Introduction
The liver plays a crucial role in immune regulation, metabolism, and detoxification, making it particularly susceptible to systemic inflammatory responses triggered by viral infections [1, 2]. Hepatocytes, which constitute approximately 70-85% of the liver volume, are essential for metabolism, detoxification, and protein synthesis and play an immunological role [3]. Respiratory viruses may potentially exert direct cytopathic effects on hepatocytes or cholangiocytes or indirectly induce liver injury through immune-mediated mechanisms, hypoxic damage, and drug-induced hepatotoxicity. These multifactorial pathways contribute to a wide spectrum of hepatic presentations, ranging from asymptomatic transaminase elevations to acute hepatic failure in rare instances [4-10].
The COVID-19 pandemic has intensified interest in the extrapulmonary manifestations of respiratory viral infections, particularly due to the body of evidence of hepatic involvement in SARS-CoV-2 infection, which has been linked to worse clinical outcomes [11-13]. This has underscored the need to explore potential liver involvement in other respiratory viral infections, such as influenza and respiratory syncytial virus (RSV). These three RNA pathogens share common transmission routes, primarily via respiratory droplets and aerosols, and partially overlap in their seasonal activity [14-16]. Clinically, they exhibit similar symptoms, including fever, cough, and respiratory distress, though their systemic effects can vary significantly [17-19]. While all three viruses can cause severe illness, particularly in vulnerable populations, SARS-CoV-2 is distinguished by its strong association with systemic inflammation and multiorgan involvement, including acute liver injury [6, 20, 21]. SARS-CoV-2, influenza viruses, and RSV are among the most prevalent respiratory viral pathogens globally, clinically and epidemiologically the most consequential, making them particularly relevant targets for investigating hepatic involvement. Therefore, understanding their comparative impact on hepatic function could provide valuable insights into their pathophysiology and guide management strategies for patients at risk of severe outcomes.
This narrative review aims to summarize the current understanding of liver involvement in three major respiratory viral infections, SARS-CoV-2, influenza viruses, and RSV, by addressing epidemiology, proposed mechanisms of injury, characteristic laboratory and histopathological findings, clinical implications, and management considerations. By comparing and contrasting hepatic involvement across these pathogens, we aim to provide clinicians with a framework for recognizing and managing this important extrapulmonary complication of respiratory viral illnesses, which may otherwise be overlooked.
Epidemiology of liver involvement in viral respiratory infections
Among the viral respiratory diseases considered in this review, liver involvement is most prominent in COVID-19, particularly among patients with preexisting liver conditions or severe disease presentations. In contrast, influenza and RSV infections are less commonly associated with significant liver injury (Table 1).
Table 1
Comparative overview of liver involvement in viral respiratory infections discussed in this review
SARS-CoV-2
The incidence of liver injury among COVID-19 patients varies across studies [4, 22-24]. A systematic review reported that 14% to 76% of hospitalized COVID-19 patients may exhibit elevated liver enzyme activity, indicating liver involvement [11]. Such a high variation may be attributed to differences in study populations, definitions of liver injury, and underlying health conditions. Several factors have been identified that increase the risk of liver injury in COVID-19 patients. Firstly, patients with severe manifestations of COVID-19 are more likely to experience liver injury. Increased activity of liver enzymes has been associated with adverse outcomes, including increased risk of intensive care unit admission, intubation, and mortality [25]. Secondly, individuals with chronic liver diseases, such as cirrhosis or nonalcoholic fatty liver disease, face a higher risk of severe COVID-19 outcomes. A study indicated that patients with liver cirrhosis had a two-fold increased risk of mortality when infected with SARS-CoV-2 [11].
The liver injury observed in COVID-19 patients typically presents as a hepatocellular pattern characterized by elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) [25]. This pattern suggests direct viral involvement or systemic inflammation. A cholestatic pattern, marked by elevated alkaline phosphatase (ALP) and γ-glutamyl transferase (GGT), is less common, though also associated with worse clinical outcomes and survival rates [26]. Importantly, a recent meta-analysis of observational studies showed no specific profile of parameters that could easily predict liver damage throughout the course of SARS-CoV-2 infection [27].
Influenza viruses
Liver involvement in seasonal influenza is relatively rare, occurring in less than 3% of cases. When present, it typically manifests as mild, transient elevations in liver enzyme activity [28]. Studies in hospitalized subgroups found that abnormal liver tests may occur in 20-30% of individuals, with influenza patients tending to show earlier peaks in transaminase elevations [29]. In pediatric populations, influenza B appears particularly associated with hepatic involvement, with one study reporting elevated liver enzymes activity in approximately one-fifth of affected children [28]. The pattern of liver injury is, similarly to SARS-CoV-2 infection, predominantly hepatocellular, with AST activity often exceeding that of ALT [30]. This elevation may reflect combined hepatic and muscular injury components. In rare instances, particularly among pediatric patients, influenza A infection has led to acute hepatitis and acute liver failure, even in the absence of pulmonary complications [31-33]. This may suggest a potential hepatotropic nature of the virus in certain populations [32]. In the case of avian influenza, such as the H5N1 virus, its severe infections may be associated with liver dysfunction as a part of multiorgan failure [34].
RSV
Data on liver involvement in RSV infection are more limited compared to SARS-CoV-2 and influenza. However, elevated ALT and AST have been observed in children with severe RSV infections requiring mechanical ventilation [33]. Studies indicate that these elevations may correlate with the severity of respiratory illness, suggesting that liver involvement could serve as a marker for disease severity [35]. In certain instances, RSV infection has been linked to significant liver impairment. For example, a case report detailed a 1-month-old infant who developed severe sepsis and liver failure following RSV infection. Despite extensive supportive care, the child exhibited marked liver injury, underscoring the potential severity of RSV-associated hepatic complications [36]. In addition, pregnant women may also experience RSV-related liver issues. A reported case involved a pregnant patient who developed RSV-associated hepatitis, characterized by elevated activity of liver enzymes and gastrointestinal symptoms [37]. This case highlights the importance of considering RSV in the differential diagnosis of hepatitis during pregnancy.
Special populations
Respiratory viral infections may have a varied impact on liver function across different patient groups. Certain populations, including pediatric patients, individuals with chronic liver disease, and transplant recipients, may experience distinct hepatic manifestations and complications. Therefore, we briefly highlight the main points related to these groups that should be taken into account in relation to respiratory viral infections and liver involvement.
Pediatric patients
Children with respiratory viral infections may show distinct patterns of liver involvement:
approximately 10% of hospitalized children with acute respiratory tract infections reveal elevated activity of liver enzymes [34],
in the case of influenza, type B viruses may show a higher association with hepatic involvement compared to influenza A, possibly due to a higher incidence in children compared to adults, though the precise mechanisms remain under investigation [36],
children infected with SARS-CoV-2 may have an increased risk of developing liver abnormalities [38],
although rare, severe hepatitis has been reported in children infected with influenza, SARS-CoV-2, and RSV [33, 39-41].
the possibility of (co)infections with other viruses related to the respiratory system in hepatic manifestation in the pediatric group should be taken into account, including human adenovirus (HAdV) infections, particularly HAdV-7 and HAdV-55, which can often lead to abnormal liver function test and increased hepatitis risk in children [42].
Patients with chronic liver disease
Those with preexisting liver disease, especially patients with liver cirrhosis, are particularly vulnerable:
Transplant recipients
Liver transplant recipients may face unique challenges in the context of respiratory viral infections and liver involvement that shall be considered:
these patients are at a higher risk of severe respiratory viral infections due to lifelong immunosuppression [48],
potential drug interactions between antivirals and immunosuppressants should be addressed [49],
there is a risk of allograft dysfunction during acute infections, which can lead to graft loss or death [50].
Mechanisms of liver injury during viral respiratory infection
The pathophysiology of liver injury during respiratory viral infections is multifaceted, involving both direct viral effects and indirect mechanisms. The relative contribution of these pathways varies among different viruses and clinical contexts. The following overview underscores the multifactorial nature of liver injury during respiratory viral infections, highlighting the interplay between direct viral effects, systemic inflammation, hypoxia, preexisting liver conditions, and therapeutic interventions (Table 2).
Table 2
Summary of potential mechanisms of liver injury in respiratory viral infections
Direct viral effects
SARS-CoV-2 can directly infect liver cells through binding to angiotensin-converting enzyme 2 (ACE2) receptors, which are expressed on cholangiocytes (60%) and, to a much lesser extent, hepatocytes (3%) [51]. Autopsy studies have detected SARS-CoV-2 RNA in up to 69% of liver specimens from COVID-19 fatalities, with viral particles identified in hepatocytes using in situ hybridization [52]. The experimental investigations evidenced the liver tropism of SARS-CoV-2, leading to hepatocyte death in a replication-dependent manner, though this effect was less pronounced in the case of the Omicron SARS-CoV-2 variant [53]. The virus appears to impair bile acid transport function and disrupt tight junctions in cholangiocytes, further supporting the potential for direct hepatotropic effects [54].
In contrast, influenza and RSV are not generally considered hepatotropic. However, some experimental studies have reported the presence of influenza RNA in liver tissues, suggesting possible direct infection under specific circumstances [55], though the evidence is not compelling due to contradictory observations [56]. Human studies involving cases infected with the H5N1 avian influenza virus did not detect RNA in liver samples [57]. In the case of RSV, evidence for direct liver infection is lacking.
Systemic inflammatory response
The robust systemic inflammatory response characteristic of severe respiratory viral infections represents a major pathway for hepatic injury. The “cytokine storm” observed in severe COVID-19 and influenza, characterized by elevated interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and other pro-inflammatory cytokines, can lead not only to systemic inflammation but also to hepatocellular damage [57]. The liver’s anatomical location ensures constant exposure to circulating cytokines, increasing its vulnerability to inflammation-induced injury. In response to wide-spread immune activation, liver-resident macrophages, known as Kupffer cells, become hyperactivated and produce high levels of reactive oxygen species (ROS), nitric oxide, and inflammatory cytokines. This inflammatory environment promotes hepatocyte apoptosis and necrosis through TNF-α-mediated pathways and mitochondrial dysfunction [58].
This mechanism is particularly relevant in SARS-CoV-2 infection, where the degree of liver test abnormalities often correlates with markers of systemic inflammation such as C-reactive protein (CRP) and ferritin [13]. Similarly, in influenza, hepatic involvement has been associated with hypoxemia and elevated CRP levels [7].
Hypoxic injury
Severe respiratory failure can result in tissue hypoxia, adversely affecting liver function. The liver’s unique dual blood supply and oxygen gradient render it particularly susceptible to hypoxic injury, especially in the centrilobular areas [7]. This vulnerability may contribute to the predominantly hepatocellular pattern of liver injury observed in severe cases of respiratory viral infections, with AST activity often rising more than ALT due to additional release from other hypoxic tissues. Additionally, oxidative stress from reperfusion injury and inflammatory cytokine release further amplifies hepatocellular damage, linking vascular injury in COVID-19 to the broader mechanisms of hypoxic liver injury in respiratory viral infections [59].
Preexisting liver disease
Patients with chronic liver disease, especially those with liver cirrhosis, appear particularly vulnerable to hepatic decompensation during respiratory viral infections. In COVID-19, those with advanced liver disease (Child-Pugh class B or C) have significantly higher mortality rates [60]. Notably, patients with alcohol-related liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), cirrhosis, and hepatocellular carcinoma (HCC) have significantly higher SARS-CoV-2 infection rates and mortality. In contrast, patients with viral hepatitis (HBV, HCV) and autoimmune liver disease (AILD) show no significant difference in infection and mortality rates compared to those without liver disease [61]. The mechanisms likely involve reduced hepatic reserve, portal hypertension-related immune dysfunction, and potential upregulation of viral entry receptors in the cirrhotic liver [46]. A global meta-analysis found that individuals with liver disease who contracted H1N1 were five times more likely to be hospitalized for influenza-related complications and faced a seventeen-fold increase in mortality risk compared to those without liver conditions [62]. Regarding RSV, data on its impact on patients with preexisting liver disease are limited, but there may be an elevated risk of severe outcomes in this population [63].
Drug-induced liver injury
Various medications used in the treatment of respiratory viral infections, especially in the early stage, including antipyretics or herbal medications, can cause liver injury. Paracetamol, a widely used antipyretic, is particularly concerning as it is known to impair liver function, especially when taken in high doses or by individuals with preexisting liver conditions. Additionally, drug interactions may further increase the risk [59]. Therapeutic interventions for severe respiratory viral infections may also cause hepatic injury. Certain medications used in treating COVID-19 have been associated with elevated activity of liver enzymes. For instance, remdesivir has been linked to increased liver enzyme activity in approximately 15% of patients [64]. Tocilizumab, an immunomodulatory agent for patients at risk of the most severe course of COVID-19 [65], is known to cause transient or intermittent mild to moderate elevation of hepatic transaminases [66]. Conversely, oral anti-SARS-CoV-2 agents, molnupiravir and ritonavir-boosted nirmatrelvir revealed favorable hepatic safety profiles [67, 68], though there are rare cases of fatal cases of nirmatrelvir/ritonavir-induced severe liver injury. Certain antiviral treatments for influenza (e.g., oseltamivir) and supportive medications for RSV infection (e.g., ribavirin) may also rarely cause hepatic toxicity [69, 70]. An analysis of the US Food and Drug Administration Adverse Event Reporting System linked oseltamivir use with the risk of fulminant hepatitis, especially in patients with liver-related diseases. The study also indicated that baloxavir marboxil may be a safer alternative in such a group due to lower hepatic toxicity [71].
Management considerations
While no specific causal treatments exist for respiratory virus-associated liver injury, several management principles apply:
Monitoring – regular liver tests in hospitalized patients, especially those with severe disease or preexisting liver conditions, and treated with remdesivir (COVID-19), neuraminidase inhibitors (influenza), and ribavirin (RSV);
Medication review – careful assessment of potential hepatotoxic drugs, with dose adjustments as needed;
Supportive care – hepatic perfusion should be maintained, with optimized oxygenation and nutritional support;
Hepatoprotective agents in adults can be considered depending on the degree of liver injury and the mechanism of hepatotoxicity [72];
Discontinuation of suspected offending antiviral agents – prompt cessation of suspected hepatotoxic drugs is recommended, especially when there is evidence of rapidly rising liver enzymes or liver dysfunction. Re-exposure to the offending agent should be avoided, particularly if the initial injury involved significant aminotransferase elevations or jaundice [73];
Referral considerations – hepatology/gastroenterology consultation is pivotal for severe cases with special management in case of liver failure and early intensive care involvement for patients showing rapid progression [74-76].
One should also note that all the discussed respiratory viral infections, i.e., SARS-CoV-2, influenza, and RSV, are currently vaccine-preventable [77-79]. Although vaccinated individuals may still experience breakthrough infection, the primary aim of these vaccinations is to decrease the severity and long-term consequences. These vaccinations, among others, are also recommended for patients with chronic liver disease, as they reduce the mortality and the risk of exacerbation of the underlying condition and treatment failure [80]. Therefore, it is crucial to engage hepatologists in recommending prophylactic vaccinations to their patients in a proactive manner.
Future research prospects
Despite significant advances in understanding liver involvement in respiratory viral infections, several important issues remain to be studied, including:
further elucidation of precise pathways of liver injury, particularly for influenza and RSV,
long-term outcomes of liver dysfunction after viral infection,
identification of specific markers differentiating direct viral injury from secondary mechanisms,
evaluation of potential hepatoprotective strategies in high-risk patients,
exploration of the impact of viral co-infections and reinfections on liver injury.
Conclusions
Liver involvement and clinically significant complications of respiratory viral infections vary among SARS-CoV-2, influenza viruses, and RSV. While the patterns and mechanisms of injury may differ among these pathogens, hepatic dysfunction consistently correlates with disease severity and worse outcomes across all three infections. However, it is important to note that liver involvement during influenza and RSV infections has been less extensively studied and is generally considered uncommon. This underscores the need for further research to better understand the prevalence and implications of hepatic dysfunction in these infections. Clinicians should integrate liver monitoring into the management of severe respiratory viral illnesses to optimize patient outcomes, particularly for those with preexisting liver disease or other risk factors. Future research should aim to better elucidate the mechanisms underlying hepatic injury and develop targeted management strategies.
