World Journal of

WJ G Gastroenterology
Submit a Manuscript: [Link] World J Gastroenterol 2023 January 14; 29(2): 241-256

DOI: 10.3748/wjg.v29.i2.241 ISSN 1007-9327 (print) ISSN 2219-2840 (online)

REVIEW

Liver injury in COVID-19: Clinical features, potential mechanisms,

risk factors and clinical treatments

Shu-Wu Zhao, Yi-Ming Li, Yi-Lin Li, Chen Su

Specialty type: Gastroenterology Shu-Wu Zhao, Department of Anesthesiology, Hunan Cancer Hospital/The Affiliated Cancer
and hepatology Hospital of Xiangya School of Medicine, Changsha 410013, Hunan Province, China

Provenance and peer review: Yi-Ming Li, School of Basic Medical Science, Naval Medical University/Second Military
Invited article; Externally peer University, Shanghai 200433, China
reviewed.
Yi-Lin Li, Department of Pathology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of
Peer-review model: Single blind Xiangya School of Medicine, Changsha 410013, Hunan Province, China

Peer-review report’s scientific Chen Su, Department of Anesthesiology and Pain, Hunan Cancer Hospital/The Affiliated
quality classification Cancer Hospital of Xiangya School of Medicine, Changsha 410013, Hunan Province, China
Grade A (Excellent): 0 Corresponding author: Chen Su, MD, PhD, Assistant Professor, Doctor, Department of
Grade B (Very good): B Anesthesiology and Pain, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya
Grade C (Good): C, C School of Medicine, No. 283 Tongzipo Road, Yuelu District, Changsha 410013, Hunan
Grade D (Fair): 0 Province, China. suchen@[Link]
Grade E (Poor): 0

P-Reviewer: Bredt LC, Brazil;

Gheshlaghi S, Iran; Yao G, China
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has been a serious threat to
Received: September 14, 2022 global health for nearly 3 years. In addition to pulmonary complications, liver
Peer-review started: September 14, injury is not uncommon in patients with novel COVID-19. Although the
2022 prevalence of liver injury varies widely among COVID-19 patients, its incidence is
First decision: October 19, 2022 significantly increased in severe cases. Hence, there is an urgent need to
Revised: November 11, 2022 understand liver injury caused by COVID-19. Clinical features of liver injury
Accepted: December 8, 2022 include detectable liver function abnormalities and liver imaging changes. Liver
Article in press: December 8, 2022 function tests, computed tomography scans, and ultrasound can help evaluate
Published online: January 14, 2023 liver injury. Risk factors for liver injury in patients with COVID-19 include male
sex, preexisting liver disease including liver transplantation and chronic liver
disease, diabetes, obesity, and hypertension. To date, the mechanism of COVID-
19-related liver injury is not fully understood. Its pathophysiological basis can
generally be explained by systemic inflammatory response, hypoxic damage,
ischemia-reperfusion injury, and drug side effects. In this review, we systemat-
ically summarize the existing literature on liver injury caused by COVID-19,
including clinical features, underlying mechanisms, and potential risk factors.
Finally, we discuss clinical management and provide recommendations for the
care of patients with liver injury.

Key Words: Liver injury; COVID-19; Clinical feature; Risk factor; Treatment and

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Zhao SW et al. Liver injury in COVID-19

management strategy

©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.

Core Tip: A growing body of evidence suggests that patients with coronavirus disease 2019 (COVID-19)
may experience varying degrees of liver injury. The characteristics and mechanisms of liver injury
associated with COVID-19 are not fully understood. In this review, we summarized the clinical features,
mechanisms, and management strategies of liver injury associated with COVID-19. Moreover, we
collected all the information about high risk factors for liver injury from COVID-19, which is of
significance and help for further study of liver damage related to severe acute respiratory syndrome
coronavirus 2.

Citation: Zhao SW, Li YM, Li YL, Su C. Liver injury in COVID-19: Clinical features, potential mechanisms, risk
factors and clinical treatments. World J Gastroenterol 2023; 29(2): 241-256
URL: [Link]
DOI: [Link]

INTRODUCTION
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) virus. Since the first outbreak in late December 2019 in China, it
has unleashed a matchless public health crisis worldwide. The COVID pandemic has been going on for
nearly 3 years, and there is still no end in sight. Initially, it was considered solely an atypical pneumonia
until patients started to show signs of multiorgan involvement[1]. Now we know that the effects of
COVID-19 on the body are extensive. In addition to the respiratory system, almost all systems in the
body, including the circulatory system, cardiovascular system, urinary system, gastrointestinal and
hepatobiliary system, endocrine system, nervous system, ophthalmic system, and skin system can be
affected[2,3]. SARS-CoV-2 virus mainly affects the respiratory system, causing common symptoms such
as fever, fatigue, cough, and dyspnea. Relatively, diarrhea, myalgia, hemoptysis, and sore throat are less
common[4]. Other reports show that liver dysfunction is a common manifestation of COVID-19 and is
associated with higher mortality[5]. It is worth mentioning that the incidence of liver injury in severe
COVID-19 cases can reach 93%[6]. However, the exact mechanism of how COVID-19 impairs liver
function remains unclear. This comprehensive literature review is aimed at providing useful guidance
for diagnosis, risk factor identification, and management of liver injury associated with COVID-19.

CLINICAL FEATURES OF LIVER INJURY IN COVID-19

Liver injury is mainly manifested as abnormal liver function (ALF) indexes. Alterations in hepatocyte
damage biomarkers (HDBs), such as alanine aminotransferase (ALT), aspartate aminotransferase (AST),
bilirubin, alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT), are commonly used to
evaluate COVID-19-related liver injury[6,7]. In some cases, elevated lactate dehydrogenase (LDH),
hypoproteinemia, prolonged prothrombin time, total bilirubin (TBil), and direct bilirubin (DBiL) are also
used to assess liver function in COVID-19 patients[8-10].
In COVID-19 patients, transaminase elevations are usually mild [1-2 times the upper limit of normal
(ULN)][9]. These changes in laboratory values may persist for a long time, even after hospital discharge.
ALF was defined as at least one test HDB exceeding the ULN. Xu et al[10] evaluated the proportion of
patients with abnormal HDBs, and found on admission ALT 13.2%, AST 8.5%, ALP 2.0%, GGT 7.4%,
LDH 37.6%, TBiL 4.0%, DBiL 7.8%, and albumin 10.1%, and peak during the hospitalization ALT 29.4%,
AST 17.5%, ALP 2.6%, GGT 13.4%, LDH 49.4%, TBiL 10.1%, DBiL 18.0%, and albumin 30.6%. In another
study, the proportion of patients with at least one of the HDBs and TBil exceeding the ULN for the first
time immediately after hospitalization, before discharge, a median of 14.0 d after discharge, and 1 year
after discharge was 32.2%, 45.8%, 54.8%, and 28.8%, respectively[11]. In addition, a single-center
prospective cohort study found that the proportion of patients with any ALF was 25.1% at 1 mo, 13.2%
at 3 mo, 16.7% at 6 mo, and 13.2% at 12 mo after discharge[12]. Based on these data, long-term
monitoring of liver enzymes may be warranted in patients with a history of COVID-19.
AST is generally considered to be less specific for liver injury than ALT due to additional extra-
hepatic production[13,14]. Nevertheless, in liver damage, elevated AST levels appear earlier, and the
increase in AST levels at admission is usually more pronounced than ALT levels. In cases of severe

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COVID-19, however, ALT levels typically rise rapidly, exceed the ULN value and peak within 10-15 d of
admission. Subsequently, ALT levels remained stable in all patients with liver injury and then gradually
decreased with longer hospital stay. ALT is a more effective indicator of liver injury in COVID-19
patients with severe manifestations[15]. However, if serum AST and LDH levels are elevated but ALT
levels remain normal, other causes of elevated liver biochemical responses rather than liver injury
should be considered, such as myositis (especially AST > ALT), cardiac injury, ischemia, and cytokine
release syndrome (CRS)[16].
The reported prevalence of liver injury in COVID-19 patients varied widely across studies, ranging
from 4.8% to 78%[17]. This is mainly due to a variety of factors, including dynamic changes in liver
function, small sample sizes, different admission criteria, lack of adjustment for baseline chronic liver
disease (CLD), use of different HDBs, and inconsistent definitions of “liver injury”[10,18-20]. Notably,
almost all studies were conducted on hospitalized patients, ignoring non-hospitalized patients, thus
resulting in unclear overall morbidity (Table 1).

LIVER INJURY AND PROGNOSIS

COVID-19 patients with moderate or severe liver injury (SLI) have an increased risk of admission to the
intensive care unit (ICU), disease progression, and death compared with patients without elevated liver
chemistries[9,19,23]. Cai et al[6] have reported that patients with liver injury have a 9-fold greater risk
for developing severe COVID-19. In a retrospective cohort study, when compared with moderate liver
injury (2-5 ULN) and no/mild liver injury (< 2 ULN), COVID-19 patients with SLI (ALT > 5 ULN) had
more severe clinical outcomes, including higher ICU admission rates (69% vs 42% vs 16%), intubation
(65% vs 38% vs 13%), renal replacement therapy (33% vs 15% vs 7.5%), and mortality (42% vs 23% vs
21%). Among SLI patients, 70% required vasopressors, 12% received inotropes, 39% were paralyzed,
10% were proned, and 2.8% required extracorporeal membrane oxygenation[19].
Changes in liver function are predictors of severity and mortality in patients with COVID-19[5,23].
Abnormal liver biochemical parameters are closely related to an increased risk of mortality in critically
ill patients with COVID-19. The levels of ALT, AST, GGT, LDH, TBil, and DBil in severe patients were
significantly higher than those in mild-moderate patients. Conversely, severe patients had significantly
lower albumin levels than non-severe patients[5,20]. In a study of 151 hospitalized patients, 5 liver
injury parameters, ALT, AST, TBil, DBil, and indirect bilirubin, were identified as notable prognostic
factors, while total protein, albumin, ALP, GGT, and total bile acid appeared to be less related to
prognosis[25]. In other studies, low albumin is also a marker of severe infection and poor prognosis[10,
26]. Lei et al[15] emphasized the association of ALF tests, especially AST and TBil, with higher mortality.
They observed that AST was more frequently elevated than ALT in severe patients. However, elevated
ALP and peak ALT were significantly associated with discharge to hospice and death[19,27].

ABDOMINAL IMAGING FINDINGS

Possible imaging signs of liver damage on computed tomography (CT) scans of the hepatobiliary
system include hepatomegaly, decreased liver density, periportal edema, fat stranding around the
gallbladder, portal lymphadenopathy, and dilated gallbladder and bile ducts[28,29]. Portal venous gas
can be seen in patients with mesenteric ischemia, especially in critically ill patients[30]. CT-quantified
liver density can be assessed by the liver-spleen attenuation ratio, which correlates with the severity of
liver injury. A common manifestation of liver damage caused by COVID-19 is homogeneous or hetero-
geneous low density of the liver. Liver hypodensity is more common in critically ill cases[28].
Ultrasound can be easily performed in COVID-19 patients to help identify liver damage quickly and
effectively. The most frequent sonographic finding is hepatomegaly with increased parenchymal
echogenicity, followed by biliary disease, including gallbladder sludge and distention, gallbladder wall
thickening, mural hyperemia, intraluminal mud, and pericholecystic fluid[29-31]. Portal venous gas
suggests mesenteric ischemia. Further, gallbladder cholestasis is common in critically ill patients of
COVID-19[30]. Collectively, imaging of liver injury can reveal changes in liver density, gallbladder and
bile duct dilation, portal pneumatosis and/or mesenteric ischemia.

PROPOSED MECHANISMS OF LIVER INJURY

The pathological basis of liver injury following COVID-19 infection is puzzling and not fully
understood. Studies suggest that direct cytotoxicity, hypoxic hepatitis, cytokine storm syndrome,
exacerbation of preexisting liver disease, and drug-induced liver injury (DILI) may be major
mechanisms of COVID-19-related liver injury.

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Table 1 Criteria, grading, and incidence of abnormal liver function or injury

Sample
Ref. Study type Criteria and grading of ALF or injury Comments
size
Salık et al[5] 533 Retrospective Liver biochemical parameters: ALT, AST, and TBiL > NA
study ULN. Liver injury: ALT and/or AST > 3 ULN, and/or
TBiL > 3 ULN

Cai et al[6] 417 Retrospective, ALF: > ULN. Liver injury: ALT and/or AST > 3 ULN, 76.3% had ALF and 21.5% had liver injury during
single-center ALP, GGT, and/or TBiL > 2 ULN hospitalization
study

Fan et al[8] 148 Retrospective, Increased levels of ALT, AST, GGT, ALP, and total 37.2% had ALF at hospital admission
single-center bilirubin
study

Kulkarni et 20874 Meta-analysis ELC: AST or ALT > ULN. SLI: Any elevation of ELC: 23.1% at initial presentation. 24.4%
al[9] enzymes > ULN and bilirubin over 2 ULN developed ELC during the illness

Xu et al[10] 1003 Retrospective Mild liver injury: 1-2 ULN. Moderate liver injury: 2-5 Most patients with abnormal liver function
cohort study ULN. Significant liver injury: > 5 ULN parameters had mild elevations (1-2 ULN) at
admission and peak hospitalization

Hundt et al 1827 Retrospective ELC: AST, ALT, ALP, TBiL, albumin: > ULN ELC at pre-hospitalization (AST 25.9%, ALT
[13] observational 38.0%, ALP 56.8%, and TBiL 44.4%). Admission
cohort study (AST 66.9%, ALT 41.6%, ALP 13.5%, and TBiL
4.3%). Peak hospitalization (AST 83.4%, ALT
61.6%, ALP 22.7%, and TBiL 16.1%)

Balderramo 298 Multicenter study ALEx2: The elevation of at least one of the following: During admission, 29.2% out of 298 patients
et al[14] TBil, ALT, AST, GGT, or ALP > 2 ULN presented ALEx2

Phipps et al 6913 Retrospective Mild: ALT 1-2 ULN. Moderate: ALT between 2-5 ULN. Among patients who tested positive, 45% had
[19] cohort study Severe: ALT > 5 ULN mild, 21% moderate, and 6.4% SLI

Wang et al 156 Retrospective, 2- Elevated aminotransferases 41.0% patients with elevated aminotransferases
[21] centers study

Liu et al[22] 245 Retrospective, Mild liver dysfunction: AST ≥ ULN. Moderate liver 43.7% experienced mild liver dysfunction, 40.4%
single-center dysfunction: AST ≥ ULN combined with any parameter experienced moderate liver dysfunction, and
study being greater than the ULN values of ALT, GGT, and 20.4% experienced severe liver dysfunction
TBiL. Severe liver dysfunction: AST ≥ ULN combined
with ALT ≥ 3 ULN and/or GGT, TBiL ≥ 2 ULN

Chaibi et al 281 Retrospective ALF: AST, ALT, GGT, ALP or TBil > ULN 36.3 % had liver dysfunctions. Only a minority of
[23] cohort study patients (6.4%) had perturbations above 5 times
the ULN

Shousha et al 547 Multicenter Liver injury: Transaminase > 3 ULN 26% and 32% of patients had elevated ALT and
[24] cohort study AST, respectively. 4.91 and 3.70%patients,
respectively, had AST or ALT elevation > 3 ULN

ALEx2: Abnormal liver enzymes over twice the upper limit of normal; ALF: Abnormal liver function; ALP: Alkaline phosphatase; ALT: Alanine
aminotransferase; AST: Aspartate aminotransferase; ELC: Elevated liver chemistries; DBiL: Direct bilirubin; GGT: Gamma-glutamyl transferase; NA: Not
available; TBil: Total bilirubin; ULN: Upper limit of normal.

Direct cytotoxicity
The dual blood supply to the liver may be a route of infection. It is speculated that retrograde liver
infection occurs after intestinal infection with SARS-CoV-2[32,33]. It is known that the S protein of
SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) receptor to facilitate virus entry into
host cells. ACE2 receptors are widely expressed in multiple organs, including the liver[34]. Although
the expression of ACE2 is much lower in hepatocytes compared to type 2 pneumocytes, its expression
levels are similar in cholangiocytes and type 2 pneumocytes[35], indicating that the hepatobiliary
system is a potential target organ of SARS-CoV-2.
SARS-CoV-2 RNA has been reported to be detectable in the liver of COVID-19 patients. Electron
microscopy also revealed larger numbers of coronavirus particles in the livers of these patients[21,36].
Postmortem liver biopsies showed typical coronavirus particles in the cytoplasm and typical viral
infection lesions, such as mitochondrial swelling, endoplasmic reticulum dilation, and decreased
glycogen granules. Besides, massive hepatocyte apoptosis and some binuclear hepatocytes were also
observed[21].

Cytokine storm syndrome

Cytokine storm refers to the rapid and massive production of various cytokines in body fluids, which
plays an important role in acute respiratory distress syndrome and multiple organ failure. The liver

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cannot escape the cytokine storm. The pathogenesis of cytokine-mediated liver injury may stem from
inflammation, altered coagulation, and activation of the renin-angiotensin-aldosterone system,
culminating in microvascular insult, hepatocyte damage, and perpetuation of inflammation[37]. It has
been reported that plasma levels of interleukin (IL)-2, IL-6, IL-7, IL-10, interferon (IFN)-γ, granulocyte
colony-stimulating factor, IFN-inducible protein-10, monocyte chemoattractant protein-1, recombinant
macrophage inflammatory protein 1 alpha, and tumor necrosis factor alpha (TNF-α) were higher in
severe COVID-19 patients than in mild and moderate cases[38,39].
The IL-6 signaling complex causes deleterious changes in hepatic sinusoidal endothelial cells and
may promote blood clotting. This may be a possible mechanism behind liver injury in these patients
[40]. Animal experiments have demonstrated that TNF-α has a moderate contribution to ALT elevation,
necroinflammation, and apoptosis[41]. The role of other cytokines in liver injury in COVID-19 patients
still requires further study.

Hypoxia, endotheliitis, and coagulation dysfunction

Patients with COVID-19, especially with severe manifestations, may have varying degrees of
hypoxemia. Interestingly, some of them have no experience with breathing difficulties[42]. In vivo and in
vitro studies have observed the occurrence of hepatic ischemia and hypoxia, hepatic cell death, and
inflammatory cell infiltration[43]. Moreover, studies have found that SARS-CoV-2 enters endothelial
cells, destroys vascular endothelium, and causes diffuse endothelial inflammation that can rapidly
induce vasoconstriction and procoagulant tendency[44,45].
Spiezia et al[46] found that COVID-19 patients with acute respiratory failure presented with severe
hypercoagulability rather than consumptive coagulopathy. In these patients, plasma levels of fibrinogen
and D-dimer were significantly elevated and a marked hypercoagulable thromboelastometry profile
was observed. Rampotas and Pavord[47] examined 20 random blood films from COVID-19 patients
receiving invasive ventilation and observed the presence of platelet aggregates and macrothrombocytes,
indicating increased platelet activity.

Reactivation of pre-existing liver disease

Liu et al[48] evaluated hepatitis B virus (HBV)-DNA viral load in 19 hospitalized patients with COVID-
19. They found that three patients had HBV reactivation (HBVr) and one patient had a high HBV-DNA
viral load throughout the hospital stay. This study suggests that COVID-19 patients with pre-existing
chronic HBV infection, with or without corticosteroids use, may be at risk for hepatitis B reactivation. In
a review, Perrillo et al[49] divided the drugs that induce HBVr into three categories. High-risk drugs are
anticipated to induce HBVr in > 10% of cases, moderate-risk drugs are anticipated to induce HBVr in
1%-10% of cases, and low-risk drugs are anticipated to induce HBVr in < 1% of cases. Moderate/high-
dose corticosteroid therapy for ≥ 4 wk is a high-risk factor for HBVr. Anthracycline derivatives are
moderate/high-risk drugs. Moderate-risk drugs include TNF-α and other cytokine inhibitors, integrin
inhibitors, tyrosine kinase inhibitors, and ≥ 4 wk of low-dose corticosteroid therapy. Therefore, patients
receiving any of these drugs for COVID-19 are at risk of inducing HBVr and its complications.

DILI
Various potentially hepatotoxic drugs such as remdesivir, lopinavir, azithromycin, hydroxychloroquine,
acetaminophen, antibiotics, and corticosteroids are thought to induce liver injury[50,51]. In some cases,
the extent of liver damage depends on the dose[52]. Antiviral drugs have been used against SARS-CoV-
2, examples of such antivirals are remdesivir, lopinavir-ritonavir, and others. They have all been
documented to be potentially hepatotoxic. Although some small-scale trials have reported ALT/AST
elevations with remdesivir, most clinical trials have not shown significant hepatotoxicity in the
treatment of COVID-19[53]. Lopinavir/ritonavir and remdesivir have similar hepatotoxicity profiles
[54].
Dexamethasone, used for hypoxic respiratory failure in patients with COVID-19, is known to induce
the elevation of liver enzymes, increase hepatic lipid peroxidation, and decrease antioxidant activity
[55]. The liver-damaging effects of azithromycin and acetaminophen have been proven for many years
[56,57]. Acetaminophen, an analgesic and antipyretic drug widely used for mild-to-moderate pain and
fever, may cause dose-dependent hepatotoxicity[52].

RISK FACTORS FOR LIVER INJURY

Studies have shown that the incidence of liver injury in severe/critically ill patients is much higher than
the incidence in moderate cases[17,58]. Apparently, male sex, older age, and higher body mass index are
also associated with liver damage from COVID-19[6,17,58,59]. Besides, coexisting diseases such as
hypertension, diabetes, cardiovascular disease, malignancy, and some liver diseases may all be risk
factors for liver damage[60,61]. Currently, the susceptibility of children and pregnant women to liver
injury is not fully understood.

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Male sex
Multiple studies show that men with COVID-19 have an increased risk of liver damage[6,17,59,62].
Among younger patients, men also have higher odds of severe pneumonia, acute kidney injury, and
acute liver injury than women. However, among elderly patients, there was no difference in the
likelihood of poor outcomes between men and women[62].
Possible mechanisms are attributed to the activity of sex hormones and X-linked genes and differ-
ential regulation of innate and adaptive immune responses to viral infection. Compared with women,
men have higher circulating levels of ACE2 and ACE2 levels in the lungs. Moreover, testes have much
higher levels of ACE2 than ovaries. Additionally, men have lower expression of protective cytokines but
higher levels of pro-inflammatory cytokines and chemokines[62].

Elderly
In a study of 900 patients with COVID-19, those aged 40-69 were at particularly high risk of liver injury
and liver-related death. COVID-19-related deaths were more frequent in patients 40-69 years and ≥ 70
years of age with elevated AST levels. Although only a small proportion (1.7%) of patients without prior
liver disease also died from liver-related causes, severe liver impairment and acute liver failure are rare
but important complications of COVID-19[63]. Liver dysfunction is associated with poor prognosis in
elderly patients with higher mortality due to liver cell damage[64].

Liver transplant
According to recent reports, liver transplant (LT) patients have a higher incidence of COVID-19,
possibly due to long-term immunosuppression. Despite the increased risk of acquiring COVID-19, LT
patients have lower mortality rates than matched general individuals[65]. In another study, the
prevalence of COVID-19 in LT patients was 6.05%, twice that of the general population of the same age,
possibly due to higher susceptibility to the virus[66]. Verbeek et al[67] suggested that organ transp-
lantation should be avoided in patients with active infection and respiratory symptoms because of the
risk of COVID-19 progression and subsequent organ failure, as well as the risk of exposure to the virus
for transplant operators.
Furthermore, patients with LT are at high risk for hepatic decompensation and increased mortality,
and may suffer from severe extrahepatic sequelae of COVID-19[68,69]. Due to lack of evidence that LT
children are at a greater risk of contracting COVID-19, routine withdrawal of immunosuppressive drugs
is not recommended for LT children or patients with autoimmune liver disease[70]. Generally, LT
recipients do not appear to have an increased risk of death following COVID-19 infection compared to
the matched general population[71].

CLD
The most common cause of CLD is nonalcoholic fatty liver disease (NAFLD), followed by HBV
infection, alcohol-related liver disease, and hepatitis C virus infection[72]. Liver injury and pre-existing
CLD are significantly associated with disease severity and mortality in COVID-19 patients[73,74]. Yang
et al[75] found that CLD is independently associated with COVID-19 severity and mortality, especially
in a male-dominated elderly population. However, some studies believe that liver injury is indeed an
independent predictor of key outcomes, but CLD and HBV infection status are not significant
comorbidities of COVID-19[73,74,76].
Similar to other CLDs, metabolically associated fatty liver disease (MAFLD) has been shown to have
longer viral shedding, a higher risk of disease progression, a higher all-cause mortality, and higher
COVID-19-related mortality than patients without MAFLD[72,77]. Compared with other causes of CLD,
patients with autoimmune hepatitis have a worse prognosis for COVID-19[78,79].
In adult studies, certain populations, such as those with cirrhosis, nonalcoholic steatohepatitis, and
liver cancer, have been found to have an increased risk of severe COVID-19 and a poorer prognosis[69,
80-82]. In adults with COVID-19, cirrhosis is a risk factor associated with worse outcomes. A large
survey of 220727 patients found that COVID-19 infection in patients with cirrhosis was associated with a
2.38-fold risk of death, while cirrhosis in CLD patients with COVID-19 was associated with a 3.31-fold
risk of death[83]. These results suggest that cirrhotic patients with COVID-19 infection are associated
with an increased risk of all-cause mortality. Zecher et al[84] concluded that there were no differences in
age, sex, autoimmune liver disease, and cirrhotic status between COVID-19 and non-COVID-19 cases.
Children with CLD, including obese children with suspected or confirmed NAFLD, may be at an
increased risk for COVID-19 infection and severe COVID-19[70,85]. Children with CLD may experience
decompensation of end-stage liver disease during COVID-19 infection[70]. Compared with LT
recipients, children with CLD, including children with end-stage liver disease, are more likely to be
hospitalized and require intensive care[86]. However, in the study by Di Giorgio et al[87], the suscept-
ibility of different pediatric patient groups to COVID-19 infection was similar, and underlying liver
disease may not increase the risk of severe COVID-19. The inconsistency between these findings may be
related to the different sample sizes collected.

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Obesity
Cumulative evidence support obesity as a risk factor for severe COVID-19 and related death, directly or
indirectly increasing inflammation, hypercoagulability, and mechanical obstruction[88]. Obesity has
emerged as a strong independent determinant of increased risk of morbidity and mortality in patients
infected with COVID-19. In addition, data suggest that visceral obesity and hyperglycemia in non-
diabetic and diabetic patients may also be significant independent risk factors for severe COVID-19[89].
In another study, patients aged 40-69 had a higher prevalence of obesity (44.4%), suggesting that a
certain proportion of patients with hepatic steatosis in this age group may be predisposed to COVID-19-
related liver damage[63,78,90]. Furthermore, one study showed that > 50% of COVID-19 cases in
patients with underlying hepatic steatosis were severe, with a mortality rate of 17%[91].

Diabetes mellitus
Diabetes mellitus, whether due to insufficient pancreatic beta cells or peripheral insulin resistance, is
considered a risk factor for COVID-19 infection. Numerous studies have shown that new-onset
hyperglycemia, ketoacidosis, and diabetes are frequently observed in patients with COVID-19[88,89,92,
93]. Individuals with diabetes often have associated comorbidities, such as obesity, hypertension, and
cardiovascular disease, as well as diabetic complications, including chronic kidney disease, vascular
disease, and related immune dysfunction, all of which put them at risk for infectious complications[94].
In a study of 458 patients with COVID-19 and diabetes, those with liver injury and chronic kidney
disease had significantly higher mortality rates than other complications[95]. In other words, chronic
kidney disease and liver disease are the two main contributors to the rise in mortality among patients
with diabetes and COVID-19.

Malignancy
Hepatocellular carcinoma (HCC) has been identified as a predictor of poor prognosis in COVID-19
patients[72,76]. HCC is often associated with cirrhosis, suggesting that decreased immunity may
increase the risk of severe COVID-19, and that infection with COVID-19 can exacerbate pre-existing
liver disease, complicating cancer management[96]. Furthermore, COVID-19 vaccination is
recommended for LT candidates and patients with CLD or HCC as they are susceptible to severe
COVID-19[68]. Overall, cancer patients are considered to be at high risk of developing severe COVID-19
due to comorbidities and immunosuppressive status, especially among those who have recently
received chemotherapy or had surgery within a month[96,97].

Hypertension
In a study of 300 patients with COVID-19, 33.2% were diagnosed with hypertension at admission. These
hypertensive patients displayed higher levels of Troponin T and creatinine near hospital discharge[93].
Notably, the proportion of hypertensive patients in severe COVID-19 was significantly higher, and the
mortality rate of severe patients was higher[93]. In addition, high blood pressure may increase the risk
of liver damage following COVID-19 infection in elderly patients without pre-existing CLD[73].
It has been reported that hypertensive patients have a higher probability of liver damage and a
poorer prognosis. The underlying mechanism may be related to the activation of the renin-angiotensin
system and the damage of ACE2-positive cholangiocytes and hepatocytes, which further lead to cholan-
giocyte and hepatocyte-associated disorders[69,81,98,99]. ACE2-stimulating drugs for high blood
pressure have been hypothesized to increase the risk of fatal COVID-19. Fang et al[100] reported that
patients using ACE2-elevating drugs for hypertension, diabetes or heart disease are at increased risk of
COVID-19 infection.

Pregnancy
Pregnant woman with COVID-19 have significantly decreased blood lymphocytes, increased
neutrophils, and elevated C-reactive protein and TBil levels[101]. In the study by Deng et al[102], the
incidence of liver injury in pregnant women infected with COVID-19 was 29.7%. Despite a higher
frequency of ICU admissions, in-hospital mortality was lower among pregnant patients compared with
non-pregnant patients with COVID-19 viral pneumonia, at 1.1% for pregnant women and 3.5% for non-
pregnant women. Pregnancy is not an independent risk factor for in-hospital mortality in COVID-19
patients[103]. In the study by Tunç et al[104], COVID-19-related hospitalization rates were 24.1% in the
first trimester, 36% in the second trimester, and 57.3% in the third trimester; there was no significant
relationship between pregnancy duration and the need for ICU admission.
However, pregnant women may have many comorbidities, including hypertension, chronic lung
disease, diabetes, and obesity, compared with non-pregnant women[103]. Pregnant patients with
COVID-19 and chronic complications such as hypertension and diabetes have an increased risk of
developing inflammation and liver damage[101]. Pregnant women taking antiviral drugs have several
options, including continuing treatment, stopping or switching to safer drugs. Patients with high
pretreatment ALT or less than 1 year of treatment prior to pregnancy have a high risk of severe hepatitis
flares after cessation of antiviral agents[105].

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Zhao SW et al. Liver injury in COVID-19

The perinatal outcomes of all reported cases were reassuring, with 98% live births, 78% full-term
births without neonatal complications, and a 20% neonatal ICU admission rate. The stillbirth rate was as
low as 1.7%, and the neonatal mortality rate was 0.8%. No vertical transmission was found in 98.4% of
neonates[106,107].

Children
Children with COVID-19 infection often have minimal or no increase in liver enzymes[60]. COVID-19
may impair liver function, usually resulting in transient and moderate elevations in liver markers
without significant impairment of hepatic synthesis. COVID-19-infected patients with elevated ALT are
at risk for a more severe disease course, including longer hospital stay and ICU stay[85]. Compared
with adult patients, pediatric patients have relatively lower rates of lymphopenia, higher inflammatory
markers, and possible thrombocytopenia[108].

MANAGEMENT OF LIVER INJURY IN PATIENTS WITH COVID-19

Liver injury in mild cases of COVID-19 is usually transient, self-limiting, and reversible without
treatment. However, some COVID-19 patients who present with liver injury may become critically ill
and require medical attention[16]. The cause of liver injury should be analyzed and judged in all
patients. Initial screening includes careful review of preexisting liver disease, exposure to hepatotoxins
(alcohol, drugs, herbs, and chemicals), hypoxia, and circulation status (Table 2). Liver function
indicators including ALT, AST, TBil, DBiL, albumin, prothrombin activity, and international normalized
ratio should be closely monitored[109,110].
Prophylactic use of hepatoprotective and enzyme-lowering drugs is not recommended[109]. Theoret-
ically, reducing viral load with antiviral therapy is the most effective way to reduce organ damage.
However, there is currently a lack of clinical data to support it, and more attention is paid to antiviral
drug-related liver injury. This may be one reason for the lack of particularly effective antiviral drugs
until recently.
The management of liver injury from COVID-19 is largely empirical and mainly supportive. Patients
with severe liver damage associated with COVID-19 should be treated with hepatoprotective, anti-
inflammatory, and jaundice-reducing agents such as glycyrrhizic acid, polyene phosphatidyl choline
(PPC), bicyclol, and vitamin E[111,112]. Glycyrrhizic acid can effectively inhibit the replication and
cytopathic effect of coronavirus without obvious cytotoxicity to host cells[113]. Glycyrrhizin has anti-
inflammatory properties that may offer protection against liver disease[109]. PPC may be a drug that
enhances the hepatoprotective function through glutathione and magnesium isoglycyrrhizinate[114].
Currently, there is no specific treatment for critically ill patients with COVID-19. Effective
suppression of the host’s uncontrolled immune response during cytokine storm may be a critical step in
preventing disease progression and reducing mortality[115,116]. Anakinra is an IL-1 receptor antagonist
that blocks the release of IL-β. A study concluded that early anakinra treatment is associated with
significantly lower ICU admissions and mortality in patients with moderate/severe COVID-19[117].
Successful anakinra therapy includes treatment duration ≥ 10 d, dose ≥ 100 mg, intravenous adminis-
tration, and early initiation of therapy[118]. Canakinumab is a human monoclonal anti-IL-1β specific
antibody. Studies have shown that canakinumab therapy provides rapid and durable improvement in
oxygenation levels, reduced proinflammatory markers and reduced need for mechanical ventilation
resulting in better outcomes[119,120].
IL-6 is one of the key mediators of cytokine storm-induced damage[121]. Currently, there are two
main types of IL-6 inhibitors that target IL-6 itself (siltuximab) or its receptors (tocilizumab and
sarilumab)[115]. IL-6 levels drop after administration of siltuximab, suggesting that the inhibitor may
reduce CRS and mortality[122]. The literature supports the early use of tocilizumab as it has been
observed to lower mortality in adults with COVID-19 pneumonia[123,124] and achieve better clinical
recovery at day 28[125]. In another study, clinical improvement and mortality were not statistically
different between tocilizumab and standard treatment[125]. The reason may be a higher risk of bacterial
or fungal infection in patients within tocilizumab application[123,124,126]. Sarilumab is a high-affinity
anti-IL-6 receptor antibody. In a phase II, open-label, randomized, controlled clinical trial of hospitalized
patients with COVID-19, early use of sarilumab was safe and associated with a trend for better
outcomes[127]. However, in some other studies, the efficacy of sarilumab in hospitalized patients with
moderate-to-severe COVID-19 has not been established[128-130]. Inhibition of IL-6-mediated signaling
may not be sufficient to reduce CRS, and the answer may lie in combination therapy and interfere with
other related pathways. So far, conflicting results hinder efforts to use IL inhibitors to combat COVID-19
infection[131].
Anti-TNF therapy has also shown conflicting results. In a case-cohort study, patients treated with
anti-TNF-α inhibitors were hospitalized less frequently[132]. This was a systematic review and meta-
analysis of COVID-19 and outcomes in patients with inflammatory bowel diseases (IBD). Compared
with patients on corticosteroids, those on anti-TNF-α therapy had a lower risk of hospitalization and
ICU admission. Moreover, similar results were seen in patients treated with anti-TNF-α compared to

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 Zhao SW et al. Liver injury in COVID-19

Table 2 Treatments of liver injury in coronavirus disease 2019

Mechanisms of
Treatments Caution Ref.
liver damage
Hepatocellular injury Hepatoprotective, anti-inflammatory, and jaundice-reducing Preventive administration is not recommended [109,
agents 111,
112]

Cytokine storm Continuous renal replacement therapy. IL-1 inhibitor, IL-6 IL-1 or IL-6 inhibitors could reduce inflammation; [109,
syndrome inhibitor, TNF inhibitor however, they have a potential to cause DILI and 139,
worsen clinical conditions 140]

DILI Prompt discontinuation or reduction of doses of suspected Requires a trade-off between therapeutic effects and [109]
triggers. Medication reconciliation is important. Discontinue all side effects
non-vital therapy, redundant types/doses, modify course
duration

Reactivation of pre- Continue treatment for hepatitis B and hepatitis C if already on Difficulty distinguishing between new-onset liver [16,
existing liver disease treatment injury and reactivation of pre-existing liver disease 109]

Hypoxic hepatitis Circulation and respiratory support Higher PEEP, which may be needed to improve [139,
oxygenation, may affect cardiac output, decreasing 140]
hepatic arterial flow, thus enhancing arterial
dysfunction

DILI: Drug-induced liver injury; IL: Interleukin; PEEP: Positive end-expiratory pressure; TNF: Tumor necrosis factor alpha.

patients treated with mesalamine[133]. Colonic ACE2 expression was downregulated after anti-TNF-α
therapy in IBD patients[134], but no liver-related data have been reported. In another meta-analysis and
systematic review of 84 studies, no difference was found in the risk of hospitalization in patients
receiving anti-TNF-α therapy compared to patients not receiving anti-TNF-α therapy[135]. Foods rich in
vitamins, minerals, polyphenols, and other bioactive compounds may decrease inflammatory pathway
activity and prevent liver damage in COVID-19 patients[136].
Corticosteroids have a dual effect. They have been associated with DILI, especially at high doses,
however they are used to treat drug-induced cholestatic hepatitis and DILI associated with hypersens-
itivity reactions[137,138]. The only specific antidote for acute DILI remains N-acetylcysteine for
acetaminophen poisoning. Glycyrrhizin, ursodeoxycholic acid, and silymarin have been used for
decades to treat DILI, but success remains anecdotal[138]. The most effective treatment for suspected
DILI is to discontinue drug therapy before progression to irreversible liver failure, which results in
spontaneous recovery in approximately 90% of cases[139].

CONCLUSION
Nearly 3 years later, there is still no sign that the COVID-19 pandemic is over. COVID has long-term
devastating effects involving multiple organs. Particular attention should be given to liver injury
associated with COVID-19. There is growing evidence that liver injury is a typical long-term effect of
COVID-19, especially in critically ill cases, and may require monitoring after the patient is discharged.
The exact incidence and underlying mechanism of liver damage are not well known. Fortunately, most
patients with mild liver damage recover without special treatment. However, SLI is believed to worsen
the prognosis and increase mortality from COVID-19. Increased research efforts are needed to identify
those patients at higher risk of complications, better definition of liver injury, better understanding of
the pathophysiology, and effective therapies.

ACKNOWLEDGEMENTS
Thanks are due to Ivet Torres Cordoba MD for assistance with editing and polishing to our work.

FOOTNOTES
Author contributions: Zhao SW performed the majority of the writing, prepared the figures and tables; Li YM
performed data accusation and writing; Li YL provided the input in writing the paper; Su C designed the outline and
coordinated the writing of the paper.

Supported by the National Natural Science Foundation of China, No. 81901141; and the Scientific Research Project of

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Zhao SW et al. Liver injury in COVID-19

Hunan Provincial Health Commission, No. 202204114480.

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by
external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-
NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license
their derivative works on different terms, provided the original work is properly cited and the use is non-
commercial. See: [Link]

Country/Territory of origin: China

ORCID number: Shu-Wu Zhao 0000-0001-7635-1702; Yi-Ming Li 0000-0001-8186-5062; Yi-Lin Li 0000-0003-0206-4713;

Chen Su 0000-0002-7568-8036.

S-Editor: Wang JJ
L-Editor: Filipodia
P-Editor: Wang JJ

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