key: cord-355395-rckzi8vz
authors: Tian, Dandan; Ye, Qing
title: Hepatic complications of COVID‐19 and its treatment
date: 2020-05-21
journal: J Med Virol
DOI: 10.1002/jmv.26036
sha: 
doc_id: 355395
cord_uid: rckzi8vz

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. SARS‐CoV‐2 can cause liver injury through systemic inflammatory response syndrome (SIRS), cytokine storms, ischemia‐reperfusion injury, side effects of treatment drugs, and underlying liver disease and can attack liver cells directly via ACE2. 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 for progresses and worsens in patients with COVID‐19, and it is necessary to pay attention to the occurrence of liver injury in the diagnosis and treatment of COVID‐19. This article is protected by copyright. All rights reserved.

Coronavirus disease 2019 (COVID- 19) is an acute respiratory infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1-3 .

Because 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 intensive care unit (ICU) of Wuhan Jin Yin-tan hospital (Wuhan, China) between late December, 2019, and Jan 26, 2020 showed that 32 (61.5%) patients had died within 28 days, and the median duration from ICU admission to death was 7 (IQR 3-11) days in the non-survivors 5 . Many clinical studies have also suggested that patients with COVID-19 have multiple organ damage, including the circulatory system, urinary system, nervous system, and digestive system, among others. The presence and number of these complications are high-risk factors that aggravate a patient's condition and correlate with a poor prognosis.

The whole genome sequencing results showed that SARS-CoV-2 shares 82% genome sequence similarity to SARS-CoV, and 50% genome sequence homology to Middle East respiratory syndrome coronavirus (MERS-CoV) 22 SARS-CoV, Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and SARS-CoV-2 are all coronaviruses and known to cause severe respiratory symptoms 11 . As many as 60% of patients infected with SARS-CoV have liver damage 23 , and some patients infected with MERS-CoV also have liver damage 24 19 .

The above indicate that the incidence of liver injury in severe or critically ill cases is significantly higher than that in mild cases of COVID-19, and the probability of patients with liver function impairment requiring ICU treatment is increased. 19 . Another single-center study of 138 patients with COVID-19 showed that the levels of ALT and AST in patients who required ICU treatment were significantly higher than those in patients who did not require ICU treatment 10 . Moreover, in a large cohort of 1099 patients from 552 hospitals in 31 provinces or provincial municipalities, the total incidence of elevated total bilirubin was approximately 10%, of which the incidence in severe and nonsevere patients was approximately 13.3% and 9.9%, respectively; the incidence of increased total bilirubin in patients who needed to be moved to the ICU, needed mechanical ventilation, or died was higher than in other patients (20.8% vs 9.8%) 5 . The above studies suggest that liver biochemical indicators may be used as predictors of severity and prognosis of COVID-19 patients. Thus, clinicians should pay more attention to changes in liver biochemical indicators and also identify patients with liver damage in a timely manner.

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 in a death COVID-19 patient showed mild zone 3 sinusoidal dilatation, patchy hepatic necrosis, mild increase in sinusoidal lymphocytes are the main pathologic changes of liver in case 3 and case 4, and RT-PCR showed direct evidence of the SARS-CoV-2 RNA sequence in the liver tissues in case 1 26 .

Through learning of Tian et al report 26 , Li et al observed foci of hepatic necrosis in adjacent to terminal hepatic veins and peri-portal area, and found no significant surrounding inflammatory cellular infiltration, which consistent with the pattern of acute liver injury 27 . 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 This article is protected by copyright. All rights reserved.

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 gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) have also been seen in some patients 31 , and consistent with injury to biliary epithelial cells, and about 10% of COVID-19 patients have elevated total bilirubin level.These might suggest that SARS-CoV-2 might directly bind to cholangiocytes expressing ACE2 result in cholangiocyte injury.

Huang C 18 and colleagues found that liver injury in COVID-19 patients differed from that in SARS patients. Liver injury as the first manifestation in COVID-19 patients was very rare, with most being secondary liver injury. It was speculated that in addition to the virus itself causing liver injury, immune injury, systemic inflammatory response syndrome (SIRS), cytokine storms, ischemia and hypoxia reperfusion injury, and drug-induced injury may be the main mechanisms that cause secondary liver injury in patients with COVID-19 [11] [12] 14, 27 .

In addition to receptor-mediated viral infection, antibody-dependent enhancement of infection (ADE) may occur in patients with SARS 32 . ADE refers to the interaction of a virus-specific antibody with Fc receptor (FcR) and/or complement receptor (CR) to enhance the ability of the virus to enter granulocytes, monocytes, and macrophages. The virus constantly replicates in the above cells, resulting in increased virus production and aggravating infection.

Previous studies have reported that antibodies against the SARS-CoV spike protein trigger ADE, causing SARS-CoV to enter immune cells that do not express ACE2 and immune damage 33 . The liver contains a large number of cells related to the immune response. Whether ADE can also mediate SARS-CoV-2 to This article is protected by copyright. All rights reserved.

infect immune cells by a non-ACE2-dependent pathway and participate in liver injury caused by SARS-CoV-2 is a concern.

Systemic Inflammatory Response Syndrome (SIRS) and Cytokine Storms( 

as the liver, myocardium and kidney. These results suggest that the SIRS and cytokine storms caused by SARS-CoV-2 infection may be one of the important mechanisms of liver injury.

Patients with COVID-19 have varying degrees of hypoxemia, with more than 40% requiring oxygen therapy 5 Drug hepatotoxicity( Figure 2) In China, the incidence of drug-induced liver injury is second only to viral hepatitis and fatty liver disease (including alcoholic and non-alcoholic). 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 This article is protected by copyright. All rights reserved.

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, etc, they can be covalent binding with macromolecular substances within the liver cells, cause system membrane lipid peroxidation, destruction of membrane integrity and membrane Ca 2 + -ATPase, disrupt cell internal and external Ca 2 + homeostasis, influence 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 [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 is 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.

Chronic liver disease is a major disease burden globally. Liver diseases, including chronic viral hepatitis, alcohol-related liver disease, non-alcoholic fatty liver disease, and autoimmune hepatitis, affect approximately 300 million people in China. A retrospective analysis of 333 COVID-19 inpatients 19 showed that 12 Accepted Article had a history of hepatitis B and that 2 had a history of hepatitis C. In another study of baseline liver biochemical parameters in 324 cases in the Shanghai area, the HBsAg-positivity rate in COVID-19 patients reached 6.5% 46 

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 no 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 anti-inflammatory 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, but 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 This article is protected by copyright. All rights reserved.

but also to preventing the occurrence of systemic inflammatory response syndrome to reduce the probability of mild disease developing into severe or critical disease.

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, among others.

Since 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.

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Figure 1. Systemic Inflammatory Response Syndrome (SIRS) and Cytokine Storms in COVD-19 with liver injury