Accepted Article

DR. ALEXANDER J. KOVALIC (Orcid ID : 0000-0002-5211-5200)

DR. SANJAYA SATAPATHY (Orcid ID : 0000-0003-0153-2829)

Article type : Original

Elevated Liver Biochemistries in Hospitalized Chinese Patients with Severe COVID-19: Systematic
Review and Meta-analysis

Alexander J. Kovalic,1 Glen Huang,2 Paul J. Thuluvath,3,4 and Sanjaya K. Satapathy5,6

From the 1Department of Internal Medicine, Novant Forsyth Medical Center, Winston-Salem, NC;
2Department of Internal Medicine, Division of Infectious Diseases, University of California, Los
Angeles, CA; 3Institute of Digestive Health & Liver Diseases, Mercy Medical Center, Baltimore, MD;
4Department of Medicine, University of Maryland School of Medicine, Baltimore, MD; 5Department
of Internal Medicine, Division of Transplantation, Sandra Atlas Bass Center for Liver Diseases &
Transplantation, Barbara and Zucker School of Medicine for Hofstra/Northwell Health, Manhasset,
NY; 6Department of Internal Medicine, Division of Hepatology, Sandra Atlas Bass Center for Liver
Diseases & Transplantation, Barbara and Zucker School of Medicine for Hofstra/Northwell Health,
Manhasset, NY.

Potential conflict of interest: Nothing to report.

Total word count (excluding references): 2786

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/HEP.31472
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Accepted Article
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:

Sanjaya K. Satapathy, M.B.B.S., M.D., D.M., M.S., FACG, FASGE, AGAF, FAASLD
Department of Internal Medicine, Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases
& Transplantation, Barbara and Zucker School of Medicine for Hofstra/Northwell Health
400 Community Drive, Manhasset, NY 11030
E-mail: ssatapat@northwell.edu
Tel.: +1-516-562-2096

Abbreviations: ACE2, angiotensin-converting enzyme 2; ACEI, angiotensin-converting enzyme

inhibitor; ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; ARB,
angiotensin receptor blocker; AST, aspartate aminotransferase; CAD, coronary artery disease;
cells/L, cells per liter; CI, confidence interval; COPD, chronic obstructive pulmonary disease; COVID-
19, coronavirus disease 2019; df, degrees of freedom; g/L, grams per liter; IV, inverse variance; LDH,
lactate dehydrogenase; M-H, Mantel-Haenszel; MD, mean difference; mg/dL, milligrams per
deciliter; OD, odds ratio; PT, prothrombin time; s, seconds; SARS, severe acute respiratory
syndrome; U/L, units per liter; WBC, white blood count.

Abstract

Background & Aims: Several recent studies have reported an abnormal liver chemistry profile among
patients with coronavirus disease 2019 (COVID-19), although its clinical significance remains
unknown.

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 Approach & Results: This novel systematic review and meta-analysis identified six studies of 586
Accepted Article
patients delineating liver chemistries among patients with severe/critical illness versus mild cases of
COVID-19 infection. Patients with severe/critical illness with COVID-19 infection have increased
prevalence of coronary artery disease (CAD), cerebrovascular disease, and chronic obstructive
pulmonary disease (COPD) as compared to mild cases. A significant association between
severe/critical COVID-19 infections with elevations in aspartate aminotransferase (AST) (pooled
mean difference [MD], 11.70 U/L; 95% confidence interval [CI], 2.97, 20.43; P = 0.009), elevated total
bilirubin (pooled MD, 0.14 mg/dL; 95% CI, 0.06, 0.22; P = 0.0005), and decreased albumin (pooled
MD, –0.68 g/L; 95% CI, –0.81, –0.55; P < 0.00001) was noted. There was also a trend toward
elevated alanine aminotransferase (ALT) levels among these severe cases (pooled MD, 8.84 U/L; 95%
CI, –2.28, 19.97; P = 0.12); however, this did not reach statistical significance. More severe/critically
ill cases were associated with leukocytosis, neutrophilia, lymphopenia, elevated creatinine kinase,
elevated lactate dehydrogenase (LDH), and elevated prothrombin time (PT).
Conclusions: Comorbidities, including CAD, cerebrovascular disease, and COPD, are more prevalent
in hospitalized Chinese patients with severe/critical illness from COVID-19, and these patients are
more likely to manifest with abnormal liver chemistries. Further prospective studies are crucial to
understand the pathophysiologic mechanisms underlying the hepatic manifestations of the novel
COVID-19 infection and its clinical significance.

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Accepted Article

After recently being declared a global pandemic, the novel severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2), or coronavirus disease 2019 (COVID-19), has spread to more than 200
countries with close to 2 million confirmed cases in the United States alone.(1) Although this infection
typically presents with an incubation period followed by pulmonary manifestations, the presence of
concomitant liver injury among patients with COVID-19 has recently been described.(2) However, the
significance of liver injury remains unknown.

It is still relatively early in the evolution of the COVID-19 pandemic. The exact pathophysiologic
mechanism remains uncertain, especially regarding the hepatobiliary involvement of this disease.
The primary aim of this novel systematic review and meta-analysis is to further characterize liver
injury and other unique clinical characteristics across COVID-19 severity.

Materials and Methods

Literature Search
We searched three major databases—MEDLINE/PubMed, Embase, and Cochrane Central Register of
Controlled Trials (CENTRAL)—for clinical studies dated from inception to March 22, 2020. In an effort
to broadly identify studies detailing liver chemistry testing among patients with COVID-19, the
following search criteria were used: (coronavirus OR cov2 OR “cov 2” OR ncov OR (sars AND cov2)

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 OR “sars cov 2” OR covid) AND (liver OR ast OR “aspartate aminotransferase” OR alt OR “alanine
Accepted Article
aminotransferase”). This meta-analysis was conducted according to the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA)(3) and Meta-Analyses of Observational Studies
in Epidemiology (MOOSE).(4) Identification of studies reporting liver chemistries were prioritized in
order to ascertain an association among patients who had severe or critical illness versus mild cases
of COVID-19 infection. Severe cases were defined as significant respiratory distress from the COVID-
19 infection based on work of breathing or degree of hypoxia (diagnosed by either pulse oximetry or
arterial blood gas). Critical cases were defined as patients requiring admission to the intensive care
unit (ICU) for either mechanical ventilation, shock, or multisystem organ failure. Mild cases were
defined as patients who tested positive for COVID-19, but did not meet criteria for severe or critical
cases and were either asymptomatic or the symptoms from their infection were self-limiting.

Inclusion Criteria
Articles and clinical studies that met the following inclusion criteria were eligible for this meta-
analysis: (1) studies performed in adult, human subjects; (2) studies written in English; (3) studies
measuring liver chemistries among COVID-19 patients (aspartate aminotransferase [AST], alanine
aminotransferase [ALT], total bilirubin); (4) studies comparing patients with severe or critical illness
versus mild cases.

Exclusion Criteria
Studies with the following characteristics were excluded from this meta-analysis: (1) studies in
nonhuman subjects; (2) studies written in a language other than English; (3) studies that were not a
clinical trial, such as a review paper or letter; (4) studies that were out of scope of the study question
detailed above; (5) studies that lacked proper controls; (6) studies that did not provide raw data in
order to perform quantitative meta-analysis; (7) studies conducted in pediatric subjects; (8) studies
that did not have an available manuscript; (9) studies that were duplicates; (10) studies there were
ongoing or not completed.

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 Outcomes and Endpoints
Accepted Article
The primary outcomes for this meta-analysis were as follows: (1) liver chemistries (AST, ALT, total
bilirubin, albumin); (2) demographic data (age, gender, comorbidities); (3) laboratory parameters
from complete blood count (CBC), comprehensive metabolic panel (CMP), or coagulation testing
(white blood count [WBC], neutrophils, lymphocytes, platelets, creatinine, creatinine kinase, lactate
dehydrogenase [LDH], prothrombin time [PT], activated partial thromboplastin time [aPTT]); (4)
mortality.

Data Extraction
The authors extracted data from the literature search, and any disagreements were resolved by
consensus. Ambiguity in the reported data was attempted to be resolved by e-mailing the
corresponding author of the study where appropriate. Author names, dates, study type, setting of
study, number and characteristics of patients, and treatment outcomes were gathered for all
included studies.

Risk of Bias
Nonrandomized studies were assessed by the Newcastle-Ottawa Scale (NOS).(5) The authors
determined the quality of selection, comparability, and exposure/outcome in the NOS. Each form of
bias was awarded either a low, high, or unclear risk of bias. A funnel plot was calculated to
determine the presence of publication bias.

Statistical Analysis
This meta-analysis was performed using Review Manager (RevMan, version 5.3, The Cochrane
Collaboration, Denmark). Odds ratios (ORs) were used as a summary measure of efficacy for
dichotomous data, and mean differences (MDs) were used between groups for continuous variables;
95% confidence intervals (CIs) were reported for both measures. If medians and interquartile ranges
(IQRs) were provided in the included studies instead of MDs and standard deviations, the MD and
standard deviations were imputed as described in other studies(6-7, 8) as well as the Cochrane

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 Handbook for Systematic Reviews of Interventions.(9) Data were considered statistically insignificant
Accepted Article
if P > 0.05, OR includes 1.00, or MD includes 0. Statistical heterogeneity was assessed using the I2
statistic. I2 values of 0% to 25%, 25% to 50%, 50% to 75%, and more than 75% were awarded values
of homogeneity, mild heterogeneity, moderate heterogeneity, and high heterogeneity, respectively.
If significant heterogeneity was present (I2  50%), the random effects model was used to pool the
effect sizes of included studies and subgroup analyses; if no significant heterogeneity was found (I2 <
50%), the fixed-effect model was used.(10, 11) Publication bias was determined by Egger’s regression
asymmetry test.(12) Funnel plots were qualitatively assessed by visual inspection based on
logarithmic ORs plotted versus their standard errors.(13) Asymmetric funnel plots represented
studies with high risk of publication bias.

Results
Study Selection
The data search, literature review, and study selection are outlined in Fig. 1. Overall, 455 clinical
studies were identified based on the predefined inclusion and exclusion criteria. Studies that did not
have an appropriate clinical comparison between groups or present enough data to perform a
quantitative meta-analysis were excluded. In the end, six studies with 586 patients were finalized
that satisfied all of these criteria.(14-19) Also of note, all of these studies present data from COVID-19
positive patients from China. Five are from Wuhan and the province of Hubei. The final study details
a patient cohort from the neighboring province of Chongqing.(16) All data were included from
hospitalized patients with laboratory data collected and analyzed upon presentation. Quality
assessment of the included studies is provided in Supporting Table S1.

Higher burden of increased age and comorbidities among patients with severe or critical COVID-19
infection
The characteristics of patients with severe/critical illness versus mild cases of COVID-19 are shown in
Figs. 2 and Supporting Fig. S1. Comorbidities were not uniformly reported in all six studies. Overall,

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 severe/critical cases of COVID-19 infection were significantly associated with patients who had
Accepted Article
coronary artery disease (CAD) (pooled OR, 2.68; 95% CI, 1.43, 5.01; P = 0.002), cerebrovascular
disease (pooled OR, 20.20; 95% CI, 2.34, 174.44; P = 0.006), and chronic obstructive pulmonary
disease (COPD) (pooled OR, 12.22; 95% CI, 2.57, 58.09; P = 0.002) at baseline as compared to
patients with mild cases. Increased age (pooled MD, 11.15; 95% CI, –1.75, 24.0; P < 0.09) and
diabetes mellitus (pooled OR, 2.34; 95% CI, 0.66, 8.26; P = 0.19) demonstrated a trend toward
association with severe/critical COVID-19 cases; however, these differences not reach statistical
significance. These studies failed to show a significant link of severe cases with gender,
hypertension, active smoking or tobacco use, chronic liver disease, chronic kidney disease,
malignancy, or current treatment with angiotensin-converting enzyme inhibitor (ACEI)/angiotensin 2
receptor blocker (ARB). However, these studies did not delineate the definition of “chronic liver
disease” into the underlying etiology, such as cirrhosis or viral hepatitis.

Elevated liver chemistries more pronounced among COVID-19 patients with severe or critical illness
The comparison of liver chemistries among patients with severe/critical illness versus mild COVID-19
cases is provided in Fig. 3. Overall, there was a significant correlation of severe or critical COVID-19
infections with elevations in AST (pooled MD, 11.70; 95% CI, 2.97, 20.43; P = 0.009), elevated total
bilirubin (pooled MD, 0.14; 95% CI, 0.06, 0.22; P = 0.0005), and decreased albumin (pooled MD, –
0.68; 95% CI, –0.81, –0.55; P < 0.00001) upon presentation. There was also a trend toward
association of severe/critical cases with elevated ALT (pooled MD, 8.84; 95% CI, –2.28, 19.97; P =
0.12). However, this did not reach statistical significance.

Other laboratory aberrancies associated with severe or critical COVID-19 infection

A more comprehensive battery of laboratory testing provided among these studies is further
detailed in Supporting Fig. 2. Overall, more severe or critical illness from COVID-19 was statistically
associated with leukocytosis (pooled MD of WBC, 2.14; 95% CI, 0.20, 4.08; P = 0.03), neutrophilia
(pooled MD, 1.68; 95% CI, 0.38, 2.97; P = 0.01), lymphopenia (pooled MD, –0.40; 95% CI, –0.58, –
0.22; P < 0.001), elevated creatinine kinase (pooled MD, 39.95; 95% CI, 20.94, 58.95; P < 0.0001),

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 elevated LDH (pooled MD, 96.39; 95% CI, 65.92, 126.87; P < 0.0001), and elevated PT (pooled MD,
Accepted Article
0.48; 95% CI, 0.25, 0.72; P < 0.0001). Platelet count appeared to be decreased among more severe
infections; however, this did not achieve statistical significance (pooled MD, –18.36; 95% CI, –50.22,
13.51; P = 0.26). No significant relationship was established between serum creatinine or aPTT
among patients with severe/critical illness versus mild cases.

Mortality data among severe or critical illness in patients with COVID-19 infection
Mortality data are presented in Fig. 4. Overall, only three studies reported mortality data. Although
there was no outpatient analysis for these patients, the mortality data included follow-up
throughout the duration of their inpatient stay. Unsurprisingly, there was a significantly increased
rate of mortality (pooled OR, 21.70; 95% CI, 7.01, 67.24; P < 0.00001) in studies reporting survival
among patients with severe versus mild COVID-19 infections.

Publication Bias
Funnel plots were generated for the outcomes of this meta-analysis and are demonstrated in
Supporting Figs. S3-S7. Where appropriate, 95% CIs were included for fixed-effect model analysis.
Overall, there was no asymmetry noted in the funnel plots to suggest a large degree of publication
bias.

Discussion
As the current pandemic continues to sweep the globe, there will inevitably be an increasing amount
of clinical data from Europe and North American regarding liver injury among patients with COVID-
19, however at the time of this meta-analysis, the data have come exclusively from China. There
remains a paucity of data on liver histopathology and limited autopsy case reports reveal
microvesicular steatosis in addition to lobular and portal inflammation, although not as exaggerated
as inflammation seen in the lungs.(20) Our study shows that abnormalities of liver chemistries are
more common in severe COVID-19 disease and more likely to be seen in those with other serious

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 comorbidities. Based upon circumstantial evidence, the CDC and the AASLD Expert Panel has
Accepted Article
suggested that there will be a heightened health care burden among patients with chronic liver
diseases, especially those requiring liver transplantation.(21,22) Our study appears to support the
above statement since patients with NASH cirrhosis or those waiting liver transplant are likely to
have significant comborbidities.

Several studies from Europe and North America have emerged recently.(23 24) Among 5700
hospitalized patients in New York, only 19 total patients (0.4%) had cirrhosis with only 11 patients
(0.2%) described having either HBV or HCV.(23) Another Italian study reports chronic liver disease
only among 28 out of 1591 patients admitted to the ICU.(24) Mildly increased liver chemistries is a
common finding, particularly among severe COVID-19 infections, however has been previously
demonstrated to lack significant, standalone impact on mortality.(25,26) One the other hand, a large
propensity-matched study has reported that patients with chronic liver disease and COVID-19 have a
three-fold higher mortality risk as compared to patients without liver disease.(27) Conversely, two
other meta-analyses have recently failed to demonstrate a link between chronic liver disease and
either mortality or severity of COVID-19 infection.(28, 29)

Mechanism of liver injury and its relationship with severity of COVID-19 infection is largely
speculative. Similar to previous SARS-CoV infections, the binding and uptake by the angiotensin-
converting enzyme 2 (ACE2) cholangiocyte receptor has been demonstrated to mediate liver
damage among patients with COVID-19.(30) Not only does the degree of AST or ALT elevation appear
to correlate with the severity of COVID-19 infection, but this mechanism for liver injury appears to
be mediated by an up-regulation of ACE2 also among hepatocytes in a mouse model.(31) Other
etiologies for liver injury include underlying liver disease, medications including experimental drugs,
and in severe cases, the cytokine storm (through tumor necrosis factor α (TNF-), interleukin [IL]-6,
or IL-18) as well as the ischemic hypoxia-reperfusion that accompanies more severe COVID-19
infections.(32)

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 Although this manuscript reports novel findings in this area, it is not without limitations. First, our
Accepted Article
analysis is limited to hospitalized patients from China and hence cannot be generalizable to other
geographical areas. Studies detailing liver chemistries and other clinical characteristics remain
extremely limited for outpatient population. In our study, significant heterogeneity was found with
respect to outcomes of age (I2 = 95%), history of hypertension (I2 = 82%), history of diabetes mellitus
(I2 = 68%), AST (I2 = 78%), ALT (I2 = 81%), WBC (I2 = 86%), neutrophil count (I2 = 70%), lymphocyte
count (I2 = 77%), platelet count (I2 = 69%), and serum creatinine (I2 = 63%). This phenomenon is most
likely related to small sample size, limited study data, and skewed representation of patient
populations. Another potential limitation is the definition used to stratify severe/critical COVID-19
disease. Some studies included only patients requiring ICU admission, whereas others included
severe respiratory distress not requiring intubation in their severe patient cohort. Laboratory
parameters were all collected from patients upon presentation for their inpatient admission to the
hospital. A more comprehensive trend of liver chemistries may be a future focus in order to capture
the peak of these laboratory parameters and compare them based on clinical outcomes.
Furthermore, characterization of baseline “chronic liver disease” remains ill-defined among these
studies and warrants further investigation. Many of these laboratory findings, such as aberrancies in
liver chemistries, low platelet count, decreased albumin, or prolonged PT, could be explained by an
acute COVID-19 infection but also may be influenced by underlying cirrhosis or viral hepatitis that is
not clearly reported among these included studies.

The characterization of liver injury among COVID-19 infection remains paramount with respect to
potential therapeutic options. Hydroxychloroquine (HCG) has been used in many countries as a
potential therapeutic option against COVID-19,(33) and although hepatotoxicity is relatively
uncommon, this drug is metabolized by the liver and has been reported to cause acute liver injury in
select cases.(34) Furthermore, the use of antiviral therapies has undergone increased investigation.
Remdesivir, a novel antiviral agent that acts as an RNA-chain terminator, has been demonstrated to
be effective in vitro, and in early clinical trials in the US.(35) Recent published studies on remdesvir
have shown infrequent liver test abnormalities among other side effects.(36-38) However, elevation of

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 AST or ALT greater than five times the upper limit of normal remains an exclusion criterion for
Accepted Article
initiation of remdesivir among COVID-19 patients, and this may exclude many patients with
preexisting liver disease from receiving remdesvir. The true incidence of remdesvir hepatotoxicity is
an area for further research. Preliminary studies of IL-6 inhibitor, tocilizumab in patients with
COVID-19 also suggest that this drug also may be associated with uncommon hepatotoxicity.(39)
Among preliminary data from a study reporting the first hospitalized cases of COVID-19 in the United
States, all patients treated with remdesivir developed transaminitis during their clinical course.(40)

As demonstrated in this systematic review and meta-analysis, the patients suffering from more
severe or critical COVID-19 infections have significantly increased liver chemistries. This clinical
finding poses quite a dilemma for future patients infected with COVID-19 because many of the
current investigational or ongoing randomized controlled trials are excluding patients with values of
AST or ALT greater than five times the upper limit of normal.(41-43) Therefore, further characterization
and recognition of liver injury is vital among patients harboring severe/critical COVID-19 infections,
particularly if one of the few therapeutic options is predicated on the status of underlying liver
chemistries.

As the COVID-19 pandemic continues to afflict more individuals across the globe, both the incidence
and clinical significance of liver injury among this patient population will be important to analyze. In
this novel systematic review and meta-analysis, the characterization of severe or critically ill patients
as compared to individuals suffering from mild cases of COVID-19 is described in detail. There
appears to be a significant correlation of aberrant liver chemistries, in addition to CAD,
cerebrovascular disease, COPD, leukocytosis, neutrophilia, lymphopenia, elevated creatinine kinase,
elevated LDH, and increased PT, among patients with severe or critical illness from COVID-19 as
compared to mild cases. Current knowledge of contributing factors, such as underlying liver disease
or use of concomitant medications, remains unknown. It is imperative for future prospective studies
to continue to examine the role of multiple confounders in the pathogenesis of liver injury in COVID-
19 infection.

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Accepted Article
Acknowledgment: We thank Alexander Kovalic for substantial contributions to conception and
design of the study, acquisition of data/analysis and interpretation of data, and drafting, critical
revisions, and final approval of the article; Glen Huang for substantial contributions to acquisition of
data/analysis and interpretation of data and drafting, critical revisions, and final approval of the
article; Muhammad Ali Khan and Fuad Zain for contributions with the finalization of figures and
tables; and Paul Thuluvath and Sanjaya Satapathy for substantial contributions to conception and
design of the study, interpretation of data, and critical revisions and final approval of the article.

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Covid-19. New England Journal of Medicine 2020.
39. Zhang S, Li L, Shen A, et al. Rational Use of Tocilizumab in the Treatment of Novel
Coronavirus Pneumonia. Clin Drug Investig 2020;40:511-518.
40. Kujawski SA, Wong KK, Collins JP, et al. First 12 patients with coronavirus disease 2019
(COVID-19) in the United States. medRxiv 2020.
41. ClinicalTrails.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2020 March 6
- . Identifier NCT04292899. Study to Evaluate the Safety and Antiviral Activity of Remdesivir
(GS-5734™) in Participants With Severe Coronavirus Disease (COVID-19) [accessed 30 March
2020].
42. ClinicalTrails.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2020 March
15 - . Identifier NCT04292730. Study to Evaluate the Safety and Antiviral Activity of
Remdesivir (GS-5734™) in Participants With Moderate Coronavirus Disease (COVID-19)
Compared to Standard of Care Treatment [accessed 30 March 2020].
43. ClinicalTrails.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2020 February
21 - . Identifier NCT04280705. Adaptive COVID-19 Treatment Trial (ACTT) [accessed 30 March
2020].

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Accepted Article
Figure Legends

FIG. 1. Study flow diagram.

FIG. 2. Forest plot comparison of demographic data among patients with severe/critical illness
versus mild COVID-19 infection.

FIG. 3. Forest plot comparison of liver chemistries among patients with severe/critical illness versus
mild COVID-19 infection.

FIG. 4. Forest plot comparison of mortality reported among patients with severe/critical illness
versus mild COVID-19 infection.

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Accepted Article
Records identified Additional records
through database identified through other
searching sources

(N-438) (N=17)

Total number of records

assessed Duplicates removed

(N=455) (N=3)

Records screened by title Records excluded after

and abstracts
screening title and abstract
(N=452)
(N=420)

24 full text articles excluded

Full text articles assessed
for the following reasons:
for eligibility
• Out of scope: (N=15)
(N=32) • Lack of proper
controls: (N=4)
• Not a clinical trial:
(N=5)

Studies included in
qualitative synthesis Studies that did not include
enough raw data to perform
(N=8) quantitative meta-analysis

(N=2)

Studies included in
quantitative synthesis

(N=6)

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 A B
Severe/Critical Illness Mild Cases Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M – H, Fixed, 95% Cl M – H, Fixed, 95% Cl
Severe/Critical Illness Mild Cases Odds Ratio Odds Ratio
2.6.6 Active smoker
Study or Subgroup Events Total Events Total Weight M – H, Random, 95% Cl M – H, Random, 95% Cl
Accepted Article
2.1.1 Female gender
Cao et al,. 2020
9
Huang et al., 2020
2
Peng et al., 2020
7
Wan et al., 2020
19
14
Wang et al., 2020
Subtotal (95% Cl)
9
2
7
19
14
21
13
16
40
36
126
59
9
52
43
49
107
28
96
95
102
428
19.2%
5.9%
15.1%
31.2%
28.6%
100.0%
0.61 [0.24, 1.57]
0.38 [0.07, 2.11]
0.66 [0.23, 1.91]
1.09 [0.52, 2.29]
0.69 [0.32, 1.49]
0.75 [0.49, 1.13]
Huang et al., 2020
Wan et al., 2020
Subtotal (95% Cl)
Total events
0
1

1
13
40
53

Heterogeneity: Chi2 = 0.00, df = 1 (P = 0.99); I2 = 0%

Test for overall effect: Z = 1.45 (P = 0.99)
3
8

11
28
95
32.2%
67.8%
123 100.0%
0.27 [0.01, 5.62]
0.28 [0.03, 2.31]
0.28 [0.05, 1.56]

Total events 51 212 0.01 0.1 1 10 100

Heterogeneity: Tau2 = 0.00; Chi2 = 1.88, df = 4 (P = 0.76); I2 = 0% Favors [mild] Favors [severe/critical]

Severe/Critical Illness Mild Cases Odds Ratio Odds Ratio

Study or Subgroup Events Total Events Total Weight M – H, Fixed, 95% Cl M – H, Fixed, 95% Cl
0.05 0.2 1 5 20 2.7.7 Chronic obstructive pulmonary disease
Favors [mild] Favors [severe/critical] Huang et al., 2020 1 13 0 28 28.1% 6.84 [0.26, 179.78]
Wan et al., 2020 4 40 0 95 25.7% 23.55 [1.24, 448.35]
Severe/Critical Illness Mild Cases Odds Ratio Odds Ratio
Wang et al., 2020 3 36 1 102 46.2% 9.18 [0.92, 91.31]
Study or Subgroup Events Total Events Total Weight M – H, Random, 95% Cl M – H, Random, 95% Cl Subtotal (95% Cl) 89 225 100.0% 12.22 [2.57, 58.09]
2.2.2 Hypertension
Total events 8 1
Huang et al., 2020 2 13 4 28 20.5% 1.09 [0.17, 6.88]
Heterogeneity: Chi2 = 0.37, df = 2 (P = 0.83); I2 = 0%
Peng et al., 2020 10 16 82 96 25.9% 0.28 [0.09, 0.91]
Test for overall effect: Z = 3.15 (P = 0.002)
Wan et al., 2020 4 40 9 95 25.3% 1.06 [0.31, 3.67]
Wang et al., 2020 21 36 22 102 28.4% 5.09 [2.26, 11.48]
Subtotal (95% Cl) 105 321 100.0% 1.18 [0.29, 4.90] 0.01 0.1 1 10 100
Total events 37 117 Favors [mild] Favors [severe/critical]
Heterogeneity: Tau2 = 1.68; Chi2 = 16.87, df = 3 (P = 0.0008); I2 = 82% Severe/Critical Illness Mild Cases Odds Ratio Odds Ratio
Test for overall effect: Z = 0.23 (P = 0.82) Study or Subgroup Events Total Events Total Weight M – H, Fixed, 95% Cl M – H, Fixed, 95% Cl
2.8.8 Chronic liver disease
0.02 0.1 1 10 50 Huang et al., 2020 0 13 1 28 24.4% 0.68 [0.03, 17.80]
Favors [mild] Favors [severe/critical] Wan et al., 2020 1 40 1 95 14.9% 2.41 [0.15, 39.51]
Wang et al., 2020 0 36 4 102 60.7% 0.30 [0.02, 5.71]
Severe/Critical Illness Mild Cases Odds Ratio Odds Ratio Subtotal (95% Cl) 89 225 100.0% 0.71 [0.14, 3.50]
Study or Subgroup Events Total Events Total Weight M – H, Random, 95% Cl M – H, Random, 95% Cl Total events 1 6
2.3.3 Diabetes mellitus 2 2
Heterogeneity: Chi = 1.06, df = 2 (P = 0.59); I = 0%
Huang et al., 2020 1 13 7 28 17.5% 0.25 [0.03, 2.28] Test for overall effect: Z = 0.42 (P = 0.67)
Peng et al., 2020 4 16 19 96 27.6% 1.35 [0.39, 4.66]
Wan et al., 2020 9 40 3 95 26.1% 8.90 [2.27, 34.99]
Wang et al., 2020 8 36 6 102 28.8% 4.57 [1.46, 14.28] 0.01 0.1 1 10 100
Subtotal (95% Cl) 105 321 100.0% 2.34 [0.66, 8.26] Favors [mild] Favors [severe/critical]
Total events 22 35 Severe/Critical Illness Mild Cases Odds Ratio Odds Ratio
Heterogeneity: Tau2 = 1.10; Chi2 = 9.50, df = 3 (P = 0.02); I2 = 68% Study or Subgroup Events Total Events Total Weight M – H, Fixed, 95% Cl M – H, Fixed, 95% Cl
Test for overall effect: Z = 1.32 (P = 0.19) 2.9.9 Chronic kidney disease
Wang et al., 2020 2 36 2 102 100.0% 2.94 [0.40, 21.69]
Subtotal (95% Cl) 36 102 100.0% 2.94 [0.40, 21.69]
0.05 0.2 1 5 20 2 2
Favors [mild] Favors [severe/critical] Total events
Heterogeneity: Not applicable
Severe/Critical Illness Mild Cases Odds Ratio Odds Ratio Test for overall effect: Z = 1.06 (P = 0.29)
Study or Subgroup Events Total Events Total Weight M – H, Random, 95% Cl M – H, Random, 95% Cl
2.4.4 Coronary artery disease 0.01 0.1 1 10 100
Huang et al., 2020 3 13 3 28 12.4% 2.50 [0.43, 14.54] Favors [mild] Favors [severe/critical]
Peng et al., 2020 10 16 52 96 47.0% 1.41 [0.47, 4.19] Severe/Critical Illness Mild Cases Odds Ratio Odds Ratio
Wan et al., 2020 6 40 1 95 4.3% 16.59 [1.93, 142.84] Study or Subgroup Events Total Events Total Weight M – H, Fixed, 95% Cl M – H, Fixed, 95% Cl
Wang et al., 2020 9 36 11 102 36.3% 2.76 [1.03, 7.35] 2.10.10 Malignancy
Subtotal (95% Cl) 105 321 100.0% 2.68 [1.43, 5.01]
Huang et al., 2020 0 13 1 28 25.3% 0.68 [0.03, 17.80]
Total events 28 67 Wang et al., 2020 4 36 6 102 74.7% 2.00 [0.53, 7.54]
Heterogeneity: Chi2 = 4.10, df = 3 (P = 0.25); I2 = 27% Subtotal (95% Cl) 49 130 100.0% 1.67 [0.49, 5.61]
Test for overall effect: Z = 3.09 (P = 0.002) 4 7
Total events
Heterogeneity: Chi2 = 0.36, df = 1 (P = 0.55); I2 = 0%
0.02 0.1 1 10 50 Test for overall effect: Z = 0.82 (P = 0.41)
Favors [mild] Favors [severe/critical]
0.01 0.1 1 10 100
Severe/Critical Illness Mild Cases Odds Ratio Odds Ratio Favors [mild] Favors [severe/critical]
Study or Subgroup Events Total Events Total Weight M – H, Random, 95% Cl M – H, Random, 95% Cl
2.5.5 Cerebrovascular disease Severe/Critical Illness Mild Cases Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M – H, Fixed, 95% Cl M – H, Fixed, 95% Cl
Wang et al., 2020 6 36 1 102 100.0% 20.20 [2.34,174.44] 2.11.11 ACEI / ARB treatment
Subtotal (95% Cl) 36 102 100.0% 20.20 [2.34,174.44]
Peng et al., 2020 3 16 19 96 100.0% 0.94 [0.24, 3.61]
Total events 6 1
Subtotal (95% Cl) 16 96 100.0% 0.94 [0.24, 3.61]
Heterogeneity: Not applicable
Total events 3 19
Test for overall effect: Z = 2.73 (P = 0.006)
Heterogeneity: Not applicable
Test for overall effect: Z = 0.10 (P = 0.92)
0.01 0.1 1 10 100
Favors [mild] Favors [severe/critical]
0.01 0.1 1 10 100
Favors [mild] Favors [severe/critical]

hep_31472_f2.eps

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 Severe/Critical Illness Mild Cases Mean Difference Mean Difference
Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% Cl IV, Random, 95% Cl
3.1.1 AST [U/L]
Accepted Article
Cao et al,. 2020
Huang et al., 2020
44.13
48.38
36.26
29.63
21 27.98 25.8 107 13.7% 16.15 [-0.11, 32.41]
13 32.75 12.22 28 13.3% 15.63 [-1.10, 32.36]
Liu et al., 2020 41.52 32.27 4 22.9 5.77 28 5.9% 18.62 [-13.08, 50.32]
Peng et al., 2020 29.86 10.37 16 32.29 15.93 96 23.3% -2.43 [-8.43, 3.57]
Wan et al., 2020 34.56 13.7 40 23.32 10.07 95 24.3% 11.24 [6.54, 15.94]
Wang et al., 2020 50.58 29.63 36 29.35 12.59 102 19.5% 21.23 [11.25, 31.21]
Subtotal (95% Cl) 130 456 100.0% 11.70 [2.97, 20.43]
Heterogeneity: Tau2 = 75.86; Chi2 = 22.24, df = 5 (P = 0.0005); I2 = 78%
Test for overall effect: Z = 2.63 (P = 0.009)

-20 -10 0 10 20
Favors [mild] Favors [severe/critical]
Severe/Critical Illness Mild Cases Mean Difference Mean Difference
Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% Cl IV, Random, 95% Cl
3.2.2 ALT [U/L]
Cao et al,. 2020 43.87 47.8 21 28.89 31.83 107 13.0% 14.98 [-6.34, 36.30]
Huang et al., 2020 65.79 63.7 13 29.01 15.19 28 7.2% 36.78 [1.70, 71.86]
Liu et al., 2020 55.98 20.76 4 25.96 15.51 28 13.1% 30.02 [8.88, 51.16]
Peng et al., 2020 25.35 12.96 16 35.72 24.81 96 22.1% -10.37 [-18.43, -2.31]
Wan et al., 2020 24.68 13.93 40 24.65 16.37 95 23.6% 0.03 [-5.40, 5.46]
Wang et al., 2020 37.13 28.15 36 24.78 15.56 102 21.0% 12.35 [2.67, 22.03]
Subtotal (95% Cl) 130 456 100.0% 8.84 [-2.28, 19.97]
Heterogeneity: Tau2 = 129.04; Chi2 = 25.85, df = 5 (P = 0.0005); I2 = 81%
Test for overall effect: Z = 1.56 (P = 0.12)

-20 -10 0 10 20
Favors [mild] Favors [severe/critical]

Severe/Critical Illness Mild Cases Mean Difference Mean Difference

Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% Cl IV, Random, 95% Cl
3.3.3 Total bilirubin [mg/dL]
Huang et al., 2020 1.18 0.9 13 0.63 0.13 28 2.5% 0.55 [0.06, 1.04]
Liu et al., 2020 1.09 0.59 4 0.94 0.41 28 1.7% 0.15 [-0.45, 0.75]
Peng et al., 2020 0.76 0.31 16 0.68 0.27 96 23.2% 0.08 [-0.08, 0.24]
Wan et al., 2020 0.65 0.33 40 0.55 0.36 95 38.5% 0.10 [-0.03, 0.23]
Wang et al., 2020 0.78 0.39 36 0.59 0.2 102 34.1% 0.19 [0.06, 0.32]
Subtotal (95% Cl) 109 349 100.0% 0.14 [0.06, 0.22]
Heterogeneity: Chi2 = 4.14, df = 4 (P = 0.39); I2 = 3%
Test for overall effect: Z = 3.48 (P = 0.0005)

-0.5 -0.25 0 0.25 0.5

Favors [mild] Favors [severe/critical]
Severe/Critical Illness Mild Cases Mean Difference Mean Difference
Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% Cl IV, Random, 95% Cl
3.4.4 Albumin [g/L]
Huang et al., 2020 2.84 0.34 13 3.37 0.47 28 27.2% -0.53 [-0.78, -0.28]
Liu et al., 2020 3.54 0.99 4 4.1 0.71 28 1.7% -0.56 [-1.57, 0.45]
Wan et al., 2020 3.58 0.41 40 4.32 0.46 95 71.0% -0.74 [-0.90, -0.58]
Subtotal (95% Cl) 57 151 100.0% -0.68 [-0.81, -0.55]
Heterogeneity: Chi2 = 1.96, df = 2 (P = 0.38); I2 = 0%
Test for overall effect: Z = 10.06 (P = 0.00001)

-1 -0.5 0 0.5 1
Favors [mild] Favors [severe/critical]

hep_31472_f3.eps

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 Severe/Critical Illness Mild Cases Odds Ratio Odds Ratio
Study or Subgroup
Accepted Article Events Total Events Total Weight M – H, Fixed, 95% Cl M – H, Fixed, 95% Cl
Huang et al., 2020 5 13 1 28 32.1% 16.88 [1.71, 166.21]
Peng et al., 2020 11 16 6 96 44.1% 33.00 [8.63, 126.26]
Wan et al., 2020 1 40 0 95 23.7% 7.25 [0.29, 181.90]

Total (95% Cl) 69 219 100.0% 21.70 [7.01, 67.24]

Total events 17 7
Heterogeneity: Chi2 = 0.87, df = 2 (P = 0.65); I2 = 0%
0.01 0.1 1 10 100
Test for overall effect: Z = 5.33 (P<0.00001) Favors [mild] Favors [severe/critical]

hep_31472_f4.eps

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