Open access peer-reviewed chapter
Abstract
The novel severe acute respiratory syndrome coronavirus (SARS CoV-2) is the cause of coronavirus disease (COVID-19), a pandemic that represents a global health challenge. COVID-19 is usually a self-limiting disease; however, it is associated with a significant (3–7%) mortality rate. The excessive production of pro-inflammatory cytokines because of SARS-CoV-2 infection is mainly associated with high mortality due to multiple organ failure. The global burden of chronic liver disease (CLD) is vast. Approximately 122 million people worldwide have cirrhosis, 10 million living with decompensated cirrhosis. The preexisting chronic liver disease is associated with inflammation and immune dysfunction that might predispose to poor clinical outcomes in COVID-19, such as disease severity, rate of ICU admission, and mortality. The overlapping risk factors for SARS CoV-2 and chronic liver diseases such as obesity, advanced age, diabetes, and metabolic dysregulation are the major causes of these poor outcomes. Furthermore, progressive liver disease is associated with immune dysregulation, contributing to more severe COVID-19. This book chapter will explain the natural history and pathogenesis of COVID-19 in CLD patients along with the likely underlying SARS CoV-2-related liver injury mechanisms.
Keywords
- SARS CoV-2
- COVID-19
- chronic liver disease
- cirrhosis
- hepatocellular carcinoma
- COVID-19 clinical outcomes
1. Introduction
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-20) is a novel member of the coronavirus family first reported in Wuhan, China [1]. It causes COVID-19, which has infected millions of people worldwide, representing a global challenge. COVID-19 is generally a self-limiting disease presenting with flu-like symptoms but can also be deadly with a 0.7–5.8% fatality rate [2]. However, the disease severity and fatality vary by geographic areas and country, related to distinct population and disease demographics [2]. Mild COVID-19 cases may present with dry cough, fever, fatigue, dyspnea, and diarrhea. In contrast, severe cases may give a complex picture of acute hypoxia, respiratory distress syndrome (RDS), encephalopathy, and multiple organ failure [3]. Patients with advanced age and comorbidities such as hypertension, diabetes mellitus, obesity, chronic lung disease, chronic liver disease, cardiovascular disease, and cancer are at the greater risk of having severe illness and fatality due to COVID-19 [4]. Previously healthy patients with severe and critical COVID-19 also experience some liver injury, mainly presenting with deranged liver enzymes, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH), and hypo-functioning of the liver in the form of hypoalbuminemia [3, 5, 6, 7, 8].
COVID-19 leads to host immune dysregulation and cytokine storm by producing inflammatory markers [3]. This cytokine storm has been implicated in causing lung and liver injury and multiorgan failure (Figure 2). COVID-19 patients have been studied to have an elevated level of cytokines such as interleukin (IL)-1B, interleukin-6, tumor necrosis factor (TNF) interferon-gamma (INF-γ), interferon gamma-induced protein 10, macrophage inflammatory proteins (1alpha, 1beta), and vascular endothelial growth factor (VEGF) [3]. Although COVID-19 patients exhibit a highly variable immune response, the interleukin-6 level has been associated with COVID-19 severity and mortality [9].
The world is also dealing with another ongoing obesity pandemic due to sedentary lifestyles and food habitus [10]. This pandemic has led to various diseases such as diabetes mellitus, insulin resistance, and chronic liver disease (CLD) [10, 11]. CLD is prevalent worldwide and imposes a significant burden on healthcare costs and services. The most common causes of CLD include nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), viral hepatitis B and C. CLD can further progress to fibrosis, cirrhosis, and ultimately hepatocellular carcinoma (HCC) as an end-stage liver disease [10, 11]. Hepatocytes constitute a significant source of many proteins involved in both the body’s innate and adaptive immune responses [12]. The liver plays a vital role in regulating immune homeostasis by two fundamental mechanisms. First, it prevents the systemic spread of dietary and microbial antigens from the gut; second, it produces the soluble molecules essential for effective body immune responses to the foreign antigens [12]. Thus, any liver injury can compromise the synthesis of proteins involved in the immune responses resulting in a compromised body immune surveillance against antigens [12]. It is categorized as an immune dysregulation in both CLD and liver cirrhosis.
The impairment of the liver’s homeostasis in CLD leads to specific molecular patterns from the damaged hepatocytes, which may prompt the circulating immune cells to activate and induce an inflammatory response by releasing pro-inflammatory cytokines (interleukins and tumor necrosis factor) in the serum [13]. Furthermore, this immune dysregulation process emanates the possibility of increased infection susceptibility. Margot et al. have demonstrated that patients with CLD and cirrhosis are at a higher risk of morbidity and mortality due to COVID-19 infection [14]. However, the mechanisms of COVID-19-induced liver injury are multifactorial and are not fully understood [15, 16]. Cytokine storm hypothesis suggests that immune dysregulation because of SARS CoV-2 infections plays a vital role in liver pathophysiology in COVID-19 [15, 16].
This chapter aims to discuss the COVID-19 implications on healthy liver and CLD. The effect of COVID-19 on clinical outcomes in patients with cirrhosis and hepatocellular carcinoma will also be reviewed and discussed.
2. Pathophysiology of liver injury in COVID-9
SARS CoV-2 virus has two major binding sites. The spike glycoprotein (S) is essential for viral entry into the host cell, and the inner nucleocapsid phosphoprotein (N) interacts with the host RNA [17]. There are two possible mechanisms of liver injury in COVID-19 infection.
2.1 Viral immunological injury and systemic inflammatory response
One mechanism suggests that the SARS CoV-2 virus infects the target cells by binding to the angiotensin-converting enzymes 2 receptors on cell surfaces and replicates further inside to infect other cells [17]. These receptors are present on the bile duct epithelial cells, liver parenchymal cells, and alveolar type 2 cells in the lungs [18]. Some studies have suggested that the virus does not directly infect the hepatocytes, but it enters the portal circulation and, by reaching the liver, induces the Kupffer cells to activate immune systems, and thus produces inflammatory changes [19]. These inflammatory changes are the primary source of liver injury in SARS CoV-2 infection [19]. As a result of this inflammation, the liver enzymes (AST, ALT) were reported to be elevated >2 times the upper limit of normal in 14–53% of COVID-19 cases [20].
On the other hand, gamma-glutamyl transpeptidase (GGT) has been found to be elevated in 24% of the COVID-19 hospitalized patients suggesting a biliary epithelial cell injury [20]. Higher levels of liver enzymes have been associated with the severity of COVID-19 [21]. Moreover, antiviral drugs used for COVID-19 treatment are associated with liver injury. For instance, remdesivir use in severe COVID-19 patients has also been associated with elevated liver enzymes [22]. Figure 1 illustrates the etiological factors of liver injury in COVID-19.
Figure 1.
Etiology of liver injury in COVID-19. Abbreviations: SIRS: Systemic inflammatory response syndrome; TNF-α: Tumor necrosis factor-alpha; IL18: Interleukin-18.
2.2 Hypoxic injury and cytokine storm
Hypoxia and cytokine storm following SARS CoV-2 infection can also affect the liver and are associated with multiorgan failure in some patients with severe COVID-19 (Figure 2) [23]. Hypoxia also causes Kupffer cells to produce more cytokines and triggers the recruitment and activation of other polymorphonuclear leukocytes to produce more cytokines. This cytokine storm has also been implicated in thrombocytopenia and disseminated intravascular coagulation (DIC) observed in many COVID-19 patients [24]. Furthermore, it has been associated with liver vascular endotheliitis, complement system activation, and fibrin microthrombi formation in the liver sinusoids leading to hepatic dysfunction [25, 26, 27, 28].
Figure 2.
Pathophysiology of SARS CoV-2 infection. A cytokine storm may occur following SARS CoV-2 infection, which can cause ineffective pathogen recognition with immune evasion leading to inappropriate inflammatory response or failure to return to the homeostasis mechanism.
In essence, regardless of etiology, aminotransferases elevation is commonly observed in COVID-19 patients, and it appears to mirror disease severity [29]. Both ALT and AST have been observed to be elevated in 93% of hospitalized COVID-19 patients. However, most of the COVID-19 patients have been found to have AST predominant aminotransferase elevations. AST can be higher in non-hepatic injuries such as myositis, but correlations with creatinine kinase (CK) were weak [29].
3. Impact of COVID-19 on non-alcoholic fatty liver disease
Chronic diseases such as diabetes mellitus, hypertension, and obesity are associated with severe COVID-19 and lousy prognosis [30, 31, 32, 33]. Together these conditions are part of the metabolic syndrome that predisposes to non-alcoholic fatty liver disease (NAFLD) [34]. The worldwide prevalence of NAFLD is 20–30% among Western populations and about 5–15% among Asian people. Thus, a large proportion of the population is at a higher risk of developing severe COVID-19 [35]. Shanghai et al. demonstrated that the patients with the fatty liver disease diagnosed on liver CT scan were more likely to have severe COVID-19 than the general population [36]. Elevated liver enzymes AST/ALT >2 times the upper limit are independently associated with the worst clinical COVID-19 outcomes [37, 38, 39]. Patients with NAFLD, compared with those without NAFLD, reportedly show a higher risk of liver enzymes elevation throughout the disease course (70% vs. 11.1%), a higher risk of disease progression (6.6% vs. 44.7%), and a longer viral shedding time (17.5 ± 5.2 days vs. 12.1 ± 4.4 days) [40].
The severity of liver fibrosis in NAFLD is associated with the worst COVID-19 clinical outcomes [41]. Furthermore, the patients with NAFLD who have been diagnosed with hepatic fibrosis on liver CT scan (OR, 4.32; 95% CI, 1.94–9.59) or with intermediate or high fibrosis index (Fib-4) (OR, 5.73; 95% CI, 1.84–17.9) have a significantly higher risk of developing severe COVID-19, regardless of the presence of other comorbidities [41, 42]. Moreover, the need for mechanical ventilation and ICU admission among COVID-19 patients was independently associated with diabetes mellitus, obesity, and FIB-4. FIB-4 is also associated with increased 30-day mortality (OR, 8.4; 95% CI, 2.23–31.7) [43].
It has been proposed that the patients with NAFLD/NASH have a higher expression of genes for ACE2 and TMPRSS2 receptors, which may explain the worse COVID-19 clinical outcomes among these patients. However, further studies are needed to support this hypothesis [44]. Because there is no therapy for NAFLD/NASH, it has been demonstrated that the patients with NAFLD/NASH are at a higher risk of COVID-19 severity, ICU admission, and mortality.
Similarly, metabolic-associated fatty liver disease (MAFLD) is one of the most common causes of chronic liver disease. It affects approximately 26–39% of the global population [45]. It is also a well-known risk factor for chronic diseases such as cardiovascular disease and diabetes mellitus, resulting in higher morbidity and mortality among these patients [45]. The criteria to diagnose MAFLD are based on hepatic steatosis and three other measures, including the presence of obesity, DM2, metabolic dysregulation [45]. Studies have demonstrated that preexisting MAFLD is linked with severe COVID-19 outcomes such as a high hospitalization rate and disease severity [46]. According to a proposed mechanism of liver injury in COVID-19 patients, the presence of MAFLD could release more pro-inflammatory cytokines to exacerbate the SARS CoV-2-induced inflammatory response [46]. SARS CoV-2 uses angiotensin-converting enzyme 2 (ACE2) receptors for cellular entry. The patients with MAFLD had reported having an increased expression of ACE 2 receptors, thus leading to more severe disease and worst clinical outcomes [47]. Lastly, MAFLD patients have an increased production of reactive oxygen species that further swirls the inflammatory storm responsible for disease severity [48].
4. COVID-19 and alcohol-associated liver disease
Worldwide alcohol consumption has been increased lately [49]. Social distancing and lockdown situations in the COVID-19 pandemic have further accelerated alcohol abuse, aggravating the alcohol-associated liver injury and chronic liver disease [50]. Alcohol consumption causes approximately 3.3 million annual deaths. CLD and cirrhosis are the main pathologies linked to alcohol consumption [50]. It has been suggested that excessive alcohol consumption may have immune-modulating effects in the human body and may predispose to bacterial and viral infections [51, 52]. Moreover, there has been an unprecedented rise in the listing rate for hepatic transplantation of ALD patients compared with HCV and NASH combined [53].
Patients with alcoholic liver disease (ALD) exhibit more severe liver injury if they have COVID-19 [14]. Therefore, ALD is independently associated with a 1.8-fold increased mortality risk among COVID-19 patients [14]. A recent study has indicated that alcoholic liver damage (OR, 7.05; 95% CI, 6.30–7.88) and alcoholic cirrhosis (OR, 7.00; 95% CI, 6.15–7.97) are significantly associated with the severity of COVID-19 [54]. Another study reported the higher severity of COVID-19 among patients with ALD. They have suggested this increase due to an increased proportion of alcoholic hepatitis among these patients due to a substantial increase in alcohol consumption since the pandemic’s beginning [53, 54]. Future studies are needed to explore the mechanism and pathogenesis of how alcohol consumption and ALD are related to the severe COVID-19.
5. COVID-19 and liver cirrhosis
Cirrhosis is the end-stage of chronic liver disease characterized by advanced fibrosis. The liver is an essential part of the reticuloendothelial system and plays a vital role in immune regulation [13, 15]. It is responsible for innate immunity and responds to bacterial and viral infections. SARS CoV-2 binds to the selective ACE2 receptors on the surface of bile duct epithelial cells responsible for liver regeneration and immune response [50]. Thus, cirrhosis impairs this homeostasis response of the reticuloendothelial liver component and causes immune dysfunction leading to severe COVID-19 and a bad prognosis [54]. In severely decompensated liver cirrhosis, the pro-inflammatory state of the liver switches to the immune-deficient state [13].
Patients with cirrhosis are at an increased risk for SARS CoV-2 infection, a higher risk of developing severe disease, and a substantial risk for hepatic decompensation [55]. A large multicenter cohort study has demonstrated that COVID-19 infection was strongly associated with hepatic decompensation, increasing the mortality rate from 26.2% to 63.2% [56]. Moreover, studies have shown that cirrhosis is an independent predictor of overall and 30-day mortality in COVID-19 patients [57, 58, 59]. A recent analysis on 745 CLD patients infected with SARS CoV-2 virus in 28 countries indicated that cirrhosis was strongly associated with COVID-19 mortality (OR, 9.32; 95% CI, 4.80–18.08) [14]. Among the total, 150 patients died due to COVID-19, and among those, 123 had cirrhosis. The study also revealed that only 19% of the total deaths were due to cirrhosis-related complications, and for rest of the patients, the cause of death was lung injury [14]. These findings suggest that cirrhosis is a strong driving force for lung injury development in COVID-19 patients. This association is related to the cirrhosis-related immune dysfunction triggered by SARS CoV-2 infection [15]. Thus, the potential mechanism for severe COVID-19 in cirrhosis is the combination of cirrhosis-related immune dysfunction, an overwhelming systemic inflammatory response to SARS CoV-2 infection, and coagulopathy [60]. Lastly, cirrhotic patients have a poor response to Hepatitis B and pneumococcal vaccine, suggesting an inadequate response to SARS CoV-2 vaccination [61, 62]. The impact of cirrhosis on SARS CoV-2 infection and vice versa has been described in Figure 3.
Figure 3.
COVID-19 and hepatic cirrhosis interrelationship. The impact of cirrhosis on SARS CoV-2 infection and vice versa.
6. COVID-19 and hepatocellular carcinoma
Hepatocellular carcinoma accounts for 6% of all the malignancies globally and is the sixth most common cancer [63]. Patients suffering from any malignancy are more prone to developing SARS CoV-2 infection and are at a higher risk of developing severe COVID-19 clinical outcomes [64]. Since SARS CoV-2 directly affects the liver parenchyma and leads to immune dysfunction, it can be hypothesized that the patients with HCC are more susceptible to the severity of the disease and have worse clinical outcomes than the patients with other cancers [65]. Moreover, cancer patients are more likely to be admitted to ICU and have mechanical ventilation and die (39%) than non-cancer patients (8%) [66]. A retrospective study on 28 cancer patients with two HCC patients has demonstrated that the patients with malignancies had poor outcomes compared with the general population [67]. It is also attributed to their advanced age, different comorbidities, and underlying cirrhosis. Also, these patients were more vulnerable to severe infection because of their compromised immunity resulting from poor nutrition status [67]. Additionally, recent chemotherapy treatment within the last month also increased the risk of COVID-19 severity [66].
AASL recommends restricting physician visits in this pandemic. They have also recommended continuing surveillance imaging for HCC with an acceptable delay of 2 months [68]. However, the management of these patients is becoming more and more challenging. It is expected that the interruption of the surveillance programs in high-risk patients and patients with cirrhosis will result in advanced HCC [65].
7. COVID-19 and viral hepatitis
Hepatitis B virus (HBV) and Hepatitis C (HCV) constitute two primary sources of chronic liver disease [69]. About 300 million and 70 million people are currently infected with HBV and HCV, respectively, instigating a significant burden to the healthcare system. HBV accounts for approximately 12%, and HCV constitutes about 11% of the underlying causes of chronic liver disease [69, 70]. The susceptibility of the HBV and HCV patients to get infected with SARS CoV-2 remains unclear. Similarly, there is only limited data available to conclude the association of HBV and HCV with the severity of COVID-19 [71]. Some studies have reported that viral hepatitis is not associated with the severity of the COVID-19 [72, 73, 74]. However, a small retrospective study has shown that COVID-19 patients with HBV disease had more severe disease e (46.7% vs. 24.1%) and a higher mortality rate (13.3% vs. 2.8%) than those without HBV disease [75]. The overall COVID-19 severity and mortality were found to be higher if the viral hepatitis patients have baseline liver injury and liver fibrosis than those without any liver injury (28.57% vs. 3.30%, P = 0.004) [76].
SARS CoV-2-induced lymphopenia and the use of immunosuppressive drugs such as corticosteroids may increase the risk of severe COVID-19 in patients with active or past HBV infection [76]. A retrospective study demonstrated that immunosuppressive therapy in COVID-19 has a low risk of HBV reactivation in patients with resolved HBV infection [77]. AASLD recommends continuing HBV and HCV treatment in COVID-19 patients if started before acquiring SARS CoV-2 infection [68].
8. COVID-19 and liver transplantation
Liver transplant patients are immune-compromised, thus vulnerable to SARS CoV-2 infection. It also makes them a potential source of infection dissemination to others, especially healthcare workers, by serving as super spreaders [78]. On the other hand, immunosuppression is considered protective against the severe COVID-19 infection as it suppresses the cytokine storm responsible for inflammatory changes [79]. Surprisingly, an international cohort study with 151 liver transplant recipients who had COVID-19 demonstrated that liver transplantation was not an independent predictor of mortality [80]. However, another study revealed that patients with liver transplants and COVID-19 had a higher mortality risk than those without transplantation (OR, 6.91; 95% CI, 1.68–28.48) [81]. COVID-Hep and SECURE-CIRRHOSIS registries described 159 liver transplant patients in their recent report. Of all, 81% were hospitalized, 30% were admitted to the ICU and required mechanical ventilation, and the overall mortality rate was 19% [82, 83]. The European Liver and Intestine Transplant Association (ELITA) revealed that the older patients with liver transplants had higher mortality [84]. In a systematic review of patients with solid organ transplants (SOT) who had COVID-19, the mortality rate among liver transplant recipients was 37.5% [85]. However, the risk of SARS CoV-2 infection and clinical outcomes of COVID-19 remained unclear among liver transplant patients and need further studies for factual inferences [86].
9. Conclusions
In essence, preexisting liver disease and liver injury are associated with the COVID-19 severity and mortality. The indicators of liver disease such as elevated liver enzymes, liver steatosis, and fibrosis are considered the prognostic markers of severe COVID-19. Additionally, CLD patients with severe COVID-19 tend to develop changes in fibrinolytic and coagulative pathways due to the dysfunctional innate immune response of the body against SARS CoV-2, leading to a lousy prognosis.
Moreover, the current co-occurring worldwide NAFLD/NASH pandemic is particularly relevant in the COVID-19 era as this mortal combination results in worse clinical outcomes. CLD patients should be given special attention for screening and treatment of COVID-19. Furthermore, patients with advanced liver disease and cirrhosis should be vaccinated on a priority basis. Lastly, the COVID-19 pandemic may have significantly delayed diagnosing and treating chronic liver disease and contributed to the significant morbidity and mortality associated with liver disease. Unhealthy behaviors and sedentary lifestyle changes in the pandemic can increase the global burden of liver disease in the future. Thus, the ongoing effect of the COVID-19 pandemic on the liver warrants robust measures and further investigation.
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