Coronavirus disease 2019 was an important health problem worldwide in the recent past, and on March 11, 2020, it was accepted as a pandemic by WHO [1]. The causative agent of the COVID-19 pandemic is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is a positive-sense single-stranded RNA virus. This virus belongs to the betacoronavirus family [2,3]. Widely known effects of COVID-19 are pulmonary manifestations, i.e., pneumonia and acute respiratory distress syndrome. In addition, COVID-19 exerted extrapulmonary manifestations on a variety of other organs and organ systems, i.e., liver, heart, or kidneys [4,5]. Various worldwide researches have confirmed that the liver is affected to varying degrees in SARS-CoV-2-infected patients [6,7].

The liver is a vital organ that performs various functions, i.e., glycogen storage and blood glucose regulation, synthesis of proteins, drug metabolism, and metabolism of toxic substances [6,7]. Early COVID-19 figures confirmed that healthy persons and persons having previous liver disease infected with SARS-CoV-2 show abnormality in liver function tests (LFTs), indicating that this virus may be directly responsible for liver injury [8]. A greater increase in transaminase enzymes has been observed in patients with severe disease, particularly those admitted to the ICU [9].

Liver damage is present in 58.0% of COVID-19-related deaths [10]. This virus causes liver damage that is characterized by elevated levels of alanine transaminase (ALT) and aspartate transaminase (AST), hypoalbuminemia, and hyperbilirubinemia [8,10]. Alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) may rise, suggesting damage to the liver bile duct cells [10]. There is a positive association between the severity of the illness and the extent of liver damage. Low albumin levels (26.3-30.9 g/L) and high AST are statistically linked with mortality [10].

Although the exact pathogenic mechanism by which SARS-CoV-2 harms liver cells is still unknown, potential mechanisms may be immune-mediated, ischemia and hypoxia, thrombosis, direct damage, and drug-induced [8,10]. The purpose of this article is to analyze the impact of SARS-CoV-2 on the liver as well as the risk factors associated with this virus.

Pathophysiology

There are various mechanisms that lead to liver injury in SARS-CoV-2 infected patients [11]. Direct SARS-CoV-2 invasion of the hepatic parenchyma is one possible theory regarding the cause of liver damage [11].

SARS-CoV-2 has the ability to infect cells by the angiotensin-converting enzyme 2 (ACE2) receptor, which is found largely on the alveolar type II cells in the lungs [12]. In humans, the ACE2 receptors are primarily found in various organ systems of the body, i.e., the liver, lungs, heart, kidneys, and gastrointestinal tract [13]. In the liver, cholangiocytes (59.7%) express ACE2 at a higher level than hepatocytes (2.9%) [14]. The entry of SARS-CoV-2 in liver cells is facilitated by S protein that selectively binds with the host’s ACE2 receptor and transmembrane serine protease 2 [15]. From many studies it is found that SARS infection directly damages the hepatic parenchyma while also impairing the liver's capacity to regenerate [16]. In cholangiocytes, SARS-CoV-2 may result in malfunction of the bile duct. Cholangiocytes perform a vital part in the regeneration of the liver and immunological responses, suggesting that viral immunologic injury may play a significant role in COVID-19 liver injury [17].

According to recent studies, COVID-19 infected patients have increased levels of various enzymes, i.e., aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH), but not of alkaline phosphatase and gamma glutamyl transferase, which are indicators of damage to the bile duct [17].

In the course of infection by a virus, the innate and acquired immune responses identify molecular patterns linked with the pathogen and specific antigens associated with that virus. Elevated cytokines are released by the immune system as a result of SARS activating the immune system (innate and acquired immune systems) [18]. These immune responses then produce inflammatory substances, i.e., cytokines and chemokines, which stimulate macrophages and T cells to destroy virus-infected cells and remove the virus. Large quantities of inflammatory cytokines have been seen in COVID-19 patients, and when SARS-CoV-2 infects host hepatocytes, this situation may result in serious harm to the liver. Tumor necrosis factor, IL-2, IL-6, IL-7, IL-18, granulocyte-colony stimulating factor, interferon-γ, and ferritin are the most active inflammatory molecules in this infection [19]. Following this, an early increase in cytokines in the body leads to hypercytokinemia, which can cause harm to many organs of the body along with the liver (Figure 1). The related literature suggests that patients with early cytokine surge had poor COVID-19 outcomes [20]. In 28.0% of deadly COVID cases, the cytokine storm resulting from rigorous SARS infections is the cause of death [21]. This cytokine storm can result in multiorgan failure, along with liver failure. Patients in critical condition showed elevated levels of TGF-α, IL-16, IL-23, IL-33, thymic stromal lymphopoietin, interferon-lambda (IFN-λ), and coagulopathy-related markers like thrombopoietin [18]. Liver thrombosis and congestive hepatopathy are additional complications of hepatic injury caused by the release of increased cytokines. The above complications have been found during autopsy of severe COVID-19 patients. Increased ALT and total bilirubin were observed in severe COVID-19 patients, along with a rise in inflammatory biomarkers like D-dimer, IL-6, IL-10, and C-reactive protein (CRP) [22].

Hypoxic injury is one more destructive mechanism. Due to its intricate vascularization, the liver is notably vulnerable to circulatory changes that may arise from cardiac, circulatory, or respiratory failure or septic shock and result in reduced liver perfusion [17]. Severe COVID patients frequently experience anoxia as a result of respiratory failure. Such patients must be on vasopressor support or on mechanical ventilation. The liver hemodynamics are negatively impacted by reduced cardiac output [18]. Cholestasis and/or anoxic hypoxic hepatitis may result from decreased hepatic blood flow [21].

Drugs also play a role in damage mechanisms as well, most notably through liver injury. Antibiotics and non-steroidal anti-inflammatory medications are among the known causes of drug-induced liver injury and might cause liver injury in COVID-19 infected patients when given to cure myalgias, fever, and bacterial superinfection. Moreover, it has been demonstrated that 15.2% of patients on remdesivir and 37.2% of patients on lopinavir/ritonavir suffer from drug-induced liver injury [23]. Lastly, certain COVID-19 medications, dexamethasone, tocilizumab, and tofacitinib, may cause hepatic damage by reactivating chronic liver diseases caused by hepatitis B virus [24]. Some medications can worsen hepatic injury in COVID-19 infection that raises ALT and AST levels. Remdesivir has demonstrated antiviral activity against SARS-CoV-2 in vitro and a shortened recovery period against this virus in clinical trials; however, increased levels of hepatic enzymes have been observed as a negative effect of this drug, and further, remdesivir also elevates the risk of hepatotoxicity. Hepatic injury has also been reported with other commonly used drugs, such as lopinavir/ritonavir, that are used to treat COVID-19. More specifically, angiotensin II receptor blockers and ACE drugs have also been known to increase the level of various liver enzymes in people infected with COVID-19. Microvesicular steatosis and lobular and portal activity were noticed when autopsies of COVID-19 death patients were done, and these findings were likely linked to drug-induced liver injury. Steroids, antiviral medicines like ribavirin, and antibiotic medicines like macrolides and quinolones are among the other drugs prescribed to COVID-19 patients that may cause damage to the liver [25].

Figure 1: Structure of SARS-CoV-2 ACE-2 That Causes Hepatic Injury by Cytokine Storm.

IL: Interleukin; GC-SF: Granulocyte colony stimulating factor; ACE-2: Angiotensin-converting enzyme 2.

Associated Clinical Symptoms

In SARS-CoV-2 infection, patients may be asymptomatic or symptomatic, i.e., fever, dry cough, headache, dyspnea, fatigue, and likely acute respiratory distress syndrome, shock, and heart failure [26,27]. Recent studies say that the primary liver injury due to COVID-19 is less than secondary liver injury [28,29]. In this infection, liver injury includes progression of chronic liver disease, which progresses to hepatic decompensation and acute-on-chronic liver failure. Diarrhea, nausea, vomiting, and appetite loss are the symptoms related to liver injury and gastrointestinal involvement. The elevation of AST, ALT, LDH, and bilirubin and the low level of albumin were also symptoms of abnormal liver function [28-32].

Increased levels of liver enzymes are found mainly in serious COVID-19 patients. i.e., elevated AST level was seen in 62% of patients admitted to ICU in comparison to 25% of non-ICU patients [30].

According to Chen et al findings [28], non-survivors had considerably higher levels of AST, ALT, ALP (alkaline phosphatase), GGT (gamma-glutamyl transferase), and bilirubin than survivors had. In addition, hypoalbuminemia was shown to be markedly lower in dead patients compared to living patients. Moreover, Bangash et al. [31] reported that patients with underlying chronic liver disease had a death rate of 0%–2%. By analyzing data from the literature, it is shown that severely ill individuals with diabetes and hypertension are most likely to suffer liver damage [29,32].

The repeated rise of ALT, AST, and LDH compared to that of ALP and GGT indicates that COVID-19-induced liver injury is generally hepatocellular instead of cholestatic, and jaundice is not prevalent [17,33]. Furthermore, it was found that AST may serve as a main indicator of hepatic injury, and its increased level is linked to significant mortality risk [34].

In a meta-analysis of 12 studies with 1267 patients, abnormal liver function was found in 19% of patients, and further, in subgroup analysis, serious COVID-19 patients had more chances of gastric cramps and abnormality in liver function, i.e., elevated ALT and AST levels [35].

The various factors that cause liver damage in COVID-19 infected individuals are as follows. Figure 2 shows an outline of liver injury in COVID-19 patients.

Drugs: Various drugs or therapeutic agents (antiviral drugs, antibiotics, acetaminophen, various nimmunomodulators, corticosteroids, steroids, and antipyretics) are given for the treatment of COVID-19 affected patients [36,37]. These agents are metabolized or detoxified by the liver, and their continuous usage causes hepatotoxicity or toxic liver disease. Various medications such as lopinavir, ritonavir, hydroxychloroquine, arbidol, and oseltamivir may cause varying degrees of hepatotoxicity [38].

Hypoxia: Hypoxia plays a significant role in lowering oxygen saturation levels in COVID-19 patients, which in turn lowers systemic blood pressure [39]. In the end, this will result in hypoxia reperfusion injury from liver cell hypoxia and a decrease in liver arterial perfusion through liver ischemia [40].

Cytokine Surge: A cytokine storm that occurs in COVID-19 disease is another factor that causes damage to the liver. Strong immunity to the SARS-CoV-2 virus is found in moderate and severe disease, in which endothelial damage occurs [41]. After this step, inflammasomes are stimulated, resulting in caspase-1 activation and cytokine release, such as IL-1β, IL-6, and IL-18 [42]. In the next step, the immune response developed by these cytokines and through intracellular signaling, involving IL-6 and other pro-inflammatory cytokine biomarkers, causes the stimulation of gene expression [43]. Furthermore, by forming complexes with its receptor, IL-6 triggers various downstream signal pathways [44]. It is also the cause of elevated levels of ferritin and C-reactive protein, decreased lymphocyte counts, and increased neutrophil counts [45].

Underlying Liver Diseases: During COVID-19 infection, underlying liver diseases may make liver damage worse. Various studies reported the occurrence of underlying liver diseases ranging from 3% to 11% in COVID-19 patients [46-48]. These underlying diseases may be liver transplantation, non-alcoholic fatty liver disease, cirrhosis, and chronic liver disease [46].

Figure 2: An Outline of Liver Injury in COVID-19 Patients.

Elevated Liver Function Tests

Nearly 50% of COVID-19 patients who are admitted to the hospital have altered LFTs [49]. Liver injury has been observed in these patients, specifically in relation to increased levels of ALT, AST, glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), and bilirubin [10,50].

Elevated AST and ALT are the cause of these abnormal tests, and AST was more prevalent than ALT. According to reports, COVID-19-related liver damage can also result in hypoalbuminemia, which is more common in men than in women [51]. Liver function abnormalities such as hypoalbuminemia and increased levels of GGT, aminotransferases, and bilirubin were more common in individuals with severe COVID-19 infection compared to mild/moderate forms of the infection [52]. Severity of the infection was correlated with the extent of COVID-19- induced liver damage, which showed up as varying degrees of abnormal liver function [53].

Figure 3 shows the manifestations of liver damage from SARS-CoV-2.

Figure 3: Manifestations of Liver Damage from SARS-CoV-2.

ALT: Alanine transaminase; AST: Aspartatetransaminase; GGT: Gamma-glutamyl transferase; ALP: Alkaline phosphatase.

Alteration in Liver Biopsies

The liver biopsies of COVID-19 patients revealed mild microvascular steatosis involving portal and lobular veins on histopathological examination [54]. Hepatocyte degeneration was examined, accompanied by sinusoidal enlargement of the central lobule. Neutrophil infiltration in hepatic lobes, periportal necrosis and centrilobular necrosis, lymphocytic infiltration of the lobes, and congestion of the hepatic sinuses were observed [55]. In addition, fatty degeneration, cellular infiltration, high mitotic frequency in hepatocytes, and liver necrosis were also observed [56].

Additionally, eosinophilic bodies and dilated hepatocytes were found to be increased in COVID-19 induced liver injury [10]. Autopsy specimens from the later stages of the infection showed evidence of acinar atrophy [57]. Moreover, elevated levels of liver injury biomarkers like ALT and GGT are connected with increased liver stiffness, indicating hepatocellular and cholangiocellular damage [58]. It has been found that COVID-19 infection results in cholangiocellular damage, cholestasis, and obstructive cholestasis.

The mechanisms of liver damage in either adults or children with COVID-19 are not fully clear, and the impact of liver injury caused by new variants of COVID-19 in patients is unexplained. Further investigation is required to determine liver involvement and the impact of COVID-19 on various ages with liver disease. Also, the pathogenic mechanisms of COVID-19 on liver injury of patients in different age groups need to be investigated.

Moreover, hepatic alterations are mainly represented by the worsening of underlying chronic liver disease leading to hepatic decompensation and liver failure with higher mortality, and they appear to be mediated more by systemic inflammation, direct cytopathic effect on liver cells, hypoxic injury, and drugs.

Education can ultimately save lives and lessen the pandemic's long-term effects on our population. Greater understanding of the disease's effect on the liver can lead to improved management and therapeutics.

Funding

No financial support

Acknowledgement

Nil

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