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Features of Liver Injury in COVID-19 Pathophysiological, Biological and Clinical Particularities

Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
Pediatrics Department, University of Medicine and Pharmacy “Carol Davila”, 020021 Bucharest, Romania
Department of Pediatric Cardiology, “Marie Curie” Emergency Children’s Hospital, 041451 Bucharest, Romania
Department of Pediatric and Adult Congenital Cardiology, Bordeaux University Hospital, 33600 Pessac, France
Department of Endocrinology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
Department of Toxicology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
Department of Cardiology, University and Emergency Hospital, 050098 Bucharest, Romania
Ph.D. School Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
Authors to whom correspondence should be addressed.
Gastroenterol. Insights 2023, 14(2), 156-169;
Received: 6 March 2023 / Revised: 23 March 2023 / Accepted: 27 March 2023 / Published: 1 April 2023
(This article belongs to the Collection Gastroenterological Aspects of COVID-19 Infection)


The outbreak of the coronavirus pandemic in March 2020 has caused unprecedented pressure on public health and healthcare. The spectrum of COVID-19 onset is large, from mild cases with minor symptoms to severe forms with multi-organ dysfunction and death. In COVID-19, multiple organ damage has been described, including lung damage, acute kidney injury, liver damage, stroke, cardiovascular and digestive tract disorders. The aspects of liver injury are different, sometimes presenting with only a slight increase in liver enzymes, but sometimes with severe liver injury, leading to acute liver failure requiring liver transplantation. In patients with chronic liver disease, especially liver cirrhosis, immune dysfunction can increase the risk of infection. Immune dysfunction has a multifactorial physiopathological mechanism, implying a complement system and macrophage activation, lymphocyte and neutrophil activity dysfunction, and intestinal dysbiosis. This review aims to evaluate the most relevant studies published in the last years related to the etiopathogenetic, biochemical, and histological aspects of liver injury in patients diagnosed with COVID-19. Liver damage is more evident in patients with underlying chronic liver disease, with a significantly higher risk of developing severe outcomes of COVID-19 and death. Systemic inflammation, coagulation disorders, endothelial damage, and immune dysfunction explain the pathogenic mechanisms involved in impaired liver function. Although various mechanisms of action of SARS-CoV-2 on the liver cell have been studied, the impact of the direct viral effect on hepatocytes is not yet established.

1. Introduction

COVID-19 clinical presentation falls on a wide spectrum, from mild cases complaining of minor symptoms to severe illness with multiorgan dysfunctions and death. Multiple organ injuries have been described in COVID-19, such as pulmonary affliction, acute kidney damage, liver injury, stroke, cardiovascular and digestive tract disorders [1,2]. The literature recognizes the threat of hepatocyte infection and subsequent hepatic injury, the virus using angiotensin 2 converting receptor protein (ACE2) to infiltrate the cells. The aspects of liver injury are also large, sometimes manifested only with a mild increase in liver enzymes, but sometimes with severe liver injury, determining acute liver failure that requires liver transplantation [3].
This literature review aims to outline some of the most important and recent aspects of COVID-19 infection on liver function based on the comprehensive data reported since the pandemic outbreak.

2. Materials and Methods

The purpose of this review is to make a comprehensive and integrated approach to the essential aspects of liver involvement in COVID-19 disease, including pathogenic mechanisms, biochemical abnormalities, and correlations between preexisting liver diseases and effects of SARS-CoV-2, researching the most exhaustive publications in the current literature.
A series of electronic searches in PubMed was conducted using the following keywords: “COVID-19”, “SARS-CoV-2”, “chronic liver disease”, “cirrhosis”, “drug-induced liver injury”, and “NAFLD”. Articles obtained from these search queries were manually assessed for information quality and results significance. References cited in selected papers were also evaluated and included if deemed relevant.

3. Pathophysiology and Histology

In SARS-CoV-2 replication, tissue reservoirs are not completely elucidated due to difficulties in collecting biopsy samples and in isolating the samples in high-level laboratories.
SARS-CoV-2 binds to ACE2 to penetrate host cells [3]. Transmembrane protease serine 2 (TMPRSS2) and essential amino acid cleavage enzyme (FURIN) are also crucial in the production of the infection [4]. ACE2 cellular entry receptor is widely expressed in human tissues such as in the lungs (predominantly type II alveolar cells), gastrointestinal tract cells (esophageal epithelium cells, also enterocytes), liver (hepatocytes and cholangiocytes), cardiovascular system (myocardial cells), kidney (proximal tubular cells and urothelium), as well as in the pancreas [5].
Recent studies have found that ACE2 expression in cholangiocytes is significantly increased versus in hepatocytes (59.7% vs. 2.6%) [6], which suggests that SARS-CoV-2 determines a direct cytopathic effect by binding to cholangiocytes that express ACE2. Cholangiocytes have a definite role in hepatocyte regeneration mechanisms and immune response; thus, alteration of their function can cause hepatobiliary lesions, an aspect suggested by an increased titer of enzymatic cholestasis markers (gamma-glutamyl transferase) [7,8,9].
The histological changes in patients infected with SARS-CoV-2 and underlying liver disease have not yet been established. However, a significant increase in ACE2 expression in the liver of patients with chronic hepatitis C virus infection (HCV) compared to healthy individuals is documented in previous studies. The expression of ACE2 in human cirrhosis liver was described in 2005 by Paizis et al., with researchers detecting the receptor in most hepatocytes contained inside cirrhotic nodules and endothelial cells [10]. Pre-existing liver damage and inflammation appear to potentiate SARS-CoV-2 liver tropism by modulating ACE2 receptor expression [11,12].
SARS-CoV-2 PCR is positive in stool samples until one week after viral lung elimination [13,14,15]. Enterocyte infection was objected to by identifying RNA and viral proteins that persist in the intestinal mucosa for several months after recovery [16].
There is no clear evidence of direct specific liver tropism of SARS-CoV-2 [17], although liver histological lesions induced by SARS-CoV-2 cannot be denied.
Vascular abnormalities such as venous and sinusoidal micro thrombosis (100%), micro and macrovesicular steatosis (50%), mild inflammation of the portal spaces (66%), and portal fibrosis (60%) were histologically evidentiated in several studies, which suggests the presence of pre-existing liver disease, especially non-alcoholic hepatic steatosis (NASH), with or without associated metabolic risk factors, such as hypertension or impaired glucose tolerance.
It was postulated that the liver is a target for SARS-CoV-2 adhesion, because the similarity between ACE2 expression in alveolar cells and cholangiocytes [18,19] and hepatocyte degeneration, focal necrosis, and canalicular cholestasis were observed in a microscopic study [20]. Glycogen accumulation in hepatocytes, sinusoidal dilatation, moderate lymphocytic infiltration, and necrosis were also described in the centrolobular areas [19,21].
Underlying liver disease, hepatotoxic drugs, and hyperinflammatory status due to SARS-CoV-2 infection can determine moderate to severe histological liver lesions favored by tissue hypoxia (Figure 1).

4. Biochemical Abnormalities in COVID-19

Hepatic biochemical abnormalities are commonly encountered in patients with COVID-19. Their incidence is between 15% and 65% of people infected with SARS-CoV-2, according to recently published studies [22,23,24,25,26,27,28,29,30].
Alterations in liver biochemistry in COVID-19 consist of generally slight increases (×1–2 more than the upper limit) in serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) [23,24,25,31]. These appear both in previously healthy subjects and individuals with pre-existing hepatic injury [28]. Based on the results from the study conducted by Fu et al., patients with raised AST levels and total bilirubin (TBIL) had an unfavorable prognosis [25].
Another study by Hajifathalian et al. on a target group of 1059 patients diagnosed with COVID-19 showed that 62% had a minimum of one elevated liver enzyme [32]. Similar results were reported based on the study conducted by Cholankeril et al. on a smaller group of 115 patients [33].
High levels of AST and GGT were not associated with survival rates, according to Bernal-Monterde et al.’s retrospective study, on a lot of 540 subjects [34].
Various factors are responsible for biochemical anomalies, with possible contributing mechanisms being the immune-mediated inflammatory response, liver congestion, drug-induced liver damage, and direct liver cell infection [35]. In hospitalized patients, increased AST correlates positively with ALT but not with CRP (C-reactive protein), ferritin, or creatine kinase [7], suggesting that COVID-related liver enzyme elevation is a result of direct liver injury and that systemic inflammatory syndrome may be associated [36].
In most cases, AST is more increased than ALT, atypical for the classic model of hepatocellular lesions outside known circumstances, such as alcoholic liver disease or specific drug-induced liver lesions [7]. The responsible mechanisms that determine a predominant increase in AST in COVID-19 are incompletely studied and can be attributed to hepatic steatosis induced by SARS-CoV-2 [29], mitochondrial dysfunction associated with COVID-19 [30,35], as well as by hepatic perfusion impairment due to micro-thrombotic status [37,38]. Increased AST also correlates with systemic hypoxia, affecting patients with COVID-19 [39,40].
Increased liver enzymes are also correlated with the release of proinflammatory cytokines [41], with a significant increase in CRP, D-dimers, IL-6, and serum ferritin being described [8,31,42,43]. Increased levels of IL-6 are associated with liver damage [27,44]. The serum concentration of IL-6 correlates with the severity of the infection, increasing during the disease and decreasing post-recovery [45].
Hepatocytic ischemia, tissue congestion, and hepatic arteriovenous thrombosis [37,44] are the main factors that alter hepatic biochemical tests [46,47,48,49].
The predictive value of elevated liver enzymes in patients with SARS-CoV-2 infection is continuously studied. Some studies have shown correlations between increased serum liver enzymes and severe disease, sometimes requiring admission to intensive care and mechanical ventilation [30,50,51,52,53,54]. In contrast, other studies have reported no clear association between raised hepatic enzymes and mortality [52,55]. A study by Mohamed et al. highlighted statistically significant severe outcomes in patients with abnormal liver function and histopathological lesions [56].
The prognostic significance of abnormal hepatic biochemistry could be correlated with the host’s immune response and the use of aggressive therapies in severe patients [24,31,57,58,59].

5. Drug-Induced Liver Damage

Drug-induced liver damage (DILI) is generally rare but represents a significant cause of acute liver failure with high mortality; many drugs can cause it, and differential diagnosis is difficult.
Hospitalized COVID-19 patients need complex treatment [60]. In this context, concerted studies on pharmacological agents’ hepatotoxicity are essential in diagnosis because drug hepatotoxicity may vary depending on patients’ race, age, or gender [61].
Many drugs can impair liver function; some may cause an asymptomatic increase in liver enzymes; in other cases, they determine acute liver failure.
Drug-induced liver injury most commonly increases liver enzymes due to experimental antiviral therapies (Figure 2) [49]. Liver damage caused by antivirals such as lopinavir–ritonavir [50,62] and remdesivir has been studied, with the hepatotoxicity being extensively studied. Antibiotics, antivirals, and anti-inflammatories, paracetamol, and tocilizumab [63,64] can cause liver damage [65].
Combining antivirals with a risk of overdose (Ritonavir and Lopinavir) can induce hepatocyte apoptosis by activating the endoplasmic reticulum course by the caspase cascade system, causing oxidative stress through consecutive inflammatory reactions. A study conducted by Cai et al. on 417 patients from Shenzhen, China, reported that antivirals are correlated with 4× increased risk of hepatic damage [51].
Low molecular-weight heparin (LMWH) liver damage is an uncommon and reversible adverse effect. The mechanism is unknown, with a possible idiosyncratic effect being described [66]. LMWH has been associated with an elevation of ALT and AST in 4–13% of patients. However, values over 5× the upper limit of normal are uncommon and appear in individuals treated with high doses. ALT/AST usually increases within 3–7 days of anticoagulant treatment and are generally moderate or asymptomatic, improving quickly after discontinuing anticoagulant therapy. Liver enzyme values often decrease even when anticoagulant administration is continued in therapeutic doses [64].
Generalized inflammation determined by the activation of the cytokine cascade can determine multiorgan dysfunction and severe complications in patients with SARS-CoV-2 infection, with both pulmonary and cardiac or liver damage. IL-6 inhibitors, such as tocilizumab used in COVID-19 to reduce hyperactive inflammation, can determine severe liver damage, such as acute hepatitis or acute liver failure, requiring the need for liver transplant [67].
Liver injury incidence varies by drug but registers an increased parallel to the number of agents administered.
Colchicine, medication used in COVID-19 patients to reduce inflammatory status [68,69], is associated with liver damage, although low colchicine doses seem to have an excellent hepatic safety profile [70,71]. A meta-analysis published by Kedar et al. evaluating the efficacy and safety of colchicine showed no significant reduction in mortality risk [72]. Most data indicate no benefit from including colchicine in the standard treatment regimen in these patients.
Medical history, exclusion of other liver disorders using testing, and proof of injury associated with suspected therapeutic agents are required to diagnose DILI.
Several countries used hydroxychloroquine (HCQ) as one of the potential therapeutic strategies against COVID-19, despite the scarcity of scientific evidence and conflicting opinions regarding this drug [73,74]. Adverse musculoskeletal, hematological, cardiac, ophthalmological, and hepatic events are correlated with HCQ use [75]. However, severe liver dysfunction was rarely documented in the literature [76].
Corticosteroids have been widely administered during COVID-19 [77]. Prolonged use of these drugs can cause liver steatosis, while high doses can result in acute liver failure [78].

6. Clinical Correlations between SARS-CoV-2 Infection and Underlying Chronic Liver Disease

6.1. COVID-19 and Liver Cirrhosis

Ongoing studies are currently trying to determine the relationship between SARS-CoV-2 and chronic liver disease patients regarding their susceptibility to infection. To date, published studies have not suggested that patients with underlying chronic liver disease could have an increased susceptibility to SARS-CoV-2 infection [79], and United States medical data have indicated a reduced rate of positive testing among patients with liver cirrhosis [80,81]. However, chronic liver disease, including liver cirrhosis, is unlikely to protect against contracting SARS-CoV-2 infection. The lower rate of positive tests is probably due to strict adherence to prophylactic measures (e.g., social distancing and wearing a protective mask).
Patients with liver cirrhosis infected with SARS-CoV-2 show a gradual increase in morbidity and mortality related to the severity of liver disease, assessed by the Child–Pugh class. Thus, an increase in mortality was observed in patients with cirrhosis of Child–Pugh C, whose survivals decrease to 10% once subjected to mechanical ventilation. COVID-19 disease-related mortality was significantly associated with the severity of underlying liver cirrhosis, with the risk of death increasing in parallel with the severity class of liver disease: CP-A class 1.90%, CP-B 4.14%, and CP-C 9.32%, according to ongoing studies [82]. Strong evidence for increased disease severity in patients associated both COVID-19 and cirrhosis was presented in a large meta-analysis evaluating clinical data obtained from over 900,000 patients [83].
Cirrhosis disrupts both the local immunity of the liver and systemic immunity. This immune impairment may account for susceptibility to severe forms of COVID-19 and grave outcomes observed in this group [84].
Although acute mortality in patients with liver cirrhosis and COVID-19 is increased, in those patients who survive the initial episode, the risk of death or readmission at 90 days is similar to the risk observed in patients with liver cirrhosis without COVID-19 [85]. Therefore, except for the acute infectious period, the SARS-CoV-2 condition does not appear to precipitate liver disease progression.
On the other hand, other studies using multivariable analysis have published results depicting no correlation between cirrhosis and COVID-19 mortality [86,87]. A recent study performed by Simon et al. in 2021 did not find a specific relation between COVID-19 and the outcome or clinical course of cirrhosis [88].

6.2. COVID-19 and MAFLD

The etiology of liver diseases could influence the clinical evolution of SARS-CoV-2 infection. Risk factors associated with higher morbidity and mortality rates in SARS-CoV-2 infection are represented by age, obesity, and diabetes. However, there are inconsistencies in the literature regarding the influence of metabolic-associated fatty liver disease (MAFLD) on the clinical course of the SARS-CoV-2 condition, related to the difficulties in the differential diagnosis of MAFLD and other metabolic comorbidities [89,90].
Some reports describe a strong association between MAFLD and the progression of SARS-CoV-2 infection. Some studies show that people with MAFLD have an increased risk of symptomatic SARS-CoV-2 disease, a higher risk of progression to severe forms, and a longer time for viral clearance [91]. In MAFLD, the polarization status of macrophages could be disrupted, modulating inflammatory response to SARS-CoV-2 [91].
A meta-analysis of available data shows that among MAFLD patients with SARS-CoV-2 infection, obesity increases the risk of severe SARS-CoV-2 disease. These findings support the specific role of MAFLD in modulating susceptibility to SARS-CoV-2 infection and progression (Table 1) [92].
MAFLD is associated not only with COVID-19 but also with other systemic disorders, such as hyperglycemia, insulin resistance, altered immune status, obesity, vitamin D deficiency, diverticulosis, and anemia of chronic disease, through systemic inflammation [93,94,95].

6.3. COVID-19 and Chronic Hepatitis

A study of 1193 patients by Ronderos et al. [96] showed that chronic hepatitis C was correlated with increased in-hospital mortality in acute SARS-CoV-2 infection. Patients with chronic hepatitis C might have an increased risk of severe respiratory complications without previous comorbidity or COVID-19 liver damage [97]. The effects are correlated with the extrahepatic manifestations of HCV infection, which stimulate ACE2/TMPRSS mechanisms, and endothelial dysfunction and are secondary to the inflammatory process. However, more available data are needed for a clear conclusion.
A study conducted on 2482 patients by Kang et al. [98] documented the paradoxical relation between chronic hepatitis B and SARS-CoV-2 infection—the condition does not increase the risk of developing severe forms of COVID-19 and does not negatively influence disease outcomes, even if it appears that preexisting B virus infection and treatment with antiviral agents have a protective effect, decreasing the risk of contracting SARS-CoV-2 infection. The outcome of SARS-CoV-2 infection in HBV patients depends on the previous stage of chronic liver disease, described by Shanshan Yang et al. in a large study [99].

6.4. COVID-19 and Autoimmune Hepatitis

Many authors have focused their studies on the evolution of autoimmune hepatitis (AIH) in patients with SARS-CoV-2 infection. It was postulated that immunosuppressive treatment of AIH would increase these patients’ risk of SARS-CoV-2 infection. Still, a prevalence of severe forms of COVID-19 was not observed, probably due to the prevention effect of a systemic inflammatory response by immunosuppressive therapy. Conversely, immunosuppressive treatment increases the time of SARS-CoV-2 virus clearance, and these patients become a source of contamination for a prolonged period [100].
An international multicentric study by Efe et al. related to outcomes of COVID-19 in patients with autoimmune hepatitis revealed that patients with AIH were not at higher risk for a worse prognosis with COVID-19 than other related causes of CLD [101].
A recent study, documented by Ashley L. Faulx et al. in 2021, suggested that AIH does not determine a more severe prognosis in co-infection with COVID-19, even in those patients receiving immunosuppressive drugs; thus, immunosuppressive treatment should not be interrupted in patients with AIH who develop severe forms of COVID-19, as there are no conclusive indications of worsening the clinical outcome in these patients [102].
Other studies on the relation between immunosuppressive medication and the prognosis of COVID-19 in patients diagnosed with AIH have concluded that systemic glucocorticoids or immunosuppressive therapy prescribed before the onset of COVID-19 was significantly associated with COVID-19-increased severity in patients with AIH [103].
Neeraj Kumar et al. describe a case of severe evolution of COVID-19 in a young man with autoimmune hepatitis, considering that morbidity in COVID-19 associated with liver disease is due to hyperinflammation and cytokine storm with increased IL-6 levels. Significant cytokine release and inflammatory responses affect both the onset and severity of disease progression. Consequently, a rapid and appropriate diagnostic evaluation and accurate estimation and prognosis are necessary [104].

6.5. COVID-19 and Vascular Diseases

A study conducted by Baiges et al. on patients with SARS-CoV-2 infection and underlying vascular liver diseases, including Budd–Chiari syndrome, portosinusoidal vascular disease and noncirrhotic splanchnic vein thrombosis, revealed a higher risk of SARS-CoV-2 infection and a higher risk of severe forms of COVID-19 [105]. Further studies in this area are needed.

7. COVID-19 and Cholangitis

Secondary sclerosing cholangitis is a chronic condition characterized by progressive fibrosis and biliary tract destruction, which can lead to biliary cirrhosis.
Post-COVID-19 cholangiopathy is a unique concept, defined as a variant of secondary sclerosing cholangitis. It can be determined by SARS-CoV-2 infection, or it can be drug induced. Cholangiopathy may be present in many other associated diseases, such as AIDS, cholangiolithiasis, diffuse intrahepatic metastases, and histiocytosis C [106].
The molecular mechanism can be explained due to the predominance of the ACE2 receptor in cholangiocytes. The presence of viral receptors on the host cell’s surface significantly determines viral tropism. The penetration of SARS-CoV-2 in the host’s cells is mediated by the S protein, which specifically interacts with ACE2 and transmembrane serine protease 2 (TMPRSS2) receptors. ACE2 expression is relatively low in hepatocytes and is significantly increased in cholangiocytes, while transmembrane serine protease 2 expression is higher in hepatocytes.
The binding of SARS-CoV-2 to the ACE2-receptors in cholangiocytes affects the barrier and the biliary acid transport mechanism by affecting gene regulation, leading to cholestasis [107].
Diagnosis depends on history, clinical evaluation, biological tests, and imaging studies.
In a study of 2047 patients admitted in hospital with COVID-19, 12 patients with severe COVID-18 developed cholangiopathy syndrome characterized by cholestasis and biliary tract abnormalities similar to the particularities observed in patients with secondary sclerosing cholangitis.
Histologic features included inflammation, strictures, cholangiocyte injury with microvascular anomalies, and fibrosis periportal hepatocytes metaplasia [106].
Biliary tract disorder in COVID-19 patients can be suspected when clinical and biological tests reveal cholestasis and elevated liver enzymes. Biliary imaging methods confirm the diagnosis of secondary sclerosing cholangitis.
Further research is needed to assess the pathogenesis in cholangiopathy associated with SARS-CoV-2 infection and to find preventive and optimal therapeutic measures [53].

8. COVID-19 and High-Risk Groups

According to their immunocompromised status, liver transplant recipients have an increased risk of severe clinical forms of SARS-CoV-2 infection. A retrospective study conducted by Colmenero et al. in hospitalized patients with liver transplants and COVID-19 highlighted a mortality rate of 18%, lower than in the general population, despite the evidence of a more severe disease outcome [108,109]. Similar results were cited in another multicentric study on 112 patients conducted by Rabbie et al., showing a mortality rate of 22.3%, lower than in patients without liver transplants [110].
This is due to these patients’ immunomodulatory therapy, which can improve the systemic inflammatory response, reducing mortality [109,111]. However, immunosuppressive treatment can delay viral clearance, arguing for more severe clinical evolution [107]. An increased risk of severe forms and exitus in transplanted patients was correlated with young age, metabolic syndrome association, prescription of antibiotics and vasopressor treatment [110].
Pregnant women are a high-risk population category for severe outcomes of SARS-CoV-2 infection, with an increased prevalence of premature births. Among important maternal mortality causes are HELLP syndrome, hemolysis, liver cytolysis and preeclampsia. The studies carried out support an increased risk of preeclampsia in pregnant women with SARS-CoV-2 infection, suggesting a possible overlap of physiopathological hypotheses [112].
Risk factors correlated with severe forms of COVID-19 in pregnant women include smoking, obesity, diabetes, and preeclampsia [113,114].
Although pregnancy is not associated with increased susceptibility to contracting SARS-CoV-2 infection, pregnant women are at higher risk of severe outcomes [112,115] and complications, such as preeclampsia or HELLP syndrome [112,116,117]. Thrombocytopenia, increased liver enzymes and hemolysis are markers present both in HELLP syndrome and in patients with multiorgan dysfunction in critical condition [112], suggesting that SARS-CoV-2 infection has similarities with HELLP syndrome in pregnant women [109] and raises real challenges in the differential diagnosis. It is assumed that there is a pathogenetic link between SARS-CoV-2 and HELLP syndrome, an association that requires extensive future research.

9. Conclusions

Liver damage in SARS-CoV-2 infection plays an essential role in COVID-19 disease. This is clinically significant, especially in patients with pre-existing liver diseases that have a higher risk of severe COVID-19 and death.
Systemic inflammation, coagulation disorder, endothelial damage, and immune dysfunction explain the pathogenic mechanisms involved in the deterioration of liver function.
Although various mechanisms of action of the SARS-CoV-2 virus on liver cells have been studied, the clinical impact of the direct viral effect on liver cells has not been established. Some severe COVID-19 cases have reported acute liver damage associated with increased mortality.
Immune dysfunction related to liver cirrhosis has a much more harmful effect on the clinical outcome of SARS-CoV-2 infection than medication-induced immunosuppression in these patients.
More extensive observational studies are required to establish the impact of COVID-19 infection on liver function.

Author Contributions

Conceptualization, C.M.M., C.M.V., E.C. and P.M.; methodology, M.P.; software, A.O.D. and R.M.; validation, C.M.M., P.M. and C.M.V.; formal analysis, C.M.M.; investigation, V.B.; resources, C.M.M. and M.P.; data curation, M.S.P.; writing—original draft preparation, C.M.M. and E.C.; writing—review and editing, C.M.V.; visualization, C.M.M.; supervision, P.M. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Yang, X.; Yu, Y.; Xu, J.; Shu, H.; Xia, J.; Liu, H.; Wu, Y.; Zhang, L.; Yu, Z.; Fang, M.; et al. Clinical Course and Outcomes of Critically Ill Patients with SARS-CoV-2 Pneumonia in Wuhan, China: A Single-Centered, Retrospective, Observational Study. Lancet Respir. Med. 2020, 8, 475–481. [Google Scholar] [CrossRef] [PubMed][Green Version]
  2. Marginean, C.M.; Popescu, M.; Vasile, C.M.; Cioboata, R.; Mitrut, P.; Popescu, I.A.S.; Biciusca, V.; Docea, A.O.; Mitrut, R.; Marginean, I.C.; et al. Challenges in the Differential Diagnosis of COVID-19 Pneumonia: A Pictorial Review. Diagnostics 2022, 12, 2823. [Google Scholar] [CrossRef] [PubMed]
  3. Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.-H.; Nitsche, A.; et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020, 181, 271–280.e8. [Google Scholar] [CrossRef] [PubMed]
  4. McGrowder, D.A.; Miller, F.; Anderson Cross, M.; Anderson-Jackson, L.; Bryan, S.; Dilworth, L. Abnormal Liver Biochemistry Tests and Acute Liver Injury in COVID-19 Patients: Current Evidence and Potential Pathogenesis. Diseases 2021, 9, 50. [Google Scholar] [CrossRef] [PubMed]
  5. Liu, F.; Long, X.; Zhang, B.; Zhang, W.; Chen, X.; Zhang, Z. ACE2 Expression in Pancreas May Cause Pancreatic Damage after SARS-CoV-2 Infection. Clin. Gastroenterol. Hepatol. 2020, 18, 2128–2130.e2. [Google Scholar] [CrossRef]
  6. Fan, Z.; Chen, L.; Li, J.; Cheng, X.; Yang, J.; Tian, C.; Zhang, Y.; Huang, S.; Liu, Z.; Cheng, J. Clinical Features of COVID-19-Related Liver Functional Abnormality. Clin. Gastroenterol. Hepatol. 2020, 18, 1561–1566. [Google Scholar] [CrossRef]
  7. Zhang, C.; Shi, L.; Wang, F.-S. Liver Injury in COVID-19: Management and Challenges. Lancet Gastroenterol. Hepatol. 2020, 5, 428–430. [Google Scholar] [CrossRef]
  8. Xu, L.; Liu, J.; Lu, M.; Yang, D.; Zheng, X. Liver Injury during Highly Pathogenic Human Coronavirus Infections. Liver Int. 2020, 40, 998–1004. [Google Scholar] [CrossRef][Green Version]
  9. Albillos, A.; Lario, M.; Álvarez-Mon, M. Cirrhosis-Associated Immune Dysfunction: Distinctive Features and Clinical Relevance. J. Hepatol. 2014, 61, 1385–1396. [Google Scholar] [CrossRef][Green Version]
  10. Paizis, G.; Tikellis, C.; Cooper, M.E.; Schembri, J.M.; Lew, R.A.; Smith, A.I.; Shaw, T.; Warner, F.J.; Zuilli, A.; Burrell, L.M.; et al. Chronic Liver Injury in Rats and Humans Upregulates the Novel Enzyme Angiotensin Converting Enzyme 2. Gut 2005, 54, 1790–1796. [Google Scholar] [CrossRef][Green Version]
  11. Chua, R.L.; Lukassen, S.; Trump, S.; Hennig, B.P.; Wendisch, D.; Pott, F.; Debnath, O.; Thürmann, L.; Kurth, F.; Völker, M.T.; et al. COVID-19 Severity Correlates with Airway Epithelium-Immune Cell Interactions Identified by Single-Cell Analysis. Nat. Biotechnol. 2020, 38, 970–979. [Google Scholar] [CrossRef] [PubMed]
  12. Ziegler, C.G.K.; Allon, S.J.; Nyquist, S.K.; Mbano, I.M.; Miao, V.N.; Tzouanas, C.N.; Cao, Y.; Yousif, A.S.; Bals, J.; Hauser, B.M.; et al. SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues. Cell 2020, 181, 1016–1035.e19. [Google Scholar] [CrossRef] [PubMed]
  13. Zuo, T.; Liu, Q.; Zhang, F.; Lui, G.C.-Y.; Tso, E.Y.; Yeoh, Y.K.; Chen, Z.; Boon, S.S.; Chan, F.K.; Chan, P.K.; et al. Depicting SARS-CoV-2 Faecal Viral Activity in Association with Gut Microbiota Composition in Patients with COVID-19. Gut 2021, 70, 276–284. [Google Scholar] [CrossRef] [PubMed]
  14. Lamers, M.M.; Beumer, J.; van der Vaart, J.; Knoops, K.; Puschhof, J.; Breugem, T.I.; Ravelli, R.B.G.; Paul van Schayck, J.; Mykytyn, A.Z.; Duimel, H.Q.; et al. SARS-CoV-2 Productively Infects Human Gut Enterocytes. Science 2020, 369, 50–54. [Google Scholar] [CrossRef]
  15. Qian, Q.; Fan, L.; Liu, W.; Li, J.; Yue, J.; Wang, M.; Ke, X.; Yin, Y.; Chen, Q.; Jiang, C. Direct Evidence of Active SARS-CoV-2 Replication in the Intestine. Clin. Infect. Dis. 2021, 73, 361–366. [Google Scholar] [CrossRef]
  16. Gaebler, C.; Wang, Z.; Lorenzi, J.C.C.; Muecksch, F.; Finkin, S.; Tokuyama, M.; Cho, A.; Jankovic, M.; Schaefer-Babajew, D.; Oliveira, T.Y.; et al. Evolution of Antibody Immunity to SARS-CoV-2. Nature 2021, 591, 639–644. [Google Scholar] [CrossRef]
  17. Berlin, D.A.; Gulick, R.M.; Martinez, F.J. Severe COVID-19. N. Engl. J. Med. 2020, 383, 2451–2460. [Google Scholar] [CrossRef]
  18. Chai, X.; Hu, L.; Zhang, Y.; Han, W.; Lu, Z.; Ke, A.; Zhou, J.; Shi, G.; Fang, N.; Fan, J.; et al. Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage after 2019-NCoV Infection. bioRxiv 2020, bioRxiv:2020.02.03.931766. [Google Scholar]
  19. Li, Y.; Xiao, S.-Y. Hepatic Involvement in COVID-19 Patients: Pathology, Pathogenesis, and Clinical Implications. J. Med. Virol. 2020, 92, 1491–1494. [Google Scholar] [CrossRef]
  20. Yao, X.H.; Li, T.Y.; He, Z.C.; Ping, Y.F.; Liu, H.W.; Yu, S.C.; Mou, H.M.; Wang, L.H.; Zhang, H.R.; Fu, W.J.; et al. A pathological report of three COVID-19 cases by minimal invasive autopsies. Zhonghua Bing Li Xue Za Zhi 2020, 49, 411–417. [Google Scholar] [CrossRef]
  21. Hamming, I.; Timens, W.; Bulthuis, M.; Lely, A.; Navis, G.; van Goor, H. Tissue Distribution of ACE2 Protein, the Functional Receptor for SARS Coronavirus. A First Step in Understanding SARS Pathogenesis. J. Pathol. 2004, 203, 631–637. [Google Scholar] [CrossRef] [PubMed]
  22. Onabajo, O.O.; Banday, A.R.; Stanifer, M.L.; Yan, W.; Obajemu, A.; Santer, D.M.; Florez-Vargas, O.; Piontkivska, H.; Vargas, J.M.; Ring, T.J.; et al. Interferons and Viruses Induce a Novel Truncated ACE2 Isoform and Not the Full-Length SARS-CoV-2 Receptor. Nat. Genet. 2020, 52, 1283–1293. [Google Scholar] [CrossRef] [PubMed]
  23. Sultan, S.; Altayar, O.; Siddique, S.M.; Davitkov, P.; Feuerstein, J.D.; Lim, J.K.; Falck-Ytter, Y.; El-Serag, H.B.; AGA Institute. AGA Institute Rapid Review of the Gastrointestinal and Liver Manifestations of COVID-19, Meta-Analysis of International Data, and Recommendations for the Consultative Management of Patients with COVID-19. Gastroenterology 2020, 159, 320–334.e27. [Google Scholar] [CrossRef] [PubMed]
  24. Richardson, S.; Hirsch, J.S.; Narasimhan, M.; Crawford, J.M.; McGinn, T.; Davidson, K.W.; the Northwell COVID-19 Research Consortium; Barnaby, D.P.; Becker, L.B.; Chelico, J.D.; et al. Presenting Characteristics, Comorbidities, and Outcomes among 5700 Patients Hospitalized with COVID-19 in the New York City Area. JAMA 2020, 323, 2052–2059. [Google Scholar] [CrossRef]
  25. Goyal, P.; Choi, J.J.; Pinheiro, L.C.; Schenck, E.J.; Chen, R.; Jabri, A.; Satlin, M.J.; Campion, T.R.; Nahid, M.; Ringel, J.B.; et al. Clinical Characteristics of Covid-19 in New York City. N. Engl. J. Med. 2020, 382, 2372–2374. [Google Scholar] [CrossRef]
  26. Youssef, M.; Hussein, M.H.; Attia, A.S.; Elshazli, R.M.; Omar, M.; Zora, G.; Farhoud, A.S.; Elnahla, A.; Shihabi, A.; Toraih, E.A.; et al. COVID-19 and Liver Dysfunction: A Systematic Review and Meta-Analysis of Retrospective Studies. J. Med. Virol. 2020, 92, 1825–1833. [Google Scholar] [CrossRef] [PubMed]
  27. Hundt, M.A.; Deng, Y.; Ciarleglio, M.M.; Nathanson, M.H.; Lim, J.K. Abnormal Liver Tests in COVID-19: A Retrospective Observational Cohort Study of 1827 Patients in a Major U.S. Hospital Network. Hepatology 2020, 72, 1169–1176. [Google Scholar] [CrossRef] [PubMed]
  28. Elmunzer, B.J.; Spitzer, R.L.; Foster, L.D.; Merchant, A.A.; Howard, E.F.; Patel, V.A.; West, M.K.; Qayed, E.; Nustas, R.; Zakaria, A.; et al. Digestive Manifestations in Patients Hospitalized with Coronavirus Disease 2019. Clin. Gastroenterol. Hepatol. 2021, 19, 1355–1365.e4. [Google Scholar] [CrossRef]
  29. Fu, Y.; Zhu, R.; Bai, T.; Han, P.; He, Q.; Jing, M.; Xiong, X.; Zhao, X.; Quan, R.; Chen, C.; et al. Clinical Features of Patients Infected with Coronavirus Disease 2019 with Elevated Liver Biochemistries: A Multicenter, Retrospective Study. Hepatology 2021, 73, 1509–1520. [Google Scholar] [CrossRef]
  30. Mao, R.; Qiu, Y.; He, J.-S.; Tan, J.-Y.; Li, X.-H.; Liang, J.; Shen, J.; Zhu, L.-R.; Chen, Y.; Iacucci, M.; et al. Manifestations and Prognosis of Gastrointestinal and Liver Involvement in Patients with COVID-19: A Systematic Review and Meta-Analysis. Lancet Gastroenterol. Hepatol. 2020, 5, 667–678. [Google Scholar] [CrossRef]
  31. Phipps, M.M.; Barraza, L.H.; LaSota, E.D.; Sobieszczyk, M.E.; Pereira, M.R.; Zheng, E.X.; Fox, A.N.; Zucker, J.; Verna, E.C. Acute Liver Injury in COVID-19: Prevalence and Association with Clinical Outcomes in a Large U.S. Cohort. Hepatology 2020, 72, 807–817. [Google Scholar] [CrossRef] [PubMed]
  32. Hajifathalian, K.; Krisko, T.; Mehta, A.; Kumar, S.; Schwartz, R.; Fortune, B.; Sharaiha, R.Z. Gastrointestinal and Hepatic Manifestations of 2019 Novel Coronavirus Disease in a Large Cohort of Infected Patients From New York: Clinical Implications. Gastroenterology 2020, 159, 1137–1140.e2. [Google Scholar] [CrossRef]
  33. Cholankeril, G.; Podboy, A.; Aivaliotis, V.I.; Tarlow, B.; Pham, E.A.; Spencer, S.P.; Kim, D.; Hsing, A.; Ahmed, A. High Prevalence of Concurrent Gastrointestinal Manifestations in Patients with Severe Acute Respiratory Syndrome Coronavirus 2: Early Experience From California. Gastroenterology 2020, 159, 775–777. [Google Scholar] [CrossRef]
  34. Bernal-Monterde, V.; Casas-Deza, D.; Letona-Giménez, L.; de la Llama-Celis, N.; Calmarza, P.; Sierra-Gabarda, O.; Betoré-Glaria, E.; Martínez-de Lagos, M.; Martínez-Barredo, L.; Espinosa-Pérez, M.; et al. SARS-CoV-2 Infection Induces a Dual Response in Liver Function Tests: Association with Mortality during Hospitalization. Biomedicines 2020, 8, 328. [Google Scholar] [CrossRef] [PubMed]
  35. Singh, S.; Khan, A. Clinical Characteristics and Outcomes of Coronavirus Disease 2019 among Patients with Preexisting Liver Disease in the United States: A Multicenter Research Network Study. Gastroenterology 2020, 159, 768–771.e3. [Google Scholar] [CrossRef] [PubMed]
  36. Li, T.; Guo, Y.; Zhuang, X.; Huang, L.; Zhang, X.; Wei, F.; Yang, B. Abnormal Liver-Related Biomarkers in COVID-19 Patients and the Role of Prealbumin. Saudi J. Gastroenterol. 2020, 26, 272–278. [Google Scholar] [CrossRef]
  37. Sonzogni, A.; Previtali, G.; Seghezzi, M.; Grazia Alessio, M.; Gianatti, A.; Licini, L.; Morotti, D.; Zerbi, P.; Carsana, L.; Rossi, R.; et al. Liver Histopathology in Severe COVID 19 Respiratory Failure Is Suggestive of Vascular Alterations. Liver Int. 2020, 40, 2110–2116. [Google Scholar] [CrossRef]
  38. Zhang, Y.; Xiao, M.; Zhang, S.; Xia, P.; Cao, W.; Jiang, W.; Chen, H.; Ding, X.; Zhao, H.; Zhang, H.; et al. Coagulopathy and Antiphospholipid Antibodies in Patients with COVID-19. N. Engl. J. Med. 2020, 382, e38. [Google Scholar] [CrossRef]
  39. Yang, L.; Han, Y.; Nilsson-Payant, B.E.; Gupta, V.; Wang, P.; Duan, X.; Tang, X.; Zhu, J.; Zhao, Z.; Jaffré, F.; et al. A Human Pluripotent Stem Cell-Based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids. Cell Stem Cell 2020, 27, 125–136.e7. [Google Scholar] [CrossRef]
  40. Papic, N.; Pangercic, A.; Vargovic, M.; Barsic, B.; Vince, A.; Kuzman, I. Liver Involvement during Influenza Infection: Perspective on the 2009 Influenza Pandemic. Influenza Other Respir. Viruses 2012, 6, e2–e5. [Google Scholar] [CrossRef][Green Version]
  41. Farcas, G.A.; Poutanen, S.M.; Mazzulli, T.; Willey, B.M.; Butany, J.; Asa, S.L.; Faure, P.; Akhavan, P.; Low, D.E.; Kain, K.C. Fatal Severe Acute Respiratory Syndrome Is Associated with Multiorgan Involvement by Coronavirus. J. Infect. Dis. 2005, 191, 193–197. [Google Scholar] [CrossRef] [PubMed][Green Version]
  42. Wang, Y.; Liu, S.; Liu, H.; Li, W.; Lin, F.; Jiang, L.; Li, X.; Xu, P.; Zhang, L.; Zhao, L.; et al. SARS-CoV-2 Infection of the Liver Directly Contributes to Hepatic Impairment in Patients with COVID-19. J. Hepatol. 2020, 73, 807–816. [Google Scholar] [CrossRef] [PubMed]
  43. Shi, Y.; Wang, Y.; Shao, C.; Huang, J.; Gan, J.; Huang, X.; Bucci, E.; Piacentini, M.; Ippolito, G.; Melino, G. COVID-19 Infection: The Perspectives on Immune Responses. Cell Death Differ. 2020, 27, 1451–1454. [Google Scholar] [CrossRef][Green Version]
  44. Lagana, S.M.; Kudose, S.; Iuga, A.C.; Lee, M.J.; Fazlollahi, L.; Remotti, H.E.; Del Portillo, A.; De Michele, S.; de Gonzalez, A.K.; Saqi, A.; et al. Hepatic Pathology in Patients Dying of COVID-19: A Series of 40 Cases Including Clinical, Histologic, and Virologic Data. Mod. Pathol. 2020, 33, 2147–2155. [Google Scholar] [CrossRef] [PubMed]
  45. Diao, B.; Wang, C.; Tan, Y.; Chen, X.; Liu, Y.; Ning, L.; Chen, L.; Li, M.; Liu, Y.; Wang, G.; et al. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19). Front. Immunol. 2020, 11, 827. [Google Scholar] [CrossRef]
  46. Manolis, A.S.; Manolis, T.A.; Manolis, A.A.; Papatheou, D.; Melita, H. COVID-19 Infection: Viral Macro- and Micro-Vascular Coagulopathy and Thromboembolism/Prophylactic and Therapeutic Management. J. Cardiovasc. Pharm. 2021, 26, 12–24. [Google Scholar] [CrossRef]
  47. Bikdeli, B.; Madhavan, M.V.; Jimenez, D.; Chuich, T.; Dreyfus, I.; Driggin, E.; Nigoghossian, C.D.; Ageno, W.; Madjid, M.; Guo, Y.; et al. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review. J. Am. Coll. Cardiol. 2020, 75, 2950–2973. [Google Scholar] [CrossRef]
  48. Middeldorp, S.; Coppens, M.; van Haaps, T.F.; Foppen, M.; Vlaar, A.P.; Müller, M.C.A.; Bouman, C.C.S.; Beenen, L.F.M.; Kootte, R.S.; Heijmans, J.; et al. Incidence of Venous Thromboembolism in Hospitalized Patients with COVID-19. J. Thromb. Haemost. 2020, 18, 1995–2002. [Google Scholar] [CrossRef]
  49. Olry, A.; Meunier, L.; Délire, B.; Larrey, D.; Horsmans, Y.; Le Louët, H. Drug-Induced Liver Injury and COVID-19 Infection: The Rules Remain the Same. Drug Saf. 2020, 43, 615–617. [Google Scholar] [CrossRef]
  50. Weber, S.; Hellmuth, J.C.; Scherer, C.; Muenchhoff, M.; Mayerle, J.; Gerbes, A.L. Liver Function Test Abnormalities at Hospital Admission Are Associated with Severe Course of SARS-CoV-2 Infection: A Prospective Cohort Study. Gut 2021, 70, 1925–1932. [Google Scholar] [CrossRef]
  51. Cai, Q.; Huang, D.; Yu, H.; Zhu, Z.; Xia, Z.; Su, Y.; Li, Z.; Zhou, G.; Gou, J.; Qu, J.; et al. COVID-19: Abnormal Liver Function Tests. J. Hepatol. 2020, 73, 566–574. [Google Scholar] [CrossRef] [PubMed]
  52. Ponziani, F.R.; Del Zompo, F.; Nesci, A.; Santopaolo, F.; Ianiro, G.; Pompili, M.; Gasbarrini, A.; “Gemelli against COVID-19” group. Liver Involvement Is Not Associated with Mortality: Results from a Large Cohort of SARS-CoV-2-Positive Patients. Aliment. Pharm. 2020, 52, 1060–1068. [Google Scholar] [CrossRef]
  53. Yip, T.C.-F.; Lui, G.C.-Y.; Wong, V.W.-S.; Chow, V.C.-Y.; Ho, T.H.-Y.; Li, T.C.-M.; Tse, Y.-K.; Hui, D.S.-C.; Chan, H.L.-Y.; Wong, G.L.-H. Liver Injury Is Independently Associated with Adverse Clinical Outcomes in Patients with COVID-19. Gut 2021, 70, 733–742. [Google Scholar] [CrossRef] [PubMed]
  54. Ding, Z.; Li, G.; Chen, L.; Shu, C.; Song, J.; Wang, W.; Wang, Y.; Chen, Q.; Jin, G.; Liu, T.; et al. Association of Liver Abnormalities with In-Hospital Mortality in Patients with COVID-19. J. Hepatol. 2021, 74, 1295–1302. [Google Scholar] [CrossRef] [PubMed]
  55. 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 Centre in Wuhan City, China. Liver Int. 2020, 40, 2095–2103. [Google Scholar] [CrossRef] [PubMed][Green Version]
  56. Mohammed, S.A.; Eid, K.M.; Anyiam, F.E.; Wadaaallah, H.; Muhamed, M.A.M.; Morsi, M.H.; Dahman, N.B.H. Liver Injury with COVID-19: Laboratory and Histopathological Outcome-Systematic Review and Meta-Analysis. Egypt. Liver J. 2022, 12, 9. [Google Scholar] [CrossRef] [PubMed]
  57. Yadav, D.K.; Singh, A.; Zhang, Q.; Bai, X.; Zhang, W.; Yadav, R.K.; Singh, A.; Zhiwei, L.; Adhikari, V.P.; Liang, T. Involvement of Liver in COVID-19: Systematic Review and Meta-Analysis. Gut 2021, 70, 807–809. [Google Scholar] [CrossRef]
  58. Lei, F.; Liu, Y.-M.; Zhou, F.; Qin, J.-J.; Zhang, P.; Zhu, L.; Zhang, X.-J.; Cai, J.; Lin, L.; Ouyang, S.; et al. Longitudinal Association Between Markers of Liver Injury and Mortality in COVID-19 in China. Hepatology 2020, 72, 389–398. [Google Scholar] [CrossRef]
  59. Bangash, M.N.; Patel, J.M.; Parekh, D.; Murphy, N.; Brown, R.M.; Elsharkawy, A.M.; Mehta, G.; Armstrong, M.J.; Neil, D. SARS-CoV-2: Is the Liver Merely a Bystander to Severe Disease? J. Hepatol. 2020, 73, 995–996. [Google Scholar] [CrossRef]
  60. David, S.; Hamilton, J.P. Drug-Induced Liver Injury. US Gastroenterol. Hepatol. Rev. 2010, 6, 73–80. [Google Scholar]
  61. Björnsson, E.S. Hepatotoxicity by Drugs: The Most Common Implicated Agents. Int. J. Mol. Sci. 2016, 17, 224. [Google Scholar] [CrossRef] [PubMed][Green Version]
  62. Cao, B.; Wang, Y.; Wen, D.; Liu, W.; Wang, J.; Fan, G.; Ruan, L.; Song, B.; Cai, Y.; Wei, M.; et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe COVID-19. N. Engl. J. Med. 2020, 382, 1787–1799. [Google Scholar] [CrossRef] [PubMed]
  63. Muhović, D.; Bojović, J.; Bulatović, A.; Vukčević, B.; Ratković, M.; Lazović, R.; Smolović, B. First Case of Drug-Induced Liver Injury Associated with the Use of Tocilizumab in a Patient with COVID-19. Liver Int. 2020, 40, 1901–1905. [Google Scholar] [CrossRef] [PubMed]
  64. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury; National Institute of Diabetes and Digestive and Kidney Diseases: Bethesda, MD, USA, 2012.
  65. Cascella, M.; Rajnik, M.; Aleem, A.; Dulebohn, S.C.; Di Napoli, R. Features, Evaluation, and Treatment of Coronavirus (COVID-19). In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2022. [Google Scholar]
  66. Hahn, K.J.; Morales, S.J.; Lewis, J.H. Enoxaparin-Induced Liver Injury: Case Report and Review of the Literature and FDA Adverse Event Reporting System (FAERS). Drug Saf. Case Rep. 2015, 2, 17. [Google Scholar] [CrossRef] [PubMed][Green Version]
  67. Ferrara, F.; Granata, G.; Pelliccia, C.; La Porta, R.; Vitiello, A. The Added Value of Pirfenidone to Fight Inflammation and Fibrotic State Induced by SARS-CoV-2: Anti-Inflammatory and Anti-Fibrotic Therapy Could Solve the Lung Complications of the Infection? Eur. J. Clin. Pharm. 2020, 76, 1615–1618. [Google Scholar] [CrossRef]
  68. Hu, T.Y.; Frieman, M.; Wolfram, J. Insights from Nanomedicine into Chloroquine Efficacy against COVID-19. Nat. Nanotechnol. 2020, 15, 247–249. [Google Scholar] [CrossRef][Green Version]
  69. Feng, G.; Zheng, K.I.; Yan, Q.-Q.; Rios, R.S.; Targher, G.; Byrne, C.D.; Poucke, S.V.; Liu, W.-Y.; Zheng, M.-H. COVID-19 and Liver Dysfunction: Current Insights and Emergent Therapeutic Strategies. J. Clin. Transl. Hepatol. 2020, 8, 18–24. [Google Scholar] [CrossRef][Green Version]
  70. Abbott, C.E.; Xu, R.; Sigal, S.H. Colchicine-Induced Hepatotoxicity. ACG Case Rep. J. 2017, 4, e120. [Google Scholar] [CrossRef]
  71. Vitiello, A.; Ferrara, F. Remdesivir versus Ritonavir/Lopinavir in COVID-19 Patients. Ir. J. Med. Sci. 2021, 190, 1249–1250. [Google Scholar] [CrossRef]
  72. Mehta, K.G.; Patel, T.; Chavda, P.D.; Patel, P. Efficacy and Safety of Colchicine in COVID-19: A Meta-Analysis of Randomised Controlled Trials. RMD Open 2021, 7, e001746. [Google Scholar] [CrossRef]
  73. Gautret, P.; Lagier, J.-C.; Parola, P.; Hoang, V.T.; Meddeb, L.; Mailhe, M.; Doudier, B.; Courjon, J.; Giordanengo, V.; Vieira, V.E.; et al. Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an Open-Label Non-Randomized Clinical Trial. Int. J. Antimicrob. Agents 2020, 56, 105949. [Google Scholar] [CrossRef] [PubMed]
  74. Cortegiani, A.; Ingoglia, G.; Ippolito, M.; Giarratano, A.; Einav, S. A Systematic Review on the Efficacy and Safety of Chloroquine for the Treatment of COVID-19. J. Crit. Care 2020, 57, 279–283. [Google Scholar] [CrossRef] [PubMed]
  75. Mahase, E. Covid-19: Six Million Doses of Hydroxychloroquine Donated to US despite Lack of Evidence. BMJ 2020, 368, m1166. [Google Scholar] [CrossRef] [PubMed][Green Version]
  76. Makin, A.J.; Wendon, J.; Fitt, S.; Portmann, B.C.; Williams, R. Fulminant Hepatic Failure Secondary to Hydroxychloroquine. Gut 1994, 35, 569–570. [Google Scholar] [CrossRef] [PubMed]
  77. Sanders, J.M.; Monogue, M.L.; Jodlowski, T.Z.; Cutrell, J.B. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA 2020, 323, 1824–1836. [Google Scholar] [CrossRef] [PubMed]
  78. Ortiz, G.X.; Lenhart, G.; Becker, M.W.; Schwambach, K.H.; Tovo, C.V.; Blatt, C.R. Drug-Induced Liver Injury and COVID-19: A Review for Clinical Practice. World J. Hepatol. 2021, 13, 1143–1153. [Google Scholar] [CrossRef] [PubMed]
  79. Noor, M.T.; Manoria, P. Immune Dysfunction in Cirrhosis. J. Clin. Transl. Hepatol. 2017, 5, 50–58. [Google Scholar] [CrossRef][Green Version]
  80. Fan, V.S.; Dominitz, J.A.; Eastment, M.C.; Locke, E.R.; Green, P.; Berry, K.; O’Hare, A.M.; Shah, J.A.; Crothers, K.; Ioannou, G.N. Risk Factors for Testing Positive for Severe Acute Respiratory Syndrome Coronavirus 2 in a National United States Healthcare System. Clin. Infect. Dis. 2021, 73, e3085–e3094. [Google Scholar] [CrossRef]
  81. Ioannou, G.N.; Liang, P.S.; Locke, E.; Green, P.; Berry, K.; O’Hare, A.M.; Shah, J.A.; Crothers, K.; Eastment, M.C.; Fan, V.S.; et al. Cirrhosis and Severe Acute Respiratory Syndrome Coronavirus 2 Infection in US Veterans: Risk of Infection, Hospitalization, Ventilation, and Mortality. Hepatology 2021, 74, 322–335. [Google Scholar] [CrossRef]
  82. Marjot, T.; Moon, A.M.; Cook, J.A.; Abd-Elsalam, S.; Aloman, C.; Armstrong, M.J.; Pose, E.; Brenner, E.J.; Cargill, T.; Catana, M.-A.; et al. Outcomes Following SARS-CoV-2 Infection in Patients with Chronic Liver Disease: An International Registry Study. J. Hepatol. 2021, 74, 567–577. [Google Scholar] [CrossRef]
  83. Nagarajan, R.; Krishnamoorthy, Y.; Rajaa, S.; Hariharan, V.S. COVID-19 Severity and Mortality among Chronic Liver Disease Patients: A Systematic Review and Meta-Analysis. Prev. Chronic Dis. 2022, 19, E53. [Google Scholar] [CrossRef]
  84. Wang, Y.; Hu, M.; Yang, H. Cirrhosis Is an Independent Predictor for COVID-19 Mortality: A Meta-Analysis of Confounding Cofactors-Controlled Data. J. Hepatol. 2023, 78, e28–e31. [Google Scholar] [CrossRef]
  85. Bajaj, J.S.; Garcia-Tsao, G.; Wong, F.; Biggins, S.W.; Kamath, P.S.; McGeorge, S.; Chew, M.; Pearson, M.; Shaw, J.; Kalluri, A.; et al. Cirrhosis Is Associated with High Mortality and Readmissions over 90 Days Regardless of COVID-19: A Multicenter Cohort. Liver Transpl. 2021, 27, 1343–1347. [Google Scholar] [CrossRef]
  86. Bushman, D.; Davidson, A.; Pathela, P.; Greene, S.K.; Weiss, D.; Reddy, V.; New York City Fatal Case-Control Study Team; Latash, J. Risk Factors for Death among Hospitalized Patients Aged 21–64 Years Diagnosed with COVID-19—New York City, March 13–April 9, 2020. J. Racial Ethn. Health Disparities 2022, 9, 1584–1599. [Google Scholar] [CrossRef]
  87. Castilla, J.; Guevara, M.; Miqueleiz, A.; Baigorria, F.; Ibero-Esparza, C.; Navascués, A.; Trobajo-Sanmartín, C.; Martínez-Baz, I.; Casado, I.; Burgui, C.; et al. Risk Factors of Infection, Hospitalization and Death from SARS-CoV-2: A Population-Based Cohort Study. J. Clin. Med. 2021, 10, 2608. [Google Scholar] [CrossRef]
  88. Simon, T.G.; Hagström, H.; Sharma, R.; Söderling, J.; Roelstraete, B.; Larsson, E.; Ludvigsson, J.F. Risk of Severe COVID-19 and Mortality in Patients with Established Chronic Liver Disease: A Nationwide Matched Cohort Study. BMC Gastroenterol. 2021, 21, 439. [Google Scholar] [CrossRef]
  89. Eslam, M.; Newsome, P.N.; Sarin, S.K.; Anstee, Q.M.; Targher, G.; Romero-Gomez, M.; Zelber-Sagi, S.; Wai-Sun Wong, V.; Dufour, J.-F.; Schattenberg, J.M.; et al. A New Definition for Metabolic Dysfunction-Associated Fatty Liver Disease: An International Expert Consensus Statement. J. Hepatol. 2020, 73, 202–209. [Google Scholar] [CrossRef]
  90. Stan, I.S.; Biciuşcă, V.; Durand, P.; Petrescu, A.M.; Oancea, D.M.; Ciuciulete, A.R.; Petrescu, M.; Udriştoiu, I.; Camen, G.C.; Bălteanu, M.A.; et al. Diagnostic and Prognostic Significance of Hepatic Steatosis in Patients with Chronic Hepatitis C. Rom. J. Morphol. Embryol. 2021, 62, 765–775. [Google Scholar] [CrossRef]
  91. Bucurica, S.; Ionita Radu, F.; Bucurica, A.; Socol, C.; Prodan, I.; Tudor, I.; Sirbu, C.A.; Plesa, F.C.; Jinga, M. Risk of New-Onset Liver Injuries Due to COVID-19 in Preexisting Hepatic Conditions—Review of the Literature. Medicina 2023, 59, 62. [Google Scholar] [CrossRef]
  92. Asemota, J.; Aduli, F. The Impact of Nonalcoholic Fatty Liver Disease on the Outcomes of Coronavirus Disease 2019 Infection. Clin. Liver Dis. 2022, 19, 29–31. [Google Scholar] [CrossRef]
  93. Adenote, A.; Dumic, I.; Madrid, C.; Barusya, C.; Nordstrom, C.W.; Rueda Prada, L. NAFLD and Infection, a Nuanced Relationship. Can. J. Gastroenterol. Hepatol. 2021, 2021, 5556354. [Google Scholar] [CrossRef]
  94. Singer, C.E.; Vasile, C.M.; Popescu, M.; Popescu, A.I.S.; Marginean, I.C.; Iacob, G.A.; Popescu, M.D.; Marginean, C.M. Role of Iron Deficiency in Heart Failure—Clinical and Treatment Approach: An Overview. Diagnostics 2023, 13, 304. [Google Scholar] [CrossRef]
  95. Pantic, I.; Lugonja, S.; Rajovic, N.; Dumic, I.; Milovanovic, T. Colonic Diverticulosis and Non-Alcoholic Fatty Liver Disease: Is There a Connection? Medicina 2022, 58, 38. [Google Scholar] [CrossRef]
  96. Ronderos, D.; Omar, A.M.S.; Abbas, H.; Makker, J.; Baiomi, A.; Sun, H.; Mantri, N.; Choi, Y.; Fortuzi, K.; Shin, D.; et al. Chronic Hepatitis-C Infection in COVID-19 Patients Is Associated with in-Hospital Mortality. World J. Clin. Cases 2021, 9, 8749–8762. [Google Scholar] [CrossRef]
  97. Afify, S.; Eysa, B.; Hamid, F.A.; Abo-Elazm, O.M.; Edris, M.A.; Maher, R.; Abdelhalim, A.; Abdel Ghaffar, M.M.; Omran, D.A.; Shousha, H.I. Survival and Outcomes for Co-Infection of Chronic Hepatitis C with and without Cirrhosis and COVID-19: A Multicenter Retrospective Study. World J. Gastroenterol. 2021, 27, 7362–7375. [Google Scholar] [CrossRef]
  98. Kang, S.H.; Cho, D.-H.; Choi, J.; Baik, S.K.; Gwon, J.G.; Kim, M.Y. Association between Chronic Hepatitis B Infection and COVID-19 Outcomes: A Korean Nationwide Cohort Study. PLoS ONE 2021, 16, e0258229. [Google Scholar] [CrossRef]
  99. Yang, S.; Wang, S.; Du, M.; Liu, M.; Liu, Y.; He, Y. Patients with COVID-19 and HBV Coinfection Are at Risk of Poor Prognosis. Infect. Dis. 2022, 11, 1229–1242. [Google Scholar] [CrossRef]
  100. Kushner, T.; Cafardi, J. Chronic Liver Disease and COVID-19: Alcohol Use Disorder/Alcohol-Associated Liver Disease, Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis, Autoimmune Liver Disease, and Compensated Cirrhosis. Clin. Liver Dis. 2020, 15, 195–199. [Google Scholar] [CrossRef]
  101. Efe, C.; Dhanasekaran, R.; Lammert, C.; Ebik, B.; Higuera-de la Tijera, F.; Aloman, C.; Rıza Calışkan, A.; Peralta, M.; Gerussi, A.; Massoumi, H.; et al. Outcome of COVID-19 in Patients with Autoimmune Hepatitis: An International Multicenter Study. Hepatology 2021, 73, 2099–2109. [Google Scholar] [CrossRef]
  102. Marjot, T.; Buescher, G.; Sebode, M.; Barnes, E.; Barritt, A.S.; Armstrong, M.J.; Baldelli, L.; Kennedy, J.; Mercer, C.; Ozga, A.-K.; et al. SARS-CoV-2 Infection in Patients with Autoimmune Hepatitis. J. Hepatol. 2021, 74, 1335–1343. [Google Scholar] [CrossRef]
  103. Efe, C.; Lammert, C.; Taşçılar, K.; Dhanasekaran, R.; Ebik, B.; Higuera-de la Tijera, F.; Calışkan, A.R.; Peralta, M.; Gerussi, A.; Massoumi, H.; et al. Effects of Immunosuppressive Drugs on COVID-19 Severity in Patients with Autoimmune Hepatitis. Liver Int. 2022, 42, 607–614. [Google Scholar] [CrossRef] [PubMed]
  104. Kumar, N.; Satyapriya, S.; Tahaseen, S.M.; Singh, K.; Kumar, A. Severe Progression of Autoimmune Hepatitis in a Young COVID-19 Adult Patient: A Case Report. J. Acute Dis. 2022, 11, 161. [Google Scholar] [CrossRef]
  105. Baiges, A.; Cerda, E.; Amicone, C.; Téllez, L.; Alvarado-Tapias, E.; Puente, A.; Fortea, J.I.; Llop, E.; Rocha, F.; Orts, L.; et al. Impact of SARS-CoV-2 Pandemic on Vascular Liver Diseases. Clin. Gastroenterol. Hepatol. 2022, 20, 1525–1533.e5. [Google Scholar] [CrossRef] [PubMed]
  106. Roth, N.C.; Kim, A.; Vitkovski, T.; Xia, J.; Ramirez, G.; Bernstein, D.; Crawford, J.M. Post-COVID-19 Cholangiopathy: A Novel Entity. Am. J. Gastroenterol. 2021, 116, 1077–1082. [Google Scholar] [CrossRef]
  107. Zhao, B.; Ni, C.; Gao, R.; Wang, Y.; Yang, L.; Wei, J.; Lv, T.; Liang, J.; Zhang, Q.; Xu, W.; et al. Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Ductal Organoids. Protein Cell 2020, 11, 771–775. [Google Scholar] [CrossRef][Green Version]
  108. Colmenero, J.; Rodríguez-Perálvarez, M.; Salcedo, M.; Arias-Milla, A.; Muñoz-Serrano, A.; Graus, J.; Nuño, J.; Gastaca, M.; Bustamante-Schneider, J.; Cachero, A.; et al. Epidemiological Pattern, Incidence, and Outcomes of COVID-19 in Liver Transplant Patients. J. Hepatol. 2021, 74, 148–155. [Google Scholar] [CrossRef]
  109. Nasa, P.; Alexander, G. COVID-19 and the Liver: What Do We Know so Far? World J. Hepatol. 2021, 13, 522–532. [Google Scholar] [CrossRef]
  110. Rabiee, A.; Sadowski, B.; Adeniji, N.; Perumalswami, P.V.; Nguyen, V.; Moghe, A.; Latt, N.L.; Kumar, S.; Aloman, C.; Catana, A.M.; et al. Liver Injury in Liver Transplant Recipients with Coronavirus Disease 2019 (COVID-19): U.S. Multicenter Experience. Hepatology 2020, 72, 1900–1911. [Google Scholar] [CrossRef]
  111. Mehta, P.; McAuley, D.F.; Brown, M.; Sanchez, E.; Tattersall, R.S.; Manson, J.J.; HLH Across Speciality Collaboration, UK. COVID-19: Consider Cytokine Storm Syndromes and Immunosuppression. Lancet 2020, 395, 1033–1034. [Google Scholar] [CrossRef]
  112. Nasa, P.; Juneja, D.; Jain, R.; Nasa, R. COVID-19 and Hemolysis, Elevated Liver Enzymes and Thrombocytopenia Syndrome in Pregnant Women-Association or Causation? World J. Virol. 2022, 11, 310–320. [Google Scholar] [CrossRef]
  113. Gao, Y.-D.; Ding, M.; Dong, X.; Zhang, J.-J.; Kursat Azkur, A.; Azkur, D.; Gan, H.; Sun, Y.-L.; Fu, W.; Li, W.; et al. Risk Factors for Severe and Critically Ill COVID-19 Patients: A Review. Allergy 2021, 76, 428–455. [Google Scholar] [CrossRef] [PubMed]
  114. Lassi, Z.S.; Ana, A.; Das, J.K.; Salam, R.A.; Padhani, Z.A.; Irfan, O.; Bhutta, Z.A. A Systematic Review and Meta-Analysis of Data on Pregnant Women with Confirmed COVID-19: Clinical Presentation, and Pregnancy and Perinatal Outcomes Based on COVID-19 Severity. J. Glob. Health 2021, 11, 05018. [Google Scholar] [CrossRef] [PubMed]
  115. Allotey, J.; Stallings, E.; Bonet, M.; Yap, M.; Chatterjee, S.; Kew, T.; Debenham, L.; Llavall, A.C.; Dixit, A.; Zhou, D.; et al. Clinical Manifestations, Risk Factors, and Maternal and Perinatal Outcomes of Coronavirus Disease 2019 in Pregnancy: Living Systematic Review and Meta-Analysis. BMJ 2020, 370, m3320. [Google Scholar] [CrossRef] [PubMed]
  116. van Lieshout, L.C.E.W.; Koek, G.H.; Spaanderman, M.A.; van Runnard Heimel, P.J. Placenta Derived Factors Involved in the Pathogenesis of the Liver in the Syndrome of Haemolysis, Elevated Liver Enzymes and Low Platelets (HELLP): A Review. Pregnancy Hypertens. 2019, 18, 42–48. [Google Scholar] [CrossRef]
  117. Conde-Agudelo, A.; Romero, R. SARS-CoV-2 Infection during Pregnancy and Risk of Preeclampsia: A Systematic Review and Meta-Analysis. Am. J. Obs. Gynecol. 2022, 226, 68–89.e3. [Google Scholar] [CrossRef]
Figure 1. Development of COVID-19-induced liver lesions.
Figure 1. Development of COVID-19-induced liver lesions.
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Figure 2. Drug hepatotoxicity due to COVID-19 treatment.
Figure 2. Drug hepatotoxicity due to COVID-19 treatment.
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Table 1. Association between obesity and COVID-19 infection severity in patients with MAFLD (adapted from Asemota et al., 2022 [92]).
Table 1. Association between obesity and COVID-19 infection severity in patients with MAFLD (adapted from Asemota et al., 2022 [92]).
OR95% CIp
Model I 6.251.23–31.710.027
Model II 6.321.16–34.540.033
Model I: adjusted for age and gender. Model II: adjusted for age, gender, smoker status, type II diabetes mellitus, arterial hypertension, and dyslipidemia.
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MDPI and ACS Style

Marginean, C.M.; Cinteza, E.; Vasile, C.M.; Popescu, M.; Biciusca, V.; Docea, A.O.; Mitrut, R.; Popescu, M.S.; Mitrut, P. Features of Liver Injury in COVID-19 Pathophysiological, Biological and Clinical Particularities. Gastroenterol. Insights 2023, 14, 156-169.

AMA Style

Marginean CM, Cinteza E, Vasile CM, Popescu M, Biciusca V, Docea AO, Mitrut R, Popescu MS, Mitrut P. Features of Liver Injury in COVID-19 Pathophysiological, Biological and Clinical Particularities. Gastroenterology Insights. 2023; 14(2):156-169.

Chicago/Turabian Style

Marginean, Cristina Maria, Eliza Cinteza, Corina Maria Vasile, Mihaela Popescu, Viorel Biciusca, Anca Oana Docea, Radu Mitrut, Marian Sorin Popescu, and Paul Mitrut. 2023. "Features of Liver Injury in COVID-19 Pathophysiological, Biological and Clinical Particularities" Gastroenterology Insights 14, no. 2: 156-169.

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