Angiotensin-converting enzyme 2 (ACE2) is a family of receptors expressed on the host cell during replication of SARS-CoV-2 infection, thus providing a gateway for viral entry into the host cell ^[1][15]. In vitro studies revealed that trypsin facilitates the binding of ACE2 receptors to the spike protein of SARS-CoV-2 and promotes their replication in a host cell. Trypsin is also expressed in epithelial cells of the liver and facilitates viral entry into the host cell, although the expression of ACE2 is low in liver cells ^[2][16]. Single-cell RNA sequencing revealed that the expression of ACE2 receptors is higher in cholangiocytes compared to hepatocytes ^[3][17]. Cholangiocytes are epithelial cells found on the surface of the bile duct ^[4][18]. Recent studies showed that SARS-CoV-2 proliferates in a culture of liver ductal organoids and binds to cholangiocytes, damaging the liver and causing liver injury due to SARS-CoV-2 viral replication ^[5][19]. A severe attack of the COVID-19 virus blocks the bile duct, ultimately leading to bile duct dysfunction, revealing the mechanism of liver injury.

Another study reported that the expression of ACE2 was high in liver fibrosis, indicating a liver injury that directed the hepatic tropism of SARS-CoV-2 ^[6][20]. In vitro studies showed that scavenger receptor B type 1 (SR-B1) also facilitates the interaction and binding of ACE-2 with coronavirus ^[7][21]. It was shown that the spike protein of SARS-CoV-2 also binds to transmembrane serine protease 2 (TMPRSS2) and pairs with the basic amino acid-cleaving enzyme (FURIN). These receptors showed expression in liver cells, thus facilitating the attack of SARS-CoV-2 on liver cells, leading to liver injury ^[8][22].

COVID-19-associated hypoxia also impairs liver functions, which ultimately increases the risk of liver failure ^[9][23]. Liver hypoxia is one of the major causes of hepatic damage caused by microvascular thrombosis and lung injury/respiratory failure due to gas exchange defects in the lungs ^[10][24]. In the case of a severe COVID-19 attack, an inadequate supply of oxygen to hepatocytes promotes necrosis, which in turn, promotes the development of myocardial infarction. The risk of heart attack and respiratory failure is ultimately increased, and the lung’s function is impaired by decreasing oxygen uptake ^[11][25].

Hypoxic hepatitis is another major cause of liver injury, also known as ischemic hepatitis ^[12][27]. The ischemic injury also contributes to gut damage by promoting intestinal endotoxin. Ischemic injury promotes hepatocyte death caused by disturbances in metabolic processes, resulting in the depletion of ATP, low oxygen supply, more glycogen consumption, and lipid metabolism disorders ^[13][28]. Reperfusion injury also contributes to liver injury, followed by metabolic processes and immune reaction disturbances. DAMPs are released as a result of cell death, which activates the complement system and ROS production. These immune reactions lead to the activation of a variety of cells in the liver, including dendritic cells, neutrophils, Kupffer, NK, and T cells ^[13][14][15][28,29,30].

Liver injury is mainly followed by hepatic ischemia/hypoxia and abnormal coagulation mechanisms. A series of inflammatory reactions and activation of immune cells usually follow abnormal coagulation in COVID-19 patients. Monocytes move to the endothelial cells and release tissue factors that activate the extrinsic coagulation pathway. These inflammatory reactions promote fibrin deposition and ultimately endorse blood clotting. Neutrophils move to the sites of infection and release NETs that activate the coagulation pathway by triggering a series of inflammatory reactions. This results in platelet activation to aid blood clotting ^[16][31].

Cytokines are inflammatory biomarkers that play an important role in the severity of COVID-19 patients presenting with complaints of liver injury. Different kinds of inflammatory cytokines are involved in liver injuries, such as IL-6, IL-10, and C-reactive protein (CRP), a well-known inflammatory biomarker. Different studies reported that among inflammatory cytokines, IL-6 is an early indicator in the acute phase in COVID-19 patients, indicating liver injury ^[17][32].

Cytokine storm syndrome is one of the most frequently occurring syndromes in COVID-19-infected patients and affects the functions of multiple organs, such as the liver, brain, and lungs. Cytokine release syndrome is caused by the massive release of cytokines that leads to SIRS and ARDS. Increased concentrations of cytokines lead to liver injury, acute respiratory distress syndrome, and brain disorders. A recent study revealed that COVID-19 patients have elevated levels of biomarkers such as CRP, LDH, and IL-6 in case of extreme cytokine storm syndrome ^[18][5].

In the liver, IL-6 is involved in tissue regeneration and involved in metabolic functions, followed by cis- and trans-signaling ^[19][33]. In cis-signaling, binding of IL6 with IL-6R results in a stable complex and the formation of a gp130 dimer that regulates the downstream signaling mediated by JAKs and STAT3 pathways that lead to CRS. Expression of mIL-6R is limited to hepatocytes; thus, liver hepatocytes respond to IL-6 signaling ^[20][34]. In trans-signaling, binding of IL6 with IL-6R results in a stable complex and the formation of a gp130 dimer that regulates the downstream signaling mediated by JAKs and STAT3 pathways activated in a variety of cells that express mIL-6R and result in the cytokine storm. This type of signaling is mainly involved in a large variety of secretions, including IL-6, chemokines, and proinflammatory cytokines ^[21][35]. Thus, hyperinflammation caused by CRS in COVID-19 patients with liver injury can be reversed by targeting IL-6 signaling.

ACE2 is a group of enzymes involved in the degradation of Ang II to Ang1-7, which is important for the inactivation of RAS. Angiotensin II performs a dual function in liver cells. It acts as a vasoconstrictor and proinflammatory cytokine through the activation of AT1R-metalloprotease 17 (ADAM17), which cleaves the IL-6Rα bound to the surface of the membrane, thus generating the IL-6R that binds to IL-6 and ultimately activates the STAT3 pathway. This mechanism follows trans-signaling and is mainly involved in a large variety of secretions, including IL-6, chemokines, and proinflammatory cytokines. Therefore, IL-6 acts as an inflammatory switch to initiate the signal for cytokine storm ^[22][26].

Drug-induced hepatotoxicity mechanism mainly involves oxidative stress, insulin resistance, mitochondrial dysfunction, and lipid dystrophy ^[23][39]. COVID-19 patients also suffer from fever, and cold, so antipyretic drugs containing the acetaminophen ring are used. High-dose concentrations of antipyretic drugs induce liver toxicity and increase the risk of other metabolic diseases. Some antiviral drugs are frequently used alone or in combination, but most of them increase the risk of liver damage ^[24][40]. Therefore, there is a need to be cautious about the use of some drugs causing hepatotoxicity.

Excessive use of azithromycin can damage liver hepatocytes and increases the risk of jaundice ^[25][41]. Antiviral drugs like lopinavir/ritonavir increase liver injury chances by fourfold compared to other drugs. In some cases, COVID-19 patients received multiple doses of antiviral drugs such as lopinavir/ritonavir, oseltamivir, and abidol. Clinical results of these antiviral drugs showed that they caused liver injury in patients. Antiviral drugs or corticosteroids should be closely monitored in COVID-19 patients with abnormal LFTs ^[26][4]. Tocilizumab is also used along with corticosteroids for COVID-19 patients under a ventilator. Tocilizumab is used as an immune suppressive drug, binds to interleukin-6 (IL-6), and blocks its activity. Tocilizumab also activates the replication of hepatotropic viruses and cannot cause direct liver damage. Corticosteroids mainly suppress cytotoxic T cells and activate the replication of HBV, thus induce liver damage ^[27][28][42,43].

Mitochondrial dysfunction is another cause of liver injury in patients with COVID-19. A study showed that the severity of SARS-CoV-2 infection disrupts mitochondrial activity. In a severe attack of SARS-CoV-2 on liver hepatocytes, oxidative damage to the mitochondrial membrane results in the production of ROS species ^[29][49]. Ahmed et al. ^[30][50] reported the biological activity of mitochondrial cristae in liver cells diagnosed with COVID-19. They found that abnormalities were observed in mitochondrial cristae that impaired liver function and increased the risk of non-alcoholic fatty liver disease (NFALD) in COVID-19 patients. Another cause of liver injury is the existing liver disease, non-alcoholic steatohepatitis (NASH), in COVID-19 patients with impaired mitochondrial activity. Further study is required to differentiate the mechanisms of NFALD and NASH with impaired mitochondrial activity in severe COVID-19 attacks ^[30][31][50,51].

Obesity is one of the potential risk factors among COVID-19 patients that causes NAFLD. Inflammatory cytokines such as IL-6, produced in large amounts in such patients, cause severe inflammation and cytokine storm ^[32][52]. Different studies showed that obesity prolongs the stay of patients with liver injury diagnosed with COVID-19. Hu et al. ^[33][53] investigated a case study involving 58 COVID-19 patients with obesity. These patients gained more fat during hospitalization. Since the expression of ACE2 is enriched in adipocytes and obese people have more ACE2-expressing cells, they are more vulnerable to COVID-19 infection. This activates immunological reactions and results in poor liver function. The authors conclude that obesity is a predisposing factor that increases the risk of other metabolic disorders ^[33][34][53,54]. Another study by Meijnikman et al. ^[35][55] revealed that upregulation of ACE2 alleviates the risk of NAFLD in COVID-19 patients as it promotes the development of fat storage in liver and visceral adipose tissues. Storage fat stimulates the penetration of viral particles into liver cells, thus increasing the chance of liver damage ^[35][55]. Another retrospective cohort study involving 202 COVID-19 patients with NAFLD had a higher rate of liver disease progression ^[36][56]. Another study reported that patients with NAFLD had a higher chance of developing COVID-19 disease ^[36][56].

A recent study revealed that ARLD contributes to liver injury in COVID-19 patients ^[37][57]. Alcohol consumption is a cause of liver injury, but the extracting mechanism of action of ARLD in COVID-19 patients is poorly understood. However, different studies revealed that poor nutritional status and compromised immune systems increase the chance of ARLD in COVID-19 patients ^[38][58]. The Charlson Comorbidity Index indicated that the mortality rate among COVID-19 patients with ARLD in hospitalized patients is significantly different from other localities and non-hospitalized patients. The outcomes depend on the healthcare resources available to manage COVID-19 patients with ARLD. These findings suggested that a high incidence of alcohol drinking might be a potential risk for ARLD in COVID-19 patients. Hospital-based admissions and healthcare allocation for COVID-19 patients with developing ARLD are potential strategies to reduce the risk of liver injury ^[39][40][59,60].

COVID-19 patients have a high risk of developing cirrhosis as these patients have compromised immune systems and are susceptible to other infections. A recent study revealed that COVID-19 patients with cirrhosis have a higher mortality rate than non-cirrhosis liver disease. The severity of liver cirrhosis is associated with high-risk mortality among COVID-19 patients ^[41][61]. A case study with 50 patients diagnosed with COVID-19 had a mortality rate of 40%. The study revealed that COVID-19 patients were categorized in Child-Pugh (CP) A, B, and Class C liver cirrhosis with mortality rates of 24%, 43%, and 63%, respectively ^[37][57]. COVID-19 patients have a high chance of developing hepatocellular carcinoma (HCC). COVID-19 patients are more susceptible to inflammatory responses as they secrete excessive IL-6 cytokines and have a high chance of developing post-hepatectomy liver failure (PHLF) following hepatectomy ^[42][43][62,63]. Patients with cirrhosis who develop COVID-19 illness have a higher risk of fatal outcomes. These patients need proper management and hospital-based medical treatment ^[44][64].

Liver transplant recipients have high risks of liver injury and graft rejection with progressing COVID-19. Some liver transplant patients may have other metabolic complications in addition to liver injury. Such patients have compromised immune systems and high mortality rates. A recent study investigated 1522 patients diagnosed with positive COVID-19 under liver transplantation with a mortality rate of 17.4%. Transplant recipients showed about 2.3% graft dysfunction ^[45][66]. Another study reported that 80% of liver transplant recipients with positive COVID-19 needed intensive care and were admitted to the hospital, while 20% of patients needed a ventilator for survival, and the mortality rate was about 17% ^[46][67]. Such patients should be monitored with proper medical resources to crossmatch donor and recipient transplants. It will be helpful for the detection of graft rejection at an early stage ^[47][68].

NAFLD patients with severe COVID-19 infection may have a high risk of developing metabolic diseases such as obesity and diabetes. Such patients should be hospitalized, and monitoring liver biomarkers, glucose assessment, blood pressure, and cholesterol levels should be done carefully to reduce the severity of NAFLD–COVID-19 ^[48][72]. Proper medications should be continued in such patients in order to reduce adiponectin or block the secretion of lipid mediators that cause severe inflammation in obese patients. NAFLD patients with COVID-19 infection need additional medical therapy ^[49][50][73,74]. ANGPTL3 is a potential regulator of lipid metabolism. Monoclonal antibodies are widely used for targeting fatty acid compounds in obese individuals. One of the newly discovered antibodies, VHH-Fc, is effective in treating NAFLD, which binds to ANGPTL3 (Angiopoietin-like protein-3) and inhibits its activity ^[51][75].

Antiviral therapy should be recommended for patients co-infected with HBV/HCV before using an antiviral drug combination for COVID-19 infection ^[52][76]. Patients infected with hepatitis B and C also take medical therapy to inhibit viral replication to maintain a healthy lifestyle. Nucleoside analogs should be continued for the inactivation of the hepatitis B virus, as their discontinuation may result in the reactivation of HBV ^[53][77]. Some antiviral drugs for COVID-19 have direct interactions with HCV drugs, such as protease inhibitors that showed drug–drug interactions with lopinavir/ritonavir. Thus, drug combinations in HCV must be monitored regularly and prescribed by a physician ^[52][76]. Regular serological testing of hepatitis B and C for all COVID-19 patients should be carried out in the presence of an expert analyst, as false positive results can increase the spread of viral infection. COVID-19 patients diagnosed with hepatitis B and C should be hospitalized in separate isolation rooms, and proper medical attention should be given in the presence of an expert physician and healthcare staff ^[54][78]. Patients infected with hepatitis A also have a risk of developing liver disease. Such patients should take regular medication and hygienic precautions and avoid large gatherings during the pandemic period ^[55][79].

Patients with cirrhosis also have a chance of developing HCC. Such patients need proper medication and regulation of HCC through ultrasound testing and alpha-fetoprotein (AFP) after every six months. It will be helpful for the physician to access patient history and medication to reduce the risk of HCC ^[56][80]. A delay in HCC detection leads to the development of severe liver injury. Radiotherapy, immunotherapy, and medical attention should be needed for patients newly diagnosed with HCC ^[57][81]. COVID-19 patients with a chronic stage of HCC should be treated with tyrosine kinase inhibitors that may continue with the advice of a physician ^[58][59][82,83]. Priority is given to patients diagnosed at an early stage with HCC. Such patients should be allocated to separate rooms, and medical resources should be provided regularly. Monitoring and surveillance of patients should be carried out as guided by health regulatory authorities or WHO ^[59][83]. Proper medical attention should be given to older patients diagnosed with COVID-19. Such patients have a high chance of developing liver injury and risk liver damage due to the poor function of hepatocytes. Moreover, the functions of liver biomarkers for all COVID-19 patients should be monitored carefully with an advanced automated system, as antiviral drugs given to target viral replication have several toxic effects on the liver and can cause liver damage if not monitored regularly. Therefore, anti-viral drugs should be started after accessing the results of liver biomarkers and viral load ^[60][61][84,85].