See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/383001374

Recent advances in COVID-19-induced liver injury: causes, diagnosis, and

management

Article in Inflammopharmacology · August 2024

DOI: 10.1007/s10787-024-01535-7

CITATIONS READS

0 103

5 authors, including:

Samar A. Antar Nada Aniss Ashour

Horus University Tanta University
29 PUBLICATIONS 506 CITATIONS 7 PUBLICATIONS 225 CITATIONS

SEE PROFILE SEE PROFILE

Amir Osama Hamouda Ahmed A. Al-Karmalawy

Faculty of pharmacy Horus university University of Mashreq
12 PUBLICATIONS 21 CITATIONS 237 PUBLICATIONS 5,163 CITATIONS

SEE PROFILE SEE PROFILE

All content following this page was uploaded by Nada Aniss Ashour on 11 August 2024.

The user has requested enhancement of the downloaded file.

Inflammopharmacology
https://doi.org/10.1007/s10787-024-01535-7 Inflammopharmacology
REVIEW

Recent advances in COVID‑19‑induced liver injury: causes, diagnosis,

and management
Samar A. Antar1,2 · Nada A. Ashour3 · Amir O. Hamouda4 · Ayman M. Noreddin5,6 · Ahmed A. Al‐Karmalawy7,8

Received: 14 October 2023 / Accepted: 29 March 2024

© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024

Abstract
Since the start of the pandemic, considerable advancements have been made in our understanding of the effects of SARS-
CoV-2 infection and the associated COVID-19 on the hepatic system. There is a broad range of clinical symptoms for
COVID-19. It affects multiple systems and has a dominant lung illness depending on complications. The progression of
COVID-19 in people with pre-existing chronic liver disease (CLD) has also been studied in large multinational groups.
Notably, SARS-CoV-2 infection is associated with a higher risk of hepatic decompensation and death in patients with cir-
rhosis. In this review, the source, composition, mechanisms, transmission characteristics, clinical characteristics, therapy,
and prevention of SARS-CoV-2 were clarified and discussed, as well as the evolution and variations of the virus. This review
briefly discusses the causes and effects of SARS-CoV-2 infection in patients with CLD. As part of COVID-19, In addition,
we assess the potential of liver biochemistry as a diagnostic tool examine the data on direct viral infection of liver cells, and
investigate potential pathways driving SARS-CoV-2-related liver damage. Finally, we explore how the pandemic has had
a significant impact on patient behaviors and hepatology services, which may increase the prevalence and severity of liver
disease in the future. The topics encompassed in this review encompass the intricate relationships between SARS-CoV-2,
liver health, and broader health management strategies, providing valuable insights for both current clinical practice and
future research directions.

* Ahmed A. Al‐Karmalawy
akarmalawy@horus.edu.eg
1
Center for Vascular and Heart Research, Fralin Biomedical
Research Institute, Virginia Tech, Roanoke, VA 24016, USA
2
Department of Pharmacology, Faculty of Pharmacy, Horus
University-Egypt, New Damietta 34518, Egypt
3
Department of Pharmacology and Toxicology, Faculty
of Pharmacy, Tanta University, Tanta 31527, Egypt
4
Department of Biochemistry, Faculty of Pharmacy, Horus
University-Egypt, New Damietta 34518, Egypt
5
Department of Clinical Pharmacy, Faculty of Pharmacy,
Ahram Canadian University, 6Th of October City,
Giza 12566, Egypt
6
Department of Internal Medicine, School of Medicine,
University of California -Irvine, Irvine, USA
7
Department of Pharmaceutical Chemistry,
Faculty of Pharmacy, Horus University-Egypt,
New Damietta, New Damietta 34518, Egypt
8
Pharmaceutical Chemistry Department, Faculty of Pharmacy,
Ahram Canadian University, 6Th of October City,
Giza 12566, Egypt

Vol.:(0123456789)
 S. A. Antar et al.

Graphical abstract

Diagnostic
Mechanisms of hepatic
COVID-19 in
management Pharmacological
Liver transplantation
injury in patients with management
History patients with and COVID-19 Prognosis
clinical features Prevention
COVID-19 preexisting history Specific
The origin &
The structure of liver disease management Surgical
Pathophysiology
Non-alcoholic Fatty liver management
Role of endotheliitis (Metabolic syndrome)
immune-mediated
Transmission Risk groups in
damage viral. Supportive
Infection in the healthy patient
General
Epidemiology Nutritional management public health
Hypoxic injury gut–liver axis without history
management measures
Other risk groups in
Drug-induced liver Vaccinations
Inflammatory storm patients with certain Interventional procedures
damage (DILI)
history

The cytopathogenic action of SARS-direct CoV-2

Keywords SARS-CoV-2 · COVID-19 · Chronic liver disease · Cirrhosis · Liver injury · COVID-19 management

Introduction interventions like oxygen therapy and invasive ventilation,

the fatality rate for hospitalized patients remains significant
A brief history of the coronavirus outbreak (Bong et al. 2020;Geier and Geier, 2020). Now generally
accepted risk factors include advanced age, sex, and weight
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS- of comorbidities, such as heart disease, hypertension, diabe-
CoV-2) was discovered in patients in Wuhan, China, in tes, and cancer (Gao et al. 2021; Shehata et al. 2021). Due to
December 2019 (Park and pediatrics 2020; Roshdy et al. prolonged delays forced on by the pandemic, a lot of people
2022a; Zaki et al. 2022). The virus rapidly spread over the have lost their jobs, which has harmed the world economy
world and gave rise to COVID-19, which still hurts world (Atuahene et al. 2020; Al-Karmalawy et al. 2021c). Sig-
health. Most SARS-CoV-2 patients either do not have any nificant advancements in clinical research have improved
symptoms or just have minor ones like fever, coughing, our understanding of SARS-CoV-2 and COVID-19 man-
anosmia, and headache (Molteni et al. 2021; El-Masry et al. agement. However, concerns persist as the virus continues
2022; Mahmoud et al. 2022; Roshdy et al. 2022a). Severe to spread worldwide, leading to second or third waves of
respiratory illness from SARS-CoV-2 can lead to complica- outbreaks, primarily driven by mutant virus strains. (Sarhan
tions like coagulopathy and multi-organ failure, resulting in et al. 2021; Cojocaru et al. 2022). Common means of SARS-
death for about 15% of patients within 10 days. COVID-19 CoV-2 transmission involve the transfer through mucous
has caused over 6 million fatalities worldwide by March membranes in the mouth, nose, and eyes, as well as direct
2022, making it a major global health threat akin to the 1918 transmission through actions like coughing and sneezing
influenza pandemic. (Ayenigbara et al. 2020; Elebeedy et al. during human interactions are shown in Fig. 1.
2022). The World Health Organization (WHO) was forced This review covers the evolution of SARS-CoV-2
to do so and classify it as a global epidemic (Soltane et al. research, including its structure, origin, transmission, diag-
2021; Ashour et al. 2022; Kutkat et al. 2022). COVID-19 nosis, clinical features, prevention, treatment, and varia-
declared a global pandemic, which has severely impacted tions. It also examines the role of liver biochemistry, direct
countries and strained healthcare systems. Despite standard viral infection of liver cells, and the pandemic’s impact on
Recent advances in COVID‑19‑induced liver injury: causes, diagnosis, and management

Fig. 1  Transmission concepts for COVID-19 virus from the human exchange

patient behavior and hepatology services, potentially affect- and they revealed that the human and SARS-CoV-2 viruses
ing future liver disease incidence and severity. shared a similar structural composition (Al-Karmalawy et al.
2021b; Kandeil et al. 2021b; Mahmoud et al. 2021). Addi-
The origin of SARS‑CoV‑2 tionally, they mentioned that this novel coronavirus might
have its roots in bats (Elmaaty et al. 2021b; Hamed et al.
The two most probable natural pathways for the formation 2021). In addition, a lot of animal types, such as swine,
of SARS-CoV-2 are as follows: first, it evolved into a patho- avian, porcine, snakes, seafood, bovine, and frogs, may be
genic state in animals before crossing over to humans; sec- the original hosts of the SARS-CoV-2 (Cattaneo 2022) as
ond, pathogenic viruses that typically affect animals were shown in Fig. 2.
transmitted to humans, causing a pandemic (Al-Karmalawy
et al. 2021a; Elmaaty et al. 2022; Zhao et al. 2022). Com- The structure of SARS‑CoV‑2
parative genomic analysis shows that SARS-CoV-2 shares an
88% similarity with two types of SARS-CoV-like coronavi- The SARS-CoV-2 spike protein exhibits a variety of struc-
ruses from bats, 79% similarity with human SARS-CoV, and tural forms (Zaki et al. 2020; Sorokina et al. 2022). The
approximately 50% similarity with MERS-CoV (Abdallah SARS-CoV-2 spike protein, similar to SARS-CoV, forms
et al. 2021;Abo Elmaaty et al. 2021a, b;Vo et al. 2022). The a 160-trimer with a triangular structure. Research suggests
virus's spike proteins were also examined by the researchers, that many spike proteins are in a prefusion state, offering

Fig. 2  Transmission concepts for COVID-19 virus from animals to humans

 S. A. Antar et al.

insights into their arrangement on the virus's surface. Addi- SARS-CoV-2 primarily affects the lungs, causing acute
tionally, the Receptor-Binding Domain (RBD) of the spike respiratory distress syndrome (ARDS) and diffuse alveolar
protein shows diverse conformations on the virus’s surface damage. However, recent research indicates the virus can
(Jha et al. 2022). Moreover, previous investigations have also damage other vital organs and tissues, such as the heart,
identified Nsp15 as a potential therapeutic target in SARS- brain, large intestine, kidneys, and liver (Beigee et al. 2020).
CoV-2 due to its structural similarity of 95% with the Nsp15 Published research indicates that older individuals and those
in SARS-CoV. Studies have suggested that inhibiting Nsp15 with comorbidities are more severely affected. The virus
expression could effectively hinder SARS-CoV replication has infected over 212 million people across 220 nations,
(Aljuhani et al. 2022; Saramago et al. 2022). This demon- resulting in over 4.4 million deaths (Petersen et al. 2010;
strates that drugs previously used to treat the SARS-CoV COVIDSurg and GlobalSurg 2022). Since the start of the
infection may also be effective against COVID-19 (Alnajjar pandemic, there has been a warning that severe COVID-19
et al. 2020; El-Demerdash et al. 2021; El Gizawy et al. 2021; and chronic liver diseases (CLD) share risk factors, such as
Elmaaty et al. 2021a). advanced age, diabetes, and obesity, which could result in
poor outcomes after SARS-CoV-2 infection (Marjot et al.
Epidemiology 2021a; Abdelgawad et al. 2022). This infection, which can
potentially cause serious illness, can affect people of all ages
The WHO considers the increase in viral infections to be as shown in Fig. 3. An increased risk of severe COVID-19
a severe public health concern (Sohrabi et al. 2020). As of infection is noted in patients over 60 and those with under-
April 30, 2020, there were over 3,000,000 confirmed cases lying chronic conditions, such as obesity, chronic kidney
and 200,000 fatalities from COVID-19. Symptoms range disease, cardiovascular disease, diabetes, smoking, chronic
from mild fever to respiratory failure and death. SARS- lung disease, cancer, solid organ, or hematopoietic stem cell
CoV-2, like other coronaviruses, enters cells via ACE2 and transplant recipients (Harwood et al. 2022). Stokes et al.
requires TMPRSS2 for spike protein activation. It can dam- found that patients with existing medical conditions were
age multiple organs and systems, including the immune and six times more likely to require hospitalization for COVID-
nervous systems. Previous viral epidemics like SARS-CoV 19 (45.4% vs. 7.6%), with a mortality rate 12 times greater
(2002–2003), H1N1 influenza (2009), and MERS-CoV in those with prior illnesses (19.5% vs. 1.6%) (Stokes et al.
(2012) have had significant global health impacts (Con- 2020). The study also found that the mortality rate from
tini et al. 2020; Zakaria et al. 2022). According to a recent this disease was 12 times greater in patients with prior ill-
WHO epidemiological update, more than 200 countries nesses (19.5% vs. 1.6%). According to research on COVID-
have detected SARS-CoV-2 variations with 76 reporting 19 mutations connected to sexual identity, men are more
the most current VOC, Omicron, since it was first identi- likely than women to develop severe illness and pass as a
fied in November 2021 (Wang et al. 2022). In 2020, Brazil, consequence of COVID-19 (Kopel et al. 2020). In a case
India, and the United States reported the highest incidence series analysis from March 1 to November 21, 2020, which
of COVID-19-related deaths and SARS-CoV-2 cases. In the evaluated the patient mortality rates at 209 US hospitals
United States, COVID-19 ranked as the third leading cause with intensive care units with proven SARS-CoV-2 infec-
of death, with approximately 375,000 reported deaths, fol- tion, male patients had a higher risk of death (12.5%) than
lowing heart disease and cancer (Ahmad et al. 2021). female patients(9.6%) (Alguwaihes et al. 2020). Symptoms
and complications are summarized in Table 1.
The clinical features, variations by age, gender,
and presence of medical comorbidities of COVID‑19 Differences in COVID‑19 transmission between children
and adults
The SARS-CoV-2 reaction has a broad clinical spectrum,
ranging from entirely asymptomatic to quick death. Most As a result of viruses that can infect the respiratory sys-
individuals with SARS-CoV-2 infection have mild, mod- tem, such as the respiratory syncytial virus and the influ-
erate, or no symptoms and recover in 7–14 days (Elaga- enza virus, infants and young children are typically at a
wany et al. 2022). However, a small fraction of patients do high risk of hospitalization (Chen et al. 2018); in contrast,
experience severe symptoms, and a significant number of younger COVID-19 patients generally have milder symp-
these individuals require admission to the intensive care toms compared to older individuals. Children with the virus
unit (Lindan et al. 2021; Roshdy et al. 2022b). COVID- often exhibit lower viral loads and less severe symptoms
19 symptoms range from coughing, low-grade fever, and than adults, possibly due to the ongoing development of
loss of taste and smell to vomiting and diarrhea. Severe ACE2 expression after birth, as suggested by studies in mice
complications like stroke, heart attack, and pulmonary (Meiring et al. 2022). Gender may also have an impact on
embolism occur in critically ill patients (Shah et al. 2021). ACE2 expression (Raza et al. 2021). The ACE2 gene, on
Recent advances in COVID‑19‑induced liver injury: causes, diagnosis, and management

Fig. 3  Possible explanations

for the elevated mortality rate
among male COVID-19-af-
fected individuals

Table 1  Symptoms and complications of COVID-19

Symptoms/complications

1 Fever, a dry cough, trouble breathing, and exhaustion are further symptoms (Cosentino et al. 2022). The serum of 81.5% of COVID-19
patients tested positive for antibodies, a notably higher percentage than the general positivity rate observed in nucleic acid testing (Song
et al. 2022)
2 Higher risk of experiencing acute renal injury (Xu et al. 2022)
3 The neutrophil-to-lymphocyte ratio (NLR) was discovered by a different team of researchers to be a unique risk factor for people with
COVID-19 to have severe disease. As soon as necessary, patients with an NLR > 3.13 and an age > 50 years should be hospitalized in the
critical care unit (Al-Mufti et al. 2022)
4 In-hospital mortality was more frequent in patients with NT-proBNP levels above 88.64 pg/mL, which might be a distinct risk factor for
COVID-19 patients
Their observations indicated that people with COVID-19 may induce serious cardiac abnormalities such as heart failure, and myocarditis
(Pommier et al. 2022)
5 Between 2 and 40% of patients experience gastrointestinal symptoms, and diarrhea may be the first sign of an infection
Stool samples have sometimes contained large quantities of viral RNA (D’amico et al. 2020b). Taste problems were identified in up to 53%
of the patients
6 Newly developed anosmia is currently advised as a testing guideline, especially for young individuals who exhibit few other symptoms
7 MRI of a COVID-19 patient showed bilateral inflammatory blockage of olfactory clefts, despite normal olfactory bulbs or tracts. Animal
studies suggest coronaviruses could enter the brain via the olfactory nerve or bulb, damaging neurons (Majde, 2010)
8 Neurological symptoms among COVID-19 patients, such as ischemic or hemorrhagic headache, stroke, dizziness, altered mental state,
musculoskeletal disturbance, acute necrotizing encephalopathy, or Guillain–Barré syndrome
9 COVID-19 is preliminarily linked to cardiovascular events like myocardial injury, especially in severe cases. This includes myocarditis,
myopericarditis causing reduced systolic function, heart failure, cardiac arrhythmias, and instances misdiagnosed as acute coronary
syndrome (Adeboye et al. 2022)
10 A hypercoagulable state, possibly raising the risk of pulmonary embolism and other venous thromboembolic events
11 Ocular symptoms, such as chemosis, conjunctival hyperemia, and elevated secretions, were recorded in up to 32% of infected individuals,
and tears could contain SARS-CoV-2 RNA (Atum et al. 2020)

the X chromosome, influences COVID-19 severity between Infants might be vulnerable to SARS-CoV-2 due to weak-
genders, with men usually having higher levels. Addition- ened CD8 + T-cell activity, delaying viral clearance. In
ally, children may react differently to SARS-CoV-2 due to macaque studies, older animals had worse lung pathology
evolving changes in T-cell function with age. Early in life, and inflammation than younger ones when infected with
CD4 + T cells favor Th2, releasing fewer pro-inflammatory SARS-CoV (Singh et al. 2021). Old and young mice respond
cytokines associated with severe disease (Yang et al. 2022). similarly to SARS-CoV infection, indicating age-related
 S. A. Antar et al.

variations in disease severity. COVID-19 often leads to a 72% sequence similarity. TMPRSS2 or cathepsin B/L primes
cytokine storm, causing ARDS and multi-organ failure. the S protein for viral entry. A unique furin-like cleavage site
Variances in inflammatory responses between adults and between the S1 and S2 subunits distinguishes SARS-CoV-2.
children suggest the potential for immunotherapy targeting The role of furin-like proteases in viral entry is uncertain,
COVID-19 severity, leveraging children’s lower susceptibil- but inhibiting them could be a potential antiviral strategy
ity to severe cases. (Lara et al. 2020). (Cheng et al. 2020). In this meaning, the phrase “COVID-19
linked liver injury” has evolved to refer to any liver damage
Pathophysiology sustained by COVID-19 patients, while they are ill or receiv-
ing therapy, whether or not they already have liver disease.
The initial stage of COVID-19 pathogenesis involves the Research has shown that the percentage of ACE-2 varies
virus invading host cells through specific receptors. Exten- with the infection stage, with the most severe stage showing
sive discussions on the entry mechanism of the SARS-CoV-2 a drop (Sorour et al. 2020).
virus are available elsewhere. SARS-CoV-2 is composed of
four primary structural glycoproteins: spike (S), membrane Effects of COVID‑19 on liver
(M), envelope (E), and nucleocapsid (N) (Bourgonje et al.
2020). The S protein is responsible for the virus binding The liver plays a vital role in the body’s immune defense
to and entering host cells, while the M, E, and N proteins against microorganisms and is central to dealing with most
are vital for the assembly and release of viral particles. The systemic infections due to its dual circulation from both the
primary viral entry site for SARS-CoV-2 is ACE-2 receptors portal and systemic systems. Some viruses have a direct
(Vitiello and Ferrara 2021; Eweas et al. 2022), as shown cytotoxic effect on cholangiocytes and hepatocytes, but the
in Fig. 4, and they are significantly expressed in the lung, etiology in most cases appears to involve a variety of fac-
kidney, gastrointestinal tract, and hepatocytes of the liver, tors. In contrast to sepsis, which results in cellular stress
which is relevant so it suggests that SARS-CoV-2 may target brought on by cytokines or low oxygen levels, SARS-CoV
the liver (Rivera-Valdes and Martínez-Lopez, 2022). The can directly harm the liver and induce cytopathic dam-
ACE-2 cell surface receptor is expressed in liver tissue, with age (Fawzy;Cecchini and Cecchini 2020). During autopsy
cholangiocytes (59.7%) expressing it more than hepatocytes examinations of the patients, SARS-CoV was discovered in
(2.6%). According to the findings, the liver may be a major 41% of the liver tissue. There was hepatocellular necrosis,
target organ for SARS-CoV-2, because the level of ACE-2 mitoses, cellular infiltration, and fatty degeneration in the
expression in the samples provided is identical to that of type liver biopsies of SARS patients (Eskander;Dawood et al.
2 pneumocytes (Wu et al. 2020a). SARS-CoV-2 exhibits 2021). Cholangiocytes play a similar role in COVID-19 and
stronger ACE2 receptor affinity than SARS-CoV despite a SARS-CoV, both of which use the ACE2 receptor protein

Fig. 4  The structure of SARS-

CoV-2 and the ACE2 receptor
Recent advances in COVID‑19‑induced liver injury: causes, diagnosis, and management

to target the host system (Stawiski et al. 2020; Herta and and imply that viral replication may also take place within
Berg 2021). Cholangiocyte function modification can result the bile duct epithelium in Vivo, as shown in Fig. 5.
in hepatobiliary damage, since cholangiocytes play a crucial Hepatic transaminase levels that are abnormally high
role in the renewal and adaptive immune response processes indicate liver damage and are frequently found in people
of the liver (Banales et al. 2019;Lizardo-Thiebaud et al., with COVID-19, both those with and without CLD as shown
2020). After SARS-CoV-2 infection, cholangiocytes under- in Table 2.
went syncytia formation, and there was a significant increase
in the quantity of SARS-CoV-2 genomic RNA observed 24 h Mechanisms of hepatic injury in patients with COVID‑19
after infection. Comparable outcomes were obtained when
exposing adult human cholangiocyte organoids to SARS- The most frequent theories for how COVID-19 results in
CoV-2. These findings suggest that human liver ductal orga- liver damage and functioning are (a) immune-mediated dam-
noids can be vulnerable to SARS-CoV-2 infection in Vitro age as a consequence of the severe inflammatory reaction

Fig. 5  The liver damage associ-

ated with COVID-19 primarily
exhibits distinctive features,
including moderate steatosis (fat
accumulation), inflammation
in both the lobular and portal
areas, the presence of apoptotic/
necrotic areas, and elevated
levels of plasma AST and
ALT enzymes. Additionally,
COVID-19-related liver injury
also includes cholangiocellular
damage, characterized mainly
by bile duct proliferation, occa-
sional bile plug formation, and
elevated plasma ALP and γGT
enzyme levels

Table 2  Clinical evidence of elevated liver function tests in COVID-19 patients

Intervention model description

1 Clinical trial Some patients had elevate levels of ALT, AST, and total bilirubin as an adverse effect in a recent randomized-controlled trial of
ritonavir and lopinavir in patients with severe COVID-19 (Zhang et al. 2022a)
2 Clinical trial The incidence of hepatotoxicity caused by chloroquine or hydroxychloroquine should be noted (Singh et al. 2020)
3 Clinical trial Tocilizumab, which is a humanized IgG1 monoclonal antibody targeting the IL-6 receptor and functioning as an antagonist to
IL-6, has been investigated as a potential therapy for severe cases of COVID-19 associated with cytokine release (Jugler et al.
2021). Tocilizumab was recognized to cause minor liver function test increases in previous clinical studies for a variety of
reasons, but these impacts were generally temporary and resolved after 2–6 weeks of treatment (Clinton et al. 2021)
4 Clinical trial Remdesivir, an investigational coronavirus nucleotide analog, is being studied for SARS-CoV-2 infection (Ko et al. 2020)
5 Clinical trial A study of 417 people found that 76.3% of COVID-19 patients had abnormal liver test results and that 21.5% of them had a
liver injury, while they were in the hospital (Cai et al. 2020)
6 Clinical trial 1827 patients with confirmed COVID-19 were tested between March and April 2020 at the Yale-New Haven Health System in
the United States for their AST, TBI, ALP, ALT, and albumin levels (Shah et al. 2021)
7 Clinical trial ALT and AST levels vary from 16 to 53% in a small number of other trials. Elevated liver enzyme levels in the aforementioned
examples suggest that COVID-19 patients' liver morphology is compromised (Wang et al. 2020)
 S. A. Antar et al.

that follows infection, (b) the cytopathogenic action of et al. 2021). Since hepatocytes and cholangiocytes con-
SARS-direct CoV-2 on hepatic tissue, and (c) drug-induced tain ACE2 receptors, it is suspected that the virus directly
liver injury (Cichoż-Lach and Michalak 2021), as shown in causes liver damage, which results in liver involvement in
Fig. 6. Inflammatory indicators, such as “C-reactive protein SARS-CoV-2 infection. Additionally, in COVID-19 patients,
(CRP), neutrophils, lymphocytes, and cytokines, particularly immune-mediated inflammation can result in liver damage
interleukin-6 (IL-6), are markedly activated in patients with or underlying liver illnesses, such as chronic viral hepati-
COVID-19 (Montesarchio et al. 2020; El-Azab et al. 2022). tis and non-alcoholic fatty liver disease. These conditions
It is widely known that hepatic inflammation, which involves include cytokine storm and hypoxia brought on by pneu-
the initiation of innate immune cells and the production of monia (Dhama et al. 2020). In COVID-19, patients with
cytokines, is a major contributor to liver damage from a vari- pre-existing CLD are now believed to have NAFLD, the
ety of sources (Tilg et al. 2021). In a portion of the COVID- most prevalent liver condition linked to obesity, suggest-
19 case series, a connection was observed between reduced ing a potential connection between obesity, COVID-19, and
lymphocyte levels and liver damage. Additionally, it was liver function test changes (Tudoran et al. 2021). NAFLD is
identified that having a CRP of 20 mg/L or higher and a a significant contributor to more severe conditions such as
lymphocyte count below 1.1 × 10^9/L were distinct risk fac- hepatocellular cancer and liver cirrhosis. It has been shown
tors for liver damage. That induced the risk of SARS-CoV-2 that SARS-CoV-2 can infect the liver and cause cytopathic
infection and certain consequences for all patients with CLD damage to the liver (Xu et al. 2020a). Additionally, livers
or liver cirrhosis (Karnik et al. 2021). with SARS-CoV-2 infection exhibit slight lobular and por-
COVID-19 causes non-pulmonary symptoms in some tal activity, extensive apoptosis, binuclear hepatocytes with
people, including changes in liver-related enzyme levels like considerable mitochondrial inflammation, mild apoptosis,
aspartate aminotransferase (AST), alanine aminotransferase and endoplasmic reticulum dilatation. Disturbance of the
(ALT), gamma-glutamyl transferase (GGT), albumin, total host's lipid metabolism and mitochondrial function has been
bilirubin (TBIL), and alkaline phosphatase (ALP) (Zeng hypothesized as one effect of the SARS-cytopathogenic

Fig. 6  Schematic diagram

showing the different mecha-
nisms that induce hepatic injury
Recent advances in COVID‑19‑induced liver injury: causes, diagnosis, and management

CoV-2. It has been shown that the viral S protein causes face an increased risk of developing liver injury and having
stress in the endoplasmic reticulum, which can result in de unfavorable prognoses. Liver function tests, including AST,
novo lipogenesis and eventually cause steatosis in COVID- ALT, and GGT, have been suggested as potential indica-
19 patients (Flister et al. 2018). Examples of cases as shown tors for predicting the severity of COVID-19 infection and
in Table 3. patient outcomes. Monitoring liver function, particularly in
COVID-19 patients with other health conditions, is essen-
Immune‑mediated damage viral induce cytotoxic T tial for early identification of liver damage and appropriate
cells Abnormal liver function test results are frequently medical intervention (Kuhn et al. 2004; Liang et al. 2020).
detected in individuals with COVID-19 throughout their Furthermore, there is a possibility that liver impairment
infection. A comprehensive analysis of 11 studies involv- in COVID-19 patients could be caused by the direct viral
ing 2541 COVID-19 patients revealed increase levels of infection itself. Research has shown that the liver tissue
enzymes AST and/or ALT in 25% of cases, increased LDH of patients with past coronavirus infections (like SARS)
in 20%, raised bilirubin in 3%, and mostly normal ALP lev- contained the virus, implying that viral infection might be
els. These findings suggest that direct virus-related liver responsible for liver impairment. Additionally, clinical fea-
injury might be limited due to the pattern of ACE2 receptors tures such as gastrointestinal symptoms, along with posi-
being highly expressed in cholangiocytes (Holshue et al. tive results in fecal specimens and blood nucleic acid tests,
2020; Zhang et al. 2020c). suggest potential involvement of the virus in the intestines
Elevated liver enzymes, notably AST and ALT, are fre- (Walls et al. 2020; Xu et al. 2020b).
quently observed in COVID-19 patients, and their levels The receptor ACE2 plays a crucial role in viral entry,
have been linked with the severity of the infection. Patients and recent studies have confirmed its role in SARS-CoV-2
with severe COVID-19 tend to induce levels of ALT and infection. ACE2 expression is prominent in various tissues,
AST compared to those with milder cases. Additionally, ele- particularly the small intestine, hinting at possible fecal–oral
vated levels of AST, ALT, and bilirubin are linked to more transmission. Interestingly, ACE2 is more highly expressed
severe COVID-19 infections. The involvement of the liver in in cholangiocytes than hepatocytes. This suggests that the
COVID-19 could be linked to the intense immune response virus might directly affect cholangiocytes, potentially lead-
triggered by the virus, resulting in a cytokine storm. This ing to bile duct dysfunction. However, clinical data indi-
widespread inflammation could lead to secondary liver dam- cate increased levels of enzymes AST, ALT, and LDH in
age and contribute to multiple organ failure in critically ill COVID-19 patients, while markers of bile duct injury like
patients (Guan et al. 2020; Jonas et al. 2020). ALP and GGT did not show significant increases. Further-
Research has shown that liver injury in COVID-19 more, autopsies of COVID-19 patients did not reveal viral
patients is linked to poorer outcomes. Patients with liver inclusions in liver tissue. Given the complexity of multi-
impairment often experience longer hospital stays, and those organ complications, systemic inflammation, and various
with pre-existing liver conditions face an elevated risk of factors like cardiopulmonary issues, kidney problems, and
hospitalization and mortality. The occurrence of liver injury drug use, direct viral liver damage is not believed to be the
in COVID-19 patients who succumbed to the disease has primary factor (Xu et al. 2020b).
been high, ranging from 58.06 to 78%. Older patients, indi-
viduals with severe COVID-19 infections, and those with The cytopathogenic action of SARS‑direct CoV‑2 on hepatic
underlying metabolic issues like hypertension and diabetes tissue The specific mechanisms driving liver damage in

Table 3  Examples of hepatic injury in patients with COVID-19

EX Description

Ex. 1 Patients with non-alcoholic fatty liver disease (NAFLD) made up about 22.4% of the 152 cases of confirmed COVID-19 with CLD, fol-
lowed by patients with alcoholic liver disease (ALD), who made up 19.7% of the cases, patients with hepatitis B, who made up 11.8%,
and patients with hepatitis C, who made up 10.5%, while the remaining patients (35.6%) had other liver conditions
Ex. 2 For patients with COVID-19 and CLD, the median length of hospital stays or death was 10 days (IGQ 5–14 days); 23.3% were admitted
to the intensive care unit, and of those, 17.5% needed invasive ventilators while 18.6% were placed on non-invasive respiratory support
machines, and 4.9% required dialysis
Ex. 3 Patients in the intensive care unit (ICU) had a death rate of 39.8%. The majority of CLD patients who acquired COVID-19 did not require
ICU hospitalization because their condition was not severe (59.5%). Even though COVID-19 pneumonia was the leading cause of
mortality in the majority of cases (78.7%), 12.2% of them also perished from decompensated CLD. The majority of CLD patients who
acquired COVID-19 did not require ICU care because their condition was not severe (59.5%)
Ex. 4 COVID-19 pneumonia was the leading to mortality in the majority of cases (78.7%), and 12.2% of them also perished from decompen-
sated CLD (Gadour et al. 2020)
 S. A. Antar et al.

cases of direct COVID-19 infection have not been com- Studies have demonstrated significantly induced plasma
pletely clarified. However, it is hypothesized that liver levels of D-dimer and fibrinogen in severe cases of COVID-
injury results from direct harm to hepatocytes, as evidenced 19 compared to healthy controls. These markers of coagula-
by the rise in levels of enzymes associated with cytonecrosis tion activation indicate the presence of a hypercoagulable
(Sarin 2020). state in severe COVID-19 patients (Eljilany and Elzouki
A crucial receptor that the SARS-CoV-2 virus relies 2020; Sui et al. 2021).
on is ACE2, which is not limited to the lungs but is also
found in bile duct cells and healthy liver tissues. Research Inflammatory storm in COVID‑19‑associated hepatic
has demonstrated that ACE2 is expressed in about 59.7% injury The excessive immune response triggered by
of cholangiocytes, and 2.6% of hepatocytes, suggesting COVID-19 infection leads to the development of an inflam-
that the liver might be susceptible to direct viral entry matory cytokine storm, which is considered a key factor in
via these receptors. This hypothesis of direct viral harm causing liver damage. COVID-19 patients, especially those
is reinforced by findings from liver biopsies, which have in critical condition, often exhibit decreased lymphocyte
revealed indications of hepatocyte apoptosis and the pres- counts, including helper and suppressor T cells, along with
ence of viral RNA within liver tissues. These findings sug- increased plasma levels of several inflammatory cytokines.
gest that the virus may directly affect liver cells, leading to These cytokines include monocyte chemoattractant protein
cellular damage and injury (Paizis et al. 2005). 1, interleukins (IL-2, IL-10, and IL-7), GCSF, IP10, MIP1A,
Furthermore, recent studies have suggested that indi- and tumor necrosis factor-alpha. (Cao 2020; Funk and Tyson
viduals infected with COVID-19 might continue to excrete 2020). Increased concentrations of IL-6 and IL-10, coupled
the virus in their fecal samples even after respiratory tract with diminished CD4 + T cells, were identified as autono-
samples show negative results. This implies the poten- mous risk factors for severe liver injury in a group study.
tial for viral replication to take place in areas outside the Another investigation established an independent associa-
lungs, including the digestive tract and liver (Wu et al. tion between lymphopenia, C-reactive protein levels, and
2020b). liver damage. In individuals with moderate-to-severe dis-
ease, the systemic inflammatory response syndrome results
Role of endotheliitis in hepatic injury Endotheliitis is in unregulated immune-mediated inflammation triggered by
believed to play a significant role in hepatic injury associ- the release of cytokines and other inflammatory indicators.
ated with COVID-19. One suggested mechanism is related This cytokine storm can cause secondary liver injury and
to the hypercoagulable state induced by the virus, which can multiorgan failure (Lei et al. 2020a; Zhang et al. 2020b).
lead to thrombosis of the portahepatic system. This process Liver damage associated with COVID-19 is connected to
is further exacerbated by the occurrence of hypoxia result- worse patient outcomes, potentially because it affects other
ing from pulmonary involvement in severe cases of COVID- organ systems. Individuals with liver injury tend to experi-
19. Hypoxia within liver tissue results in reperfusion when ence extended hospital stays, and those with pre-existing
blood circulation is restored, leading to an influx of reactive liver conditions face an elevated risk of hospitalization and
oxygen species and exacerbating the pro-inflammatory con- mortality. The extent of liver biochemistry abnormalities
dition (Yang et al. 2020b). detected during the initial evaluation is also a marker of the
The inflammation of the vascular endothelium due to severity of the disease. (Liu et al. 2020; Zhang et al. 2020b).
SARS-CoV-2 infection results in microvascular dysfunc- A meta-analysis of over 15,000 COVID-19 patients
tion, leading to an elevated propensity for blood clotting, showed that liver injury was reported in about 23.1% of
tissue swelling, and organ ischemia. This harm to the vas- patients in the early period and had an overall incidence
cular endothelium is attributed to either direct viral effects of 24.4% during the disease course. Approximately 48.5%
or inflammation induced by the immune system. As a result, of liver injury cases occurred within the first two weeks of
the liver’s blood vessels exhibit vasoconstriction and a pro- hospitalization, with 26.7% of individuals with severe pneu-
coagulant state, contributing to the development of throm- monia exhibiting liver injury. Among COVID-19 patients
botic events (Antoniak and Mackman 2014; Antoniak 2018). who unfortunately passed away, the occurrence of liver
This hepatic injury mechanism shares similarities with injury was notably elevated, ranging from 58 to 78%. For
other viral infections, such as dengue fever virus, Ebola patients aged over 60, those with severe COVID-19 cases,
virus, and human immunodeficiency virus (HIV), which are and individuals with underlying metabolic conditions like
also recognized for their impact on the coagulation system. hypertension and diabetes, the prognosis tends to be worse
The fundamental pathophysiology of liver injury in COVID- if they develop liver injury. Therefore, close monitoring and
19 may encompass liver ischemia–reperfusion injury, a phe- individualized treatment are essential, especially for patients
nomenon that often occurs when blood circulation to liver with comorbidities (Morgan et al.;Zhang et al. 2020a), as
tissue is rapidly restored (Antoniak and Mackman 2014). shown in Fig. 7.
Recent advances in COVID‑19‑induced liver injury: causes, diagnosis, and management

Fig. 7  Molecular mechanisms

of coronavirus disease to induce
liver injury

Hypoxic injury Liver damage due to hypoxic injury is a prevalence of conditions like septic shock and heart fail-
common issue in critically ill individuals, mainly stemming ure in COVID-19 patients, it is important to note that both
from cardiac, circulatory, or respiratory problems that lead hypoxemia and disruptions in blood flow due to heart issues
to reduced blood flow or passive congestion in the liver. could contribute to liver damage in these individuals (Jin
This condition, known as hypoxic hepatitis or ischemic et al. 2020; Kang et al. 2020).
hepatitis, is particularly prevalent in those with underlying
health issues (Waseem and Chen 2016). Infection in the gut–liver axis COVID-19 has the poten-
When the body faces stress, it compensates by reducing tial to impact the gastrointestinal system and trigger liver
blood flow to various organs, including the liver. This reduc- infection by moving hepatocytes through the portal vein.
tion in blood flow, especially in a specific area called zone This leads to the virus, SARS-CoV-2, initially present in
3 of the liver, causes a lack of oxygen supply to liver cells, hepatocytes, getting transported to the bile using vesicular
resulting in hepatocellular hypoxia. Reintroduction of oxy- pathways. Subsequently, a secondary round of infection can
gen after such an episode can trigger the production of harm- take place in the biliary tract, connecting the liver and the
ful reactive oxygen species in the affected liver cells, causing gut directly. As a result, this cycle creates a favorable envi-
further damage through processes like lipid peroxidation. ronment for the virus to persist, potentially exacerbating the
Furthermore, immune cells in the liver, called Kupffer cells, prognosis for individuals with both COVID-19 and symp-
can respond to the lack of oxygen by releasing cytokines, toms related to the liver and intestines (Zhang et al. 2023).
which can then activate other immune cells and exacerbate Recent research on gut microbiota has indicated that
the damage (Rosser and Gores 1995). changes in the composition of intestinal microbiota, known
The clinical progression of this condition often involves a as dysbiosis, are linked to various immune-related inflam-
rapid increase in liver enzyme levels, specifically transami- matory conditions. Similarly, in the context of COVID-19,
nases, to levels significantly higher than normal (20 times dysbiosis of the gut microbiota might have a significant role
the upper limit). Another enzyme called LDH is also ele- in influencing the clinical course of patients who have under-
vated, but these enzyme levels tend to normalize as the lying health issues like diabetes, hypertension, and obesity
oxygen supply is restored (Waseem and Chen 2016; Huang (Yang et al. 2020a). This is particularly noteworthy in older
et al. 2020). individuals, where decreased diversity in gut microbiota is
Patients who are hospitalized due to various reasons, common and severe outcomes of COVID-19 are more preva-
including COVID-19, may experience different levels of low lent, suggesting a potential involvement of gut microbiota
oxygen in their blood (hypoxemia). To manage this, oxy- in the overall development and consequences of the disease
gen support is provided in different ways depending on the (Forbes et al. 2016).
severity of the hypoxemia, ranging from the nasal cannula to Moreover, it has been observed that COVID-19 patients
more invasive methods like mechanical ventilation or extra- exhibit a reduction in gut bacteria that have immune-regu-
corporeal membrane oxygenation (ECMO). Considering the lating properties. Additionally, the inflammation triggered
 S. A. Antar et al.

by gut dysbiosis is a significant factor in the development of thorough medical history review and perform additional
cardiometabolic and diabetic conditions, potentially contrib- diagnostic tests. (Frediansyah et al. 2021). The incidence of
uting to the heightened severity of COVID-19 in the most liver damage brought on by various medications is different,
susceptible patients (Acosta-ampudia et al. 2020). Given but the incidence increases with the number of medications
that diet significantly affects the composition of gut micro- given summarized in Table 4.
biota, there is growing interest in exploring the impact of Corticosteroids play a significant role in the treatment
dietary habits on health and disease prevention, and how of COVID-19, particularly in hospitalized patients with
they relate to improved outcomes for patients. The circula- severe disease. The use of systemic corticosteroids, such as
tory system that supplies blood to the gastrointestinal tract dexamethasone, has been shown to reduce mortality and the
is connected to the liver through the portal venous system. need for mechanical ventilation in severe cases of COVID-
Hence, disturbances in the gut microbiota and breaches in 19 (Hui et al. 2018). The World Health Organization (WHO)
the gut–mucosal barrier could lead to hepatic dysfunction recommends the use of systemic corticosteroids in hospital-
induced by sepsis (Chattopadhyay and Shankar 2021; Kari- ized patients with severe and critical COVID-19. However,
yawasam et al. 2022). it emphasizes that corticosteroids should not be routinely
administered in the treatment of viral pneumonia or acute
Drug‑induced liver damage (DILI) in COVID‑19 treat‑ respiratory distress syndrome (ARDS) (WHO 2020) unless
ment Drug-induced liver damage has also been reported recommended for other medical reasons or as part of a
while treating COVID-19. It is well recognized that nucleo- clinical trial. Clinical evidence suggests that corticosteroids
side analogs are an essential family of antiviral drugs that when used appropriately in hospitalized COVID-19 patients
can harm the liver in many ways (Ramesh et al. 2021). can help mitigate the inflammatory response associated with
The most common mechanism involves liver mitochon- severe disease. This is particularly important in cases where
drial dysfunction, which may be caused by the incorpora- the immune system becomes hyperactive, leading to worsen-
tion of nucleoside analogs into mitochondria or the inhibi- ing of symptoms (Russell et al. 2020).
tion of mitochondrial gamma polymerase from generating Corticosteroids work by suppressing inflammation and
mitochondrial DNA, leading to mitochondrial depletion or modulating the immune response, which can help reduce the
loss of function. Mitochondrial damage can affect numer- risk of death, decrease the amount of time patients remain
ous tissues and cause myopathy, pancreatitis, neuropathy, hospitalized, and lower the likelihood of needing mechani-
myelosuppression, and hepatic dysfunction. COVID-19 cal ventilation or other advanced respiratory support (Arabi
patients with severe sepsis may undergo hepatocyte injury et al. 2018). It is crucial to note that corticosteroids should
due to medication toxicity or excessive inflammation, Liver be used judiciously and under medical supervision, as they
dysfunction due to cholestasis caused by abnormalities in may have side effects and can potentially delay viral clear-
bile metabolism, and hypoxic liver disturbance caused by ance. The decision to administer corticosteroids should
shock and ischemia (Revzin et al. 2020). It can be brought be based on the individual patient’s clinical condition and
on by a wide variety of medicines, and the diagnosis can be guided by the latest evidence and treatment guidelines
challenging. Acute liver failure resulting in death or organ according to FDA approval. Additionally, the use of corti-
transplantation is frequently caused by DILI, in addition to costeroids should be accompanied by close monitoring for
being a significant source of abnormal liver tests (Sandhu any adverse effects and appropriate adjustments in dosage
and Navarro 2020). Several drugs can interfere with liver or discontinuation if necessary (WHO 2021).
function and pose a risk of harm. Some may lead to unno-
ticed increases in liver enzyme levels, while others can trig- Risk groups for patients with COVID‑19 and liver
ger acute hepatitis. The degree of liver damage can be influ- diseases
enced by the dosage of the medication administered (such as
paracetamol) or may not depend on the dosage of the medi- COVID‑19 in patients with a pre‑existing history of liver
cation taken (Villanueva-Paz et al. 2021). The increased disease
risk of thrombosis may be brought on by a prothrombotic
state in the most severe phases of COVID-19 infection. One Alarming reports of COVID-19 infections in persons with
well-known factor contributing to the potential risk of DILI hepatic disorders have appeared. Patients with pre-existing
is the use of anticoagulants (Gu et al. 2022). Additionally, liver disease might have their amount of hepatic involvement
COVID-19-related liver dysfunction may result in inappro- and treatment assessed using knowledge gained from past
priate medication metabolism in the liver, raising the risk bouts of coronavirus infection. Adults with underlying liver
of drug toxicity. To diagnose drug-induced liver lesions and illness and the elderly had the highest incidence of SARS
establish a connection with potential causative drugs while mortality (Landi et al. 2020). As a result, it is reasonable
excluding other liver disorders, it is essential to conduct a to assume that COVID-19 individuals will also be more
Table 4  Examples of drug-induced liver damage used to treat COVID-19
Drug Mechanism/purpose Evidence of hepatotoxicity Probability Ref

Colchicine A therapy used experimentally in COVID-19 Although it seems to have a favorable liver safety C (Alqahtani and Schattenberg 2020; Ortiz et al.
patients to reduce inflammatory conditions profile when used at low doses, this medication 2021; Zhang et al. 2022b)
does not exclude the possibility of DILI. Rarely
associated with liver elevations, self-limiting
Pirfenidone An antifibrotic medication is frequently prescribed The development of pulmonary fibrosis is one NR (Saleh et al. 2020), (Tashiro et al. 2022), (Hazem
to people with idiopathic pulmonary fibrosis of the severe side effects that COVID-19 may et al. 2022)
(IPF). Elevations of mild-to-moderate serum cause. In some research, antifibrotic medications
aminotransferase may be linked to pirfenidone like pirfenidone are being tested
IL-6 inhibitors such IL-6 receptor blockade reduces cytokine storm, Occurrences of severe drug-induced liver damage, C (Soiza et al. 2018)
as (tocilizumab) tested to lessen hyperactive inflammation in such as acute liver failure and acute hepatitis,
COVID-19 patients. When used with potentially have been seen in tocilizumab patients, and in
hepatotoxic medications some cases, liver transplantation was necessary.
is known to induce a transitory or intermittent rise Clinically apparent liver injury with jaundice
in mild-to-moderate levels of liver enzymes
Ritonavir Protease inhibition disrupts viral replication, Clinically apparent liver disease in 3–10% of D (Vitiello et al. 2021)
Metabolized by CPY3A4 may therefore produce patients
a toxic intermediate, which may be the cause of
potential liver damage
Remdesivir RNA polymerase inhibition hinders replication, There is evidence that high doses of lopinavir and D (Soiza et al. 2018; Ye et al. 2020; Metawea et al.
Many COVID-19 patients are now receiving ritonavir can accelerate liver damage by induc- 2021)
antivirals approved for other therapeutic reasons ing inflammatory responses and oxidative stress,
with a known risk of hepatotoxicity as well as cause hepatocyte death via the caspase
Lopinavir Protease inhibition disrupts viral replication, Many cascade system. Through the liver's cytochrome D (Ortiz et al. 2021; Sivandzadeh et al. 2021)
Recent advances in COVID‑19‑induced liver injury: causes, diagnosis, and management

COVID-19 patients are now receiving antivirals P450 (CYP 3A4) pathway, which is also an
approved for other therapeutic reasons with a inhibitor, ritonavir is extensively metabolized.
known risk of hepatotoxicity Mild-to-moderate serum ALT and AST eleva-
tions, self-limiting. Lopinavir also clinically
apparent liver disease in 3–10% of patients
Corticoids, Metho- Can cause abnormal liver function test findings They cause fatty liver patients with COVID-19 to A (Ferron et al. 2020; Kolaric et al. 2021)
trexate Antiretro- and exacerbate pre-existing steatosis, necroin- develop NASH or exacerbate steatosis, fibrosis,
viral drugs flammation, and fibrosis and necrotizing inflammation. Oxidative stress,
mitochondrial dysfunction, changes to lipid
homeostasis, and restriction of exogenous
metabolic enzyme activity are among the
mechanisms, that also cause Hepatomegaly, and
exacerbate viral hepatitis
Azithromycin Anti-inflammatory, viral entry inhibition Self-limited cholestatic hepatitis may appear after C (Alqahtani and Schattenberg 2020; Ortiz et al.
treatment 2021; Kariyawasam et al. 2022; Saha et al. 2022;
Zhang et al. 2022b)
Hydroxychloroquine Anti-inflammatory, viral entry inhibition Acute liver injury with sudden fever onset C (Alqahtani and Schattenberg 2020; Mcgonagle
2020; Ortiz et al. 2021; Sivandzadeh et al. 2021;
Saha et al. 2022; Zhang et al. 2022b)
 S. A. Antar et al.

susceptible to liver damage. The incidence of abnormal ALT

2021; Kariyawasam et al. 2022; Saha et al. 2022)

2021; Kariyawasam et al. 2022; Saha et al. 2022)

varied from 13.3 to 31.6% in multiple trials that included
(Alqahtani and Schattenberg 2020; Kariyawasam

(Mcgonagle 2020; Ortiz et al. 2021; Saha et al.

(Mcgonagle 2020; Ortiz et al. 2021; Saha et al.

(Alqahtani and Schattenberg 2020; Ortiz et al.

(Alqahtani and Schattenberg 2020; Ortiz et al.

(Alqahtani and Schattenberg 2020; Ortiz et al.

participants with pre-existing liver illnesses. However, up
to 50% more NAFLD patients in the two investigations had
elevated ALT levels than non-NAFLD patients (Portincasa
et al. 2020; Muthiah et al. 2022). Additionally, patients with

2021; Kariyawasam et al. 2022)

et al. 2022; Zhang et al. 2022b)

NAFLD were more likely to experience COVID-19 devel-

opment. Despite NAFLD laying the pathological ground-
work for liver injury and being linked to higher ALT and
GGT levels, there is a requirement for more definitive find-
ings. Patients with NAFLD should take protective steps
to avoid negative outcomes because of the potential liver
damage. An 11% prevalence of underlying liver disease was
2022)

2022)

found in a case series (Vitrone et al. 2021). About half of

Probability Ref

them had symptoms for above 10 days following the start

of the disease. In a different study, 9% of the participants
had cirrhosis or hepatitis as their primary liver illness. Two
patients were admitted to the hospital with baseline alco-
NR
A

D
B
E

holic liver disease; one had a slight increase in ALT (120

Minor self-limiting elevations, sporadic clinically

U/L), while the other showed no such abnormalities. There

Transient aminotransferase elevations, rare acute
Transient elevation, rarely symptomatic or jaun-
Significant ALT elevations, symptomatic cases

was no indication that the effects of the hepatitis B virus

Transient ALT elevation, rarely serious cases
Aminotransferase elevations, rapid recovery

infection, which was present in 2.7% of the first group from

China, were getting worse. The link between pre-existing
liver conditions and the prognosis and outcomes of COVID-
19 will, therefore, require assessment through comprehen-
sive data registries that have recently commenced admitting
Evidence of hepatotoxicity

patients. (Vancsa et al. 2020).

COVID‑19 in patients with pre‑existing chronic hepati‑

tis Patients with pre-existing chronic liver diseases like
apparent

chronic hepatitis are highly susceptible to liver damage from

failure
dice

SARS-CoV-2, the virus responsible for COVID-19 (Albil-

los et al. 2014). Chronic liver disease prevalence among
COVID-19 patients ranges from 3 to 11%, with a higher risk
of severe infection and mortality in those with pre-existing
liver conditions (Qi et al. 2021). Chronic hepatitis B and
viral hepatitis patients are more vulnerable to COVID-19,
but links between chronic viral hepatitis and COVID-19
Inhibition of viral entry, replication

severity vary (Oyelade et al. 2020). Existing hepatitis treat-

Reverse transcriptase inhibition

Low-molecular-weight heparin

ments should continue in co-infected patients, and starting

Fungal protease inhibition

hepatitis B treatment due to flare-up suspicion is consid-

ered. However, starting hepatitis C treatment in COVID-19
Mechanism/purpose

patients is not routinely recommended (Fix et al. 2020).

Antifungal agent
Anticoagulant

Viral hepatitis elevates the likelihood of liver damage

in COVID-19 patients due to mechanisms such as viral
reactivation and DILI. Administering high-dose hormone
therapy to COVID-19 patients could potentially lead to the
reactivation of HBV in individuals with a previous HBV
Table 4  (continued)

infection, while specific biologic medications may trigger

Anidulafungin

the activation of HBV (Fan et al. 2020). Combined lopina-

Voriconazole
Enoxaparin
Nevirapine

Ivermectin

vir and ritonavir therapy may worsen liver damage in HBV

Heparin

or HCV co-infection. Patients with SARS-CoV-2 and HBV

Drug

co-infection face worse liver injury prognosis, warranting

Recent advances in COVID‑19‑induced liver injury: causes, diagnosis, and management

consideration of hepatitis etiologies in COVID-19 patients a study of 745 patients with CLD who were infected with
with heightened liver reactions (Boettler et al. 2020). Con- SARS-CoV-2, cirrhosis was significantly associated with
tinuous antiviral therapy, especially with glucocorticoids, death (Sumida and Yoneda 2021). Cirrhosis and severe
is suggested for HBV reactivation prevention, while HCV COVID-19 may be linked by increased systemic inflamma-
treatment initiation should be delayed. Caution is advised tion, immunological dysfunction, coagulopathy, and intes-
regarding corticosteroid therapy's potential adverse effects tinal dysbiosis, among other potential disease pathways.
on COVID-19 patients co-infected with chronic HBV. This Patients who had both cirrhosis and COVID-19 experienced
includes delayed viral clearance, increased coagulopathy a significantly higher mortality rate than those admitted for
risk, and acute liver injury, supporting limited corticosteroid bacterial infections. Furthermore, the likelihood of mortal-
use in COVID-19 and HBV co-infection (Chen et al. 2020; ity was separately linked to the severity of lung and liver
Meng et al. 2022). conditions (Iavarone et al. 2020b; Wang et al. 2021a). Due
to the immunological dysfunction resulting from SARS-
COVID‑19 in patients with pre‑existing cirrhosis Cirrhotic CoV-2 infection, there is a hypothesis that individuals with
patients face increased risks with COVID-19, including sus- hepatocellular carcinoma (HCC) may face a greater vulner-
ceptibility to infection, severe disease, and hepatic decom- ability to the impact of COVID-19 compared to patients
pensation. Stress and sepsis can trigger acute-on-chronic with other types of malignancies. In general, COVID-19
liver failure in those with decompensated cirrhosis (Bollipo patients with cancer seem to have a larger likelihood of
et al. 2020). COVID-19 is associated with hepatic decom- dying (39%) or needing invasive ventilation than COVID-
pensation, and these patients might lack typical respiratory 19 patients without cancer (8%) (Desai et al. 2020). The
symptoms. Respiratory issues, rather than liver disease pro- influence of COVID-19 on Viral Hepatitis: HBV and HCV
gression, are often the primary cause of death in cirrhotic are two major agents of liver disease, infecting around 300
COVID-19 patients (Acosta-ampudia et al. 2020). million and 70 million people worldwide, ultimately lead-
Managing pre-existing liver disease or cirrhosis with ing to chronic hepatitis infections and disease. The strongest
COVID-19 involves minimizing staff exposure through tel- prognostic indicators for people with viral hepatitis who are
emedicine and restricting in-person visits to significant liver infected with SARS-CoV-2 right now are liver fibrosis and
disease cases. Testing for COVID-19 is advised in cases of liver damage status. In a Chinese research, HBV infection
acute decompensation (Iavarone et al. 2020a). Liver trans- was discovered in 12.2% (15 of 123) of COVID-19 patients,
plantation listing should prioritize patients with poor short- and it was associated with bad prognosis and an increase
term prognosis. Preventive measures against complications risk of death (13.3% vs. 2.8%).
like bacterial peritonitis and hepatic encephalopathy are cru- There is limited available information regarding alcoholic
cial to avoid decompensation and hospitalization (Hashemi liver disease or alcoholic hepatitis in the context of COVID-
et al. 2020; Bajaj et al. 2021). Cirrhotic individuals are more 19. Nevertheless, there have been reports of higher mortality
susceptible to COVID-19, potentially leading to severe out- rates among individuals with alcohol-related cirrhosis. It is
comes. Immune compromise and inflammatory responses worth mentioning that acetaminophen, commonly used to
contribute to higher infection rates and mortality (Marjot manage elevated body temperatures associated with COVID-
et al. 2021b). Acute hepatic decompensation, often an initial 19, can also lead to liver damage by initiating hepatic
sign of COVID-19, occurs frequently without typical res- cytochrome P450 2E1 (CYP2E1). This activation can par-
piratory symptoms. Managing cirrhosis during the pandemic ticularly affect individuals with severe alcohol dependence
involves telemedicine, cautious in-person visits, and atten- (Kushner and Cafardi 2020).
tion to prevent complications (Kushner and Cafardi 2020).
COVID‑19 and HCC During the COVID-19 pandemic,
Alcohol‑associated liver disease (ALD) COVID-19 is asso- patients with malignancies, including hepatocellular carci-
ciated with a 1.8 times higher risk of mortality in indi- noma (HCC), face a high risk of infection and severe out-
viduals with ALD. It's worth noting that only 6% of ALD comes. Cancer patients with underlying cirrhosis and comor-
patients without cirrhosis are compared to 62% of NAFLD bidities are particularly vulnerable due to factors like age,
patients, which suggests that those with ALD who contract anemia, compromised immunity, and poor nutrition. Studies
COVID-19 often have more severe liver damage. In a prior indicate worse outcomes in cancer patients with COVID-19
case report, two patients who were hospitalized for ALD compared to the normal population. National cohort studies
treatment were diagnosed with nosocomial COVID-19 in China highlight higher risks of severe disease, mortality,
infections and experienced severe COVID-19 pneumonia and ICU admission in cancer patients, especially those who
(Wiśniewska et al. 2020). Another study found a connec- recently underwent chemotherapy (Amaddeo et al. 2021).
tion between cirrhosis and alcohol-induced liver damage For managing liver cancer during the pandemic, telemed-
for the risk of severe COVID-19 (Wang et al. 2021b). In icine and limited in-person visits are recommended to reduce
 S. A. Antar et al.

COVID-19 transmission risk. Liver transplantation and AASLD advises against delaying liver transplantation
locoregional therapies for HCC, such as transarterial chem- whenever feasible, taking into consideration the availability
oembolization (TACE) and stereotactic body radiotherapy of local resources. They strongly recommend COVID-19
(SBRT), are indicated but may be prioritized for advanced screening for both donors and recipients, with informed con-
cases due to resource constraints. Surveillance imaging can sent for the procedure explicitly mentioning the potential
be delayed up to 2 months, while TACE is preferred over risk of acquiring nosocomial COVID-19. Following trans-
SBRT for its flexibility. Continuation of sorafenib treat- plantation, the reduction of immunosuppressive therapy is
ment without dose adjustments is advised. Immunotherapy discouraged unless warranted by severe bacterial or fungal
with nivolumab may be temporarily suspended to mini- infections in conjunction with COVID-19 or associated
mize COVID-19 exposure at infusion centers (Kushner and lymphopenia. It is advisable to closely monitor drug lev-
Cafardi 2020; Amaddeo et al. 2021). els, including calcineurin inhibitors and mTOR inhibitors,
Patients with HCC might be high susceptible to COVID- especially when co-administered with other medications like
19 due to compromised immunity. During the pandemic, hydroxychloroquine or azithromycin. Patients in stable con-
HCC diagnoses reduced significantly, and treatment delays dition are encouraged to receive vaccinations for influenza
doubled. Utilizing telemedicine for multidisciplinary care is and streptococcal pneumonia (Colmenero et al. 2021).
recommended. Extensive studies on patients with both HCC
and COVID-19 should assess mortality rates, severity, and Post‑liver transplantation recipients During the COVID-19
complications like liver failure and hepatic encephalopathy pandemic, liver transplant (LT) programs encounter diffi-
(Kushner and Cafardi 2020). culties related to donor availability, potential virus exposure
risk, and the allocation of hospital resources. LT recipients
Liver transplantation and COVID‑19 have a higher likelihood of requiring intensive care unit
(ICU) admission. Although practicing social distancing may
During pandemics, particularly when resources are limited provide some protection, mortality rates among LT recipi-
and there is an increased demand for liver transplantation, ents are similar to those in healthy individuals. Various fac-
international agreement on transplantation protocols is nec- tors, including age, ethnicity, the use of vasopressors, and
essary. While the specifics of virus transmission from donor antibiotics, influence the risk of COVID-19-induced liver
to recipient remain limited, it is thought to rely on factors injury among LT recipients, suggesting disparities based
like the extent and duration of donor viremia, the incubation on ethnicity. The use of immunosuppressive drugs places
period, and the virus’s viability in different organs. Liver LT recipients at risk due to their potentially inadequate
transplant recipients are in an immune-compromised condi- response to the virus and the potential for acute rejection.
tion, heightening their susceptibility to COVID-19, and they Drug interactions, especially involving ritonavir-boosted
may pose a risk of infection to others, particularly health- antivirals and immunosuppressants, need monitoring (Can
care workers. However, immunosuppression has also been et al. 2022).
suggested to be protective against severe COVID-19 illness Some studies suggest that LT and immunosuppression
by mitigating the cytokine storm (McCashland et al. 2000). may not increase COVID-19 risks. Corticosteroid therapy
Reported cases of COVID-19 pneumonia in liver trans- appears effective in reducing severe cases. Liver injury
plant recipients have indicated improvement through symp- is observed in a significant portion of LT recipients with
tomatic treatment and the adjustment of immunosuppres- COVID-19, mainly hepatocellular pattern with enzyme
sion, but further research is required to determine the most elevations. Regular liver enzyme monitoring can identify
effective treatment strategy. Studies have suggested that the at-risk recipients early. Preventive measures include moni-
clinical progression and severity of COVID-19 in organ toring immunocompromised status, continuing immunosup-
transplant recipients are not significantly different from pressant therapy, and adjusting doses according to antiviral
the general population. According to a global multi-center treatments. Comorbidities influence outcomes, with LT
survey, most liver transplant centers prioritized the sick- linked to better outcomes than advanced chronic liver dis-
est patients during the pandemic, while others made indi- ease. LT programs should continue, but delays are suggested
vidualized decisions. Widespread COVID-19 screening except for critical cases. The choice between transplanta-
for donors and recipients was recommended, with donors tion and bridging therapy depends on organ scarcity. Vac-
having positive contact histories or respiratory issues being cination is crucial for LT recipients, aligned with guidelines
excluded. Initially, transplantation protocols remained for liver disease patients. However, vaccine effectiveness in
mostly unchanged at the onset of the pandemic, except for LT recipients and those with autoimmune liver disease and
centers in Singapore, which, based on their prior experi- immunosuppression requires further assessment, as some
ence with SARS-CoV in 2003, restricted liver transplants to show poor response due to immunosuppression (Kushner
urgent medical cases. (Colmenero et al. 2021). and Cafardi 2020) as shown in Fig. 8.
Recent advances in COVID‑19‑induced liver injury: causes, diagnosis, and management

Fig. 8  Effect of COVID-19 on patient with healthy liver & preexisted liver diseases

Non‑alcoholic fatty liver (metabolic syndrome) virus and subsequent infection of other cells. However,
conflicting findings from Li et al. suggest that individuals
Metabolic syndrome involves a set of conditions like high with hypertension might be susceptible to SARS-CoV-2
blood pressure, abnormal lipid levels, diabetes, and obesity. due to the virus invading cells through ACE2 receptors.
These metabolic conditions are closely connected to non- Furthermore, Yang et al. have reported that patients with
alcoholic steatohepatitis/fatty liver and fatty liver disease both COVID-19 and hypertension exhibit elevated levels
associated with metabolic dysfunction. Patients with both of inflammatory markers such as IL-6, CRP, and procal-
metabolic syndrome and COVID-19 are at an increased citonin. This heightened systemic inflammatory response
likelihood of experiencing liver injury, ranging from mild could potentially influence liver metabolism, ultimately
to acute, compared to those without metabolic syndrome contributing to secondary liver injury (Imoto et al. 2019;
and COVID-19. Furthermore, the pandemic has exacerbated Li et al. 2021).
unhealthy habits within this population. Reduced physical
activity, excessive calorie consumption, and heightened Dyslipidemia and liver disease Dyslipidemia has exhib-
mental health issues have contributed to an average weight ited a notable association with COVID-19. Studies con-
gain of 1.5 kg in individuals with obesity, as reported by Pel- ducted by Lu et al. propose that increased total cholesterol
legrini et al. Additionally, heightened alcohol consumption, levels could be associated with virus replication, whereas
particularly during periods of social isolation, has become reduced blood lipid levels might create a favorable envi-
more evident, exposing individuals with metabolic syn- ronment for the synthesis and packaging of virus particles
drome to elevated risks (Li et al. 2021). during viral invasion. Conversely, Li et al. have reported
that the combination of dyslipidemia and COVID-19
Hypertension and liver disease Hypertension is asso- might result in an excessive burden on liver lipid metabo-
ciated with abnormal initiation of the renin–angioten- lism, heightening the risk of liver injury through a com-
sin system (RAS) and a relatively lower level of ACE2 bined effect. Furthermore, the virus’s ability to replicate
expression, which could potentially worsen the impact of extensively in the liver, a central site for lipid metabolism,
COVID-19. Researchers like Imoto et al. have noted that could directly contribute to liver damage and exacerbate
SARS-CoV-2 binds directly to the ACE2 receptor, facili- disruptions in lipid metabolism (Lu et al. 2008).
tating its entry into cells and leading to replication of the
 S. A. Antar et al.

Diabetes and liver disease Diabetes is associated with an liver injury severe and critical cases of COVID-19 fre-
increased susceptibility to COVID-19. Elevated blood sugar quently result in liver injury, primarily attributed to hypoxia
levels contribute to the replication of the virus, amplify- and ischemia. These conditions disrupt cellular survival sig-
ing its invasion and prompting a systemic inflammatory nals by affecting lipid and glycogen regulation, ultimately
response that can lead to damage or failure in multiple body leading to the rapid death of hepatocytes. Furthermore,
systems. This connection is particularly relevant due to dia- hypoxia-induced oxidative stress responses elevate peroxi-
betes being linked to autoimmune issues and chronic inflam- dation products and reactive oxygen species (ROS) in res-
mation, potentially resulting in dysfunction of the immune piratory distress syndrome, triggering the release of several
system and imbalances in immune cells. COVID-19 can pro-inflammatory factors that subsequently induce liver
exacerbate these effects, leading to abnormal inflammatory damage. As a result, these alterations can instigate hepato-
responses. This is particularly significant considering the cyte hypoxia and ischemia, further worsening the degree of
liver's role as a crucial immune organ; the combination of liver injury. (Li et al. 2021).
diabetes and COVID-19 might heighten the immune bur-
den on the liver. Furthermore, certain hypoglycemic medi- Inflammatory history As a complication arising from
cations like metformin could potentially raise transaminase COVID-19, Cichoz-Lach and colleagues noted that a his-
levels and contribute to immune-related liver injury (Li tory of inflammation could heighten the risk of liver func-
et al. 2021). tion impairment. The underlying mechanisms involve the
over-activation of inflammatory pathways that are already
Obesity and liver disease Obesity serves as an independ- present due to systemic inflammation, potentially leading to
ent risk factor for COVID-19. This heightened risk can extrapulmonary damage in COVID-19 patients. Addition-
be attributed to its association with non-alcoholic fatty ally, a phenomenon known as a cytokine storm, character-
liver disease (NAFLD), which triggers chronic liver injury ized by strong immune activation, can trigger secondary
through inflammatory reactions. The impact of obesity on liver injury and contribute to the sudden onset of multi-
the immune system can result in imbalances that increase organ failure. Furthermore, routine administration of medi-
susceptibility to an inflammatory surge during COVID-19, cations like antibiotics and steroids to manage inflammation
potentially leading to damage across multiple bodily sys- in COVID-19 patients has been suggested as a potential fac-
tems. Individuals with obesity who contract COVID-19 tor contributing to the occurrence of liver dysfunction dur-
may also experience more severe or frequent drug-induced ing hospitalization (Pereira et al. 2020).
liver injury (DILI) and worsened pre-existing liver condi-
tions, as certain medications can interact with obesity to Risk groups in healthy patients without a history
amplify hepatotoxic effects. This may arise from distur-
bances in lipid balance, compromised mitochondrial func- Older patients Advanced age is associated with a heightened
tion, impaired activity of enzymes that metabolize external risk of experiencing more severe cases of COVID-19 and
substances, and oxidative stress (Nave et al. 2011). compromised liver function. Li and colleagues discovered
Furthermore, the risk of cytokine storms in severe that individuals with COVID-19 and abnormal liver func-
COVID-19 cases can be escalated by DILI, where pro- tion test results (LFTs) had a notably higher median age. In a
inflammatory cytokines exacerbate the potential for hepa- study by Schattenberg et al., which focused on patients with
totoxicity from various drugs including antibiotics. Addi- an average age of 70 years, it was revealed that a substantial
tionally, impaired ventilation due to obesity can result in proportion (86%) of them had underlying health conditions,
hypoxemia, subjecting liver metabolism to an oxygen- with 38% displaying abnormal LFTs. These findings indi-
deprived environment and raising the risk of liver injury. cate that older age is linked to an increased susceptibility
Interestingly, pediatric patients with COVID-19 tend to to severe liver injury in the context of COVID-19. This risk
experience milder symptoms and better prognoses, possi- is further exacerbated when coupled with factors like bad
bly attributed to unique aspects of their immune response prognostic indicators of liver injury and pre-existing liver
system (Nave et al. 2011). diseases. Therefore, close monitoring and personalized
treatment for potential liver injury are crucial for this patient
Other risk groups in patients with a certain history group (Li et al. 2021).

Oxygen therapy Jiang and colleagues observed that more Male patient The occurrence of abnormal liver function in
than 40% of COVID-19 patients needed oxygen therapy due individuals with COVID-19 was found to be more preva-
to varying levels of hypoxemia. Similarly, Phipps and cow- lent among men, suggesting a greater susceptibility to liver
orkers found that patients admitted to the ICU and receiving injury in males compared to females. Additionally, research
vasopressors were more susceptible to COVID-19-induced by Chen and colleagues indicated that older men were more
Recent advances in COVID‑19‑induced liver injury: causes, diagnosis, and management

prone to experiencing severe cases of COVID-19 in com- inflammation and non-severe pneumonia, pregnant patients
parison to younger women. Cichoz-Lach and colleagues might have reduced exposure to liver injury-associated med-
showed that acute liver injury was commonly observed in ications like lopinavir/ritonavir. (Can et al. 2022).
younger men (below 65 years of age). The underlying mech- Although current evidence suggests that neonatal out-
anism for this phenomenon involves hormonal imbalances comes are not significantly worsened, pregnant patients
characterized by low levels of testosterone, which were with COVID-19 displayed elevated levels of inflammatory
identified in 66.7% of male patients. This hormonal imbal- markers such as IL-6 and polymerase chain reaction. These
ance has been proposed as a potential factor contributing markers are positively correlated with severe COVID-19
to liver injury in the context of COVID-19 (Li et al. 2021). cases, underscoring the necessity for vigilant liver function
monitoring in pregnant individuals diagnosed with COVID-
Pregnant women The potential impact of pregnancy as a 19 (Fan et al. 2020), as shown in Table 5.
risk factor for liver injury during the COVID-19 pandemic
remains a subject of debate. Studies have presented vary- Management for COVID‑19
ing rates of liver injury occurrence in pregnant individu-
als with COVID-19, ranging from 3.8 to 11.8%, which is Pharmacological management
notably lower than the general population’s rate of 21.5 to
45.71%. The hyperinflammatory response associated with When treating patients with COVID-19 with antiviral or
COVID-19-related fatalities has led to considerations about anti-inflammatory medications, it is important to monitor
pregnancy's protective effect. The anti-inflammatory phase liver parameters and avoid the use of drugs that protect the
experienced during the second trimester might confer a liver and reduce liver enzymes as a preventative measure
degree of protection against severe inflammation induced by (Vitiello et al. 2021). Using proper dosages based on renal
COVID-19. Alternatively, due to the presence of low-grade and hepatic function, too many medicines with a potential

Table 5  Risk groups for patients with COVID-19 and liver disease
Risk group Description and findings

Patients with Preexisting Liver Disease - Patients with liver diseases are more susceptible to liver damage from COVID-19
- Elevated ALT levels observed in pre-existing liver illnesses
- NAFLD patients have higher ALT levels and are more vulnerable to COVID-19
- Comprehensive data registries are needed to evaluate disease prognosis
Patients with Chronic Hepatitis - Patients with chronic viral hepatitis have an increased risk of severe COVID-19
- Hepatitis B reactivation is possible with high-dose hormone therapy
- Hepatitis C treatment initiation should be delayed
- Consideration of hepatitis etiologies in COVID-19 and HBV co-infection
Patients with Preexisting Cirrhosis - Cirrhotic patients face an increased risk of infection, severe disease, and hepatic decompen-
sation from COVID-19
- Acute-on-chronic liver failure triggered by stress and sepsis
- Cirrhotic COVID-19 patients may lack typical respiratory symptoms
Alcohol-Associated Liver Disease (ALD) - ALD patients with COVID-19 have an increased risk of mortality
- Cirrhosis is significantly associated with death in ALD patients with COVID-19
- Alcohol-related cirrhosis linked to higher mortality rates
COVID-19 and Hepatocellular Carcinoma (HCC) - HCC patients at increased risk of severe outcomes from COVID-19
- Liver transplantation and locoregional therapies for HCC should be prioritized for advanced
cases
- Telemedicine and limited in-person visits are recommended
Liver Transplantation and COVID-19 - Liver transplant recipients are at higher risk due to immunosuppression
- Reduction or withdrawal of immunosuppression may improve outcomes
- Screening and precautions recommended for donors and recipients
- Liver transplantation should not be delayed whenever possible
Patients with Metabolic Syndrome - Metabolic syndrome increases the likelihood of liver injury in COVID-19 patients
- Hypertension, diabetes, dyslipidemia, and obesity are factors that contribute to the risk of
liver injury
- COVID-19 exacerbates unhealthy habits in this population
Other Risk Groups - Oxygen therapy and inflammatory history can contribute to COVID-19-induced liver injury
- Older patients and males are more susceptible to liver injury
- Pregnancy's impact on liver injury is debated
 S. A. Antar et al.

for DILI (often no more than 2) should not be administered Abdominal imaging methods like ultrasonography and
to patients with COVID-19, especially those with the exist- computed tomography (CT) scans are used to investigate
ing liver problems. Patients receiving anti-HBV or anti-HCV liver involvement. Findings are generally nonspecific and
therapy should not stop taking it, but anti-COVID-19 medi- are mainly used when there is suspicion of conditions like
cines must be delivered under close observation. Consider- biliary obstruction or portal venous thrombosis. Abdomi-
ing that IL-1 or IL-6 medications can be bifacial-reducing nal CT scans might reveal liver hypo-echogenicity and peri-
inflammation while also having the potential to worsen clini- cholecystic fat stranding, but these findings are not always
cal conditions due to DILI. Obeticholic acid has recently present and should be used selectively. Liver biopsies post-
become a promising therapy option for NASH, a liver condi- mortem can show mild-to-moderate microvascular steatosis
tion that is becoming more widespread but for which there and mild activity in certain areas, but these are not unique to
are no effective treatments at the moment. The farnesoid X COVID-19 and are not routinely recommended due to their
receptor (FXR) is a nuclear receptor that is greatly expressed limited impact on clinical management (Luo et al. 2020).
in the liver and gut and is selectively and powerfully ago- The American Association for the Study of Liver Dis-
nized by obeeticholic acid. The biliary acid route, as well eases (AASLD) advises taking into account unrelated factors
as the inflammatory, fibrotic, and metabolic processes, are (e.g., HBV or HCV) and other considerations (e.g., myositis,
thought to be significantly regulated by FXR (Jiang et al. cytokine release syndrome, and ischemia) when interpret-
2021). Obeticholic acid is only employed as a scientific ing abnormal liver test results in individuals with COVID-
hypothesis for pharmacological treatment and is not sup- 19. In areas with high hepatitis prevalence, viral hepatitis
ported by research, or epidemiological scientific evidence investigations might be necessary based on clinical circum-
in the treatment of liver fibrosis brought on by COVID-19. stances, while in regions with lower prevalence, monitoring
New studies have revealed that glycyrrhizinic acid molecules hepatic function might suffice. Further investigations might
may also have antiviral effects on SARS-CoV-2 (Kandeil be warranted if liver function abnormalities persist beyond
et al. 2021a). Since it has been used in clinical settings for a reasonable timeframe. In cases of persistent liver function
a long time, glycyrrhizin has been the anti-inflammatory abnormalities, the choice of evaluation should be guided by
medication of choice for protecting against liver disease. clinical presentation and may involve investigating chronic
The use of silymarin can be thought of as hepatotoxic drug liver conditions and other potential infectious causes (Lei
intoxication (Marjani et al. 2019). et al. 2020b; Mcgonagle 2020).

Diagnostic management Specific management in patients without a history

Diagnostic approaches for assessing liver involvement in Monitoring liver functions in COVID-19 patients upon
COVID-19 patients primarily include liver function tests admission and during their hospital stay is recommended.
(LFTs) and abdominal imaging. LFTs involve monitoring Abnormal liver test results should not deter the use of inves-
liver enzymes (AST and ALT), PT, bilirubin levels, and tigational or off-label COVID-19 treatments. However,
albumin to detect potential liver damage. It is important patients receiving such treatments, which might have liver-
to note that abnormal results can be influenced by various related risks, should be closely observed. Medications with
factors, including the systemic inflammatory response trig- known liver toxicity, such as tocilizumab and lopinavir–rito-
gered by COVID-19. It is advisable to perform these tests navir, should be avoided if patients show significant liver
upon hospital admission to establish a baseline and detect damage. In cases where immune-suppressive treatments like
individuals with pre-existing liver conditions. (Da et al. corticosteroids and tocilizumab are given for over a week,
2020). Additional tests might be necessary for patients with testing for hepatitis B virus (HBV) is advised, particularly
known liver diseases like hepatitis B or C. The frequency of in regions where HBV is common (Bertolini et al. 2020).
LFT monitoring is not well defined, but it is suggested that Prescribing medications for COVID-19 patients with
patients receiving potentially liver-toxic medications have the existing liver conditions requires considering potential
LFTs checked at least twice weekly. Patients with abnormal drug interactions. Caution should be exercised with par-
LFT results or pre-existing liver conditions might need more acetamol (avoid doses > 2 g/day in chronic liver disease)
frequent monitoring. Elevated serum AST and LDH levels and nonsteroidal anti-inflammatory drugs (NSAIDs). Cor-
alongside normal ALT levels could indicate other issues ticosteroid use in COVID-19 could heighten hepatitis risk in
like muscle or heart injury. Abnormal LFT results might those with chronic HBV, necessitating careful monitoring.
be present upon admission before antiviral treatment for Specific drug combinations should be avoided in patients
COVID-19 starts. Such abnormalities could hint at chronic with prior liver issues. For instance, combining tenofovir
liver disease, and physicians should consider this possibility derivatives with lopinavir–ritonavir should be approached
(Ang et al. 2020). cautiously due to potential drug interactions that could raise
Recent advances in COVID‑19‑induced liver injury: causes, diagnosis, and management

tenofovir levels. In such instances, suitable alternatives must for the accomplishment of liver transplantation in the face
be explored (Kariyawasam et al. 2022). of pandemic constraints. It is essential to underscore that
a patient's eligibility for liver transplantation should not
Surgical management be solely dependent on PCR test outcomes, given that the
COVID-19 PCR test can show positive results even in the
The COVID-19 pandemic has had a global impact on sur- absence of an active infection (Nickerson et al. 2021; COV-
gical services, including routine surgeries for various con- IDSurg and GlobalSurg 2022).
ditions, both benign and malignant. The consequences of
surgery and anesthesia can be detrimental to COVID-19 Supportive management
patients. Moreover, healthcare workers have faced increased
exposure risks and reduced clinical training due to the post- Liver involvement is a common occurrence in children with
ponement of regular surgeries. While surgeries for hepato- COVID-19 infection. However, in the majority of cases, any
cellular carcinoma (HCC) patients should not be delayed, abnormalities in liver function are mild and typically resolve
precautionary measures like prior vaccination, appropriate without the need for specific treatment. The approach to
timing for previously infected patients, and thromboprophy- managing hepatic involvement in COVID-19 infection is pri-
laxis are essential to minimize complications (Al-Jabir et al. marily supportive, similar to how inflammatory liver issues
2020). are managed in other viral illnesses. This entails stabiliz-
Patients undergoing surgery are particularly susceptible ing vital signs, addressing fluid and electrolyte imbalances,
to pulmonary issues and venous thromboembolism, neces- and ensuring that the liver receives adequate oxygenation.
sitating preventive measures. Compulsory preoperative It is crucial to prevent hypo-perfusion and hypoxia, particu-
screening for SARS-CoV-2 and the adoption of COVID- larly in patients experiencing respiratory distress. Continual
19-free pathways have demonstrated their advantages, even improvement in the systemic inflammatory status is expected
though the need for preoperative isolation remains a subject to contribute to the recovery of liver function. In certain
of debate. During periods of societal restrictions, it is essen- situations, a combination of medications may be necessary
tial to enhance the resilience of elective surgery systems depending on the severity of lung injury and the involvement
to avoid postponements in cancer surgeries (Abahuje et al. of other organs (Wu and Yang 2020).
2021). It is crucial to avoid hepatotoxic medications, and spe-
COVID-19 has significantly impacted liver transplanta- cific virus-targeted therapies are currently used only in
tion worldwide. Individuals requiring liver transplants face clinical trial settings. Overall, the approach to managing
challenges in receiving preoperative, surgical, and post- liver involvement in COVID-19 infection is supportive and
operative care due to the pandemic’s strain on healthcare focuses on maintaining overall health and avoiding medica-
facilities. Limited resources like ICU beds and ventilators, tions that could potentially harm the liver (Bitar et al. 2023).
along with the need to exclude COVID-19-positive donors,
pose obstacles for transplantation programs. Immunosup- Nutritional management
pressive therapy in transplant recipients and potential drug
interactions increase their vulnerability to COVID-19, war- Appropriate nutrition is vital, especially for children endur-
ranting enhanced protective measures (Glasbey et al. 2021). ing prolonged critical illnesses. These children are at an
Professional associations like the European Association for increased risk of developing malnutrition, which can con-
the Study of the Liver (EASL) and AASLD advise against tribute to higher rates of morbidity and mortality. As a result,
postponing liver transplants during the pandemic. Initial data it is recommended to commence early feeding through
suggest that immunosuppressed liver transplant patients do either oral consumption or nasogastric tube feeding for
not face a higher risk of COVID-19 infection. However, fur- these patients. Enteral nutrition, which involves providing
ther research is necessary to solidify this in clinical practice nutrients through the gastrointestinal tract, is preferred over
(Meydanli and Akilli 2021). parenteral nutrition (intravenous feeding) unless severe gas-
In Italy, liver transplantation activities persisted through- trointestinal dysfunction is present (Mcgonagle 2020).
out the COVID-19 pandemic, although there was a 25% In the acute phase of the illness, energy needs do not need
decrease in procured organs during the initial four weeks to surpass the child's resting energy expenditure. According
of the outbreak. Both living and deceased donor transplants to the European Society of Pediatric and Neonatal Intensive
were carried out, and an elevated mortality rate was noted Care, the recommended approach is to gradually increase
among patients on the transplant waiting list. (Boulton caloric intake toward the target caloric requirement, based
2021). Thorough examination of symptomatic patients and on the patient’s tolerance and overall condition. Enteral
extensive screening of transplant donors for SARS-CoV-2 nutritional support should be continued as long as neces-
RNA, in conjunction with collaborative efforts, have allowed sary until the child can reliably take in adequate nutrition
 S. A. Antar et al.

through oral intake, supporting their physical and nutritional proposes primary prophylaxis with beta-blockers as a poten-
rehabilitation (Mcgonagle 2020) as shown in Fig. 9. tial alternative to conducting screening endoscopy for spe-
cific high-risk patients (Repici et al. 2020). Regarding liver
Interventional procedures biopsy, EASL recommends postponing it in specific situa-
tions, such as NAFLD and chronic viral hepatitis, and sug-
Upper endoscopy is viewed as a procedure that generates gests performing it only when there are markedly elevated
aerosols, which presents a significant risk of transmitting transaminases of unknown origin or when there are suspi-
infections to healthcare personnel. (Sultan et al. 2020). The cious liver masses. These guidelines are aimed at safeguard-
presence of COVID-19 virus RNA in a patient’s stool on the ing the well-being of both patients and healthcare workers
7th day of illness implies the potential for feco-oral trans- during endoscopic procedures in the context of the COVID-
mission, classifying upper endoscopy and colonoscopy as 19 pandemic (D’amico et al. 2020a), as shown in Table 6.
procedures with an increased risk of infection transmission
(Mcgonagle 2020). To reduce the risk, numerous endoscopy Prognosis for COVID‑19
facilities have restricted their operations to urgent and high-
risk cases, such as instances involving gastrointestinal bleed- The prognosis for children with COVID-19 and deranged
ing and bacterial cholangitis. Protective personal equipment hepatic function is generally poor, as direct liver injury is
(PPE) is provided to both endoscopy unit personnel and related to worse outcomes. increase levels of liver enzymes,
patients to reduce the risk of infection. Some organizations, such as transaminases (AST and ALT), and low levels of
such as EASL, AASLD, APSDE, AGA, and the American albumin are more common in severe cases of COVID-19
Society of Gastrointestinal Endoscopy, have issued guide- and are associated with a higher risk of poor effects (Mcg-
lines to minimize the risk of COVID-19 transmission during onagle 2020).
endoscopic procedures. These include risk assessments, pre- Studies on COVID-19 outcomes in children with chronic
screening of patients, use of N95 masks, and double gloves, liver disease (CLD) are limited and have yielded mixed
and performing procedures in negative pressure rooms for results. Some studies have suggested that CLD may not sig-
suspected COVID-19-positive patients (Chiu et al. 2020). nificantly affect outcomes, while others indicate that it can
Regarding variceal screening, EASL recommends evalu- markedly impact disease severity and mortality (Abdulla
ating risks based on Baveno VI criteria, whereas AASLD et al. 2020). A recent extensive meta-analysis has determined

Fig. 9  Different management for patients and risk groups with COVID-19
Table 6  Management of different conditions and benefits from the treatment in risk groups with COVID-19
Situation Tests and monitoring Medication considerations Non-medical recommenda- Management Benefits
tions

No Existing Liver Condition - Conduct baseline liver - Administer medications - Minimize exposure to - Continuous antiviral medi- - Avoid HBV reactivation
function tests (LFTs) on carefully to avoid interac- COVID-19 cine - Minimize risks during gluco-
admission tions - Consider COVID-19 vac- - Prevent reactivation of HBV, corticoid therapy
- Regularly repeat LFTs dur- - Monitor for possible medica- cination especially during glucocor-
ing hospital stay tion effects - Prioritize virus protection ticoid treatment
Existing Liver Condition - Perform baseline LFTs dur- - Exercise caution when using - Minimize COVID-19 - Delay initiation of antiviral - Reduce complications
ing admission medications due to potential exposure therapy - Lower secondary infections
- Regularly repeat LFTs while interactions - Promptly manage the exist- - Monitor immunocompro-
in the hospital - Monitor medication effects ing liver condition mised status
- Consider COVID-19 vac- - Adjust/continue immuno-
cination suppressants
- Protect against the virus - Apply short-term steroid
therapy
- Avoid boosted protease
inhibitors
- Delay fewer emergent liver
transplants
- Vaccination
Liver Transplant Recipients - Test for COVID-19 before - Use medications carefully - Do not delay liver trans- - Monitor immunocompromised status
liver transplant due to possible interactions plants due to COVID-19 - Monitor liver biochemical indicators
- Monitor for medication - Prioritize COVID-19 vac- - Adjust/continue immunosuppressants
effects cination - Apply short-term steroid therapy
- Consider additional vaccine - Avoid boosted protease inhibitors
Recent advances in COVID‑19‑induced liver injury: causes, diagnosis, and management

doses - Delay fewer emergent liver transplants

- Vaccination
Liver Biochemical Abnor- - - Inhibit viral replication - Apply drugs with dual - Treat primary disease
malities - Lower inflammation function - Provide antiviral and supportive treatment
- Enhance immunity - Monitor and assess adverse - Inhibit viral replication
events of potential drugs - Decrease inflammation
- Improve immunity
Table 6  (continued)
Situation Tests and monitoring Medication considerations Non-medical recommenda- Management Benefits
tions

Liver Dysfunction - Utilize medications with -Inhibit systemic inflamma- - Strengthen respiratory -Same as Monitoring - Same as medical considera-
dual purposes tion support tions
- Continuously monitor and -Protect liver functions - Circulatory support
evaluate potential drug side
effects
Acute Liver Injury - Analyze and judge the causes - Protect the liver
- Monitor markers of liver -Reduce enzyme levels
function and Prothrombin
Activity (PTA)
-Apply drugs with dual func-
tion
Acute Liver Failure - Vigilant monitoring - Prevent life-threatening
- Administer prebiotics and complications
probiotics to preserve - Improve intestinal health
balance in the intestinal
microecology
- Take measures to prevent
bacterial infections
Cytokine Storms -Strengthen respiratory sup- - Prevent severe complications -
port and comorbidity worsening
Microcirculation Ischemia - Circulatory support
Hypoxia
S. A. Antar et al.
Recent advances in COVID‑19‑induced liver injury: causes, diagnosis, and management

that chronic liver disease (CLD) exerts a notable impact on prioritize the vaccination of children awaiting liver trans-
the clinical outcomes of individuals with COVID-19. Con- plantation. (Papa et al. 2023). The selection of the vaccine
ditions, such as NAFLD, metabolic-associated fatty liver should be based on the prevailing viral strain and the guid-
disease, and cirrhosis, exhibit the highest odds ratios for ance provided by the local infectious disease authorities. It
disease severity. Specifically, cirrhosis has been recognized is imperative to ensure that the child receives both vaccine
as a significant risk factor for hospitalization, admission to doses following the prescribed protocols, irrespective of the
intensive care, and mortality (Tume et al. 2020). In children time available before the transplantation. It is not recom-
diagnosed with multisystem inflammatory syndrome (MIS- mended to conduct routine serology tests to assess the pres-
C), the majority experience complete clinical recovery, and ence of COVID-19 virus antibodies (Fix et al. 2021).
the mortality rate is low. Nonetheless, in severe cases that
involve acute liver failure (ALF) necessitating intensive care
interventions, the risk of mortality is notably elevated (Oba
et al. 2020). Conclusions
Overall, children with COVID-19 generally experience
milder disease compared to adults, but those with liver In conclusion, the impact of the COVID-19 pandemic has
involvement and underlying liver conditions may have a underscored the virus’s ability to infiltrate and replicate
higher risk of dangerous outcomes. Proper management and within crucial organs, including the lungs, heart, brain,
monitoring of liver function are crucial in improving the spleen, gastrointestinal tract, and liver, as evidenced by
prognosis for these patients (Calitri et al. 2021). emerging research. This understanding of viral entry and
distribution emphasizes the urgency for targeted therapies.
Prevention of COVID‑19 The potential of immune-based treatments, especially con-
sidering the virus’s varying effects on different age groups,
Preventative measures should be put in place to protect vul- presents a promising avenue for personalized interventions.
nerable patients who are at risk of being exposed to SARS- Notably, COVID-19 patients often exhibit abnormal liver
CoV-2, as they are more susceptible to developing severe enzyme levels, indicative of varied contributors to liver
illness. damage, such as hypoxia, medications, direct viral impact,
and infections in intensive care settings. A complex array
General public health measures of pathways, including viral infection and hyperinflamma-
tory response, contributes to liver injury. This complexity is
These preventive measures include general public health mirrored in the diverse hepatic dysfunctions experienced by
practices, such as maintaining physical distancing, practic- individuals. Temporal fluctuations in hepatic parameters are
ing good hygiene, and preventing contact with the virus. observed, with severe cases and pre-existing liver conditions
These measures are crucial not only for healthy children magnifying the risk of unfavorable outcomes. This accentu-
and the normal population but also for children with under- ates the need for tailored care and personalized therapies for
lying liver conditions. By adhering to these measures, we chronic liver disease patients, especially as they navigate
can reduce the risk of transmission and protect those who the intricacies of COVID-19-related complications. As the
are more vulnerable to severe outcomes from COVID-19, pandemic evolves, the importance of individualized care
including children with liver conditions (Bitar et al. 2023). and refined treatment pathways for chronic liver diseases
becomes more evident. This review highlights the neces-
Vaccinations sity for patient-centered approaches that acknowledge the
intricate interplay between COVID-19 and liver health. By
Children who have Chronic Liver Disease (CLD) or have recognizing these complexities, healthcare professionals and
undergone Liver Transplantation (LT) are recommended to researchers can guide informed decisions that shape the pre-
receive the COVID-19 vaccination as it is generally con- sent and future of liver disease management.
sidered safe for this group. However, in adults with non-
Acknowledgment None.
cirrhotic compensated or decompensated cirrhosis, the
production of positive SARS-CoV-2 neutralizing antibod- Author contributions Conceptualization and supervision: Ahmed A.
ies following vaccination was observed to be lower in com- Al-Karmalawy; data curation: Samar A. Antar, Nada A. Ashour, Amir
parison to individuals without liver conditions (Wang 2021). O Hamouda, Ayman M. Noreddin, and Ahmed A. Al‐Karmalawy;
visualization: Nada A. Ashour and Ahmed A. Al‐Karmalawy; writ-
Nevertheless, alternate studies indicate that individuals with ing–review & editing: Samar A. Antar, Nada A. Ashour, Amir O Ham-
liver disease who have been vaccinated against COVID-19 ouda, Ayman M. Noreddin, and Ahmed A. Al‐Karmalawy. Finally,
have an extremely low likelihood of infection and COVID- all authors revised and approved the final submitted version of the
19-associated mortality. Additionally, it is recommended to manuscript.
 S. A. Antar et al.

Funding None. A.a.J.I.N. (2022). Neutrophil–Lymphocyte ratio is associated

with poor clinical outcome after mechanical thrombectomy in
Data availability The authors confirm that the data supporting the find- stroke in patients with COVID-19. 15910199221093896
ings of this review are available within the article. Albillos A, Lario M, Álvarez-Mon M (2014) Cirrhosis-associated
immune dysfunction: distinctive features and clinical relevance.
Declarations J Hepatol 61:1385–1396
Alguwaihes, A.M., Al-Sofiani, M.E., Megdad, M., Albader, S.S.,
Conflict of interest The authors declare no conflict of interest. Alsari, M.H., Alelayan, A., Alzahrani, S.H., Sabico, S., Al-
Daghri, N.M., and Jammah, A.a.J.C.D. (2020). Diabetes and
Covid-19 among hospitalized patients in Saudi Arabia: a single-
centre retrospective study. 19, 1–12
Aljuhani A, Ahmed HEA, Ihmaid SK, Omar AM, Althagfan SS,
References Alahmadi YM, Ahmad I, Patel H, Ahmed S, Almikhlafi MA,
El-Agrody AM, Zayed MF, Turkistani SA, Abulkhair SH,
Abahuje E, Abbas A, Maksoud M, Abdelhady A, Abdelhamid S, Ott- Almaghrabi M, Salama SA, Al-Karmalawy AA, Abulkhair
lakán A (2021) BJS commission on surgery and perioperative HS (2022) In vitro and computational investigations of novel
care post-COVID-19. Br J Surg 108:1162–1180 synthetic carboxamide-linked pyridopyrrolopyrimidines with
Abdallah AE, Alesawy MS, Eissa SI, El-Fakharany EM, Kalaba MH, potent activity as SARS-CoV-2-MPro inhibitors. RSC Adv
Sharaf MH, Abo Shama NM, Mahmoud SH, Mostafa A, Al- 12:26895–26907
Karmalawy AA, Elkady H (2021) Design and synthesis of new Alnajjar R, Mostafa A, Kandeil A, Al-Karmalawy AA (2020) Molec-
4-(2-nitrophenoxy)benzamide derivatives as potential antiviral ular docking, molecular dynamics, and in vitro studies reveal
agents: molecular modeling and in vitro antiviral screening. New the potential of angiotensin II receptor blockers to inhibit the
J Chem 45:16557–16571 COVID-19 main protease. Heliyon 6:e05641
Abdelgawad SM, El Hassab MA, Abourehab MA, Elkaeed EB, Alqahtani SA, Schattenberg JM (2020) Liver injury in COVID-19:
Eldehna WM (2022) Olive Leaves as a Potential Phytotherapy in The current evidence. United European Gastroenterology Journal
the Treatment of COVID-19 Disease. A Mini-Review. Frontiers 8:509–519
in Pharmacology 13:879118 Amaddeo G, Brustia R, Allaire M, Lequoy M, Hollande C, Regnault
Abdulla, S., Hussain, A., Azim, D., Abduallah, E.H., Elawamy, H., H, Blaise L, Ganne-Carrie N, Séror O, Larrey E (2021) Impact
Nasim, S., Kumar, S., Naveed, H., and Abdulla, S.A. (2020). of COVID-19 on the management of hepatocellular carcinoma
COVID-19-induced hepatic injury: a systematic review and in a high-prevalence area. JHEP Reports 3:100199
meta-analysis. Cureus 12 do Ang TL, Li JW, Vu CKF, Ho GH, Chang JPE, Chong CH, Chua TS,
Abo Elmaaty A, Hamed MIA, Ismail MI, Elkaeed B, E., S. Abulkhair, Ong DEH, Yip BCH, Gwee KA (2020) Chapter of Gastroenter-
H., Khattab, M., and Al-Karmalawy, A.A. (2021) Computational ologists professional guidance on risk mitigation for gastroin-
Insights on the Potential of Some NSAIDs for Treating COVID- testinal endoscopy during COVID-19 pandemic in Singapore.
19: Priority Set and Lead Optimization. Molecules 26:3772 Singapore Med J 61:345
Acosta-Ampudia, Y., Monsalve, D., Rojas, M., Rodríguez, Y., Esteban, Antoniak S (2018) The coagulation system in host defense. Research
J., and Salazar-Uribe, J. (2020). The COVID-19 resource centre and Practice in Thrombosis and Haemostasis 2:e12109
is hosted on Elsevier Connect, the Company’s Public News and Antoniak S, Mackman N (2014) Multiple roles of the coagulation pro-
Information; 2020. January)[Google Scholar] tease cascade during virus infection. Blood, the Journal of the
Adeboye, A., Alkhatib, D., Butt, A., Yedlapati, N., and Garg, N.J.D. American Society of Hematology 123:2605–2613
(2022). A Review of the Role of Imaging Modalities in the Eval- Arabi YM, Mandourah Y, Al-Hameed F, Sindi AA, Almekhlafi GA,
uation of Viral Myocarditis with a Special Focus on COVID- Hussein MA, Jose J, Pinto R, Al-Omari A, Kharaba A, Almot-
19-Related Myocarditis. 12, 549 airi A, Khatib KA, Alraddadi B, Shalhoub S, Abdulmomen A,
Ahmad FB, Cisewski JA, Miniño A, Anderson RNJM, Report MW Qushmaq I, Mady A, Solaiman O, Al-Aithan AM, Al-Raddadi
(2021) Provisional mortality data—united states 2020. MMWR R, Ragab A, Balkhy HH, Harthy AA, Deeb AM, Mutairi HA,
Morb Mortal Wkly Rep 70:519 Al-Dawood A, Merson L, Hayden FG, Fowler RA (2018) Cor-
Al-Jabir A, Kerwan A, Nicola M, Alsafi Z, Khan M, Sohrabi C, O’neill, ticosteroid Therapy for Critically Ill Patients with Middle East
N., Iosifidis, C., Griffin, M., and Mathew, G. (2020) Impact of the Respiratory Syndrome. Am J Respir Crit Care Med 197:757–767
Coronavirus (COVID-19) pandemic on surgical practice-Part 2 Ashour NA, Elmaaty AA, Sarhan AA, Elkaeed EB, Moussa AM,
(surgical prioritisation). Int J Surg 79:233–248 Erfan IA, Al-Karmalawy AA (2022) A Systematic Review of
Al-Karmalawy AA, Alnajjar R, Dahab M, Metwaly A, Eissa I (2021a) the Global Intervention for SARS-CoV-2 Combating: From
Molecular docking and dynamics simulations reveal the potential Drugs Repurposing to Molnupiravir Approval. Drug Des Dev
of anti-HCV drugs to inhibit COVID-19 main protease. Pharma- Ther 16:685
ceutical Sciences 27:S109–S121 Atuahene S, Kong Y, Bentum-Micah GJQE, Studies M (2020) Covid19
Al-Karmalawy AA, Dahab MA, Metwaly AM, Elhady SS, Elkaeed pandemic, economic loses and education sector management.
EB, Eissa IH, Darwish KM (2021b) Molecular Docking and Quantit Eco Manage Stu 1(2):103–109
Dynamics Simulation Revealed the Potential Inhibitory Activity Atum M, Boz AaE, Çakır B, Karabay O, Köroğlu M, Öğütlü A,
of ACEIs Against SARS-CoV-2 Targeting the h ACE2 Receptor. Alagöz GJ (2020) Evaluation of conjunctival swab PCR results
Front Chem 9:661230 in patients with SARS-CoV-2 infection. Ocu Immunol Infla
Al-Karmalawy AA, Farid MM, Mostafa A, Ragheb AY, Mahmoud 28:745–748
S, Shehata M, Shama NMA, Gaballah M, Mostafa-Hedeab G, Ayenigbara IO, Adeleke OR, Ayenigbara GO, Adegboro JS, Olofin-
Marzouk MM (2021c) Naturally Available Flavonoid Aglycones tuyi OO (2020) COVID-19 (SARS-CoV-2) pandemic: fears, facts
as Potential Antiviral Drug Candidates against SARS-CoV-2. and preventive measures. Germs. https://d​ oi.o​ rg/1​ 0.1​ 8683/g​ erms.​
Molecules 26:6559 2020.​1208
Al-Mufti, F., Khandelwal, P., Sursal, T., Cooper, J.B., Feldstein, E., Bajaj JS, Garcia-Tsao G, Biggins SW, Kamath PS, Wong F, Mcgeorge
Amuluru, K., Moré, J.M., Tiwari, A., Singla, A., and Dmytriw, S, Shaw J, Pearson M, Chew M, Fagan A (2021) Comparison of
Recent advances in COVID‑19‑induced liver injury: causes, diagnosis, and management

mortality risk in patients with cirrhosis and COVID-19 compared Chen X, Jiang Q, Ma Z, Ling J, Hu W, Cao Q, Mo P, Yao L, Yang
with patients with cirrhosis alone and COVID-19 alone: multi- R, Gao S (2020) Clinical characteristics of hospitalized patients
centre matched cohort. Gut 70:531–536 with SARS-CoV-2 and hepatitis B virus co-infection. Virologica
Banales JM, Huebert RC, Karlsen T, Strazzabosco M, Larusso NF, Sinica 35:842–845
Gores GJ (2019) Cholangiocyte pathobiology. Nat Rev Gastro- Cheng Y-W, Chao T-L, Li C-L, Chiu M-F, Kao H-C, Wang S-H, Pang
enterol Hepatol 16:269–281 Y-H, Lin C-H, Tsai Y-M, Lee W-HJ (2020) Furin inhibitors block
Beigee FS, Toutkaboni MP, Khalili N, Nadji SA, Dorudinia A, Rezaei SARS-CoV-2 spike protein cleavage to suppress virus production
M, Askari E, Farzanegan B, Marjani M, Rafiezadeh AJ (2020) and cytopathic effects. Cell Rep 33:108254
Diffuse alveolar damage and thrombotic microangiopathy are the Chiu PWY, Ng SC, Inoue H, Reddy DN, Hu EL, Cho JY, Ho LK,
main histopathological findings in lung tissue biopsy samples of Hewett DG, Chiu H-M, Rerknimitr R (2020) Practice of endos-
COVID-19 patients. Pathol-Res Prac 216:153228 copy during COVID-19 pandemic: position statements of the
Bertolini A, Van De Peppel IP, Bodewes FA, Moshage H, Fantin A, Asian Pacific Society for Digestive Endoscopy (APSDE-COVID
Farinati F, Fiorotto R, Jonker JW, Strazzabosco M, Verkade HJ statements). Gut 69:991–996
(2020) Abnormal liver function tests in patients with COVID- Cichoż-Lach H, Michalak AJ (2021) Liver injury in the era of COVID-
19: relevance and potential pathogenesis. Hepatology 72:1864 19. WJG 27:377
Bitar R, Elghoudi AA, Rawat D, Azaz A, Miqdady M, Narchi H (2023) Clinton JW, Kiparizoska S, Aggarwal S, Woo S, Davis W, Lewis JH
COVID-19-induced liver injury in infants, children, and adoles- (2021) Drug-induced liver injury: highlights and controversies
cents. World Journal of Clinical Pediatrics 12:57 in the recent literature. Drug Saf 44:1125–1149
Boettler T, Marjot T, Newsome PN, Mondelli MU, Maticic M, Cordero Cojocaru, C., Cojocaru, E., Turcanu, A.M., Zaharia, D.C.J.E., and
E, Jalan R, Moreau R, Cornberg M, Berg T (2020) Impact of Medicine, T. (2022). Clinical challenges of SARS‑CoV‑2 vari-
COVID-19 on the care of patients with liver disease: EASL- ants. 23, 1–9.
ESCMID position paper after 6 months of the pandemic. JHEP Colmenero J, Rodríguez-Perálvarez M, Salcedo M, Arias-Milla A,
Reports 2:100169 Muñoz-Serrano A, Graus J, Nuño J, Gastaca M, Bustamante-
Bollipo S, Kapuria D, Rabiee A, Ben-Yakov G, Lui RN, Lee HW, Schneider J, Cachero A (2021) Epidemiological pattern, inci-
Kumar G, Siau K, Turnes J, Dhanasekaran R (2020) One world, dence, and outcomes of COVID-19 in liver transplant patients.
one pandemic, many guidelines: management of liver diseases J Hepatol 74:148–155
during COVID-19. Gut 69:1369–1372 Contini C, Di Nuzzo M, Barp N, Bonazza A, De Giorgio R, Tognon M,
Bong C-L, Brasher C, Chikumba E, Mcdougall R, Mellin-Olsen J, Rubino SJ (2020) The novel zoonotic COVID-19 pandemic: An
Enright AJ (2020) The COVID-19 pandemic: effects on low-and expected global health concern. J Infect Dev Ctries 14:254–264
middle-income countries. Anesthesia Analgesia. https://​doi.​org/​ Cosentino F, Moscatt V, Marino A, Pampaloni A, Scuderi D, Ceccarelli
10.​1213/​ANE.​00000​00000​004846 M, Benanti F, Gussio M, Larocca L, Boscia VJ (2022) Clini-
Boulton AJ (2021) Death following pulmonary complications of sur- cal characteristics and predictors of death among hospitalized
gery before and during the SARS-CoV-2 pandemic. Br J Surg patients infected with SARS-CoV-2 in Sicily, Italy: A retrospec-
108:1448–1464 tive observational study. Biomed Rep 16:1–8
Bourgonje AR, Abdulle AE, Timens W, Hillebrands JL, Navis GJ, Covidsurg C, Globalsurg C (2022) SARS-CoV-2 infection and venous
Gordijn SJ, Bolling MC, Dijkstra G, Voors AA, Osterhaus ADJT thromboembolism after surgery: an international prospective
(2020) Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 cohort study. Anaesthesia 77:28–39
and the pathophysiology of coronavirus disease 2019 (COVID- D’amico F, Baumgart DC, Danese S, Peyrin-Biroulet L (2020a) Diar-
19). J Pathol. https://​doi.​org/​10.​1002/​path.​5471 rhea during COVID-19 infection: pathogenesis, epidemiol-
Cai Q, Huang D, Yu H, Zhu Z, Xia Z, Su Y, Li Z, Zhou G, Gou J, Qu ogy, prevention, and management. Clin Gastroenterol Hepatol
JJ (2020) COVID-19: Abnormal liver function tests. J Hepatol 18:1663–1672
73:566–574 Da BL, Im GY, Schiano TD (2020) Coronavirus disease 2019 hango-
Calitri C, Fumi I, Ignaccolo MG, Banino E, Benetti S, Lupica MM, ver: a rising tide of alcohol use disorder and alcohol-associated
Fantone F, Pace M, Garofalo F (2021) Gastrointestinal involve- liver disease. Hepatology 72:1102–1108
ment in paediatric COVID-19—From pathogenesis to clinical Dawood RM, Salum GM, Abd El-Meguid MJ (2021) The Impact of
management: A comprehensive review. World J Gastroenterol COVID-19 on Liver Injury: COVID-19 and Liver Injury. Am J
27:3303 Med Sci. https://​doi.​org/​10.​1016/j.​amjms.​2021.​11.​001
Can E, Oğlak SC, Ölmez F (2022) Abnormal liver function tests in Desai A, Sachdeva S, Parekh T, Desai RJJGO (2020) COVID-19 and
pregnant patients with COVID-19—a retrospective cohort study cancer: lessons from a pooled meta-analysis. JCO Global Oncol.
in a tertiary center. Ginekol Pol 93:151–157 https://​doi.​org/​10.​1200/​GO.​20.​00097
Cao X (2020) COVID-19: immunopathology and its implications for Dhama K, Patel SK, Pathak M, Yatoo MI, Tiwari R, Malik YS, Singh
therapy. Nat Rev Immunol 20:269–270 R, Sah R, Rabaan AA, Bonilla-Aldana DKJ (2020) An update
Cattaneo AMJFV (2022) Reviewing findings on the polypeptide on SARS-CoV-2/COVID-19 with particular reference to its clini-
sequence of the SARS-CoV-2 S-protein to discuss the origins of cal pathology, pathogenesis, immunopathology and mitigation
the virus. Futur Virol 17:393–402 strategies. Travel Med Infect Dis 37:101755
Cecchini R, Cecchini ALJMH (2020) SARS-CoV-2 infection patho- El-Azab MF, Al-Karmalawy AA, Antar SA, Hanna PA, Tawfik KM,
genesis is related to oxidative stress as a response to aggression. Hazem RM (2022) A novel role of Nano selenium and sildenafil
Med Hypotheses 143:110102 on streptozotocin-induced diabetic nephropathy in rats by modu-
Chattopadhyay I, Shankar EM (2021) SARS-CoV-2-indigenous micro- lation of inflammatory, oxidative, and apoptotic pathways. Life
biota nexus: does gut microbiota contribute to inflammation and Sci 303:120691
disease severity in COVID-19? Front Cell Infect Microbiol 11:96 El-Demerdash A, Al-Karmalawy AA, Abdel-Aziz TM, Elhady SS,
Chen J, Hu P, Zhou T, Zheng T, Zhou L, Jiang C, Pei XJBP (2018) Darwish KM, Hassan AHE (2021) Investigating the struc-
Epidemiology and clinical characteristics of acute respiratory ture–activity relationship of marine natural polyketides as
tract infections among hospitalized infants and young children promising SARS-CoV-2 main protease inhibitors. RSC Adv
in Chengdu. West China 2009–2014(18):1–8 11:31339–31363
 S. A. Antar et al.

El-Masry RM, Al-Karmalawy AA, Alnajjar R, Mahmoud SH, Mostafa Flister KFT, Pinto B.a.S., França L.M., Coêlho C.F.F., Dos Santos
A, Kadry HH, Abou-Seri SM, Taher AT (2022) Newly synthe- P.C., Vale C.C., Kajihara D., Debbas V., Laurindo F.R.M., De
sized series of oxoindole–oxadiazole conjugates as potential anti- Andrade Paes, A.M.J. (2018) Long-term exposure to high-
SARS-CoV-2 agents: in silico and in vitro studies. New J Chem sucrose diet down-regulates hepatic endoplasmic reticulum-
46:5078–5090 stress adaptive pathways and potentiates de novo lipogenesis
El Gizawy HA, Boshra SA, Mostafa A, Mahmoud SH, Ismail MI, Als- in weaned male mice. J Nutr Biochem 62:155–166
fouk AA, Taher AT, Al-Karmalawy AA (2021) Pimenta dioica Forbes JD, Van Domselaar G, Bernstein CN (2016) The gut micro-
(L) Merr Bioactive Constituents Exert Anti-SARS-CoV-2 and biota in immune-mediated inflammatory diseases. Front Micro-
Anti-Inflammatory Activities: Molecular Docking and Dynam- biol 7:1081
ics, In Vitro, and In Vivo Studies. Molecules 26:5844 Frediansyah A, Nainu F, Dhama K, Mudatsir M, Harapan H (2021)
Elagawany M, Elmaaty AA, Mostafa A, Abo Shama NM, Santali EY, Remdesivir and its antiviral activity against COVID-19: A
Elgendy B, Al-Karmalawy AA (2022) Ligand-based design, systematic review. Clin Epidemiol Global Health 9:123–127
synthesis, computational insights, and in vitro studies of novel Funk, C., and Tyson, A. (2020). Intent to get a COVID-19 vaccine
N-(5-Nitrothiazol-2-yl)-carboxamido derivatives as potent inhib- rises to 60% as confidence in research and development process
itors of SARS-CoV-2 main protease. J Enzyme Inhib Med Chem increases. Pew Research Center 3.
37:2112–2132 Gadour E, Shrwani K, Hassan ZJWJG, Hepatol, and Endoscop,
Elebeedy D, Badawy I, Elmaaty AA, Saleh MM, Kandeil A, Ghanem (2020) Covid-19 induced hepatitis (CIH), definition and diag-
A, Kutkat O, Alnajjar R, Abd El Maksoud AI, Al-Karmalawy nostic criteria of a poorly understood new clinical syndrome.
AA (2022) In vitro and computational insights revealing the Gut 1:1–6
potential inhibitory effect of Tanshinone IIA against influenza Gao YD, Ding M, Dong X, Zhang JJ, Kursat Azkur A, Azkur D, Gan
A virus. Comput Biol Med 141:105149 H, Sun YL, Fu W, Li WJA (2021) Risk factors for severe and
Eljilany, I., and Elzouki, A.-N. (2020). D-dimer, fibrinogen, and IL-6 in critically ill COVID-19 patients: a review. Allergy 76:428–455
COVID-19 patients with suspected venous thromboembolism: a Geier MR, Geier, D.a.J.M.H. (2020) Respiratory conditions in coro-
narrative review. Vascular health and risk management, 455–462 navirus disease 2019 (COVID-19): Important considerations
Elmaaty AA, Alnajjar R, Hamed MIA, Khattab M, Khalifa MM, Al- regarding novel treatment strategies to reduce mortality. Med
Karmalawy AA (2021a) Revisiting activity of some glucocor- Hypotheses 140:109760
ticoids as a potential inhibitor of SARS-CoV-2 main protease: Glasbey JC, Nepogodiev D, Simoes JF, Omar O, Li E, Venn ML, Abou
theoretical study. RSC Adv 11:10027–10042 Chaar MK, Capizzi V, Chaudhry D, Desai A (2021) Elective
Elmaaty AA, Darwish KM, Khattab M, Elhady SS, Salah M, Hamed cancer surgery in COVID-19–free surgical pathways during the
MIA, Al-Karmalawy AA, Saleh MM (2021b) In a search for SARS-CoV-2 pandemic: an international, multicenter, compara-
potential drug candidates for combating COVID-19 computa- tive cohort study. J Clin Oncol 39:66
tional study revealed salvianolic acid B as a potential therapeu- Gu Z-C, Wang J, Zhang C, Zhao B, Li Z-LJ (2022) Non-Vitamin K
tic targeting 3CLpro and spike proteins. J Biomole Struct Dyn. Antagonist Oral Anticoagulants (NOACs) do not Increase the
https://​doi.​org/​10.​1080/​07391​102.​2021.​19182​56 Risk of Hepatic Impairment in Patients with Non-Valvular Atrial
Elmaaty AA, Eldehna WM, Khattab M, Kutkat O, Alnajjar R, El- Fibrillation: Insights from Multi-Source Medical Data. Reviews
Taweel AN, Al-Rashood ST (2022) Anticoagulants as Potential Cardiovasc Med 23:98
SARS-CoV-2 Mpro Inhibitors for: In Vitro, Molecular Dock- Guan W-J, Ni Z-Y, Hu Y, Liang W-H, Ou C-Q, He J-X, Liu L, Shan H,
ing, Molecular Dynamics, DFT, and SAR Studies. Int J Mol Sci. Lei C-L, Hui DS (2020) Clinical characteristics of coronavirus
https://​doi.​org/​10.​3390/​ijms2​32012​235 disease 2019 in China. N Engl J Med 382:1708–1720
Eskander, A.A. Primary Hepatic Carcinoid tumor: Dynamic CT and Hamed MIA, Darwish KM, Soltane R, Chrouda A, Mostafa A, Abo
MRI findings. http://mc. manuscriptcentral. com/uqumj, 97. Shama NM, Elhady SS, Abulkhair HS, Khodir AE, Elmaaty
Eweas AF, Osman H-EH, Naguib IA, Abourehab MA, Abdel-Moneim AA, Al-Karmalawy AA (2021) β-Blockers bearing hydroxyeth-
AS (2022) Virtual Screening of Repurposed Drugs as Potential ylamine and hydroxyethylene as potential SARS-CoV-2 Mpro
Spike Protein Inhibitors of Different SARS-CoV-2 Variants: inhibitors: rational based design, in silico, in vitro, and SAR stud-
Molecular Docking Study. Curr Issues Mol Biol 44:3018–3029 ies for lead optimization. RSC Adv 11:35536–35558
Fan Z, Chen L, Li J, Cheng X, Yang J, Tian C, Zhang Y, Huang S, Harwood R, Yan H, Da Camara NT, Smith C, Ward J, Tudur-Smith
Liu Z, Cheng J (2020) Clinical features of COVID-19-related C, Linney M, Clark M, Whittaker E, Saatci DJE (2022) Which
liver functional abnormality. Clin Gastroenterol Hepatol children and young people are at higher risk of severe disease
18:1561–1566 and death after hospitalisation with SARS-CoV-2 infection in
Fawzy, A. Genetic Polymorphisms of Glutathione S-Transferase Genes children and young people: A systematic review and individual
and Risk of Colorectal Cancer in the Saudi Population. http://mc. patient meta-analysis. EClinicalMedicine 44:101287
manuscriptcentral. com/uqumj, 61. Hashemi N, Viveiros K, Redd WD, Zhou JC, Mccarty TR, Bazarbashi
Ferron P-J, Gicquel T, Mégarbane B, Clément B, Fromenty B (2020) AN, Hathorn KE, Wong D, Njie C, Shen L (2020) Impact of
Treatments in Covid-19 patients with pre-existing metabolic chronic liver disease on outcomes of hospitalized patients with
dysfunction-associated fatty liver disease: A potential threat for COVID-19: a multicentre United States experience. Liver Int
drug-induced liver injury? Biochimie 179:266–274 40:2515–2521
Fix OK, Blumberg EA, Chang KM, Chu J, Chung RT, Goacher EK, Hazem RM, Antar SA, Nafea YK, Al-Karmalawy AA, Saleh MA,
Hameed B, Kaul DR, Kulik LM, Kwok RM (2021) American El-Azab MF (2022) Pirfenidone and vitamin D mitigate renal
association for the study of liver diseases expert panel consensus fibrosis induced by doxorubicin in mice with Ehrlich solid tumor.
statement: vaccines to prevent coronavirus disease 2019 infection Life Sci 288:120185
in patients with liver disease. Hepatology 74:1049–1064 Herta T, Berg TJLI (2021) COVID-19 and the liver–Lessons learned.
Fix OK, Hameed B, Fontana RJ, Kwok RM, Mcguire BM, Mulligan Liver Int. https://​doi.​org/​10.​1111/​liv.​14854
DC, Pratt DS, Russo MW, Schilsky ML, Verna EC (2020) Clini- Holshue ML, Debolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H,
cal best practice advice for hepatology and liver transplant pro- Spitters C, Ericson K, Wilkerson S, Tural A (2020) First case
viders during the COVID-19 pandemic: AASLD expert panel of 2019 novel coronavirus in the United States. N Engl J Med
consensus statement. Hepatology 72:287–304 382:929–936
Recent advances in COVID‑19‑induced liver injury: causes, diagnosis, and management

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu liver disease: Pathogenesis and treatment. J Clin Transl Hepatol
J, Gu X (2020) Clinical features of patients infected with 2019 9:731
novel coronavirus in Wuhan, China. The Lancet 395:497–506 Kopel J, Perisetti A, Roghani A, Aziz M, Gajendran M, Goyal HJFIPH
Hui DS, Lee N, Chan PK, Beigel JH (2018) The role of adjuvant (2020) Racial and gender-based differences in COVID-19. Front
immunomodulatory agents for treatment of severe influenza. Public Health 8:418
Antiviral Res 150:202–216 Kuhn J, Li W, Choe H, Farzan M (2004) Angiotensin-converting
Iavarone M, D’ambrosio R, Soria A, Triolo M, Pugliese N, Del enzyme 2: a functional receptor for SARS coronavirus. Cell and
Poggio P, Perricone G, Massironi S, Spinetti A, Buscarini E Mole Life Sci CMLS 61:2738–2743
(2020a) High rates of 30-day mortality in patients with cir- Kushner T, Cafardi J (2020) Chronic liver disease and COVID-19:
rhosis and COVID-19. J Hepatol 73:1063–1071 alcohol use disorder/alcohol-associated liver disease, nonalco-
Imoto K, Kohjima M, Hioki T, Kurashige T, Kurokawa M, Tashiro holic fatty liver disease/nonalcoholic steatohepatitis, autoimmune
S, Suzuki H, Kuwano A, Tanaka M, Okada S (2019) Clinical liver disease, and compensated cirrhosis. Clin Liver Dis 15:195
features of liver injury induced by immune checkpoint inhibi- Kutkat O, Moatasim Y, Al-Karmalawy AA, Abulkhair HS, Gomaa
tors in Japanese patients. Can J Gastroenterol Hepatol. https://​ MR, El-Taweel AN, Abo Shama NM, Gaballah M, Mahmoud
doi.​org/​10.​1155/​2019/​63917​12 DB, Kayali G, Ali MA, Kandeil A, Mostafa A (2022) Robust
Jha P, Saluja D, Chopra MJJOBS, Dynamics, (2022) Structure- antiviral activity of commonly prescribed antidepressants against
guided pharmacophore based virtual screening, docking, and emerging coronaviruses: in vitro and in silico drug repurposing
molecular dynamics to discover repurposed drugs as novel studies. Sci Rep 12:12920
inhibitors against endoribonuclease Nsp15 of SARS-CoV-2. Landi F, Barillaro C, Bellieni A, Brandi V, Carfì A, D’angelo M,
J Biomol Struct Dyn. https://​doi.​org/​10.​1080/​07391​102.​2022.​ Fusco D, Landi G, Lo Monaco R, Martone AJTJON, Health,
20795​61 and Aging, (2020) The new challenge of geriatrics: saving frail
Jiang L, Zhang H, Xiao D, Wei H, Chen YJC, Journal SB (2021) older people from the SARS-COV-2 pandemic infection. J Nut
Farnesoid X receptor (FXR): Structures and ligands. Comput Health Aging 24:466–470
Struct Biotechnol J 19:2148–2159. https://d​ oi.o​ rg/1​ 0.1​ 016/j.c​ sbj.​ Lara PC, Macías-Verde D, Burgos-Burgos J (2020) Age-induced
2021.​04.​029 NLRP3 inflammasome over-activation increases lethality of
Jin X, Lian J-S, Hu J-H, Gao J, Zheng L, Zhang Y-M, Hao S-R, Jia SARS-CoV-2 pneumonia in elderly patients. Aging Dis. https://​
H-Y, Cai H, Zhang X-L (2020) Epidemiological, clinical and doi.​org/​10.​14336/​AD.​2020.​0601
virological characteristics of 74 cases of coronavirus-infected Lei F, Liu YM, Zhou F, Qin JJ, Zhang P, Zhu L, Zhang XJ, Cai J, Lin
disease 2019 (COVID-19) with gastrointestinal symptoms. Gut L, Ouyang S (2020a) Longitudinal association between markers
69:1002–1009 of liver injury and mortality in COVID-19 in China. Hepatology
Jonas MM, Squires RH, Rhee SM, Lin CW, Bessho K, Feiterna-Sper- 72:389–398
ling C, Hierro L, Kelly D, Ling SC, Strokova T (2020) Phar- Lei P, Zhang L, Han P, Zheng C, Tong Q, Shang H, Yang F, Hu Y,
macokinetics, safety, and efficacy of glecaprevir/pibrentasvir in Li X, Song Y (2020b) Liver injury in patients with COVID-19:
adolescents with chronic hepatitis C virus: part 1 of the DORA clinical profiles, CT findings, the correlation of the severity with
study. Hepatology 71:456–462 liver injury. Hep Intl 14:733–742
Jugler C, Sun H, Chen QJV (2021) SARS-CoV-2 spike protein-induced Li R, Tang Y, Liang M, Ding J (2021) Liver injury in COVID-19
interleukin 6 signaling is blocked by a plant-produced anti-inter- patients with metabolic syndrome—a narrative review. Ann Pal-
leukin 6 receptor monoclonal antibody. Vaccines 9:1365 liat Med 10:8264–8270
Kandeil A, Mostafa A, Kutkat O, Moatasim Y, Al-Karmalawy AA, Liang W, Feng Z, Rao S, Xiao C, Xue X, Lin Z, Zhang Q, Qi W (2020)
Rashad AA, Kayed AE, Kayed AE, El-Shesheny R, Kayali G Diarrhoea may be underestimated: a missing link in 2019 novel
(2021) Bioactive polyphenolic compounds showing strong anti- coronavirus. Gut 69:1141–1143
viral activities against severe acute respiratory syndrome coro- Lindan CE, Mankad K, Ram D, Kociolek LK, Silvera VM, Boddaert
navirus 2. Pathogens 10:758 N, Stivaros SM, Palasis S, Akhtar S, Alden DJTLC, Health A
Kandeil A, Mostafa A, Kutkat O, Moatasim Y, Al-Karmalawy AA, (2021) Neuroimaging manifestations in children with SARS-
Rashad AA, Kayed AE, Kayed AE, El-Shesheny R, Kayali G, CoV-2 infection: a multinational, multicentre collaborative study.
Ali MA (2021b) Bioactive Polyphenolic Compounds Showing Lancet Child Adolescent Health 5:167–177
Strong Antiviral Activities against Severe Acute Respiratory Liu, J., Li, S., Liu, J., Liang, B., Wang, X., Wang, H., Li, W., Tong, Q.,
Syndrome Coronavirus 2. Pathogens 10:758 Yi, J., and Zhao, L. (2020). Longitudinal characteristics of lym-
Kang L, Li Y, Hu S, Chen M, Yang C, Yang BX, Wang Y, Hu J, Lai J, phocyte responses and cytokine profiles in the peripheral blood
Ma X (2020) The mental health of medical workers in Wuhan, of SARS-CoV-2 infected patients. EBioMedicine 55.
China dealing with the 2019 novel coronavirus. The Lancet Psy- Lizardo-Thiebaud, M.J., Cervantes-Alvarez, E., Limon-De La Rosa,
chiatry 7:e14 N., Tejeda-Dominguez, F., Palacios-Jimenez, M., Mendez-Guer-
Kariyawasam JC, Jayarajah U, Abeysuriya V, Riza R, Seneviratne SL rero, O., Delaye-Martinez, M., Rodriguez-Alvarez, F., Romero-
(2022) Involvement of the liver in COVID-19: A systematic Morales, B., and Liu, W.-H. (Year). “Direct or collateral liver
review. Am J Trop Med Hyg 106:1026 damage in SARS-CoV-2–infected patients”, In: Seminars in
Karnik M, Beeraka NM, Uthaiah CA, Nataraj SM, Bettadapura ADS, Liver Disease: Thieme Medical Publishers), 321–330
Aliev G, Madhunapantula SVJMN (2021) A review on SARS- Lu Y, Liu DX, Tam JP (2008) Lipid rafts are involved in SARS-
CoV-2-induced neuroinflammation, neurodevelopmental com- CoV entry into Vero E6 cells. Biochem Biophys Res Commun
plications, and recent updates on the vaccine development. Mol 369:344–349
Neurobiol 58:4535–4563 Luo S, Zhang X, Xu H (2020) Don’t overlook digestive symptoms in
Ko W-C, Rolain J-M, Lee N-Y, Chen P-L, Huang C-T, Lee P-I, Hsueh, patients with 2019 novel coronavirus disease (COVID-19). Clin
P.-R.J.I.J.O.a.A. (2020) Arguments in favour of remdesivir for Gastroenterol Hepatol 18:1636–1637
treating SARS-CoV-2 infections. Int J Antimicrobial Agents Mahmoud A, Mostafa A, Al-Karmalawy AA, Zidan A, Abulkhair HS,
55:105933 Mahmoud SH, Shehata M, Elhefnawi MM, Ali MA (2021) Tel-
Kolaric TO, Nincevic V, Kuna L, Duspara K, Bojanic K, Vukadin S, aprevir is a potential drug for repurposing against SARS-CoV-2:
Raguz-Lucic N, Wu GY, Smolic M (2021) Drug-induced fatty computational and in vitro studies. Heliyon 7:e07962
 S. A. Antar et al.

Mahmoud DB, Bakr MM, Al-Karmalawy AA, Moatasim Y, El Taweel Infection Should Undergo Liver Transplantation. Clinical Liver
A, Mostafa A (2022) Scrutinizing the feasibility of nonionic sur- Disease 18:230
factants to form isotropic bicelles of curcumin: a potential antivi- Oba J, Carvalho WBD, Silva CA, Delgado AF (2020) Gastrointes-
ral candidate against COVID-19. AAPS PharmSciTech 23:1–12 tinal manifestations and nutritional therapy during COVID-
Majde JA (2010) Neuroinflammation resulting from covert brain inva- 19 pandemic: a practical guide for pediatricians. Einstein
sion by common viruses–a potential role in local and global neu- (sao Paulo). https://​doi.​org/​10.​31744/​einst​ein_​journ​al/​2020R​
rodegeneration. Med Hypoth 75:204–213 W5774
Marjani M, Fahim F, Sadr M, Dizaji MK, Moniri A, Khabiri S, Tabarsi Ortiz GX, Lenhart G, Becker MW, Schwambach KH, Tovo CV, Blatt
P, Velayati AAJG, Bench HFBT (2019) Evaluation of Silymarin CR (2021) Drug-induced liver injury and COVID-19: A review
for management of anti-tuberculosis drug induced liver injury: a for clinical practice. World J Hepatol 13:1143
randomized clinical trial. J Hepatol 12:138 Oyelade T, Alqahtani J, Canciani G (2020) Prognosis of COVID-19
Marjot T, Moon AM, Cook JA, Abd-Elsalam S, Aloman C, Arm- in patients with liver and kidney diseases: an early systematic
strong MJ, Pose E, Brenner EJ, Cargill T, Catana M-aJ (2021a) review and meta-analysis. Tropical Medicine and Infectious
Outcomes following SARS-CoV-2 infection in patients with Disease 5:80
chronic liver disease: an international registry study. J Hepatol Paizis G, Tikellis C, Cooper ME, Schembri JM, Lew RA, Smith AI,
74:567–577 Shaw T, Warner FJ, Zuilli A, Burrell LM (2005) Chronic liver
Marjot T, Webb GJ, Barritt Iv AS, Moon AM, Stamataki Z, Wong VW, injury in rats and humans upregulates the novel enzyme angio-
Barnes E (2021b) COVID-19 and liver disease: mechanistic and tensin converting enzyme 2. Gut 54:1790–1796
clinical perspectives. Nat Rev Gastroenterol Hepatol 18:348–364 Papa A, Covino M, De Lucia SS, Del Gaudio A, Fiorani M, Polito
Mccashland TM, Preheim LC, Gentry-Nielsen MJ (2000) Pneumo- G, Settanni CR, Piccioni A, Franceschi F, Gasbarrini A (2023)
coccal vaccine response in cirrhosis and liver transplantation. J Impact of COVID-19 in individuals with and without pre-exist-
Infect Dis 181:757–760 ent digestive disorders with a particular focus on elderly patients.
Mcgonagle, D. (2020). Since January 2020 Elsevier has created a World J Gastroenterol 29:4099
COVID-19 resource centre with free information in English and Park SEJC, Pediatrics E (2020) Epidemiology, virology, and clinical
Mandarin on the novel coronavirus COVID-19. The COVID-19 features of severe acute respiratory syndrome-coronavirus-2
resource centre is hosted on Elsevier Connect, the company‘s (SARS-CoV-2; Coronavirus Disease-19). Clin Exp Paedia
public news and information. 63:119
Meiring S, Tempia S, Bhiman JN, Buys A, Kleynhans J, Makhasi M, Pereira MR, Mohan S, Cohen DJ, Husain SA, Dube GK, Ratner LE,
Mcmorrow M, Moyes J, Quan V, Walaza SJCID (2022) Pro- Arcasoy S, Aversa MM, Benvenuto LJ, Dadhania DM (2020)
longed Shedding of Severe acute respiratory syndrome corona- COVID-19 in solid organ transplant recipients: initial report from
virus 2 (SARS-CoV-2) at High Viral Loads Among Hospitalized the US epicenter. Am J Transplant 20:1800–1808
Immunocompromised Persons Living With Human Immunodefi- Petersen LA, Byrne MM, Daw CN, Hasche J, Reis B, Pietz KJHSR
ciency Virus (HIV). South Africa. https://​doi.​org/​10.​1016/j.​ijid.​ (2010) Relationship between clinical conditions and use of Vet-
2021.​12.​060 erans Affairs health care among Medicare-enrolled veterans.
Meng M, Chu Y, Zhang S, Li X, Sha J, Wang P, Cui Y, Han M, Dong Health Serv Res 45:762–791
X, Sun W (2022) Corticosteroid treatment in severe patients with Pommier T, Benzenine E, Bernard C, Mariet A-S, Béjot Y, Giroud M,
SARS-CoV-2 and chronic HBV co-infection: a retrospective mul- Morgant M-C, Steinmetz E, Guenancia C, Bouchot OJB (2022)
ticenter study. BMC Infect Dis 22:891 Trends of Myocarditis and Endocarditis Cases before, during,
Metawea MI, Yousif WI, Moheb I (2021) COVID 19 and liver: An A-Z and after the First Complete COVID-19-Related Lockdown in
literature review. Dig Liver Dis 53:146–152 2020 in France. Biomedicines 10:1231
Meydanli, M., and Akilli, H. (2021). Preoperative nasopharyngeal swab Portincasa P, Krawczyk M, Smyk W, Lammert F, Di Ciaula AJEJOCI
testing and postoperative pulmonary complications in patients (2020) COVID-19 and non-alcoholic fatty liver disease: two
undergoing elective surgery during the SARS-CoV-2 pandemic. intersecting pandemics. Eur J Clin Invest 50:e13338
Molteni E, Sudre CH, Canas LS, Bhopal SS, Hughes RC, Antonelli M, Qi X, Liu Y, Wang J, Fallowfield JA, Wang J, Li X, Shi J, Pan H, Zou
Murray B, Kläser K, Kerfoot E, Chen LJTLC, Health A (2021) S, Zhang H (2021) Clinical course and risk factors for mortality
Illness duration and symptom profile in symptomatic UK school- of COVID-19 patients with pre-existing cirrhosis: a multicentre
aged children tested for SARS-CoV-2. Lancet Child Adolescent cohort study. Gut 70:433–436
Health 5:708–718 Ramesh D, Vijayakumar BG, Kannan TJC (2021) Advances in Nucleo-
Montesarchio V, Parrella R, Iommelli C, Bianco A, Manzillo E, Fra- side and Nucleotide Analogues in Tackling Human Immuno-
ganza F, Palumbo C, Rea G, Murino P, De Rosa RJ (2020) Out- deficiency Virus and Hepatitis Virus Infections 16:1403–1419
comes and biomarker analyses among patients with COVID-19 Raza HA, Sen P, Bhatti OA, Gupta LJRI (2021) Sex hormones, auto-
treated with interleukin 6 (IL-6) receptor antagonist sarilumab at immunity and gender disparity in COVID-19. Rheumatol Int
a single institution in Italy. J Immun Cancer 8(2):123 41:1375–1386
Morgan K, Samuel K, Vandeputte M, Hayes P, Plevris, (2020) SARS- Repici A, Pace F, Gabbiadini R, Colombo M, Hassan C, Dinelli
CoV-2 infection and the liver. Pathogens. https://d​ oi.o​ rg/1​ 0.3​ 390/​ M, Maselli R, Spadaccini M, Mutignani M, Gabbrielli A
patho​gens9​060430 (2020) Endoscopy units and the coronavirus disease 2019
Muthiah MD, Cheng Han N, Sanyal AJJD, Obesity, and Metabolism, outbreak: a multicenter experience from Italy. Gastroenterol
(2022) A clinical overview of non-alcoholic fatty liver disease: 159(363–366):e363
a guide to diagnosis, the clinical features, and complications— Revzin MV, Raza S, Srivastava NC, Warshawsky R, D’agostino C,
what the non-specialist needs to know. Diabetes Obe Metabolism Malhotra A, Bader AS, Patel RD, Chen K, Kyriakakos CJR
24:3–14 (2020) Multisystem imaging manifestations of COVID-19, part
Nave H, Beutel G, Kielstein JT (2011) Obesity-related immunodefi- 2: from cardiac complications to pediatric manifestations. Radio-
ciency in patients with pandemic influenza H1N1. Lancet Infect graphics 40:1866
Dis 11:14–15 Rivera-Valdes JJ, Martínez-Lopez EJ (2022) The growing need to
Nickerson AM, Sobotka LA, Kelly SG (2021) PRO: Liver Transplan- monitor the liver function after SARS-CoV-2 infection in the
tation in the Times of COVID-19: Patients with COVID-19 Mexican population with obesity. Ann Hepatol 27:100698
Recent advances in COVID‑19‑induced liver injury: causes, diagnosis, and management

Roshdy WH, Kandeil A, El-Shesheny R, Khalifa MK, Al-Karmalawy Jannet HB, Gharbi J, Ali MA (2021) Strong Inhibitory Activity
AA, Showky S, Naguib A, Elguindy N, Fahim M, Abu Elsood and Action Modes of Synthetic Maslinic Acid Derivative on
H, El Taweel A, Salamony A, Mohsen A, Kayali G, Ali MA, Highly Pathogenic Coronaviruses: COVID-19 Drug Candidate.
Kandeel A (2022a) Insight into Genetic Characteristics of Iden- Pathogens 10:623
tified SARS-CoV-2 Variants in Egypt from March 2020 to May Song C, Li Z, Li C, Huang M, Liu J, Fang Q, Cao Z, Zhang L, Gao P,
2021. Pathogens 11:834 Nie WJ (2022) SARS-CoV-2: The Monster Causes COVID-19.
Roshdy WH, Khalifa MK, San JE, Tegally H, Wilkinson E, Showky S, Front Cell Infec Microbiol 12:835750
Martin DP, Moir M, Naguib A, Elguindy N, Gomaa MR, Fahim Sorokina M, Belapure J, Tüting C, Paschke R, Papasotiriou I, Rodri-
M, Abu Elsood H, Mohsen A, Galal R, Hassany M, Lessells RJ, gues JP, Kastritis PLJJOMB (2022) An electrostatically-steered
Al-Karmalawy AA, El-Shesheny R, Kandeil AM, Ali MA, De conformational selection mechanism promotes SARS-CoV-2
Oliveira T (2022b) SARS-CoV-2 Genetic Diversity and Lineage Spike protein variation. J Mol Biol 434:167637
Dynamics in Egypt during the First 18 Months of the Pandemic. Sorour, K., Sarhan, H., and El-Menshawy, H. (2020). ACE-2 in the
Viruses 14:1878 highlight of COVID-19, A proposed pathology and potential
Rosser BG, Gores GJ (1995) Liver cell necrosis: cellular mechanisms correlations.
and clinical implications. Gastroenterology 108:252–275 Stawiski EW, Diwanji D, Suryamohan K, Gupta R, Fellouse FA,
Russell CD, Millar JE, Baillie JK (2020) Clinical evidence does not Sathirapongsasuti JF, Liu J, Jiang Y-P, Ratan A, Mis MJB
support corticosteroid treatment for 2019-nCoV lung injury. (2020) Human ACE2 receptor polymorphisms predict SARS-
Lancet 395:473–475 CoV-2 susceptibility. BioRxiv 576:106
Saha L, Vij S, Rawat K (2022) Liver injury induced by COVID 19 Stokes EK, Zambrano LD, Anderson KN, Marder EP, Raz KM, Felix
treatment–what do we know? World J Gastroenterol 28:6314 SEB, Tie Y, Fullerton KEJM, Report MW (2020) Coronavirus
Saleh MA, Antar SA, Hazem RM, El-Azab MFJP (2020) Pirfenidone disease 2019 case surveillance—United States, january 22–
and vitamin D ameliorate cardiac fibrosis induced by doxoru- may 30, 2020. MMWR Morb Mortal Wkly Rep 69:759
bicin in Ehrlich ascites carcinoma bearing mice: modulation of Sui J, Noubouossie DF, Gandotra S, Cao L (2021) Elevated plasma
monocyte chemoattractant protein-1 and Jun N-terminal kinase-1 fibrinogen is associated with excessive inflammation and dis-
pathways. Pharmaceuticals 13:348 ease severity in COVID-19 patients. Front Cell Infect Micro-
Sandhu N, Navarro VJHC (2020) Drug-Induced Liver Injury in Gi biol 11:734005
Practice 4:631–645 Sultan S, Lim JK, Altayar O, Davitkov P, Feuerstein JD, Siddique
Saramago M, Costa VG, Souza CS, Bárria C, Domingues S, Viegas SM, Falck-Ytter Y, El-Serag HB (2020) AGA rapid recommen-
SC, Lousa D, Soares CM, Arraiano CM, Matos RGJM (2022) dations for gastrointestinal procedures during the COVID-19
The nsp15 Nuclease as a Good Target to Combat SARS-CoV-2: pandemic. Gastroenterology 159(739–758):e734
Mechanism of Action and Its Inactivation with FDA-Approved Sumida Y, Yoneda M (2021) COVID-19-associated liver injury
Drugs. Microorganisms 10:342 (COVALI): role of hepatologists. J Gastroenterol J Gastroen-
Sarhan AA, Ashour NA, Al-Karmalawy AA (2021) The journey of terol 56:786–787
antimalarial drugs against SARS-CoV-2: Review article. Infor- Tashiro S, Tanaka M, Goya T, Aoyagi T, Kurokawa M, Imoto K,
matics in Medicine Unlocked 24:100604 Kuwano A, Takahashi M, Suzuki H, Kohjima M (2022) Pir-
Sarin S (2020) Fast, faster, and fastest: science on the run during fenidone Attenuates Acetaminophen-Induced Liver Injury via
COVID-19 drama”—“ do not forget the liver. Hepatol Int. https://​ Suppressing c-Jun N-Terminal Kinase Phosphorylation. Toxi-
doi.​org/​10.​1007/​s12072-​020-​10042-0 col Appl Pharmacol 434:115817
Shah MD, Sumeh AS, Sheraz M, Kavitha MS, Maran, B.a.V Rodrigues Tilg H, Adolph TE, Dudek M, Knolle P (2021) Non-alcoholic fatty
KF (2021) A mini-review on the impact of COVID 19 on vital liver disease: the interplay between metabolism, microbes and
organs. Biomedicine Pharmacotherapy 143:112158 immunity. Nat Metab 3:1596–1607
Shehata MM, Mahmoud SH, Tarek M, Al-Karmalawy AA, Mahmoud Tudoran M, Tudoran C, Lazureanu VE, Marinescu AR, Pop GN,
A, Mostafa A, Elhefnawi M, M., and Ali, M.A. (2021) In Silico Pescariu AS, Enache A, Cut TG (2021) Alterations of left
and In Vivo Evaluation of SARS-CoV-2 Predicted Epitopes- ventricular function persisting during post-acute COVID-19 in
Based Candidate Vaccine. Molecules 26:6182 subjects without previously diagnosed cardiovascular pathol-
Singh AK, Singh A, Shaikh A, Singh R, Misra AJ (2020) Chloroquine ogy. JPM 11:225
and hydroxychloroquine in the treatment of COVID-19 with or Tume LN, Valla FV, Joosten K, Jotterand Chaparro C, Latten L,
without diabetes: A systematic search and a narrative review Marino LV, Macleod I, Moullet C, Pathan N, Rooze S (2020)
with a special reference to India and other developing countries. Nutritional support for children during critical illness: Euro-
Diabet Metabolic SynClinical Res Rev 14:241–246 pean Society of Pediatric and Neonatal Intensive Care (ESP-
Singh DK, Singh B, Ganatra SR, Gazi M, Cole J, Thippeshappa R, NIC) metabolism, endocrine and nutrition section position
Alfson KJ, Clemmons E, Gonzalez O, Escobedo RJNM (2021) statement and clinical recommendations. Intensive Care Med
Responses to acute infection with SARS-CoV-2 in the lungs of 46:411–425
rhesus macaques, baboons and marmosets. Nat Microbiol 6:73 Vancsa S, Hegyi PJ, Zadori N, Szako L, Vörhendi N, Ocskay K, Földi
Sivandzadeh GR, Askari H, Safarpour AR, Ejtehadi F, Raeis-Abdol- M, Dembrovszky F, Dömötör ZR, Janosi K (2020) Pre-existing
lahi E, Lari AV, Abazari MF, Tarkesh F, Lankarani KB (2021) liver diseases and on-admission liver-related laboratory tests in
COVID-19 infection and liver injury: Clinical features, biomark- COVID-19: a prognostic accuracy meta-analysis with systematic
ers, potential mechanisms, treatment, and management chal- review. Front Med 7:572115
lenges. World Journal of Clinical Cases 9:6178 Villanueva-Paz M, Morán L, López-Alcántara N, Freixo C, Andrade
Sohrabi C (2020) World Health Organization declares global emer- RJ, Lucena MI, Cubero FJ (2021) Oxidative stress in drug-
gency: A review of the 2019 novel coronavirus (COVID-19). induced liver injury (DILI): from mechanisms to biomarkers for
Int J Sur 76:71–76 use in clinical practice. Antioxidants 10:390
Soiza RL, Donaldson A, Myint P (2018) Vaccine against arterioscle- Vitiello A, Ferrara FJEJOPS (2021) Therapeutic strategies for SARS-
rosis: an update. Ther Adv Vaccines 9:259–261 CoV-2 acting on ACE-2. Eur J Pharm Sci 156:105579
Soltane R, Chrouda A, Mostafa A, Al-Karmalawy AA, Chouaïb K, Vitiello A, La Porta R, D’aiuto V, Ferrara F (2021) The risks of liver
Dhahri A, Pashameah RA, Alasiri A, Kutkat O, Shehata M, injury in COVID-19 patients and pharmacological management
 S. A. Antar et al.

to reduce or prevent the damage induced. Egypt Liver Journal Yang Q, Liang Q, Balakrishnan B, Belobrajdic DP, Feng Q-J, Zhang
11:1–6 W (2020a) Role of dietary nutrients in the modulation of gut
Vitrone, M., Mele, F., Durante-Mangoni, E., and Zampino, R.J.J.O.C. microbiota: a narrative review. Nutrients 12:381
(2021). Drugs and liver injury: a not to be overlooked binomial Yang R-X, Zheng R-D, Fan J-G (2020b) Etiology and management of
in COVID-19. liver injury in patients with COVID-19. World J Gastroenterol
Vo V, Tillett RL, Chang C-L, Gerrity D, Betancourt WQ, Oh EC (2022) 26:4753
SARS-CoV-2 variant detection at a university dormitory using Ye Y, Wang H, Liu J, Zhao F, Xu P (2020) Polygalasaponin F treats
wastewater genomic tools. Sci Tot Environ 805(805):149930 mice with pneumonia induced by influenza virus. Inflammop-
Walls AC, Park Y-J, Tortorici MA, Wall A, Mcguire AT, Veesler D harmacology 28:299–310
(2020) Structure, function, and antigenicity of the SARS-CoV-2 Zakaria MY, Zaki I, Alhomrani M, Alamri AS, Abdulaziz O, Aboure-
spike glycoprotein. Cell 181(281–292):e286 hab MA (2022) Boosting the anti MERS-CoV activity and oral
Wang H, Wang H, Sun Y, Ren Z, Zhu W, Li A, Cui GJFIM (2021a) bioavailability of resveratrol via PEG-stabilized emulsomal
Potential Associations Between Microbiome and COVID-19. nano-carrier: Factorial design, in vitro and in vivo assessments.
Front Med 8:785496 Drug Delivery 29:3155–3167
Wang, L., Didelot, X., Bi, Y., and Gao, G.F. (2022). SARS-CoV-2 Zaki AA, Al-Karmalawy AA, El-Amier YA, Ashour A (2020) Molecu-
transmissibility compared between variants of concern and vac- lar docking reveals the potential of Cleome amblyocarpa isolated
cination status. compounds to inhibit COVID-19 virus main protease. New J
Wang Q, Davis PB, Xu RJE (2021b) COVID-19 risk, disparities and Chem 44:16752–16758
outcomes in patients with chronic liver disease in the United Zaki AA, Ashour A, Elhady SS, Darwish KM, Al-Karmalawy AA
States. EClinicalMedicine 31:100688 (2022) Calendulaglycoside A showing potential activity against
Wang X (2021) Safety and efficacy of the BNT162b2 mRNA Covid-19 SARS-CoV-2 main protease: Molecular docking, molecular
vaccine. N Engl J Med 384:1577–1578 dynamics, and SAR studies. J Tradit Complement Med 12:16–34
Wang Y, Liu S, Liu H, Li W, Lin F, Jiang L, Li X, Xu P, Zhang L, Zhao Zeng Q-L, Yu Z-J, Ji F, Li G-M, Zhang G-F, Xu J-H, Lin W-B, Zhang
LJ (2020) SARS-CoV-2 infection of the liver directly contributes G-Q, Li G-T, Cui G-LJBID (2021) Dynamic changes in liver
to hepatic impairment in patients with COVID-19. J Hepatol function parameters in patients with coronavirus disease 2019: a
73:807–816 multicentre, retrospective study. BMC Infect Dis 21:1–15
Waseem N, Chen P-H (2016) Hypoxic hepatitis: a review and clinical Zhang B, Zhou X, Qiu Y, Song Y, Feng F, Feng J, Song Q, Jia Q,
update. J Clin Transl Hepatol 4:263 Wang J (2020a) Clinical characteristics of 82 cases of death from
Who (2020). Clinical management of COVID-19. COVID-19. PLoS ONE 15:e0235458
Who (2021). Coronavirus (COVID-19) Update: FDA Authorizes Drug Zhang H, Liao Y-S, Gong J, Liu J, Zhang H (2020b) Clinical charac-
for Treatment of COVID-19. teristics and risk factors for liver injury in COVID-19 patients in
Wiśniewska H, Skowron M, Bander D, Hornung M, Jurczyk K, Wuhan. World J Gastroenterol 26:4694
Karpińska E, Laurans Ł, Socha Ł, Czajkowski Z, Wawrzyno- Zhang J, Wang S, Xue Y (2020c) Fecal specimen diagnosis 2019 novel
wicz-Syczewska MJ (2020) Nosocomial COVID-19 infection coronavirus–infected pneumonia. J Med Virol 92:680–682
and severe COVID-19 pneumonia in patients hospitalized for Zhang R, Wang Q, Yang J, Hepatology T (2022a) Impact of liver func-
alcoholic liver disease: a case report. The American Journal of tions by repurposed drugs for COVID-19 treatment. J Clin Transl
Case Reports 21:e927452–e927451 Hepatol. https://​doi.​org/​10.​14218/​JCTH.​2021.​00368
Wu J, Song S, Cao H-C, Li L-JJ (2020a) Liver diseases in COVID- Zhang X, Yu Y, Zhang C, Wang H, Zhao L, Wang H, Su Y, Yang M
19: Etiology, treatment and prognosis. World J Gastroenterol (2022b) Mechanism of SARS-CoV-2 invasion into the liver and
26:2286 hepatic injury in patients with COVID-19. Medi J Hematol Infect
Wu Y, Guo C, Tang L, Hong Z, Zhou J, Dong X, Yin H, Xiao Q, Tang Dis 14:e2022003
Y, Qu X (2020b) Prolonged presence of SARS-CoV-2 viral RNA Zhang Y, Tan W, Wang X, Zheng X, Huang Y, Li B, Meng Z, Gao Y,
in faecal samples. Lancet Gastroenterol Hepatol 5:434–435 Qian Z, Liu F (2023) Metabolic biomarkers significantly enhance
Wu Z-H, Yang DL (2020) A meta-analysis of the impact of COVID-19 the prediction of HBV-related acute-on-chronic liver failure prog-
on liver dysfunction. Eur J Med Res 25:1–9 nosis. J Hepatol. https://​doi.​org/​10.​1016/j.​jhep.​2023.​07.​011
Xu L, Liu J, Lu M, Yang D, Zheng XJLI (2020a) Liver Injury dur- Zhao S, Hou Y, Zhang X, Hughes A, Liu N, Peng M, Wang Q, Xue Y,
ing Highly Pathogenic Human Coronavirus Infections. Liver Int Chen HJJOG, Genomics, (2022) Pinpointing the animal origins
40:998–1004 of SARS-CoV-2: a genomic approach. J Genet Genomics. https://​
Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, doi.​org/​10.​1016/j.​jgg.​2022.​05.​002
Liu H, Zhu L (2020b) Pathological findings of COVID-19 asso-
ciated with acute respiratory distress syndrome. Lancet Respir Publisher's Note Springer Nature remains neutral with regard to
Med 8:420–422 jurisdictional claims in published maps and institutional affiliations.
Xu Z, Zhang Y, Zhang C, Xiong F, Zhang J, Xiong JJA, Disease,
(2022) Clinical Features and Outcomes of COVID-19 Patients Springer Nature or its licensor (e.g. a society or other partner) holds
with Acute Kidney Injury and Acute Kidney Injury on Chronic exclusive rights to this article under a publishing agreement with the
Kidney Disease. Aging Dis 13:884 author(s) or other rightsholder(s); author self-archiving of the accepted
Yang H, Wang Y, Xu S, Ren J, Tang L, Gong J, Lin Y, Fang H, Su D manuscript version of this article is solely governed by the terms of
(2022) Hesperetin, a Promising Treatment Option for Diabetes such publishing agreement and applicable law.
and Related Complications: A Literature Review. J Agric Food
Chem 70:8582–8592

View publication stats