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Hepatic complications of COVID‐19 and its treatment

Abstract Coronavirus disease 2019 (COVID‐19) is highly contagious and has a variety of clinical manifestations, it can affect a number of other organs in addition to the lungs, and liver injury may occur. Severe acute respiratory syndrome coronavirus 2 can cause liver injury through systemic inflammatory response syndrome, cytokine storms, ischemia‐reperfusion injury, side effects of treatment drugs, and underlying liver disease and can attack liver cells directly via angiotensin‐converting enzyme 2. Clinical studies have found that liver injury in COVID‐19 patients mainly manifests as abnormal liver biochemical indicators, but there have been no reports of liver failure caused by this disease. The number of COVID‐19 patients with liver injury is increasing, and the incidence of liver injury in COVID‐19 patients with severe disease are higher than in patients with mild disease. Liver injury may be a risk factor, which worsens in patients with COVID‐19, and hence it is necessary to pay attention to the occurrence of liver injury in the diagnosis and treatment of COVID‐19.


| INTRODUCTION
Coronavirus disease 2019 (COVID- 19) is an acute respiratory infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). [1][2][3] As it is highly contagious, people are generally susceptible, and it is mainly transmitted via respiratory droplets, COVID-19 is spreading all over the world. It has been reported in more than 200 countries, and the number of deaths worldwide is also increasing. SARS-CoV-2 infection mainly affects the respiratory tract, and the main clinical manifestations are fever, dry cough, rhinorrhea, and fatigue. Many cases of COVID-19 are acute and resolve quickly, but the disease can also be fatal, with a mortality rate of approximately 3%. 4 The fatality rate of critically ill patients admitted to the intensive care unit (ICU) is relatively high, the results from a study of 52 critically ill patients with COVID-19 who were admitted to the ICU of Wuhan Jin Yin-tan hospital (Wuhan, China) between late December 2019 and 26 January 2020 showed that 32 (61.5%) patients had died within 28 days, and the median duration from ICU admission to death was 7 (IQR, [3][4][5][6][7][8][9][10][11] days in the nonsurvivors. 5 Many clinical studies have also suggested that patients with COVID-19 have multiple organ and multiple system damage, including circulatory system, urinary system, nervous system, and digestive system. The presence and number of these complications are high-risk factors that aggravate a patient's condition and correlate with poor prognosis.
Thus, clinicians should pay more attention to changes in liver biochemical indicators and also identify patients with liver damage in a timely manner.
1.2 | The mechanism by which COVID-19 causes liver injury The results from biopsies in a death COVID-19 patient showed moderate microvascular steatosis and mild portal and lobular activity in liver tissue. 25 In another four autopsy of COVID-19 patients The above studies may indicate that hepatic injuries may be related to direct viral attack. It has been confirmed that SARS-CoV-2 enters host cells through binding of its S protein to angiotensin-converting enzyme 2 (ACE2) on the surface of the host cell. ACE2 is the most important cell receptor that mediates the entry of SARS-CoV-2 into target cells. 28,29 However, based on single-cell sequencing and animal model analysis of liver tissue, ChaiX's team found that the expression level of ACE2 in liver tissue was only approximately 0.31% and that specific expression of ACE2 in bile duct epithelial cells was 20 times higher than that in hepatocyte. 30 Considering limited number of autopsy cases in patients with COVID-19 studied and the relatively low expression of ACE2 in liver, liver damage directly caused by SARS-CoV-2 infection of hepatocytes deserves further investigation.
Moreover, biomarkers for cholangiocyte injury, such as γ-glutamyl transferase (GGT) and alkaline phosphatase (ALP) have also been seen in some patients, 31

| Ischemia and hypoxia reperfusion injury
Patients with COVID-19 have varying degrees of hypoxemia, with more than 40% requiring oxygen therapy. 5 Complications such as

| Drug hepatotoxicity
In China, the incidence of drug-induced liver injury is second only to viral hepatitis and fatty liver disease (including alcoholic and nonalcoholic). Drugs commonly causing liver injury include traditional Chinese patent medicines containing components of saikosaponins, 38,39 antitumor drugs, antituberculosis drugs, antimalarial drugs, and antibiotics. 40,41 Most patients with COVID-19 have fever, and many of them use antipyretic and analgesic drugs, which contain acetaminophen and are known to cause liver damage; overdose of these drugs can cause liver damage. Currently, there is no clearly effective antiviral drug, and many patients in the outbreak were given lopinavir, abidor, ritonavir, and other antiviral drugs. The latest study published in JCI 42 reported that CYP3A4 plays an important role in ritonavir's mediating of hepatotoxicity and the CYP3A metabolic pathways can produce electrophilic content, oxygen-free radical, which can be covalent binding with macromolecular substances within the liver cells that cause system membrane lipid peroxidation, destruct membrane integrity and membrane Ca 2+ -ATPase, disrupt cell internal and external Ca 2+ homeostasis, and influence the function of critical organelles such as mitochondria, endoplasmic reticulum, and eventually lead to liver cell damage and even death.
Moreover, the combination of overdose of lopinavir and ritonavir can activate the endoplasmic reticulum stress pathway in the liver, inhibit the proliferation of hepatocytes, induce apoptosis of hepatocytes through the caspase cascade system, induce inflammatory reactions, and accelerate liver injury by aggravating oxidative stress ( Figure 2). 43,44 Some scholars believe that HIV protease inhibitors can effectively suppress SARS-CoV-2 replication, nevertheless, Shen's team confirmed that the risk of liver damage was increased in patients taking both hormones and HIV protease inhibitors. 45 The incidence of liver injury caused by different drugs varies, but the incidence increases with the increase in drug types. The diagnosis of drug-induced liver injury requires the combination of medical history and relevant tests to exclude other liver diseases and assess the association between liver injury and suspected drugs by causality.

| Recurrence or aggravation of existing liver disease
Chronic liver disease is a major disease burden globally. Liver diseases, including chronic viral hepatitis, alcohol-related liver disease,

| Prevention and treatment
For COVID-19 patients with mild liver biochemical abnormalities, the primary disease should be treated actively when antiviral and supportive treatments are given to inhibit viral replication, reduce inflammation, and improve immunity, and preventive application of liver-protecting and enzyme-lowering drugs is not recommended.
With acute liver injury, clinicians should analyze and judge the causes of liver injury and take appropriate measures, while closely monitoring ALT, AST, total bilirubin, direct bilirubin, albumin, and PTA (INR). The occurrence of acute liver failure should also be identified, and liver-protecting and enzyme-lowering drugs, for which the composition and mechanism of action are relatively clear, should be chosen. Nonetheless, too many drug types should not be administered (generally not more than 2), and the dosage should not be too large. For patients with severe and critical COVID-19 disease with liver injury, which should be considered to be caused by cytokine storms and microcirculation ischemia and hypoxia, respiratory and circulatory support should be strengthened. If necessary, extracorporeal membrane oxygenation should be performed to improve the blood oxygen saturation of patients. Patients with acute liver failure should be given intensive monitoring and symptomatic and supportive treatment, and hypoproteinemia should be corrected. In cases of liver injury caused by drugs, in addition to conventional antiinflammatory liver protection treatment, stopping or reducing the amount of the suspected drugs should be considered, and the degree of liver damage should be assessed, followed by adjustment of the treatment plan. Anti-HBV or anti-HCV treatment should not be discontinued, and large doses of hormones should not be used simultaneously. Overall, the prevention and treatment experience of liver injury in SARS patients can provide some reference for COVID-19 patients with liver injury. For example, active prevention and control of the inflammatory response in the early stage of the disease is not only conducive to reducing the nonspecific inflammation of the liver, but also prevent the occurrence of systemic inflammatory response syndrome to reduce the probability of mild disease developing into severe or critical disease.

| CONCLUSIONS
COVID-19 combined with liver injury is very common, and the incidence of liver injury in patients with severe or critical COVID-19 disease is higher than that in patients with mild disease. Liver injury in patients with COVID-19 may be caused by a variety of mechanisms, such as direct virus infection, immune injury, drug-induced liver injury, systemic inflammatory response, ischemia and hypoxia, and recurrence or exacerbation of the underlying liver disease. As the liver is an important processing organ of the body, impaired liver function seriously affects the body's anabolism and prognosis of the disease. Therefore, clinicians should pay more attention to the occurrence of liver damage in the diagnosis and treatment of COVID-19 and analyze comprehensively the pathogenesis of liver injury in COVD-19 patients to develop a reasonable individualized treatment strategy.