key: cord-289655-umc2t7du authors: Parohan, Mohammad; Yaghoubi, Sajad; Seraj, Asal title: Liver injury is associated with severe Coronavirus disease 2019 (COVID‐19) infection: a systematic review and meta‐analysis of retrospective studies date: 2020-05-09 journal: Hepatol Res DOI: 10.1111/hepr.13510 sha: doc_id: 289655 cord_uid: umc2t7du AIM: The Coronavirus disease 2019 (COVID‐19) outbreak is a major threat to human beings. Lung injury has been reported as the major outcome of COVID‐19 infection. However, liver damage has also been considered to occur in severe cases. Current meta‐analysis of retrospective studies was done to summarize available findings on the association between liver injury and severity of COVID‐19 infection. METHODS: Online databases including PubMed, Scopus, Web of Science and Cochrane Library were searched to detect relevant publications up to 1 April 2020, using relevant keywords. To pool data, a fixed‐ or random‐effects model was used depending on the heterogeneity between studies. Furthermore, publication bias test and sensitivity analysis were also done. RESULTS: In total, 20 retrospective studies with 3,428 COVID‐19 infected patients (severe cases = 1,455 and mild cases = 1,973), were included in this meta‐analysis. Higher serum levels of Aspartate aminotransferase (weighted mean difference = 8.84 U/L, 95% CI = 5.97 to 11.71, P<0.001), Alanine aminotransferase (weighted mean difference = 7.35 U/L, 95% CI = 4.77 to 9.93, P<0.001), total Bilirubin (weighted mean difference = 2.30 mmol/L, 95% CI = 1.24 to 3.36, P<0.001) and lower serum levels of Albumin (weighted mean difference = ‐4.24 g/L, 95% CI = ‐6.20 to ‐2.28, P<0.001), were associated with a significant increase in the severity of COVID‐19 infection. CONCLUSIONS: The incidence of liver injury, as assessed by serum analysis (AST, ALT, total Bilirubin and Albumin levels), seems to be higher in patients with severe COVID‐19 infection. In December 2019, a cluster of severe acute respiratory syndrome (SARS), now known as SARS, MERS and COVID-19 can cause intestinal, respiratory, neuronal and hepatic diseases, and may lead to respiratory distress syndrome, organ failure, and even death in severe cases [5] [6] [7] . Several studies have reported the clinical characteristics and laboratory findings associated with different degrees of liver injury in patients with COVID-19 infection [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] . We are aware of no meta-analysis that summarized available findings in this regard. Thus, in this systematic review and meta-analysis, the laboratory findings and mechanism of liver injury caused by COVID-19 infection were summarized. A systematic literature search and a quantitative meta-analysis were planned, conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 28 . We conducted a literature search using the online databases of PubMed, Scopus, Web of Science and Cochrane Library for relevant publications up to 1 April 2020. The following medical subject headings (MeSH) and non-MeSH keywords were used in our search strategy: ("COVID-19" OR "severe acute respiratory syndrome coronavirus 2" OR "SARS-CoV-2" OR "novel coronavirus" OR "2019-nCoV") AND ("Alanine Transaminase" OR "Alanine aminotransferase" OR "SGPT" OR "Aspartate Aminotransferases" OR "SGOT" OR "Bilirubin" OR "Serum Albumin" OR "Liver"). The literature search was performed by two reviewers (MP and SY). We also searched the reference lists of the articles to identify missed studies. No restriction was applied on time of publication and language. To facilitate the screening process of studies from online databases, all search results were downloaded into an EndNote library (version X8, Thomson Reuters, Philadelphia, USA). The search strategy is presented in detail in Supplementary Table 1 . Studies were included if they met the following inclusion criteria: (1) observational studies with retrospective design; (2) all articles assessing the association between serum levels of Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Albumin, Bilirubin and severe outcome from COVID-19 infection as the major outcomes of interest and reported mean (SD) or median (IQR) for serum levels of AST, ALT, Albumin, Bilirubin in both severe and This article is protected by copyright. All rights reserved. non-severe COVID-19 infected patients. Expert opinion articles, review articles, books and theses were excluded. Two reviewers (MP and AS) extracted the following data from the studies: author's name, publication year, study design, sample size, age and gender of patients, serum levels of AST, ALT, Albumin and Bilirubin and outcome assessment methods. The Newcastle-Ottawa Scale was used for assessing the quality of the included studies 29 . Based on the NOS, a maximum of nine points can be awarded to each article. In this review, studies with the Newcastle-Ottawa Scale score of ≥ 5 were considered as high quality publications. Mean (SD) or median (IQR) for serum levels of AST, ALT, Albumin and Bilirubin were used to estimate the effect size. The fixed or random-effect model was used based on heterogeneity test. The heterogeneity between studies was evaluated using the Cochrane Q test 30 . The publication bias was evaluated by the visual inspection of funnel plot and Egger's regression tests 31 .The sensitivity analysis was done to assess the effect of each study on the pooled effect size. All statistical analyses were performed using the Stata 14 software package (Stata Corp, College Station, TX, USA). Overall, 212 articles were identified in our initial literature search. Of these, 35 duplicates, 29 non-English, 3 non-human, 18 reviews and 95 papers that did not fulfill our inclusion criteria were excluded, leaving 32 articles for further evaluation. Out of remaining 32 articles, 12 were excluded because of the following reason: did not report mean (SD) or median (IQR). Finally, we included 20 articles in this systematic review and meta-analysis ( Figure 1 ). All studies were conducted in China and used retrospective design 8-27 . The sample size of studies ranged from 21 to 651 patients (mean age, 53.3 years). All studies used real-time reverse transcriptase-polymerase chain reaction (RT-PCR) to identify COVID-19 infection. The Newcastle-Ottawa Scale scores ranged between 4 to 9. The characteristics of the included articles are presented in Table 1 . In the overall pooled estimate of 20 studies with 3,428 COVID-19 infected patients (severe cases = 1,455 and mild cases = 1,973), it was shown that higher serum levels of AST (weighted Figures 1-4) . Furthermore, findings from sensitivity analysis showed that overall estimates did not depend on a single study ( Supplementary Figures 5-8 ). Findings from this meta-analysis supported the hypothesis that liver injury is associated with severe outcomes in patients with COVID-19 infection. To our knowledge, this study is the first systematic review and meta-analysis to assess the association between serum levels of AST, ALT, total Bilirubin and Albumin with severity of COVID-19 infection. Our results are in agreement with previous narrative review 32 . Previously, liver damage has been reported as an important risk factor for severe outcome and death in SARS and MERS 33- Mild cases of COVID-19 showed symptoms of dry cough, fever, fatigue, myalgia and diarrhea. In severe cases, viral pneumonia, dyspnea and hypoxemia occurred 1 week after the onset of the disease, which may progress to acute respiratory distress syndrome, metabolic acidosis, septic shock and even death 12 . Previous studies have shown that the incidence of liver injury in severe COVID-19 patients ranged from 58% to 78% 37, 38 , mainly indicated by elevated AST, ALT and total Bilirubin levels accompanied by slightly decreased Albumin levels 12, 21, 24, 39 . Currently, studies on the mechanisms of COVID-19 related liver dysfunction are limited. COVID-19 uses the angiotensin converting enzyme 2 (ACE2) as the binding site to enter the host cell in lungs, kidneys and heart 40 . Previous study showed that both liver and bile duct cells express ACE2 41 This article is protected by copyright. All rights reserved. The present study has some limitations. First, interpretation of our meta-analysis findings might be limited by the small sample size. Second, there is a lack of reports that liver failure occurs in COVID-19 patients with chronic liver diseases and our meta-analysis did not include data such as chronic hepatitis B or C. Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection: a single-center experience in Saudi Arabia Characteristics and Outcomes of Middle East Respiratory Syndrome Coronavirus Patients Admitted to an Intensive Care Unit in Jeddah, Saudi Arabia Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study. The Lancet Infectious diseases Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China. medRxiv Clinical characteristics of 82 death cases with COVID-19. medRxiv Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection Cholangiocyte pathobiology