key: cord-0830545-vhh9y3je
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: 2020-04-11
journal: nan
DOI: 10.1101/2020.04.09.20056242
sha: f3959de141636460ded8993c5eedeebae88fe87d
doc_id: 830545
cord_uid: vhh9y3je

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 seems to be higher in patients with severe COVID-19 infection. This finding could help physicians to identify patients with poor prognosis at an early stage.

In December 2019, a cluster of severe acute respiratory syndrome (SARS), now known as Coronavirus disease 2019 , occurred in Wuhan city, the capital of Hubei Province, China 1-3 . The disease has rapidly spread from China to other countries. As of April 4, 2020, a total of 1,051,635 COVID-19 confirmed cases and 56,985 deaths in 206 countries and territories have been reported 4 . Full-genome sequencing indicated that COVID-19 is a distinct clade from the beta-coronaviruses associated with human SARS and Middle East respiratory syndrome (MERS) 5 .

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 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 .

. CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https: //doi.org/10.1101 //doi.org/10. /2020 

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] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [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 mean difference = 8.84 U/L, 95% CI = 5.97 to 11.71, P<0.001, I 2 = 73.4%, P heterogeneity <0.001) ( Figure   2 ), ALT (weighted mean difference = 7.35 U/L, 95% CI = 4.77 to 9.93, P<0.001, I 2 = 57.2%, P heterogeneity = 0.001) ( Figure 3 ) and total Bilirubin (weighted mean difference = 2.30 mmol/L, 95% CI = 1.24 to 3.36, P<0.001, I 2 = 68.8%, P heterogeneity <0.001) (Figure 4 ), were associated with . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https: //doi.org/10.1101/2020.04.09.20056242 doi: medRxiv preprint a significant increase in the severity of COVID-19 infections. In addition, combined results from the random-effects model showed that lower serum levels of Albumin (weighted mean difference = -4.24 g/L, 95% CI = -6.20 to -2.28, P<0.001, I 2 = 95.7%, P heterogeneity <0.001) ( Figure 5 ), significantly increased severity of the disease.

Based on the results of Egger's test (AST; P = 0.465, ALT; P = 0.171, total Bilirubin; P = 0.663 and Albumin; P=0.802) and visual inspection of funnel plots, we found no evidence of publication bias ( Supplementary Figures 1-4) . Furthermore, findings from sensitivity analysis showed that overall estimates did not depend on a single study .

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 33-36 .

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 . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https: //doi.org/10.1101 //doi.org/10. /2020 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 .

In addition, the ACE2 expression of bile duct cells is much greater than that of liver cells. Bile duct epithelial cells are known to play important roles in initiation and regulation of immune responses and liver regeneration 42 . So there is at least theoretical potential possibility of direct liver and bile duct involvement by the virus.

Serum concentrations of pro-inflammatory cytokines, including IL-1β, IL-6 and TNF-α increased in the majority of severe cases, suggesting cytokine storm syndrome might be associated with disease severity 43 . Similarly, SARS and MERS were also characterized by exuberant inflammatory responses and end-organ damage 44, 45 . Besides, the cytokine storm syndrome was observed in severe COVID-19 cases 43 , yet whether it results in liver injury in patients remains to be investigated.

Mild lobular and portal activity along with moderate microvascular steatosis were observed in liver biopsy specimens, which might be caused by either COVID-19 infection or drug-induced liver injury 46 . Similar to the situation in SARS and MERS, steroids, antivirals and antibiotics are widely used for the treatment of COVID-19 patients [47] [48] [49] . Although these drugs are potential causes of liver dysfunction, there is little evidence that currently available drug combinations impair liver function in patients with COVID-19 infection 24 . Actually, a recent study showed . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10. 1101 that the liver dysfunction might be caused by lopinavir/litonavir, which is used as antivirals for the treatment of COVID-19 patients 50 .

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.

In this meta-analysis of 3,428 patients with confirmed COVID-19 in China, liver dysfunction was associated with severe outcome from COVID-19 infection. From a clinical perspective, attention should be paid to monitor the occurrence of liver dysfunction, and to the application of drugs which may induce liver injury, such as steroids and antibiotics of quinolone or macrolides.

Patients with liver dysfunction are advised to be treated with drugs that could both inhibit inflammatory responses and protect liver functions, such as ammonium glycyrrhizinate 51 , which in turn accelerates the process of disease recovery.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . 1 1 1 9 R u a n Q , Y a n g K , W a n g W , J i a n g L , S  o  n  g  J  .  C  l  i  n  i  c  a  l  p  r  e  d  i  c  t  o  r  s  o  f  m  o  r  t  a  l  i  t  y  d  u  e  t  o  C  O  V  I  D  -1  9  b  a  s  e  d  o  n  a  n  a  n  a  l  y  s  i  s  o  f  d  a  t  a  o  f  1  5  0  p  a  t  i  e  n  t  s  f  r  o  m  W  u  h  a  n  ,  C  h  i  n  a  .  I  n  t  e  n  s  i  v  e  c  a  r  e  m  e  d  i  c  i  n  e  .  2  0  2  0  M  a  r  3  .  2  0  W  a  n  S  ,  X  i  a  n  g  Y  ,  F  a  n  g  W  ,  e  t  a  l  .  C  l  i  n  i  c  a  l  f  e  a  t  u  r  e  s  a  n  d  t  r  e  a  t  m  e  n  t  o  f  C  O  V  I  D  -1  9  p  a  t  i  e  n  t  s  i  n  n  o  r  t  h  e  a  s . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.04.09.20056242 doi: medRxiv preprint . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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41.21) 3.30 (-0

WMD (95% CI)