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Manuscript Number:

Title: COVID-19 Impact on Liver: Is Liver Overlooked in Rush?

Article Type: Review article

Keywords: Coronavirus; COVID-19; Liver Injury; Liver Disease; SARS-CoV-2;

Liver Failure

Corresponding Author: Professor Liang Tingbo, M.D., Ph.D, FACS

Corresponding Author's Institution: the First Affiliated Hospital,

Zhejiang University, Hangzhou, China

First Author: Dipesh Kumar Yadav, M.D., Ph.D.

Order of Authors: Dipesh Kumar Yadav, M.D., Ph.D.; Wei Zhang, M.D.,
Ph.D.; Akanand Singh, M.D., Ph.D.; Qi Zhang, M.D., Ph.D.; Vishnu
Adhikari, M.D., Ph.D.; Zhiwei Li, M.D., Ph.D.; Bai Xue Li, M.D., Ph.D.;
Tingbo Liang, M.D., Ph.D., FACS

Abstract: The ongoing coronavirus disease 2019 (COVID-19) pandemic

challenges doctors and healthcares from different fields to intensely
manage their patient without compromising outcomes and decrease patients
visit to hospital and admission. Since COVID-19 is a new disease, very
less is known about the disease, and guidance to treatment are often
being made on the basis of experiences or experts opinions. Now it is
known that COVID-19 is caused by a new Severe Acute Respiratory Syndrome
Coronavirus-2 (SARS-CoV-2) virus which elicit infection to the cells by
binding of the spike protein to angiotensin converting enzyme 2 (ACE2).
Apart from lungs, heart, esophagus, ileum, colon, kidney, and bladder,
high expression of ACE2 has also been identified in the liver; thus,
liver is a potential target to SARS-CoV-2 infection. However, the vast
number of recently published studies on COVID-19 has only highlighted the
disease severity and deaths on the basis of respiratory complications,
and might have overlooked the of involvement of the liver. Given the high
transmissibility rate of the SARS-Cov-2 virus and known to have cytokine
dysregulation by inducing immune-mediated systemic inflammation, patients
with underlying liver disease might be at a increased risk of severe
infection and death. Here we report different mechanisms based on the
scientific evidences that how COVID-19 patients are prone to have liver
injury. Additionally, we discuss risk of infection in patients with
underlying liver disease, and also puts some necessary questions that
have not been addressed by the recent studies concerning the effects of
COVID-19 on the liver.
Cover Letter

Cover Letter
2020/5/19
Editor-in-Chief
Journal of clinical virology
SUBJECT: SUBMISSION OF A MANUSCRIPT FOR EVALUATION
Dear Chief Editor,
I am enclosing herewith a manuscript entitled “COVID-19 Impact on Liver: Is
Liver Overlooked in Rush?” for publication in Journal of clinical virology.
With the submission of this manuscript I would like to undertake that the mentioned
manuscript has not been published, accepted or under editorial review for publication
elsewhere. We believe that this manuscript is appropriate for publication in Journal of
clinical virology as it has been prepared to meet its criteria. All authors have
contributed to, read and approved the final manuscript for submission and the authors
declare no competing interests.
Consequently, the positive point regarding this article is that it has been written on the
current ongoing pandemic COVID-19 and possible mechanisms of liver injury due to
SARS-CoV-2 infection, further this articles also put some important questions which
might be helpful for future researchers. Thus, we believe that this article has its
novelty for its audience.
Please address all correspondence to
Author:
Dipesh Kumar Yadav
MD, PhD
Department of Hepatobiliary Surgery & Liver Transplantation, the First Affiliated
Hospital, Zhejiang University, Hangzhou, China.

- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.

- Innovation Center for the Study of Pancreatic Diseases, Hangzhou, China.

Email: 2338507593@qq.com
Corresponding Author:

Prof. Tingbo Liang

MD, PhD
Department of Hepatobiliary Surgery & Liver Transplantation, the First Affiliated
Hospital, Zhejiang University, Hangzhou, China.

- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.

- Innovation Center for the Study of Pancreatic Diseases, Hangzhou, China.

Address: Hangzhou 310003, China. Phone and Fax: +86-571-87236688/ 87236884;

E-mail: liangtingbo@zju.edu.cn
Sincerely,

Dipesh Kumar Yadav

Conflicts of Interest Statements

Competing interests statement

Authors declare no competing interests.

*Title Page (including author details, affiliations and word count)

Title Page

Title: COVID-19 Impact on Liver: Is Liver Overlooked in Rush?

Authors Contribution

Dipesh Kumar Yadav1,2,3, Wei Zhang 1, Akanand Singh4, Qi Zhang1,2,3, Vishnu Prasad Adhikari1,

Zhiwei Li1, Bai Xue Li1,2,3, and Tingbo Liang 1,2,3

1
Department of Hepatobiliary Surgery & Liver Transplantation, the First Affiliated Hospital,

Zhejiang University, Hangzhou, China.

2
Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.

3
Innovation Center for the Study of Pancreatic Diseases, Hangzhou, China.

4
Department of Liver Transplantation, Hepatobiliary and Pancreatic Surgery Unit, Indraprastha,

Apollo Hospitals, Sarita Vihar, Delhi, 110076, India.

Correspondence to: Tingbo Liang, - Department of Hepatobiliary Surgery & Liver

Transplantation, the First Affiliated Hospital, Zhejiang University, Hangzhou, China.

- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.

- Innovation Center for the Study of Pancreatic Diseases, Hangzhou, China.

Address: Hangzhou 310003, China. Phone and Fax: +86-571-87236688/ 87236884; E-mail:

liangtingbo@zju.edu.cn

Authors :

Dipesh Kumar Yadav

Email: 2338507593@qq.com

Wei Zhang:

Email: zhangweigyz@163.com

Akanand Singh

Email: akanand@live.com

Qi Zhang:

Email: zhangqi86@gmail.com

Vishnu Prasad Adhikari:

Email: 377798388@qq.com

Zhiwei Li:

Email: zylzw@zju.edu.cn

Bai Xue Li:

Email: shirleybai@zju.edu.cn

Tingbo Liang :

Email: liangtingbo@zju.edu.cn

Word Counts: 2621 words

Number of Figure: 1

Number of Table 1
*Abstract

The ongoing coronavirus disease 2019 (COVID-19) pandemic challenges doctors and

healthcares from different fields to intensely manage their patient without compromising

outcomes and decrease patients visit to hospital and admission. Since COVID-19 is a new

disease, very less is known about the disease, and guidance to treatment are often being made on

the basis of experiences or experts opinions. Now it is known that COVID-19 is caused by a new

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus which elicit infection

to the cells by binding of the spike protein to angiotensin converting enzyme 2 (ACE2). Apart

from lungs, heart, esophagus, ileum, colon, kidney, and bladder, high expression of ACE2 has

also been identified in the liver; thus, liver is a potential target to SARS-CoV-2 infection.

However, the vast number of recently published studies on COVID-19 has only highlighted the

disease severity and deaths on the basis of respiratory complications, and might have overlooked

the of involvement of the liver. Given the high transmissibility rate of the SARS-Cov-2 virus and

known to have cytokine dysregulation by inducing immune-mediated systemic inflammation,

patients with underlying liver disease might be at a increased risk of severe infection and death.

Here we report different mechanisms based on the scientific evidences that how COVID-19

patients are prone to have liver injury. Additionally, we discuss risk of infection in patients with

underlying liver disease, and also puts some necessary questions that have not been addressed by

the recent studies concerning the effects of COVID-19 on the liver.

Highlights (for review)

Highlights

1. The ongoing coronavirus disease 2019 (COVID-19) pandemic challenges doctors

and healthcares from different fields.
2. COVID-19 is caused by a new Severe Acute Respiratory Syndrome Coronavirus-2
(SARS-CoV-2) virus which elicit infection to the cells by binding of the spike protein
to angiotensin converting enzyme 2 (ACE2).
3. SARS-Cov-2 virus has high transmissibility rate and can lead to cytokine
dysregulation by inducing immune-mediated systemic inflammation, patients with
underlying liver disease might be at a increased risk of severe infection and death.
4. SARS-CoV-2 can directly infext liver cells and can damage liver, as ACE2 is
abundantly expressed in the liver. Further, liver injury in COVID-19 patients can also
be as a result of DILI, cytokine storm, and organ crosstalks.
*Manuscript
Click here to view linked References

COVID-19 Impact on Liver: Is Liver Overlooked in Rush?

Dipesh Kumar Yadav1,2,3, Wei Zhang 1, Akanand Singh4, Qi Zhang1,2,3, Vishnu Prasad

Adhikari1, Zhiwei Li1, Bai Xue li1,2,3, and Tingbo Liang 1,2,3

1
Department of Hepatobiliary Surgery & Liver Transplantation, the First Affiliated Hospital,

Zhejiang University, Hangzhou, China.

2
Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.

3
Innovation Center for the Study of Pancreatic Diseases, Hangzhou, China.

4
Department of Liver Transplantation, Hepatobiliary and Pancreatic Surgery Unit,

Indraprastha, Apollo Hospitals, Sarita Vihar, Delhi, 110076, India.

Correspondence to: Tingbo Liang, - Department of Hepatobiliary Surgery & Liver

Transplantation, the First Affiliated Hospital, Zhejiang University, Hangzhou, China.

- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.

- Innovation Center for the Study of Pancreatic Diseases, Hangzhou, China.

Address: Hangzhou 310003, China. Phone and Fax: +86-571-87236688/ 87236884; E-mail:

liangtingbo@zju.edu.cn

Abstract

The ongoing coronavirus disease 2019 (COVID-19) pandemic challenges doctors and

healthcares from different fields to intensely manage their patient without compromising

outcomes and decrease patients visit to hospital and admission. Since COVID-19 is a new

disease, very less is known about the disease, and guidance to treatment are often being made

on the basis of experiences or experts opinions. Now it is known that COVID-19 is caused by
a new Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus which elicit

infection to the cells by binding of the spike protein to angiotensin converting enzyme 2

(ACE2). Apart from lungs, heart, esophagus, ileum, colon, kidney, testes, and bladder, high

expression of ACE2 has also been identified in the liver; thus, liver is a potential target to

SARS-CoV-2 infection. However, the vast number of recently published studies on COVID-

19 has only highlighted the disease severity and deaths on the basis of respiratory

complications, and might have overlooked the of involvement of the liver. Given the high

transmissibility rate of the SARS-Cov-2 virus and known to have cytokine dysregulation by

inducing immune-mediated systemic inflammation, patients with underlying liver disease

might be at a increased risk of severe infection and death. Here we report different

mechanisms based on the scientific evidences that how COVID-19 patients are prone to have

liver injury. Additionally, we discuss risk of infection in patients with underlying liver

disease, and also puts some necessary questions that have not been addressed by the recent

studies concerning the effects of COVID-19 on the liver.

Keywords: Coronavirus; COVID-19; Liver Injury; Liver Disease; SARS-CoV-2; Liver

Failure

1. Introduction

In December 2019, an outbreak of Coronavirus Disease 2019 (COVID-19) began in Wuhan,

China, possibly from Bat or Pangolin as an intermediate host.[1] Since then, it has now

emerged as a pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that

has claimed over 3.7 million cases and approximately 260,000 deaths (fatality rate

approximately 6.8%) as of 9th May 2020.[2] Soon after the outbreak, scientists were able to

share its genomic sequence and found that genome sequence of SARS-CoV-2 shows 82%
similarity to severe acute respiratory syndrome coronavirus (SARS-CoV) and 50% to that of

the middle East respiratory syndrome coronavirus (MERS-CoV).[3, 4] Both SARS-CoV and

MERS-CoV are profoundly pathogenic and infective to humans leading to global health

emergency in 2003 and 2012, respectively. [5, 6] Moreover, about 60% of patients with

SARS has been reported of having liver injury.[7] Despite of the fact that, SARS-CoV-2

share majority similarity in genome sequence with SARS-CoV, the large number of the

published studies on COVID-19 only features the disease severity and deaths on the basis of

respiratory complications, thus might has neglected the fact of involvement and effect of

COVID-19 to vital organs like liver and kidney. In addition, some patients with underlying

liver disease and liver transplantation might be at a increased risk of severe infection and

death. Therefore, understanding the impact caused by SARS-CoV-2 to the liver and the

underlying mechanisms is of the greatest importance, so that management of the patients with

liver disease can be done effectively within time; hence, reducing the morbidity and mortality.

The goal of this review is to present important evidences and correlations that why liver

should be given careful consideration during the treatment of COVID-19. Further, this review

has also arisen some necessary concerns that might be helpful for future researchers in terms

of the effects of COVID-19 on the liver.

2. Clinical Manifestations of COVID-19

COVID-19 is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which

mainly spread during close contact and by small droplets produced when those infected

persons cough, sneeze, or talk. Patients with COVID-19 shows with a wide range of clinical

manifestations, that is to say asymptomatic patients to septic shock and multiple organ

dysfunction syndrome (MODS).[8] According to the published reports, most of the patients

with COVID-19 presents with fever (99%), fatigue (70%), dry cough (59%), sputum
production (27%), and diarrhoea (2–10%).[9-11] Further, based on the severity of the

presentation patients with COVID-19 has been classified into mild, moderate, severe, and

critical cases.[10] The majority of COVID-19 cases (81%) are mild to moderate in severity

with symptoms like fever, fatigue, dry cough, and diarrhoea.[12] Additionally, patients with

severe disease (14%) presents with with severe pneumonia, acute respiratory distress

syndrome (ARDS), sepsis, or septic shock.[12] Furthermore, about 5% of patients are found

to develop a critical disease with respiratory failure, detectable serum SARS-CoV-2 viral

load (RNAaemia), acute cardiac injury, acute kidney injury, liver injury, shock, or MODS.[9,

12, 13] According to the Chinese Centers for Disease Control and Prevention (CDC) the

fatality rate is 49% in critical patients,[12] and high fatality rate is associated with prior

comorbidities like diabetes, respiratory disease, cardiovascular disease, hypertension, and

oncological complications. In contrast, the low fatality rate is seen in patients without

comorbidities i.e. 0.9% .[10]

3. COVID-19 and Angiotensin-Converting Enzyme 2 (ACE2)

From the different recent studies it is seen that both SARS-CoV and SARS-CoV-2 trigger

infection to the host cells by binding of the spike protein of the virus to the enzyme called

Angiotensin converting enzyme 2 (ACE2).[14, 15] ACE2 is a transmembrane protein

attached to the cell membranes of cells and are found to play important protective role in the

cardiovascular diseases, immune systems, and liver fibrosis.[16-19] In addition, it is most

copiously found in the type II alveolar cells of the lungs, heart, esophagus, ileum, colon,

kidney, testes, and bladder.[20, 21] Nonetheless, high expression of ACE2 has also been

identified in the liver and biliary epithelial cells.[22, 23] Thus, the expression and distribution

of the ACE2 in the liver and biliary epithelial cells put liver as a potential target to SARS-

CoV-2 infection, and this explains why different studies have frequently reported abnormal

liver functions as an extrapulmonary clinical feature in patients with COVID-19 (Table 1).[9,
13, 22, 24-39] In a study by Fan et al., the study found that more than 50% of COVID-19

patients presented with abnormal liver function at admission. Moreover, this study also

analysed liver function according to pre-hospital medication, where the study didn’t find any

significant difference between the groups, further suggesting that, liver injury in patients with

COVID-19 might be as a direct result from SARS-CoV-2 infection of liver cells.[22]

Additionally, this study further found that patient with abnormal liver function after the

admission prolonged the length of hospital stay.[22] The worsening liver function after the

admission might be as a result of the dynamic nature of COVID-19, where patients with mild

illness can speedily worsen into severe or critical cases. According to Xu et al., the liver

biopsy of COVID-19 patients revealed moderate microvesicular steatosis and mild lobular

and portal activity, suggesting that the injury was either the result of direct SARS-CoV-2

infection or due to the drug used during treatment.[40] Interestingly, in a study by Tian et al.,

RT-PCR of liver biopsy showed direct evidence of the viral sequence in the liver.[41]

However, its still not clear that, if SARS-CoV-2 infects the liver cells or cholangiocytes

directly and are able to shed infective particles of SARS-CoV-2? More mechanistic studies

are needed to address these questions.

4. Laboratory findings

Laboratory findings in COVID-19 according to most of the published studies include

prolonged prothrombin time and elevated D-dimer, creatine kinase, lactate dehydrogenase

(LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin

(TB), and C-reactive protein (CRP).[9, 13]

Early stages of the disease is characterised by a noticeable reduction in CD4 and CD8

counts.[9] Additionally, patients with COVID-19 also have high amounts of Interleukin 6

(IL-6), Interleukin 1 beta (IL-1β), interferon gamma (IFNγ), interferon gamma-induced

protein 10 (IP10), and monocyte chemotactic protein 1 (MCP1).[13, 42] Furthermore, those

patients requiring an ICU admission shows higher concentrations of granulocyte colony-

stimulating factor (GCSF), IP10, MCP1, macrophage inflammatory protein-1 alpha (MIP-

1α/CCL3), and tumor necrosis factor-α (TNFα) in compared to those not requiring an ICU

admission, suggesting that the disease severity is associated to cytokine storm, where patients

have coagulation activation, cellular immune deficiency, myocardial injury, kidney injury,

and liver injury.[9, 13, 43] Additionally, elevated D-dimer, ferritin, neutrophil counts, blood

urea, and creatinine levels are associated with severe cases and bad prognosis.[9, 13] Further,

elevated level of C-reactive protein shows the possibility of secondary infection.[44]

COVID-19 related liver injury should be characterized as any damage to liver developed

during disease progression or treatment with or without prior liver diseases. As discussed

earlier, over 50% of COVID-19 patients are found to present with abnormal liver function at

admission.[22] Overall, it is seen that there is primarily raised AST and ALT level, and

slightly raised bilirubin level in 14% to 53% cases.[9, 13, 22, 42, 43] Moreover, in a recent

study 54% of patients hospitalized for COVID-19 had elevated gamma-glutamyl transferase

(GGT), which was considered as a possibility of cholangiocyte injury.[45] Additionally, most

of the critical patients with severe infection are found to have low albumin.[42, 46] Apart

from the SARS-CoV-2 RNA detection the blood, SARS-CoV-2 RNA has also been detected

in the stool of COVID-19 patients and this should rise a concern about the transmission of

SARS-CoV-2 through faecal-oral route.[47, 48]

Liver Injury in COVID-19 patients

Liver injury in COVID-19 patients can be as a result of following mechanisms (Figure 1):

Liver injury due to the direct effect of viral replication in hepatic cells:
As discussed earlier in this review because ACE2 is richly expressed in the liver and biliary

epithelial cells; hence, SARS-CoV-2 can easily infect liver cells.[22, 23]. Based on the data,

patients taking drugs like ACE inhibitors and angiotensin II type I receptor blockers for

hypertension may have over expression of ACE2. Similarly, type 2 diabetes mellitus also

induces ACE2 expression in liver; therefore, these patients with upregulated ACE2

expression might be at a higher risk for developing COVID-19 and might have up to 10 times

greater risk of death with COVID-19.[49, 50] Besides, levels of ALT, AST, TB, LDH, and

INR are shown to be significantly higher in the patients with severe COVID-19.[24, 42] Thus,

these abnormal liver function might be as a result of direct effects of viral replication in

hepatic cells.[41]

Liver Injury due to Cytokine

Cytokine dysregulation apparently is crucial in the pathogenesis of COVID-19.[51]

Additionally, it has been seen that serious and critical COVID-19 patients commonly presents

with a cytokine release syndrome (CRS), also known as ‘cytokine storm’.[51-53] In severe

and critical COVID-19 patients, acute liver injury might have occurred due to CRS.

Additionally, hyperinflammatory condition resembling to that of secondary haemophagocytic

lymphohistiocytosis (sHLH) has been noticed in most of the COVID-19 patients admitted to

ICU, with dramatically elevated IL-6, D-dimer, ferritin, an elevated liver function, a low level

albumin, elevated C reactive protein, and neutrophil counts.[9, 13, 52, 54, 55] However,

before reaching to the diagnosis of sHLH, this needs to be verified with careful studies.

Extracorporeal membrane oxygenation (ECMO) and artificial liver support system (ALSS)

have also been proposed as an approach to remove cytokines in COVID-19 patients to

prevent CRS-induced organ damage.[44] Indeed, to mitigate the hyperinflammatory state a

multicentre, randomised controlled trial of tocilizumab (IL-6 receptor blockade) has been

approved for COVID-19 patients with elevated IL-6 in China.[52]

Lung-Liver Axis- Liver Injury due to Pneumonia-associated hypoxia

ARDS is seen as the hallmark of COVID-19. ARDS induced hypoxic hepatitis also known as

ischemic hepatitis or “Shock liver” due to anoxia and inadequate blood flow to the liver

might also contribute to the liver injury.[45] Additionally, ADRS also induces immune-

mediated inflammation and systemic inflammatory response, which may further cause acute

liver injury.[56] Yet, it is unclear that if there is any prognostic aspect of liver injury on the

prognosis of COVID-19 patients. This further requires critical consideration, which will have

clinical outcomes for effective management of COVID-19 patients.

Gut- Liver Axis- Liver Injury due to dysbiosis of Gut Microbiome

Perhaps, gastrointestinal manifestations are the most common non-respiratory symptom of

COVID-19, and about 50% of the COVID-19 patients are found to present with

gastrointestinal symptoms like diarrhea, vomiting, or abdominal pain.[57] Moreover, in a

study by Chen and colleagues viral RNA was isolated in about 67% of the stool samples they

tested in their study.[58] It is speculated that presence of gastrointestinal symptoms in

COVID-19 patients must be as the result of SARS-CoV-2 virus infecting the human gut

through ACE2 receptors present inside gastrointestinal cells.[20, 59] On the other hand,

intestinal symptoms in COVID-19 patients could also be as a result of gut-lung axis, as both

lung and gut are linked through mucosal system.[60] Regardless of different hypothesis

behind how gut is infected by SARS-CoV-2 virus, gastrointestinal symptoms in COVID-19

patients clearly indicates that there dysbiosis of gut microbiome in these patients.[61] In

recent years, there is growing evidence that dysbiosis of gut microbiome plays an important

role in the pathogenesis of liver injury and liver disease.[62-64] As discussed above in this

review, COVID-19 patients has high level of cytokines and inflammatory mediators, which

can lead to gut barrier dysfunction under stress and further leading to increased intestinal
permeability of gut microorganisms and pathogen-associated molecular patterns (PAMPs). In

addition, these gut microorganisms and pathogen-associated molecular patterns (PAMPs) can

influx directly into the portal circulation and triggering a pro-inflammatory cascade that may

cause liver injury or worsens hepatic function.[64]

Kidney-Liver Axis- Liver Injury due to AKI induced oxidative stress

According to published report incidence rate of acute kidney injury (AKI) was found to be

about 15% in COVID-19 patients.[65] Furthermore, AKI is more common is severe and

critical COVID-19 patients, and considered as a bad prognostic factor with respect to survival

of patient.[65, 66] Of note, AKI in COVID-19 patients may be due multiple factors related to

lung-kidney axis-in ARDS, like immune-mediated inflammation, systemic inflammatory

response, and CRS leading to hypoperfusion-related injury of the renal tubules.[67, 68]

Further, ACE2 is found to be highly expressed in renal tubule epithelial cells, essential for

SARS-CoV-2 infection to host cells.[69] Earlier studies has shown that AKI induce oxidative

stress and stimulate inflammation, apoptosis, and tissue injury in liver cells by a complex

amalgamation of soluble inflammatory mediators and cellular immunity.[70]

Drugs induced liver injury (DILI):

Most of the patients infected with SARS-CoV-2 were found to use antipyretic drugs like

paracetamol for fever, which can cause liver injury.[71] Moreover, antiviral drugs currently

used (Oseltamivir, Lopinavir/Ritonavir, Ribavirin, and Chloroquine Phosphate or Hydroxy

Chloroquine Sulfate) [9, 13, 44] to treat patients with COVID-19 metabolised in the liver,

and might induce hepatotoxicity, this was additionally confirmed by the pathological

findings.[40] From the published studies, patients with prior comorbidities like diabetes,

cardiovascular disease, and hypertension were more susceptible to develop severe COVID-

19.[10] Besides, patients with these comorbidities commonly develop metabolic syndrome,
which is a considerable risk factor non-alcoholic fatty liver disease (NAFLD).[72]

Furthermore, patients with NAFLD are more prone to acute liver injury due to hepatotoxic

drugs.[73, 74] Thus, it is recommended for careful consideration of drugs, alone with

frequent and careful monitoring of the liver functions in COVID-19 patients during the

course of treatment to reduce the risk of drugs induced hepatotoxicity.

Concerns about COVID-19 patients with underlying Liver Disease

COVID-19 patients with underlying liver diseases might to susceptible to develop acute on

chronic liver failure (ACLF) as a “second hit” due to immune-mediated inflammation and

systemic inflammatory response induced by SARS-CoV-2 infection. However, ACLF has not

been reported by any of the published studies on COVID-19 till the date. It is still unknown,

that how underlying liver disease such as chronic viral hepatitis, autoimmune hepatitis, non-

alcoholic fatty liver disease, and alcohol-related liver disease influence liver injury in patients

with COVID-19 should be carefully evaluated. For instance, patients with immune tolerant

chronic hepatitis B or under antiviral treatment are at a high risk to develop severe SARS-

CoV-2 infection. Additionally, COVID-19 treatment may predispose to flare up of chronic

hepatitis B due to immunosuppression. Then again, it is as yet obscure whether COVID-19

aggravate cholestasis in the patients with underlying cholestatic liver diseases, given that

SARS-CoV-2 trigger infection via ACE2, and ACE2 is abundantly expressed in

cholangiocytes, also needs to be explored.[23] Further, the prognosis and the effects of

glucocorticoids administration in the patients with autoimmune hepatitis and with SARS-

CoV-2 infection is still unclear. Moreover, patients with the liver cirrhosis or liver cancer are

usually in immunocompromised state; thus, these patients are more susceptible to develop

severe SARS-CoV-2 infection. Further, as most of the patients with severe COVID-19 are

found to have an elevated level of D-dimer,[9, 13] in some earlier studies it has been seen

that an elevated D-dimer levels was associated with an increased risk of 28-day mortality in a
patients with decompensated cirrhosis.[75, 76] Thus, special consideration should be given

for COVID-19 patients with underlying disease throughout the time of treatment and in-depth

studies are needed to address the above concerns.

Conclusion

SARS-CoV-2 cause infection by means of ACE2, and ACE2 is abundantly expressed in the

liver, while also may cause damage to the liver, although there is no published studies yet to

prove it. Further, liver injury in COVID-19 patients can also be as a result of DILI, cytokine

storm, and organ crosstalks. In addition, patients with a chronic liver diseases and SARS-

CoV-2 infection might have poor prognosis. Therefore, special attention should be given to

the liver protection during treatment for COVID-19. Additionally, multi-center clinical

studies should be carried out to evaluate the impact of COVID-19 on the liver.

Competing interests statement

Authors declare no competing interests.

Acknowledgements

This work was supported by grants from - 973 program (No. 2014CB542101), The National

Natural Science Foundation of China (No.81472212), Key Program of Medical Scientific

Research Foundation of Zhejiang Province, China (No.WKJ-ZJ-1410), Key Program of

Administration of Traditional Chinese Medicine of Zhejiang Province, China (No.2014ZZ00),

Zhejiang Provincial Program for the Cultivation of High-level Innovative Health talents.
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Figures and Table

Figure 1: SARS-CoV-2 infection and probable mechanisms of liver injury.

Table 1: Liver test abnormalities from different COVID-19 studies.

Figure 1: SARS-CoV-2 infection and probable mechanisms of liver injury.
Table 1: Liver test abnormalities from different COVID-19 studies.

Study Patient AST ALT TB Protrombin LDH Comments

s (N) (U/L) (U/L) (μmol/L e time (s) (U/L)
)

Wang 138 31 (24- 24 (16- 9.8 (8.4- 13 (12.3- 261 Patients

D et 51) 40) 14.1) 13.7) (182- admitted to
al.[9] 403) ICU had
higher
serum AST,
ALT, TB,
and LDH
level than
those not
admitted to
ICU.

Huan 41 34 (26- 32 (21- 11·7 11.1 (10.1- 286 Patients

g et 48) 50) (9·5– 12.4) (242– admitted to
al. 13·9) 408) ICU had
[13] higher
serum AST,
ALT, TB,
PT, and
LDH level
than those
not admitted
to ICU.
Guan 1099 - - - - - Serum AST,
et al. ALT, TB,
[24] and LDH
level were
raised in
more
number of
patients in
severe
group than
that of non-
severe
group.

Xu et 62 26 (20- 22 (14- - - 205 Serum

al. 32) 34) (184- levels of
[28] 260.5) AST and
LDH was
elevated in
10 (16%)
 and 17
(27%)
patients
respective.
Shi et 81 40.8±17. 46.2±29. 11.9±3.6 10.7±0.9 - No
al. 9 5 differences
[29] in serum
AST, ALT,
PT, and TB
level were
observed
between the
groups,
when the
patients
were
stratified
based on the
time interval
between
onset of
symptoms
and the CT
scan.
Mo et 155 32 (24- 23 (16- 277 Compared
al. 48) 38) (195- with general
[33] 404) patients,
refractory
patients had
a higher
level of
AST and
LDH.

Wang 69 28 (22- 25 (17- - - 224(183 Patients

Z et 42) 40) -291) with severe
al. disease had
[34] higher
serum AST ,
ALT, and
LDH level
than those
with non-
severe
disease.

Wu C 201 33 (26- 31 11.4 11.1 (10.2- 307.5 Serum AST,

et al. 45) (19.75- (9.0- 11.9) (232.2- ALT, TB,
[36] 47) 14.7) 389.2) and LDH
level were
raised more
in ARDS
patients that
that of non-
ARDS
patients.
Additionally
, ARDS
patients had
prolonged
PT
compared to
that of non-
ARDS
patients.
Wan 135 34.4 26 (12.9- 8.6 (5.9- 10.9 (10.5- 320.5 Severe case
et al. (27.8- 33.1) 13.7) 11.4) (248.5 patients had
[37] 43.7) ‐ higher
385.3) serum AST,
ALT, TB,
and LDH
level than
those mild
case
patients.
Additionally
, severe case
patients had
prolonged
PT
compared to
that of mild
case
patients.
Arent 21 273 (14- 108 (11- 10.2 Lab value
z et 4432) 1414) (3.4- for patients
al. 18.8) admitted to
[38] ICU.

Zhou 191 - 30 (17– - 11·6 (10·6– 300 Serum

et 46) 13) (234– levels of
al.[39 407) ALT and
] LDH was
elevated in
48% and
98% in non-
survivor
group
compared to
that of 24%
and 54% of
survivor
group
patients,
respectively.
Additionally
13% of
patients in
non-
survivor
group had
prolonged
PT
compared to
that of 3%
of survivor
group
patients.

Abbreviations: AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; PT:

Protrombine time; LHD: Lactate dehydrogenase; ICU: Intensive care unit.
Table

Table 1: Liver test abnormalities from different COVID-19 studies.

Stud Patien AST ALT TB Protrombi LDH (U/L) Comments

y ts (N) (U/L) (U/L) (μmol/L ne time (s)
)

Wan 138 31 24 9.8 13 261 Patients

g D (24-51) (16-40) (8.4-14.1 (12.3-13.7) (182-403) admitted to
et ) ICU had
al.[9] higher
serum
AST, ALT,
TB, and
LDH level
than those
not
admitted to
ICU.

Huan 41 34 32 11·7 11.1 286 Patients

g et (26-48) (21-50) (9·5–13· (10.1-12.4) (242–408) admitted to
al. 9) ICU had
[13] higher
serum
AST, ALT,
TB, PT,
and LDH
level than
those not
admitted to
ICU.
Guan 1099 - - - - - Serum
et al. AST, ALT,
[24] TB, and
LDH level
were raised
in more
number of
patients in
severe
group than
that of
non-severe
group.

Xu et 62 26 22 - - 205 Serum
al. (20-32) (14-34) (184-260.5) levels of
[28] AST and
LDH was
 elevated in
10 (16%)
and 17
(27%)
patients
respective.
Shi et 81 40.8±17. 46.2±29. 11.9±3.6 10.7±0.9 - No
al. 9 5 differences
[29] in serum
AST, ALT,
PT, and TB
level were
observed
between
the groups,
when the
patients
were
stratified
based on
the time
interval
between
onset of
symptoms
and the CT
scan.
Mo et 155 32 23 277 Compared
al. (24-48) (16-38) (195-404) with
[33] general
patients,
refractory
patients
had a
higher
level of
AST and
LDH.

Wan 69 28 25 (17-40 - - 224(183-29 Patients

g Z et (22-42) ) 1) with severe
al. disease had
[34] higher
serum
AST ,
ALT, and
LDH level
than those
 with
non-severe
disease.

Wu C 201 33 31 11.4 11.1 307.5 Serum

et al. (26-45) (19.75-47 (9.0-14.7 (10.2-11.9) (232.2-389. AST, ALT,
[36] ) ) 2) TB, and
LDH level
were raised
more in
ARDS
patients
that that of
non-ARDS
patients.
Additionall
y, ARDS
patients
had
prolonged
PT
compared
to that of
non-ARDS
patients.
Wan 135 34.4 26 8.6 10.9 320.5 Severe
et al. (27.8-43. (12.9-33. (5.9-13.7 (10.5-11.4) (248.5‐ case
[37] 7) 1) ) 385.3) patients
had higher
serum
AST, ALT,
TB, and
LDH level
than those
mild case
patients.
Additionall
y, severe
case
patients
had
prolonged
PT
compared
to that of
 mild case
patients.
Arent 21 273 108 10.2 Lab value
z et (14-4432 (11-1414 (3.4-18.8 for patients
al. ) ) ) admitted to
[38] ICU.

Zhou 191 - 30 - 11·6 300 Serum

et (17–46) (10·6–13) (234–407) levels of
al.[39 ALT and
] LDH was
elevated in
48% and
98% in
non-surviv
or group
compared
to that of
24% and
54% of
survivor
group
patients,
respectivel
y.
Additionall
y 13% of
patients in
non-surviv
or group
had
prolonged
PT
compared
to that of
3% of
survivor
group
patients.

Abbreviations: AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; PT:

Protrombine time; LHD: Lactate dehydrogenase; ICU: Intensive care unit.
Figure
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