan, China Clinical characteristics and 434 outcomes of patients undergoing surgeries during the incubation period of COVID-19 435 infection Clinical characteristics of 437 80 patients with COVID-19 in Zhuzhou City Preliminary study of 439 the relationship between novel coronavirus pneumonia and liver function damage: a 440 multicenter study Longitudinal characteristics of 442 lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 443 infected patients Clinical characteristics of 51 patients discharged from hospital with COVID-19 in Chongqing A descriptive study of the impact of 447 diseases control and prevention on the epidemics dynamics and clinical features of SARS-CoV-2 outbreak in Shanghai, lessons learned for metropolis epidemics 449 prevention 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. 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Recommendations for use of laboratory tests in 509 screening, diagnosis, and monitoring Significance Clinical characteristics of 513 113 deceased patients with coronavirus disease 2019: retrospective study 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 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 April 29, 2020. . https://doi.org/10.1101/2020.04.24.20074179 doi: medRxiv preprint All rights reserved. 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