SARS-CoV-2-induced liver injury: A review article on the high-risk populations, manifestations,mechanisms, pathological changes, management, and outcomes

Alvin Oliver Payus,Malehah Mohd Noh,Nornazirah Azizan, Raman Muthukaruppan Chettiar

Abstract The novel coronavirus disease 2019 is an infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and was declared a global pandemic with more than 500 million reported cases and more than 6 million deaths worldwide to date. Although it has transitioned into the endemic phase in many countries, the mortality rate and overall prognosis of the disease are still abysmal and need further improvement. There has been evidence that shows the significance of SARS-CoV-2-related liver injury. Here, we review the literature on the various spectrum of SARS-CoV-2 infection-induced liver injury and the possible mechanisms of damage to the hepatobiliary system. This review aimed to illustrate the latest understanding regarding SARS-CoV-2-induced liver injury including the high-risk populations, the characteristic clinical manifestations, the possible pathogenic mechanism, the pathological changes, the current suggestions for clinical treatment for various spectrum of populations, and the prognosis of the condition. In conclusion, SARS-CoV-2 patients with a liver injury warrant close monitoring as it is associated with the more severe and poorer outcome of the infection.

Key Words: COVID-19; SARS-CoV-2; Pandemic; Liver injury; Pandemics; Prognosis

lNTRODUCTlON

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the name given to the newly emerged zoonotic virus that causes coronavirus disease 2019 (COVID-19)[1]. It was first reported in Wuhan,China on December 29, 2019 and was declared a global pandemic on March 11, 2020[2]. SARS-CoV-2 is an enveloped, single-stranded positive-sense RNA genome virus that harbors the largest genome among currently known RNA viruses, with a genome length of around 26 to 32 kb. It has an oval shape and an average size of 100 nm in diameter. Electron microscopy revealed large club-shaped spikes of glycoprotein membrane on the viral surface making the viral particles appear like a typical crown-like shape[3].

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COVID-19 is a syndrome with various systemic and respiratory symptoms such as fever, fatigue, dry cough, and breathing difficulties. It can be critical, causing severe pneumonia and cardiorespiratory failure that requires specialized management in intensive care units[4]. SARS-CoV-2 can also affect other systems, namely the nervous system causing headache, anosmia, paresthesia, and altered consciousness[5]. Abnormal liver function parameters are commonly found in patients with SARS-CoV-2 infection, indicating that SARS-COV-2 infection is associated with liver injury and even failure. Apart from that, several studies suggested that liver injury has a significant role in determining the severity and mortality rate of the disease. Considering the ongoing global threat of SARS-CoV-2 infection and the necessity to improve the prognosis of the disease, the treating physicians need to be aware of the association and significance of SARS-CoV-2 infection-related liver injury not only for the severity of the disease but also for the mortality rate and prognosis as a whole. Therefore, this review aimed to elucidate the importance of hepatobiliary involvement in SARS-CoV-2 infections and provide helpful information for managing the condition and improving the overall prognosis of the disease.

HlGH RlSK POPULATlONS OF SARS-COV-2-lNDUCED LlVER lNJURY

Since the beginning of the pandemic, it was reported that patients with severe SARS-CoV-2 infection tended to develop liver injury compared to mild infection. Caiet al[6] reported that male patients of older age and higher body mass index have a higher tendency to develop liver injury during the course of the disease. A similar finding was seen in a study on 79 non-hospitalized SARS-CoV-2 patients by Xieet al[7], who reported that liver injury was more common among male patients. The authors also said that patients with an underlying severe chronic lung disease have a higher rate of liver injury, which was also reported by Zhanget al[8]. Caiet al[6] and Singh and Khan[9] both found that liver injury was more common among patients with underlying liver disease. According to Daet al[10], the common etiology of chronic liver disease that is prone to developing worsening liver injury during the infection is alcohol-related liver disease. Patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis are usually associated with additional metabolic risk factors, such as obesity, that can increase the susceptibility to the infection and is commonly associated with a more severe presentation[11].

There has been significant concern about the increased susceptibility to SARS-CoV-2 infection among solid organ transplant recipients. In a systematic review by Piedade and Pereira[12], patients with liver transplant were not associated with an increased risk of SARS-CoV-2 infection. The risk is highly dependent on the sex, age, body mass index, history of hepatocellular carcinoma, and the immunosuppression drug dose of the patient. However, the prevalence of severe infection was higher among liver transplanted patients. A study by Becchettiet al[13] found that alterations in liver enzymes among liver transplanted patients with SARS-CoV-2 occurs more commonly among hospitalized patients. In addition, Ali Malekhosseiniet al[14] showed that the admission rate of liver transplanted patients to the intensive care unit was as high as 33.3%.

Ritonavir is also widely metabolized by the liver through the cytochrome P450 system, where the production of toxic intermediates of any drugs that are metabolized by the system will have the potential of causing liver injury[32]. Tocilizumab, which is an IL-6 inhibitor that is used to reduce overactive inflammation, has been reported to cause drug-induced liver injury and liver failure, which in some cases requires a liver transplant[33]. The exact mechanism is still unknown but may be due to its inhibitory effect on the IL-6 pathway, which is essential for liver regeneration.

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THE CHARACTERlSTlC MANlFESTATlONS OF SARS-COV-2-lNDUCED LlVER lNJURY

The most common manifestations of SARS-CoV-2 induced liver injury was the elevation of liver enzymes, such as alanine transaminase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase, and alkaline phosphatase. In a meta-analysis completed in the first few months of the pandemic by Caiet al[6], about 25% of SARS-CoV-2 patients had increased liver enzyme levels, which showed a direct association with the disease activity. The prevalence of increased AST was higher than ALT levels and was positively correlated with the severity of cases, where the level was higher in patients with severe cases[7,8,15]. Leiet al[16] reported a significant association between inpatient mortality in SARS-CoV-2 infected patients and liver injury based on liver enzymes, specifically AST elevation.

In a study on 417 SARS-CoV-2 infected patients by Caiet al[6], 41.0% of patients had abnormal liver tests, and 5.0% had liver injury upon presentation to the hospital. Throughout hospitalization, 76.3%developed some form of abnormal liver function, and it was high enough to be considered liver injury in 21.5% of patients. A similar finding was reported by Fanet al[17], who conducted a retrospective single center study on 148 patients with SARS-CoV-2 infection, where 37.2% had an abnormal liver function at hospital admission. Patients with the abnormal liver function were also found to have an extended hospital stays. A retrospective study of 79 patients with SARS-CoV-2 by Xieet al[7] found that patients with an abnormal liver test had an extended stay in the hospital.

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SARS-CoV-2-infected patients with ongoing antiviral treatment for hepatitis B or C should be continued, but the initiation of antiviral treatment for hepatitis C may need to be delayed. Patients with an underlying liver disease requiring immunosuppressants should be continued in cases of mild infection, but in moderate to severe infection, the treatment dosage of calcineurin inhibitors should be reduced. The position statement from the European Association for the Study of the Liver-European Society of Clinical Microbiology and Infectious Diseases recommended that the dose of immunosuppressant drugs can be adjusted according to antiviral treatment regimens because the drugs in both regimens will likely interact with each other[48].

No evidence shows that pregnancy increases susceptibility to SARS-CoV-2-induced liver injury.Nevertheless, a retrospective cohort study involving 122 pregnant patients with confirmed SARS-CoV-2 infection by Canet al[15] found that 13.9% developed an abnormal liver function that was generally mild, where most of them were critically ill and had a longer stay in the hospital compared to the normal liver function group.

PROPOSED PATHOPHYSlOLOGlCAL MECHANlSM OF SARS-COV-2-lNDUCED LlVER lNJURY

The exact pathophysiological mechanism of SARS-CoV-2-induced liver injury is still poorly understood,but evidence has shown it to be multifactorial (as shown in Figure 1). One of the factors is direct invasion of SARS-CoV-2, which has been suggested in several studies. The primary receptor for SARSCoV-2 cellular entry is the angiotensin-converting enzyme 2 (ACE2) receptors, which are found not only in the lung parenchyma but also in other parts of the body[19], such as the brain[5], gastrointestinal tract, biliary tree, and liver epithelia[20]. Zhouet al[21] stated that SARS-CoV-2 patients with gastrointestinal symptoms had higher AST and ALT levels, which reflected that ACE2 receptor was expressed within the gastrointestinal tract and the biliary tree. However, even though the ACE2 receptor is expressed more within the biliary tree than the liver parenchyma, most studies showed a predominant pattern of parenchymal liver injury based on the elevated levels of AST and ALT rather than the damage to the bile ducts, which was reflected by increased gamma-glutamyl transferase and alkaline phosphatase[22].

Another simpler hypothesis is that prolonged hypoxia and tissue ischemia in critically ill SARS-CoV-2 patients who suffer from severe pneumonia and acute respiratory distress syndrome can also be one of the mechanisms of liver injury and even failure[35]. This occurs due to prolonged tissue hypoperfusion leading to ischemia, including in the liver. The anaerobic metabolism and lactic acidosis will further depress the cardiorespiratory effort, which will cause the continuation of the vicious circle[36].

Apart from the direct viral-induced hepatocytopathic hypothesis, autoinflammatory mediated injury to the liver is another plausible explanation. Immune dysregulation can occur in severe SARS-CoV-2 infection, which the overactivation of the immune system will lead to systemic hyperinflammation in extreme conditions. This condition is called ‘cytokine storm syndrome’, which is a phenomenon that will not only cause pulmonary inflammation but also multiorgan involvement, including the nervous system causing encephalitis[25] and peripheral neuritis[26] and the liver causing acute hepatitis and even failure[27,28].

Figure 1 Possible pathophysiological mechanisms of liver injury induced by severe acute respiratory syndrome coronavirus 2 infection.ACE 2: Angiotensin-converting enzyme 2.

Drug-induced liver injury is also common in SARS-CoV-2 patients, as the medications used to treat the infection can be hepatotoxic. These include lopinavir/ritonavir, remdesivir, tocilizumab, and others[29]. A study of 148 cases of SARS-CoV-2 infected patients in Shanghai by Liet al[30] found that the utilization rate of lopinavir/ritonavir among patients with abnormal liver function was higher than the patients with normal liver function. There was no significant difference in the pre-hospital medication between the two groups of patients. The exact mechanism of how lopinavir/ritonavir induces liver injury is still uncertain, but there is evidence that it activates the endoplasmic reticulum stress pathway in the liver and induces hepatocytes apoptosis[31].

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SARS-CoV-2 patients with underlying chronic liver diseases are more likely to suffer from liver injury. This may suggest that SARS-CoV-2 infection can aggravate underlying liver diseases. In addition, there is a possibility that the liver damage may be caused by the viral reactivation of existi