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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
Department of Medicine II Saarland University Medical Center, Saarland University, Homburg, GermanyLaboratory 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
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.
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 [
], 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 [
]. 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) [
]. 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 [
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 [
]. 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 [
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 [
Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples from the Hong Kong Cohort and Systematic Review and Meta-analysis.
]. 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) [
]. 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 [
]. 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 [
]. A study reported that the virus can be detected but not cultivated from stool (despite high RNA concentration), consistent with the lack of transmission [
]. 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 [
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 [
Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection.
]. 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 [
]. 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 [
]. 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 [
Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis.
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 [
]. 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 [
] 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 [
]. 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 [
], 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 [
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 [
], 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 [
], 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 [
]. 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 [
Analysis of angiotensin-converting enzyme 2 (ACE2) from different species sheds some light on cross-species receptor usage of a novel coronavirus 2019-nCoV.
Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples from the Hong Kong Cohort and Systematic Review and Meta-analysis.
]. 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 [
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 [
]), 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 [
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.
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
], 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 [
] 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 [
]. These cells actively participate to liver ischemia-reperfusion damage and promote oxidant stress via reactive oxygen species (ROS) and nitric oxide (NO) derivatives [
]. 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 [
]. 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 [
]. 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 [
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 [
]. 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 [
]. Conditions might include the ongoing liver damage due to chronic hepatitis B, combined HBV/HCV hepatitis (with risk of enhanced replication of hepatitis virus [
]), nonalcoholic fatty liver disease (NAFLD)(because of associated comorbidities of diabetes and cardiovascular disorder, and increased susceptibility to drugs) [
]. 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 [
]. 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 [
Prevalence of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among a Largely Middle-Aged Population Utilizing Ultrasound and Liver Biopsy: A Prospective Study.
]. 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 [
]. 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 [
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 [
] 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 [
]. Notably, ACE2 expression is significantly increased in liver injury in both humans and rat, likely in response to increasing hepatocellular hypoxia [
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 [
]. 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 [
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 [
], 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 [
]. 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 [
]. 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 [
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 [
]. 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 [
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 [
]. 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 [
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.
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.
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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
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 [
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 [
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).
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.
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.
Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples from the Hong Kong Cohort and Systematic Review and Meta-analysis.
Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection.
Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis.
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
Analysis of angiotensin-converting enzyme 2 (ACE2) from different species sheds some light on cross-species receptor usage of a novel coronavirus 2019-nCoV.
Overexpression of 7a, a protein specifically encoded by the severe acute respiratory syndrome coronavirus, induces apoptosis via a caspase-dependent pathway.
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.
Prevalence of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among a Largely Middle-Aged Population Utilizing Ultrasound and Liver Biopsy: A Prospective Study.
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.
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.
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