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Hepatic consequences of COVID-19 infection. Lapping or biting?

  • Piero Portincasa
    Correspondence
    Corresponding author: Piero Portincasa, MD, PhD, dr H. Causa, Chief, Clinica Medica “A. Murri”, Dept. of Biomedical Sciences & Human Oncology, University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11 - 70124 Bari – Italy. Tel.+39-080-5478892/234
    Affiliations
    Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, Bari 70124, Italy
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  • Marcin Krawczyk
    Affiliations
    Department of Medicine II Saarland University Medical Center, Saarland University, Homburg, Germany

    Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
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  • Antonia Machill
    Affiliations
    Department of Medicine II Saarland University Medical Center, Saarland University, Homburg, Germany
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  • Frank Lammert
    Affiliations
    Department of Medicine II Saarland University Medical Center, Saarland University, Homburg, Germany
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  • Agostino Di Ciaula
    Affiliations
    Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, Bari 70124, Italy
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      Abstract

      The outbreak of coronavirus disease 2019 (COVID-19) starting last December in China placed emphasis on liver involvement during infection. This review discusses the underlying mechanisms linking COVID-19 to liver dysfunction, according to recent available information, while waiting further studies. The manifestations of liver damage are usually mild (moderately elevated serum aspartate aminotransferase activities), and generally asymptomatic. Few patients can still develop severe liver problems, and therapeutic options can be limited. Liver dysfunction may affect about one-third of the patients, with prevalence greater in men than women, and in elderly. Mechanisms of damage are complex and include direct cholangiocyte damage and other coexisting conditions such as the use of antiviral drugs, systemic inflammatory response, respiratory distress syndrome-induced hypoxia, sepsis, and multiple organ dysfunction. During new COVID-19 infections, liver injury may be observed. If liver involvement appears during COVID-19 infection, however, attention is required. This is particularly true if patients are older or have a pre-existing history of liver diseases. During COVID-19 infection, the onset of liver damage impairs the prognosis, and hospital stay is longer.

      Keywords

      1. Introduction

      A novel coronavirus was reported to World Health Organization on Dec 30, 2019, as the cause of a cluster of pneumonia cases in China, city of Wuhan, Hubei Province. The first name of 2019-nCoV(human) was adopted on Jan 7, 2020, lately changed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 infection became an outbreak throughout China on Feb 11, 2020 and subsequently was identified as a global pandemic on March 11, 2020, spreading to more than 120 countries, as a major threat to public health [
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      European Centre for Disease Prevention and Control.
      ]. The COVID-19 pandemic suddenly represented an enormous burden of care [
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      ], and raised issues related to medical ethics [
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      ], since specific therapies and/or vaccines are missing, to date. COVID-19 may manifest in different ways. Many subjects may remain asymptomatic [
      • Albano D
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      ], but the exact number is still unknown. Specific settings might facilitate the spread of infection e.g., in skilled nursing facility where more than half of residents with positive test results were asymptomatic at the time of testing and most likely contributed to transmission [
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      ]. The proposed 3-stage classification system of potential increasing severity for COVID-19 infection encompasses stage I (early infection), stage II (pulmonary phase), and stage III (hyperinflammation phase) [
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      ]. Although the most frequent and critical clinical presentation is secondary to the involvement of the lung (fever, cough), the infection by SARS-CoV-2 virus may lead to a systemic and multi-organ disease [
      • Wang D
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      ], also involving the gastrointestinal tract (nausea/vomiting, or diarrhea) [
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      ,
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      ]. The liver appears to be the second organ involved, after the lung [
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      The present paper explores the available evidences on liver involvement in patients with COVID-19 infection, to provide a comprehensive understanding of the phenomenon, and to anticipate effective follow-up.

      2. Symptoms

      During COVID-19 infection, patients can be asymptomatic or present clinical symptoms ranging from fever, dry cough, headache to dyspnea and fatigue, to acute respiratory distress syndrome (ARDS), shock, and cardiac failure [
      • Siddiqi HK
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      ]. A nasopharyngeal swab is the collection method used to obtain a specimen for testing. Because the likelihood of the SARS-CoV-2 being present in the nasopharynx increases over time, repeated testing is often used [
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      ]. Multi-organ involvement secondary to COVID-19 infection occurs in a subgroup of patients [
      • Wang D
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      ]. COVID-19 infection can be associated with myocardial injury [
      • Zheng YY
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      COVID-19 and the cardiovascular system.
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      ,
      • Bonow RO
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      ], heart failure [
      • Zheng YY
      • Ma YT
      • Zhang JY
      • Xie X
      COVID-19 and the cardiovascular system.
      ], vascular inflammation, myocarditis, cardiac arrhythmias [
      • Madjid M
      • Safavi-Naeini P
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      Potential Effects of Coronaviruses on the Cardiovascular System: A Review.
      ], and hypoxic encephalopathy [
      • Chen T
      • Wu D
      • Chen H
      • Yan W
      • Yang D
      • Chen G
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      Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.
      ]. The progression and prognosis of COVID-19 infection is worse in the presence of diabetes mellitus [

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      ,

      Guo W, Li M, Dong Y, Zhou H, Zhang Z, Tian C, et al.Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes Metab Res Rev2020:e3319.

      ]. The case-fatality rate increases with age (from 8% to 15% in the age range 70-79 years, and ≥80 years, respectively) and with associated diseases, i.e., 11%. 7%, 6%, 6%, and 6% in patients with cardiovascular disease, diabetes mellitus, chronic respiratory disease, hypertension, and cancer, respectively [
      • Novel Coronavirus Pneumonia Emergency Response Epidemiology T
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      ].
      During COVID-19 infection, gastrointestinal manifestations may appear, as reported from China [
      • Gu J
      • Han B
      • Wang J
      COVID-19: Gastrointestinal Manifestations and Potential Fecal-Oral Transmission.
      ,
      • Gao QY
      • Chen YX
      • Fang JY
      Novel coronavirus infection and gastrointestinal tract.
      ] and among U.S. patient population [
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      Prevalence and Characteristics of Gastrointestinal Symptoms in Patients with SARS-CoV-2 Infection in the United States: A Multicenter Cohort Study.
      ]. The appearance of gastrointestinal symptoms could even represent the chief complaints [
      • Wang D
      • Hu B
      • Hu C
      • Zhu F
      • Liu X
      • Zhang J
      • et al.
      Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
      ,
      • Jin X
      • Lian JS
      • Hu JH
      • Gao J
      • Zheng L
      • Zhang YM
      • et al.
      Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms.
      ]. The overall prevalence of GI symptoms was 18% (diarrhea 13%, nausea, vomiting 10%, and abdominal pain 8%) in Hong Kong [
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      ], and 11.4% in another study in Zhejiang province [
      • Jin X
      • Lian JS
      • Hu JH
      • Gao J
      • Zheng L
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      Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms.
      ]. Gastrointestinal involvement could be the consequence of COVID-19- Angiotensin-Converting Enzyme 2 (ACE2) receptors at the enterocyte level (i.e. glandular cells of gastric, duodenal and distal enterocytes), resulting in malabsorption, unbalanced intestinal secretion and activated enteric nervous system, therefore diarrhoea) [
      • Zhang H
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      The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes.
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      Diarrhoea may be underestimated: a missing link in 2019 novel coronavirus.
      ]. In human small intestinal organoids, SARS-CoV-2 rapidly infects the enterocytes and strongly induces a generic viral response program, pointing to a marked viral replication in the intestinal epithelium [
      • Lamers MM
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      ] .
      Notably, continuous viral RNA shedding occurs into feces up to 11 days negativity of respiratory samples [
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      • Hong Z
      • Zhou J
      • Dong X
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      Prolonged presence of SARS-CoV-2 viral RNA in faecal samples.
      ]. It is difficult to establish if the virus is viable using nucleic acid detection [
      • Wu Y
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      • Hong Z
      • Zhou J
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      • et al.
      Prolonged presence of SARS-CoV-2 viral RNA in faecal samples.
      ,
      • Li Y
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      • et al.
      Positive result of Sars-Cov-2 in faeces and sputum from discharged patient with COVID-19 in Yiwu.
      ]. Further research is required by using fresh stool samples at later time points in patients with extended duration of faecal sample positivity to the possibility of fecal-oral route transmission [
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      Prolonged presence of SARS-CoV-2 viral RNA in faecal samples.
      ]. A study reported that the virus can be detected but not cultivated from stool (despite high RNA concentration), consistent with the lack of transmission [
      • Wolfel R
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      • et al.
      Virological assessment of hospitalized patients with COVID-2019.
      ]. In a case-control study from USA (enrolling 278 COVID-19 positive patients and 238 COVID-19 negative patients), the presence of gastrointestinal symptoms was predictive of COVID-19 positivity, and symptoms were associated with slower and less severe disease course [
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      ].

      3. General mechanisms of damage

      Most important pathogenic mechanisms act at local and systemic levels, and play a critical role in the evolution of the disease. Steps include: (i) Inoculation and multiplication in the human body, when the virus binds to ACE2 receptors [
      • Zou X
      • Chen K
      • Zou J
      • Han P
      • Hao J
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      Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection.
      ,
      • Qi F
      • Qian S
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      Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses.
      ,
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      • Sui J
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      Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.
      ] to enter the target cell [
      • Hoffmann M
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      • Mueller MA
      • Drosten C
      • Pöhlmann S
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      ]. Receptors are well expressed in epithelia of the lung, gastrointestinal tract, and vascular endothelium, also in the liver [
      • Hamming I
      • Timens W
      • Bulthuis ML
      • Lely AT
      • Navis G
      • van Goor H
      Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus.
      ]. This early period of COVID-19 infection can evolve to the second stage of viral pneumonia.; (ii) Extra-pulmonary systemic hyperinflammation syndrome occurs in the minority of infected patients, and is characterized by the so-called “cytokine storm”. At this moment, several cytokine levels increase, namely interleukin (IL)-2, IL-6, IL-7, IL-10, and tumor necrosis factor (TNF)α. Additional inflammatory biomarkers include granulocyte-colony stimulating factor, interferon (IFN)-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, lymphopenia (in CD4+ and CD8+ T cells), decreased IFNγ expression in CD4+ T cells [
      • Pedersen SF
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      ,
      • Mehta P
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      COVID-19: consider cytokine storm syndromes and immunosuppression.
      ,
      • Huang C
      • Wang Y
      • Li X
      • Ren L
      • Zhao J
      • Hu Y
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      Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
      ], and monocyte chemoattractant protein-1 (MCP-1) [
      • Huang C
      • Wang Y
      • Li X
      • Ren L
      • Zhao J
      • Hu Y
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
      ]. Increased serum levels of D-dimer, troponin and N-terminal pro B-type natriuretic peptide (NT-proBNP) can also occur, together with altered coagulation function [
      • Han H
      • Yang L
      • Liu R
      • Liu F
      • Wu KL
      • Li J
      • et al.
      Prominent changes in blood coagulation of patients with SARS-CoV-2 infection.
      ,
      • Tang N
      • Li D
      • Wang X
      • Sun Z
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      ,
      • Lillicrap D.
      Disseminated intravascular coagulation in patients with 2019-nCoV pneumonia.
      ]. An extensive meta-analysis included 21 studies describing 3,377 patients, and 33 laboratory parameters, with respect to severe and non-severe COVID-19 infection and (in another 3 studies totaling 393 patients) survivors and non-survivors of the disease. Patients with severe and fatal disease had significantly increased white blood cell count, and decreased lymphocyte and platelet counts compared to non-severe disease and survivors. Biomarkers of inflammation, muscle and cardiac injury, as well as liver and kidney function and coagulation measures also increased in patients with both severe and fatal COVID-19. Severe disease was characterized by elevated levels of interleukins 6 (IL-6) and 10 (IL-10) and serum ferritin [
      • Henry BM
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      • Benoit S
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      ].

      4. Liver involvement

      ACE2 receptors in the liver are expressed mainly in cholangiocytes (60% of cells), minimally expressed in hepatocytes (3% of cells), and absent in Kuppfer cells [
      • Qi F
      • Qian S
      • Zhang S
      • Zhang Z
      Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses.
      ,
      • Hamming I
      • Timens W
      • Bulthuis ML
      • Lely AT
      • Navis G
      • van Goor H
      Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus.
      ,
      • Uhlen M
      • Fagerberg L
      • Hallstrom BM
      • Lindskog C
      • Oksvold P
      • Mardinoglu A
      • et al.
      Proteomics. Tissue-based map of the human proteome.
      ]. The presence of these receptors, together with the local effects of systemic inflammation and possible iatrogenic toxicity seem to be the main mechanisms involved in the onset of liver damage in COVID-19 patients.
      Involvement of the liver with elevated serum alanine aminotransferase (AST), aspartate aminotransferase (ALT), and lactate dehydrogenase (LDH) activities has been firstly reported this year in 43% of the 99 COVID-19 cases from Wuhan [
      • Chen N
      • Zhou M
      • Dong X
      • Qu J
      • Gong F
      • Han Y
      • et al.
      Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
      ]. This aspect deserves further attention.
      Although the level of serum transaminases could be already elevated before the onset of COVID-19, results from clinical reports and autopsy studies [
      • Jin X
      • Lian JS
      • Hu JH
      • Gao J
      • Zheng L
      • Zhang YM
      • et al.
      Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms.
      ,
      • Guan WJ
      • Ni ZY
      • Hu Y
      • Liang WH
      • Ou CQ
      • He JX
      • et al.
      Clinical Characteristics of Coronavirus Disease 2019 in China.
      ,
      • Liu Q
      • Wang RS
      • Qu GQ
      • Wang YY
      • Liu P
      • Zhu YZ
      • et al.
      Gross examination report of a COVID-19 death autopsy.
      ] suggest that liver dysfunction can be an expression of a worse disease evolution, and that an isolated elevation of transaminases alone is likely to be the indirect expression of a systemic inflammation.
      Previous data from COVID-19 outbreak in China found that 2-11% of patients had liver comorbidities, 14-53% of patients presented with abnormal serum aminotransferases levels during the disease, and that the rates of liver dysfunction were more present in subjects with the most severe clinical presentation [
      • Jin X
      • Lian JS
      • Hu JH
      • Gao J
      • Zheng L
      • Zhang YM
      • et al.
      Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms.
      ,
      • Guan WJ
      • Ni ZY
      • Hu Y
      • Liang WH
      • Ou CQ
      • He JX
      • et al.
      Clinical Characteristics of Coronavirus Disease 2019 in China.
      ]. In another large series of 417 Chinese COVID-19 patients, abnormal liver tests (AST, ALT, total bilirubin, GGT) were present in 76.3% of patients and 21.5% of subjects showed liver injury during hospitalization, in particular during the first two weeks after admittance. In addition, patients with abnormal liver tests had higher risks of progressing to severe disease. One point was therefore that clinicians should carefully monitor the detrimental effects on liver injury mainly related to certain medications during hospital admission [
      • Cai Q
      • Huang D
      • Yu H
      • Zhu Z
      • Xia Z
      • Su Y
      • et al.
      Characteristics of Liver Tests in COVID-19 Patients.
      ]. Acute liver injury had a prevalence of 15.4% in 187 patients with confirmed COVID-19 in Wuhan [
      • Guo T
      • Fan Y
      • Chen M
      • Wu X
      • Zhang L
      • He T
      • et al.
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      ]. Whereas gastrointestinal symptoms may occur without clinically evident respiratory involvement [
      • Lee IC
      • Huo TI
      • Huang YH
      Gastrointestinal and Liver Manifestations in Patients with COVID-19.
      ], abnormal liver function tests during COVID-19 have not been linked with any specific symptoms.

      4.1 Liver test abnormalities

      Mild liver involvement occurs in more than one-third of infected patients who can show elevated serum ALT or AST, elevated LDH, creatinine kinase or myoglobin, abnormal prothrombin time and high gamma-glutamyl transferase (GGT) during COVID-19 progression, as observed at intensive care units (ICU) or normal care units (NCU) during hospitalization [
      • Wang D
      • Hu B
      • Hu C
      • Zhu F
      • Liu X
      • Zhang J
      • et al.
      Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
      ,
      • Guan WJ
      • Ni ZY
      • Hu Y
      • Liang WH
      • Ou CQ
      • He JX
      • et al.
      Clinical Characteristics of Coronavirus Disease 2019 in China.
      ,
      • Chen P
      • Lei J
      • Wu Y
      • Liu G
      • Zhou B
      Liver impairment associated with disease progression in COVID-19 patients.
      ,
      • Zhang C
      • Shi L
      • Wang FS
      Liver injury in COVID-19: management and challenges.
      ,
      • Shi H
      • Han X
      • Jiang N
      • Cao Y
      • Alwalid O
      • Gu J
      • et al.
      Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study.
      ,
      • Xu Z
      • Shi L
      • Wang Y
      • Zhang J
      • Huang L
      • Zhang C
      • et al.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      ,
      • Xu L
      • Liu J
      • Lu M
      • Yang D
      • Zheng X
      Liver injury during highly pathogenic human coronavirus infections.
      ,
      • Yang X
      • Yu Y
      • Xu J
      • Shu H
      • Xia J
      • Liu H
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      ].
      A large retrospective, multicenter study in Chinese adults with COVID-19 pneumonia described a dynamic pattern of liver injury indicators, with a first elevation of AST, followed by ALT in severe patients, and mild fluctuations of total bilirubin levels irrespective of disease severity. In this series of patients, AST levels were strongly associated with the mortality risk [
      • Lei F
      • Liu YM
      • Zhou F
      • Qin JJ
      • Zhang P
      • Zhu L
      • et al.
      Longitudinal association between markers of liver injury and mortality in COVID-19 in China.
      ] .
      Hyperbilirubinemia was observed in 11% to 18% of cases [
      • Chen N
      • Zhou M
      • Dong X
      • Qu J
      • Gong F
      • Han Y
      • et al.
      Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
      ,
      • Guan WJ
      • Ni ZY
      • Hu Y
      • Liang WH
      • Ou CQ
      • He JX
      • et al.
      Clinical Characteristics of Coronavirus Disease 2019 in China.
      ]. A clear and severe cholestatic pattern is absent during COVID-19 infection. In a comprehensive review examining 14 eligible studies [
      • Feng G
      • Zheng KI
      • Yan QQ
      • Rios RS
      • Targher G
      • Byrne CD
      • et al.
      COVID-19 and Liver Dysfunction: Current Insights and Emergent Therapeutic Strategies.
      ], elevated AST and ALT activities were reported in Guangzhou Medical University, China, in 6% to 22% and 21% to 28% of patients, respectively. In studies from Wuhan, AST levels were increased in 24% to 37% of patients, a proportion higher than in other Chinese regions (Zhejiang), reporting a proportion of 16%. A gender difference might exist in this respect [
      • Fan Z
      • Chen L
      • Li J
      • Cheng X
      • Jingmao Y
      • Tian C
      • et al.
      Clinical Features of COVID-19-Related Liver Damage.
      ], since the prevalence of AST increase is higher in men than women, as documented by six case series (i.e., average 66% vs. 35%, respectively). Case reports and case series also suggest that the probability of developing liver dysfunction increases with older age [
      • Feng G
      • Zheng KI
      • Yan QQ
      • Rios RS
      • Targher G
      • Byrne CD
      • et al.
      COVID-19 and Liver Dysfunction: Current Insights and Emergent Therapeutic Strategies.
      ]. Notably, the elevation of aminotransferases was mild, with no report about intrahepatic cholestasis or liver failure. It is a possible that abnormal liver function tests during COVID-19 infection are transient. Abnormalities often coexist with increased enzyme activities from muscle and heart. Changes may not affect liver-related morbidity and mortality.

      4.2 Mechanisms of liver damage directly or indirectly related to COVID-19 infection in the normal liver

      The main target of COVID-19 is the lung via ACE2 receptors [
      • Xu H
      • Zhong L
      • Deng J
      • Peng J
      • Dan H
      • Zeng X
      • et al.
      High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa.
      ,
      • Li R
      • Qiao S
      • Zhang G
      Analysis of angiotensin-converting enzyme 2 (ACE2) from different species sheds some light on cross-species receptor usage of a novel coronavirus 2019-nCoV.
      ]. However, SARS-CoV2 RNA has been detected in feces [
      • Cheung KS
      • Hung IF
      • Chan PP
      • Lung KC
      • Tso E
      • Liu R
      • et al.
      Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples from the Hong Kong Cohort and Systematic Review and Meta-analysis.
      ,
      • Wu Y
      • Guo C
      • Tang L
      • Hong Z
      • Zhou J
      • Dong X
      • et al.
      Prolonged presence of SARS-CoV-2 viral RNA in faecal samples.
      ,
      • Li Y
      • Hu Y
      • Yu Y
      • Zhang X
      • Li B
      • Wu J
      • et al.
      Positive result of Sars-Cov-2 in faeces and sputum from discharged patient with COVID-19 in Yiwu.
      ], with a longer presence in faecal samples, as compared with respiratory samples [
      • Wu Y
      • Guo C
      • Tang L
      • Hong Z
      • Zhou J
      • Dong X
      • et al.
      Prolonged presence of SARS-CoV-2 viral RNA in faecal samples.
      ]. The presence of the virus in gut lumen could lead to translocation into the liver via portal flow, with direct negative effects on hepatic cells (unconfirmed hypothesis). The liver damage occurring during COVID-19 infection is likely of multifactorial origin.
      In particular, during COVID-19 progression, the liver could be involved either as a direct target of the SARS-CoV-2 (e.g. hepatocyte apoptosis [
      • Chau TN
      • Lee KC
      • Yao H
      • Tsang TY
      • Chow TC
      • Yeung YC
      • et al.
      SARS-associated viral hepatitis caused by a novel coronavirus: report of three cases.
      ] or caspase-dependent pathways [
      • Tan YJ
      • Fielding BC
      • Goh PY
      • Shen S
      • Tan TH
      • Lim SG
      • et al.
      Overexpression of 7a, a protein specifically encoded by the severe acute respiratory syndrome coronavirus, induces apoptosis via a caspase-dependent pathway.
      ]) and secondary to the complex pathways of systemic alterations promoted by the viral infection, mainly including inflammation and cytokine release (including IL-1, IL-6, IL-10 [
      • Duan ZP
      • Chen Y
      • Zhang J
      • Zhao J
      • Lang ZW
      • Meng FK
      • et al.
      [Clinical characteristics and mechanism of liver injury in patients with severe acute respiratory syndrome].
      ]), immune response, altered coagulation, hepatic ischemia and hypoxia, and sepsis-related abnormalities.
      Additional elements possibly concurring to liver damage are drug-related injury and the progression of underlying liver diseases.
      It is still under debate if these alterations can really be an expression of a clinically relevant liver injury requiring particular attention in the management of the disease [
      • Bangash MN
      • Patel J
      • Parekh D
      COVID-19 and the liver: little cause for concern.
      ,
      • Zhang Y
      • Zheng L
      • Liu L
      • Zhao M
      • Xiao J
      • Zhao Q
      Liver impairment in COVID-19 patients: a retrospective analysis of 115 cases from a single center in Wuhan city, China.
      ]. In one study, patients developing abnormal liver tests had higher risks of progressing to severe disease [
      • Cai Q
      • Huang D
      • Yu H
      • Zhu Z
      • Xia Z
      • Su Y
      • et al.
      Characteristics of Liver Tests in COVID-19 Patients.
      ], and the finding is associated with longer hospital stay [
      • Fan Z
      • Chen L
      • Li J
      • Cheng X
      • Jingmao Y
      • Tian C
      • et al.
      Clinical Features of COVID-19-Related Liver Damage.
      ]. In addition, the more severe form of COVID-19 infection is a predisposing condition to a more evident liver damage [
      • Wang D
      • Hu B
      • Hu C
      • Zhu F
      • Liu X
      • Zhang J
      • et al.
      Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
      ,
      • Guan WJ
      • Ni ZY
      • Hu Y
      • Liang WH
      • Ou CQ
      • He JX
      • et al.
      Clinical Characteristics of Coronavirus Disease 2019 in China.
      ,
      • Lu H
      • Ai J
      • Shen Y
      • Li Y
      • Li T
      • Zhou X
      • et al.
      A descriptive study of the impact of diseases control and prevention on the epidemics dynamics and clinical features of SARS-CoV-2 outbreak in Shanghai, lessons learned for metropolis epidemics prevention.
      ], and therefore also patients admitted to ICU [
      • Yang X
      • Yu Y
      • Xu J
      • Shu H
      • Xia J
      • Liu H
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      ].
      Table 1 depicts the most distinctive post-mortem histopathological changes of the liver from patients with COVID-19. Remarkably, liver failure and bile duct injuries were not reported in these studies.
      Table 1Major post-mortem histopathological changes of the liver from patients with COVID-19
      ReferenceFindings
      Xu et al., 2020
      • Xu Z
      • Shi L
      • Wang Y
      • Zhang J
      • Huang L
      • Zhang C
      • et al.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      Microvescicular steatosis
      Mild lobular and portal activity
      Liu et al., 2020
      • Liu Q
      • Wang RS
      • Qu GQ
      • Wang YY
      • Liu P
      • Zhu YZ
      • et al.
      Gross examination report of a COVID-19 death autopsy.
      Hepatomegaly
      Hepatocyte degeneration
      Lobular focal necrosis
      Neutrophil infiltration
      Infiltration of lymphocytes and monocytes (portal area)
      Congestion of hepatic sinuses with microthrombosis.
      Tian et al., 2020
      • Tian S
      • Xiong Y
      • Liu H
      • Niu L
      • Guo J
      • Liao M
      • et al.
      Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies.
      Mild sinusoidal dilatation
      Mild lobular lymphocytic infiltration
      Patchy hepatic necrosis in the periportal and centrilobular areas
      Ji et al., 2020
      • Ji D
      • Qin E
      • Xu J
      • Zhang D
      • Cheng G
      • Wang Y
      • et al.
      Non-alcoholic fatty liver diseases in patients with COVID-19: A retrospective study.
      Microvesicular steatosis
      Overactivation of T cells
      Liver damage is more likely to occur in patients with more severe disease [
      • Siddiqi HK
      • Mehra MR
      COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal.
      ], in whom concomitant alterations of liver function tests are more likely [
      • Wang D
      • Hu B
      • Hu C
      • Zhu F
      • Liu X
      • Zhang J
      • et al.
      Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
      ,
      • Huang C
      • Wang Y
      • Li X
      • Ren L
      • Zhao J
      • Hu Y
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
      ]. Aggravating factors include ischemic/hypoxic liver injury [
      • Li J
      • Li RJ
      • Lv GY
      • Liu HQ
      The mechanisms and strategies to protect from hepatic ischemia-reperfusion injury.
      ], and immunologic, inflammatory and toxic mechanisms promoted by systemic sepsis [
      • Strnad P
      • Tacke F
      • Koch A
      • Trautwein C
      Liver - guardian, modifier and target of sepsis.
      ]. Viral inclusions seem to be absent in the liver [
      • Xu Z
      • Shi L
      • Wang Y
      • Zhang J
      • Huang L
      • Zhang C
      • et al.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      ], but this possibility deserves further investigations, because of potential viral RNA translocation from intestine though portal blood.
      Another possibility is the direct damage from COVID-19. Cholangiocytes express ACE2 receptors (more that 20-fold than in hepatocytes). Although cell damage can also occur at the level of bile ducts [
      • Guan GW
      • Gao L
      • Wang JW
      • Wen XJ
      • Mao TH
      • Peng SW
      • et al.
      [Exploring the mechanism of liver enzyme abnormalities in patients with novel coronavirus-infected pneumonia].
      ,
      • Chai X
      • Hu L
      • Zhang Y
      • Han W
      • Lu Z
      • Ke A
      • et al.
      Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection.
      ], specific abnormalities of bile duct chemistry [
      • Guan WJ
      • Ni ZY
      • Hu Y
      • Liang WH
      • Ou CQ
      • He JX
      • et al.
      Clinical Characteristics of Coronavirus Disease 2019 in China.
      ], major histological abnormalities [
      • Xu Z
      • Shi L
      • Wang Y
      • Zhang J
      • Huang L
      • Zhang C
      • et al.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      ], and liver failure [
      • Li J
      • Fan JG
      Characteristics and Mechanism of Liver Injury in 2019 Coronavirus Disease.
      ] are rare. A major involvement of cholangiocytes during COVID-19 would parallel increased levels of serum alkaline phosphatase, but this is an uncommon finding. Likely, COVID-19 promotes liver damage mainly through ACE2 receptors expressed in endothelial cells [
      • Hamming I
      • Timens W
      • Bulthuis ML
      • Lely AT
      • Navis G
      • van Goor H
      Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus.
      ]. These cells actively participate to liver ischemia-reperfusion damage and promote oxidant stress via reactive oxygen species (ROS) and nitric oxide (NO) derivatives [
      • Dar WA
      • Sullivan E
      • Bynon JS
      • Eltzschig H
      • Ju C
      Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms.
      ].
      COVID-19 infection can progress to the inflammatory cytokine storm [
      • Prompetchara E
      • Ketloy C
      • Palaga T
      Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic.
      ], which involve both the innate (Toll-like receptors, TLRs) and the cellular adaptive immunity (killer T lymphocytes) [
      • Tartey S
      • Takeuchi O
      Pathogen recognition and Toll-like receptor targeted therapeutics in innate immune cells.
      ,
      • Klimstra WB
      • Ryman KD
      • Bernard KA
      • Nguyen KB
      • Biron CA
      • Johnston RE
      Infection of neonatal mice with sindbis virus results in a systemic inflammatory response syndrome.
      ]. The deleterious sequence, resembling pictures evolving during sepsis, includes COVID-19 infection, activation of intrahepatic CD4+ and CD8+ T-cells, Kupffer cells, activation of B cells and release of antiviral antibodies [
      • Bangash MN
      • Patel J
      • Parekh D
      COVID-19 and the liver: little cause for concern.
      ,
      • Adams DH
      • Hubscher SG
      Systemic viral infections and collateral damage in the liver.
      ]. These pathways evolve towards apoptosis and necrosis of infected cells with release of damage-associated molecular patterns and inflammatory signals which can interact with TLRs [
      • Tartey S
      • Takeuchi O
      Pathogen recognition and Toll-like receptor targeted therapeutics in innate immune cells.
      ,
      • Klimstra WB
      • Ryman KD
      • Bernard KA
      • Nguyen KB
      • Biron CA
      • Johnston RE
      Infection of neonatal mice with sindbis virus results in a systemic inflammatory response syndrome.
      ]. Further complications include bacterial infections, more pro-inflammatory signaling pathways, macrophage activation and more inflammatory responses. The involvement of the innate immune system, becoming defective during COVID-19 infection, is further supported by depressed platelet counts, activation of coagulative and fibrinolytic pathways, increased neutrophil counts and neutrophil to lymphocyte ratios, as well as hyperferritinemia [
      • Wang D
      • Hu B
      • Hu C
      • Zhu F
      • Liu X
      • Zhang J
      • et al.
      Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
      ]. Elderly patients go worse, in this respect [
      • Simon AK
      • Hollander GA
      • McMichael A
      Evolution of the immune system in humans from infancy to old age.
      ]. This sudden and immense immune hyperactivation may result in multiple organ failure lungs but also to the liver, heart, and kidneys [
      • Prompetchara E
      • Ketloy C
      • Palaga T
      Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic.
      ]. Serum levels of the monocyte chemoattractant protein-1 (MCP-1), in particular, are increased in COVID-19 patients [
      • Huang C
      • Wang Y
      • Li X
      • Ren L
      • Zhao J
      • Hu Y
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
      ]. This chemokine has a critical role in the pathogenesis of liver disease [
      • Xie J
      • Yang L
      • Tian L
      • Li W
      • Yang L
      • Li L
      Macrophage Migration Inhibitor Factor Upregulates MCP-1 Expression in an Autocrine Manner in Hepatocytes during Acute Mouse Liver Injury.
      ], and is able to exacerbate steatohepatitis [
      • Gao QY
      • Chen YX
      • Fang JY
      Novel coronavirus infection and gastrointestinal tract.
      ].
      A further mechanism of liver damage includes the pneumonia-associated hypoxic damage in the liver, as the consequence of respiratory distress syndrome, hyperinflammatory response, and multiple organ failure [
      • Feng G
      • Zheng KI
      • Yan QQ
      • Rios RS
      • Targher G
      • Byrne CD
      • et al.
      COVID-19 and Liver Dysfunction: Current Insights and Emergent Therapeutic Strategies.
      ]. The prevalence of this condition should be lower than above-mentioned conditions [
      • Bangash MN
      • Patel J
      • Parekh D
      COVID-19 and the liver: little cause for concern.
      ]. Hepatocyte cell death will result from the ongoing status of hepatic ischemia and hypoxia-reperfusion dysfunction, leading to hyperaccumulation of lipids, production of reactive oxygen species and increased oxidant stress and further pro-inflammatory molecules [
      • Zhang XJ
      • Cheng X
      • Yan ZZ
      • Fang J
      • Wang X
      • Wang W
      • et al.
      An ALOX12-12-HETE-GPR31 signaling axis is a key mediator of hepatic ischemia-reperfusion injury.
      ]. In this context, mitochondrial damage may also play a role [
      • Nardo B
      • Grattagliano I
      • Domenicali M
      • Caraceni P
      • Catena F
      • Santoni B
      • et al.
      Mitochondrial oxidative injury in rat fatty livers exposed to warm ischemia-reperfusion.
      ,
      • Caraceni P
      • Domenicali M
      • Vendemiale G
      • Grattagliano I
      • Pertosa A
      • Nardo B
      • et al.
      The reduced tolerance of rat fatty liver to ischemia reperfusion is associated with mitochondrial oxidative injury.
      ].

      4.3 The impact of a pre-existing liver disease

      In general, an underlying liver disease represents a potential risk factor for COVID-19 evolution to severe infection [

      Centers for Disease Control and Prevention. People who are at higher risk for severe illness. 2020.

      ]. Conditions might include the ongoing liver damage due to chronic hepatitis B, combined HBV/HCV hepatitis (with risk of enhanced replication of hepatitis virus [
      • Huang Y-h
      • Gao Z-l
      Study of the relationship SARS and hepatitis virus B.
      ]), nonalcoholic fatty liver disease (NAFLD)(because of associated comorbidities of diabetes and cardiovascular disorder, and increased susceptibility to drugs) [
      • Boettler T
      • Newsome PN
      • Mondelli MU
      • Maticic M
      • Cordero E
      • Cornberg M
      • et al.
      Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper.
      ] liver cirrhosis [
      • Wang FS
      • Fan JG
      • Zhang Z
      • Gao B
      • Wang HY
      The global burden of liver disease: the major impact of China.
      ], patients undergone liver transplant and who are on immunosuppressants [
      • Strnad P
      • Tacke F
      • Koch A
      • Trautwein C
      Liver - guardian, modifier and target of sepsis.
      ], patients with hepatocellular carcinoma and immune-deficient status [
      • Wu Y
      • Guo C
      • Tang L
      • Hong Z
      • Zhou J
      • Dong X
      • et al.
      Prolonged presence of SARS-CoV-2 viral RNA in faecal samples.
      ]. Preventive measures are highly recommended in these patients [
      • Xiao Y
      • Pan H
      • She Q
      • Wang F
      • Chen M
      Prevention of SARS-CoV-2 infection in patients with decompensated cirrhosis.
      ]. The aspect related to an underlying liver disease, represents a major burden in China, where liver diseases, primarily viral hepatitis (predominantly hepatitis B virus, HBV), NAFLD and alcoholic liver disease affect approximately 300 million people [
      • Wang FS
      • Fan JG
      • Zhang Z
      • Gao B
      • Wang HY
      The global burden of liver disease: the major impact of China.
      ]. Similar aspects, e.g. liver disorder connected with underlying metabolic abnormalities, are frequent in Western industrialized countries. In particular, the issue of COVID-19 infection and underlying metabolic abnormalities should also consider liver steatosis. NAFLD refers to the development of abnormal hepatic steatosis in the absence of other causes for secondary hepatic fat accumulation. NAFLD is the most common liver disorder in Western industrialized countries, (prevalence ranging from 10 to 46% in the United States [
      • Williams CD
      • Stengel J
      • Asike MI
      • Torres DM
      • Shaw J
      • Contreras M
      • et al.
      Prevalence of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among a Largely Middle-Aged Population Utilizing Ultrasound and Liver Biopsy: A Prospective Study.
      ,
      • Vernon G
      • Baranova A
      • Younossi ZM
      Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.
      ,
      • Lazo M
      • Hernaez R
      • Eberhardt MS
      • Bonekamp S
      • Kamel I
      • Guallar E
      • et al.
      Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994.
      ]) and a median of 20% worldwide with a documented rising trend with time [
      • Younossi ZM
      • Stepanova M
      • Afendy M
      • Fang Y
      • Younossi Y
      • Mir H
      • et al.
      Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008.
      ]. This trend in North America and Europe is the consequence of the rising prevalence of major risk factors for NAFLD, including obesity, sedentary lifestyles, type 2 diabetes mellitus, dyslipidaemia, and metabolic syndrome [
      • Younossi ZM
      • Stepanova M
      • Afendy M
      • Fang Y
      • Younossi Y
      • Mir H
      • et al.
      Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008.
      ,
      • Molina-Molina E
      • Lunardi Baccetto R
      • Wang DQ
      • de Bari O
      • Krawczyk M
      • Portincasa P
      Exercising the hepatobiliary-gut axis. The impact of physical activity performance.
      ,
      • Molina-Molina E
      • Krawczyk M
      • Stachowska E
      • Lammert F
      • Portincasa P
      Non-Alcoholic Fatty Liver Disease in Non-Obese Individuals: Prevalence, Pathogenesis and Treatment.
      ,
      • Zhou J
      • Zhou F
      • Wang W
      • Zhang XJ
      • Ji YX
      • Zhang P
      • et al.
      Epidemiological feature of NAFLD from 1999 to 2018 in China.
      ]. However, lean non-alcoholic steatohepatitis (NASH) can develop as well [
      • Molina-Molina E
      • Krawczyk M
      • Stachowska E
      • Lammert F
      • Portincasa P
      Non-Alcoholic Fatty Liver Disease in Non-Obese Individuals: Prevalence, Pathogenesis and Treatment.
      ] and is frequent in Asia [
      • Loomba R
      • Sanyal AJ
      The global NAFLD epidemic.
      ]. Overall, factors contributing to NAFLD include the environment, the gut microbiome, disrupted gluco-lipid metabolic pathways, metabolic inflammation primarily mediated by innate immune signalling, comorbidities and genetic risk factors [
      • Krawczyk M
      • Bonfrate L
      • Portincasa P
      Nonalcoholic fatty liver disease.
      ,
      • Krawczyk M
      • Grünhage F
      • Mihalache F
      • Acalovschi M
      • Lammert F
      The common adiponutrin variant p. I148M, a common genetic risk factor for severe forms of NAFLD and ALD, in gallstone patients.
      ].
      In the study by Ji et al., 202 patients with COVID-19 infection and NAFLD (assessed by steatosis index and/or abdominal ultrasonography), developed liver injury in 50% and 75% of cases on admission and during hospitalization, respectively [
      • Ji D
      • Qin E
      • Xu J
      • Zhang D
      • Cheng G
      • Wang Y
      • et al.
      Non-alcoholic fatty liver diseases in patients with COVID-19: A retrospective study.
      ]. NAFLD [
      • Boettler T
      • Newsome PN
      • Mondelli MU
      • Maticic M
      • Cordero E
      • Cornberg M
      • et al.
      Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper.
      ], higher BMI [
      • Boettler T
      • Newsome PN
      • Mondelli MU
      • Maticic M
      • Cordero E
      • Cornberg M
      • et al.
      Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper.
      ], and age [
      • Simon AK
      • Hollander GA
      • McMichael A
      Evolution of the immune system in humans from infancy to old age.
      ], as well as underlying liver disease [
      • Boettler T
      • Newsome PN
      • Mondelli MU
      • Maticic M
      • Cordero E
      • Cornberg M
      • et al.
      Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper.
      ] were associated with COVID-19 progression. Thus, patients suffering from NAFLD could be vulnerable to COVID-19 infection and viral-related complications. These patients might display an increased risk of NAFLD progression to steatohepatitis in the long-term [
      • Prins GH
      • Olinga P
      Potential implications of COVID-19 in non-alcoholic fatty liver disease.
      ]. Notably, ACE2 expression is significantly increased in liver injury in both humans and rat, likely in response to increasing hepatocellular hypoxia [
      • Paizis G
      • Tikellis C
      • Cooper ME
      • Schembri JM
      • Lew RA
      • Smith AI
      • et al.
      Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2.
      ].
      Furthermore, as described above, a previous NAFLD could be exacerbated by chemokines released during SARS-CoV-2 infection [
      • Gao QY
      • Chen YX
      • Fang JY
      Novel coronavirus infection and gastrointestinal tract.
      ,
      • Xie J
      • Yang L
      • Tian L
      • Li W
      • Yang L
      • Li L
      Macrophage Migration Inhibitor Factor Upregulates MCP-1 Expression in an Autocrine Manner in Hepatocytes during Acute Mouse Liver Injury.
      ].
      In addition, the presence of NAFLD can put patients at increased risk of a severe course of COVID-19, due to the frequent coexistence of metabolic comorbidities such as diabetes, hypertension, and obesity [
      • Boettler T
      • Newsome PN
      • Mondelli MU
      • Maticic M
      • Cordero E
      • Cornberg M
      • et al.
      Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper.
      ]. Non-cirrhotic patients with NAFLD/NASH can be considered as cardio-metabolic subjects and, therefore, at very high risk of COVID-19 complications. From a pathogenic point of view, the presence of inflammatory pathways (in particular those involving cytokines) common to NAFLD [
      • Fricker ZP
      • Pedley A
      • Massaro JM
      • Vasan RS
      • Hoffmann U
      • Benjamin EJ
      • et al.
      Liver Fat Is Associated With Markers of Inflammation and Oxidative Stress in Analysis of Data From the Framingham Heart Study.
      ,
      • Feldman A
      • Eder SK
      • Felder TK
      • Paulweber B
      • Zandanell S
      • Stechemesser L
      • et al.
      Clinical and metabolic characterization of obese subjects without non-alcoholic fatty liver: A targeted metabolomics approach.
      ,
      • Jarrar MH
      • Baranova A
      • Collantes R
      • Ranard B
      • Stepanova M
      • Bennett C
      • et al.
      Adipokines and cytokines in non-alcoholic fatty liver disease.
      ] and COVID-19 [
      • Pedersen SF
      • Ho YC
      SARS-CoV-2: a storm is raging.
      ,
      • Mehta P
      • McAuley DF
      • Brown M
      • Sanchez E
      • Tattersall RS
      • Manson JJ
      • et al.
      COVID-19: consider cytokine storm syndromes and immunosuppression.
      ,
      • Huang C
      • Wang Y
      • Li X
      • Ren L
      • Zhao J
      • Hu Y
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
      ,
      • Henry BM
      • de Oliveira MHS
      • Benoit S
      • Plebani M
      • Lippi G
      Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis.
      ] might increase the risk of liver inflammation in subjects with NAFLD and further aggravate the outcome if these patients are infected with the SARS-CoV-2. In a Chinese retrospective study, the presence of NAFLD was linked with a high risk of COVID-19 progression, and with longer viral shedding time, as compared to patients without NAFLD [
      • Ji D
      • Qin E
      • Xu J
      • Zhang D
      • Cheng G
      • Wang Y
      • et al.
      Non-alcoholic fatty liver diseases in patients with COVID-19: A retrospective study.
      ].
      According to the EASL-ESCMID position paper [
      • Boettler T
      • Newsome PN
      • Mondelli MU
      • Maticic M
      • Cordero E
      • Cornberg M
      • et al.
      Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper.
      ], based on the experience on Chinese patients [
      • Guan WJ
      • Ni ZY
      • Hu Y
      • Liang WH
      • Ou CQ
      • He JX
      • et al.
      Clinical Characteristics of Coronavirus Disease 2019 in China.
      ], chronic viral hepatitis would not increase the risk of a severe course of COVID-19. However, in patients with advanced liver disease and after liver transplantation there is increased risk of infection and/or a severe course of COVID-19 [
      • Boettler T
      • Newsome PN
      • Mondelli MU
      • Maticic M
      • Cordero E
      • Cornberg M
      • et al.
      Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper.
      ,
      • Fix OK
      • Hameed B
      • Fontana RJ
      • Kwok RM
      • McGuire BM
      • Mulligan DC
      • et al.
      Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement.
      ].
      Patients with autoimmune hepatitis or on immunosuppressive medications can be at increased risk for severe COVID-19 outcomes [
      • Fix OK
      • Hameed B
      • Fontana RJ
      • Kwok RM
      • McGuire BM
      • Mulligan DC
      • et al.
      Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement.
      ,
      • Lleo A
      • Invernizzi P
      • Lohse AW
      • Aghemo A
      • Carbone M
      Highlights for management of patients with Autoimmune Liver Disease during COVID-19 pandemia.
      ]. According to the recent AASLD guidelines, this group of patients should be prioritized for testing until further will become available. Furthermore, in COVID-19 patients with autoimmune hepatitis or previous liver transplantation, a more aggressive approach is required, i.e., a suspect flare or acute cellular rejection should not be based on liver biochemistry alone but should undergo liver biopsy confirmation [
      • Fix OK
      • Hameed B
      • Fontana RJ
      • Kwok RM
      • McGuire BM
      • Mulligan DC
      • et al.
      Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement.
      ]. In addition, a flare of autoimmune liver disease due to unnecessary drug reduction or withdrawal would lead to increased doses of steroids. This possibility, in turn, will expose patients to increased risks of SARS-CoV-2 infection [
      • Lleo A
      • Invernizzi P
      • Lohse AW
      • Aghemo A
      • Carbone M
      Highlights for management of patients with Autoimmune Liver Disease during COVID-19 pandemia.
      ]. The immunosuppressive therapy in COVID-19 patients with liver disease should be minimized but not stopped [
      • Fix OK
      • Hameed B
      • Fontana RJ
      • Kwok RM
      • McGuire BM
      • Mulligan DC
      • et al.
      Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement.
      ].
      During COVID-19 pandemic and afterwards (“Phase 2”), measures of social distancing aimed at the primary prevention of the infection, see the key involvement of the national health system. Such measures can influence the regular path of care of patients with chronic liver diseases, particularly those with decompensated cirrhosis, hepatocellular carcinoma and waiting for liver transplantation [
      • Fix OK
      • Hameed B
      • Fontana RJ
      • Kwok RM
      • McGuire BM
      • Mulligan DC
      • et al.
      Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement.
      ]. This approach could lead to increased decompensation, morbidity, onset of complications or transplant waiting list dropout. In this context, the preventive care provided to these patients must be intensified and tools imply, whenever possible, telehealth programs and reorganization of care delivery [
      • Tapper EB
      • Asrani SK
      The COVID-19 pandemic will have a long-lasting impact on the quality of cirrhosis care.
      ].

      4.4 The liver damage caused by agents used for treatment of the infection

      During COVID19 infection, liver damage could originate following the use of drugs, as suggested by the presence of microvescicular steatosis, and liver inflammation [
      • Xu Z
      • Shi L
      • Wang Y
      • Zhang J
      • Huang L
      • Zhang C
      • et al.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      ]. Agents include potentially hepatotoxic antiviral drugs employed off-label to treat the infection, as well as the use of antibiotics (quinolones, macrolides) in preventing/treating bacterial superinfections, antipyretics, or steroids [
      • Fan Z
      • Chen L
      • Li J
      • Cheng X
      • Jingmao Y
      • Tian C
      • et al.
      Clinical Features of COVID-19-Related Liver Damage.
      ,
      • Boeckmans J
      • Rodrigues RM
      • Demuyser T
      • Pierard D
      • Vanhaecke T
      • Rogiers V
      COVID-19 and drug-induced liver injury: a problem of plenty or a petty point?.
      ].
      Liver toxicity might involve the drug-cytochrome P-450 interaction, as reported for azithromycin [
      • Li SQ
      • Wan XD
      • Zhu S
      • Han HM
      • Xu ZS
      • Lu HJ
      Establishment of a new animal model of azithromycin-induced liver injury and study the molecular pathological change during the process.
      ,

      Ellison CA and Blackwell SB. Acute Hepatocellular Injury Associated With Azithromycin. J Pharm Pract2020:897190019894428.

      ], lopinavir/ritonavir [
      • Fan Z
      • Chen L
      • Li J
      • Cheng X
      • Jingmao Y
      • Tian C
      • et al.
      Clinical Features of COVID-19-Related Liver Damage.
      ,
      • Yeh RF
      • Gaver VE
      • Patterson KB
      • Rezk NL
      • Baxter-Meheux F
      • Blake MJ
      • et al.
      Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers.
      ], hydroxy-chloquine [
      • Abdel Galil SM.
      Hydroxychloroquine-induced toxic hepatitis in a patient with systemic lupus erythematosus: a case report.
      ,
      • Lee JY
      • Vinayagamoorthy N
      • Han K
      • Kwok SK
      • Ju JH
      • Park KS
      • et al.
      Association of Polymorphisms of Cytochrome P450 2D6 With Blood Hydroxychloroquine Levels in Patients With Systemic Lupus Erythematosus.
      ], and acetaminophen [
      • Utkarsh D
      • Loretz C
      • Li AP
      In vitro evaluation of hepatotoxic drugs in human hepatocytes from multiple donors: Identification of P450 activity as a potential risk factor for drug-induced liver injuries.
      ,
      • Bao Y
      • Wang P
      • Shao X
      • Zhu J
      • Xiao J
      • Shi J
      • et al.
      Acetaminophen-Induced Liver Injury Alters Expression and Activities of Cytochrome P450 Enzymes in an Age-Dependent Manner in Mouse Liver.
      ].
      A study was conducted from clinical records and laboratory results from 417 laboratory-confirmed COVID-19 patients admitted to the hospital in Shenzhen, China, treatment with lopinavir/ritonavir lead to increased odds of liver injury [
      • Cai Q
      • Huang D
      • Yu H
      • Zhu Z
      • Xia Z
      • Su Y
      • et al.
      Characteristics of Liver Tests in COVID-19 Patients.
      ]. This observation is in line with results from a retrospective study in 148 patients in Shangai Hospital, showing that abnormal liver function tests was more frequent among those receiving lopinavir/ritonavir after hospital admission [
      • Fan Z
      • Chen L
      • Li J
      • Cheng X
      • Jingmao Y
      • Tian C
      • et al.
      Clinical Features of COVID-19-Related Liver Damage.
      ]. Remdesivir, a nucleoside analog prodrug developed by Gilead Sciences (USA), is effective against COVID-19 replication in vitro [
      • Wang M
      • Cao R
      • Zhang L
      • Yang X
      • Liu J
      • Xu M
      • et al.
      Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.
      ] and in infected patients [
      • Holshue ML
      • DeBolt C
      • Lindquist S
      • Lofy KH
      • Wiesman J
      • Bruce H
      • et al.
      First Case of 2019 Novel Coronavirus in the United States.
      ]. This drug produced similar effects on liver enzymes [

      Kujawski SA, Wong KK, Collins JP, Epstein L, Killerby ME, Midgley CM, et al.2020.

      ]. Hydroxy Chloroquine sulphate is also effective in vitro [
      • Wang M
      • Cao R
      • Zhang L
      • Yang X
      • Liu J
      • Xu M
      • et al.
      Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.
      ] and, in COVID-19 patients for short periods, appears to safe. Rare case of fulminant hepatic failure have been described with Hydroxy Chloroquine [
      • Makin AJ
      • Wendon J
      • Fitt S
      • Portmann BC
      • Williams R
      Fulminant hepatic failure secondary to hydroxychloroquine.
      ,
      • Liu J
      • Cao R
      • Xu M
      • Wang X
      • Zhang H
      • Hu H
      • et al.
      Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro.
      ]. Acute liver injury is also possible after azithromycin treatment, with a clinically evident presentation following about two weeks after drug cessation, and after an average duration of treatment of 4 days [
      • Martinez MA
      • Vuppalanchi R
      • Fontana RJ
      • Stolz A
      • Kleiner DE
      • Hayashi PH
      • et al.
      Clinical and histologic features of azithromycin-induced liver injury.
      ]. Several patients with concomitant diseases (i.e. diabetes type 1 or 2, or hypertensive), undergo antihypertensive therapies with ACE inhibitors and angiotensin II type I receptor blockers. In this context, a possibility is the onset of ACE2 overexpression. Whether this condition will facilitate COVID-19 infection and penetrance, deserves further attention [
      • Fang L
      • Karakiulakis G
      • Roth M
      Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?.
      ,
      • FitzGerald GA.
      Misguided drug advice for COVID-19.
      ]. There is no evidence, however, that ACE inhibitors will worsen the consequence of infection [
      • FitzGerald GA.
      Misguided drug advice for COVID-19.
      ]. Many patients with fever use antipyretic agents, namely acetaminophen [
      • Deng SQ
      • Peng HJ
      Characteristics of and Public Health Responses to the Coronavirus Disease 2019 Outbreak in China.
      ]. This drug might mediate, at least in part, the liver damage [
      • Xu Z
      • Shi L
      • Wang Y
      • Zhang J
      • Huang L
      • Zhang C
      • et al.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      ].
      Patients with underlying metabolic abnormalities and NAFLD might be more exposed to drug-induced liver damage (DILI) [
      • Ji D
      • Qin E
      • Xu J
      • Zhang D
      • Cheng G
      • Wang Y
      • et al.
      Non-alcoholic fatty liver diseases in patients with COVID-19: A retrospective study.
      ,
      • Boeckmans J
      • Rodrigues RM
      • Demuyser T
      • Pierard D
      • Vanhaecke T
      • Rogiers V
      COVID-19 and drug-induced liver injury: a problem of plenty or a petty point?.
      ]. As mentioned earlier, the cytokine MCP-1 is often increased in COVID-19 patients [
      • Huang C
      • Wang Y
      • Li X
      • Ren L
      • Zhao J
      • Hu Y
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
      ] and act as a further hit for steatohepatitis [
      • Gao B
      • Tsukamoto H
      Inflammation in Alcoholic and Nonalcoholic Fatty Liver Disease: Friend or Foe?.
      ]. In addition, patients with NAFLD/nonalcoholic steatohepatitis (NASH) COVID-19 infection, might be more susceptible to DILI, as well as to therapy with steatogenic drugs (amiodarone, sodium valproate, tamoxifen and methotrexate), and/or ischemic damage to the liver [
      • Boeckmans J
      • Rodrigues RM
      • Demuyser T
      • Pierard D
      • Vanhaecke T
      • Rogiers V
      COVID-19 and drug-induced liver injury: a problem of plenty or a petty point?.
      ].
      According to the recent AASLD guidelines, regular monitoring of liver function should be considered in all hospitalized COVID-19 patients, in particular in those treated with remdesevir or tocilizumab, irrespective of baseline value of liver biochemistry [
      • Fix OK
      • Hameed B
      • Fontana RJ
      • Kwok RM
      • McGuire BM
      • Mulligan DC
      • et al.
      Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement.
      ].
      Thus, mainly due to possible interplay between mechanisms of liver damage promoted by SARS-CoV-2 infection and potential drug-induced hepatic side-effects, liver function tests should be carefully monitored independently from the presence of a pre-existing liver disease. This is particularly true when using biological agents against targeting the inflammatory/immunological responses.

      5. Conclusion

      Preliminary observations accumulated from China, following the COVID-19 outbreak in Wuhan, show that liver involvement during COVID-19 infection may affect about one-third of the patients, with prevalence greater in men than women, and in elderly. Although the manifestations of liver damage are usually mild (elevated serum aminotransferases), mechanisms are complex, and include underlying liver injury, direct cholangiopathy, use of antiviral drugs, hyperinflammatory status, and underlying hypoxia (Figure 1). Thus, the appearance of liver involvement during COVID-19 infection requires attention. This is particularly true since typical patients are older, with a pre-existing history of liver diseases, and essentially because the prognosis of lung infection is worse, and hospital stay is longer. Furthermore, the impact of COVID-19 on subjects with pre-existing liver diseases should be clarified. Position papers from scientific societies on the management of such patients are appearing, in this respect [
      • Boettler T
      • Newsome PN
      • Mondelli MU
      • Maticic M
      • Cordero E
      • Cornberg M
      • et al.
      Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper.
      ].
      Figure 1
      Figure 1Major mechanisms involved in the pathogenesis of liver damage during COVID-19 infection. The COVID-19 infection implies the first interaction between the virus and the angiotensin-converting enzyme 2 (ACE2) receptors (expressed in the lung, gastrointestinal tract, cholangiocytes, and vascular endothelium). Several factors contribute to liver damage, namely direct viral effect, drug-induced liver injury (including the underlying effect of steatogenic drugs, see text), pree-existing liver disease, hepatic congestion, ischemic-hypoxic damage. Such factors activate the inflammatory “cytokine storm”, when pathogenic T cells are activated. Production of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6 and other proinflammatory factors is the next step. Inflammatory monocytes CD14+CD16+ respond to GM-CSF, producing a larger amount of IL-6 and other proinflammatory factors. The inflammatory “storm” evolve to immune damage in other organs such as lungs and the liver. Additional mechanisms of damage might include the intestine (abnormal permeability? Viral persistence in enterocytes? Dysbiosis? Viral translocation? Leaky gut and production of toxins travelling to the liver via portal vein?), and liver mitochondrial dysfunction, as a source of oxidant stress and production of reactive oxygen species (ROS).
      Abbreviations: ACE2, angiotensin-converting enzyme 2; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; HBV, hepatitis B; HCV, hepatitis C; IFN, interferon; LDH, lactate dehydrogenase; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.

      Declaration of Competing Interest

      The authors have no financial or other interest in the product or distributor of the product. Furthermore, they have no other kinds of associations, such as consultancies, stock ownership, or other equity interests or patent-licensing arrangements.

      Author Contribution

      Each author contributed substantially to the work with access to all materials and data. PP and ADC wrote the initial draft. MK and AM provided systematic literature review. FL and PP reviewed the final version of the paper. The corresponding author had final responsibility for the decision to submit for publication.

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