• COVID‐19 liver failure
• SARS‐CoV‐2
• acute decompensation of cirrhosis
• cirrhosis
• coronavirus
• long COVID‐19
• portal hypertension
• post COVID condition
• viral pneumonia

• Humans
• COVID-19/virology
• COVID-19/genetics
• Retrospective Studies
• Male
• Female
• SARS-CoV-2/genetics
• Middle Aged
• Liver Diseases/virology
• Liver Diseases/genetics
• Adult
• India/epidemiology
• Aged
• Mutation
• Comorbidity

• (Grant Number: BT/PR7403/MED/29/657/2012 and RAD-22017/28/2020-KGD-DBT) Department of Biotechnology, Ministry of Science and Technology, India
• Grant Number F.8 (343) ILBS/VAR/SEQ/P-I/2021/21705/CD-000654524/215). Government of National Capital Territory of Delhi

• atezolizumab
• bevacizumab
• coronavirus disease 2019
• liver function
• unresectable hepatocellular carcinoma

• NRF-2023R1A2C2006375 National Research Foundation of Korea
• NRF-2023R1A2C2004339 National Research Foundation of Korea

• ACLF
• Consensus
• Guides
• Liver cirrhosis
• Mexican

• Humans
• Acute-On-Chronic Liver Failure/therapy
• Acute-On-Chronic Liver Failure/diagnosis
• Mexico/epidemiology
• Consensus
• Gastroenterology/standards
• Liver Transplantation
• Liver Cirrhosis/complications
• Liver Cirrhosis/diagnosis

• Alcoholic cirrhosis
• COVID-19
• Chronic liver disease
• Inpatient complications
• Mortality predictors

• COVID-19
• Child Turcotte Pugh
• cirrhosis
• liver damage

• Cirrhosis
• Covid-19
• Hepatitis
• Liver transplant
• Vaccination

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a significant impact on the lives of millions of people, especially those with other concomitant diseases, such as chronic liver diseases. To date, seven coronaviruses have been identified to infect humans. The main site of pathological action of these viruses is lung tissue. However, a substantial number of studies have proven that SARS-CoV-2 shows affinity towards several organs, including the gastrointestinal tract and the liver. The current state of evidence points to several proposed mechanisms of liver injury in patients with COVID-19 and their combination. Liver impairment is considered to be the result of the direct effect of the virus on the hepatic tissue cells, a systemic reaction consisting of inflammation, hypoxia and cytokine storm, drug-induced liver injury, with the possible contribution of a perturbed gut-liver axis. Reactivation of chronic hepatic disease could be another factor for liver impairment in patients with SARS-CoV-2 infection. Acute-on-chronic liver failure (ACLF) is a relatively new syndrome that occurs in 10%–30% of all hospitalized patients with chronic liver disease. It is crucial to recognize high-risk patients due to the increased morbidity and mortality in these cases. Several published studies have reported virus infection as a trigger factor for ACLF. However, to date, there are few relevant studies describing the presence of ACLF in patients with acute SARS-CoV-2 infection. In this minireview we summarize the current state of knowledge regarding the relation between ACLF and acute SARS-CoV-2 infection.

• SARS-CoV-2
• COVID-19
• Acute-on-chronic liver failure
• ACLF, Liver
• Coronavirus

• Cirrhosis
• Outcomes
• Predictors
• Severe acute respiratory syndrome coronavirus 2

The new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in December 2019, in Wuhan, China. The virus was rapidly spread worldwide, causing coronavirus disease 2019 (COVID-19) pandemic. Although COVID-19 is presented, usually, with typical respiratory symptoms (i.e., dyspnea, cough) and fever, extrapulmonary manifestations are also encountered. Liver injury is a common feature in patients with COVID-19 and ranges from mild and temporary elevation of liver enzymes to severe liver injury and, even, acute liver failure. The pathogenesis of liver damage is not clearly defined; multiple mechanisms contribute to liver disorder, including direct cytopathic viral effect, cytokine storm and immune-mediated hepatitis, hypoxic injury, and drug-induced liver toxicity. Patients with underlying chronic liver disease (i.e., cirrhosis, non-alcoholic fatty liver disease, alcohol-related liver disease, hepatocellular carcinoma, etc.) may have greater risk to develop both severe COVID-19 and further liver deterioration, and, as a consequence, certain issues should be considered during disease management. The aim of this review is to present the prevalence, clinical manifestation and pathophysiological mechanisms of liver injury in patients with SARS-CoV-2 infection. Moreover, we overview the association between chronic liver disease and SARS-CoV-2 infection and we briefly discuss the management of liver injury during COVID-19.

• COVID-19
• Liver injury
• Cytokine storm
• Hypoxic hepatitis
• Drug-induced liver injury
• Chronic liver disease

• Humans
• COVID-19
• SARS-CoV-2
• Carcinoma, Hepatocellular
• Liver Neoplasms

• COVID-19
• SARS-CoV-2
• cholangitis
• chronic liver disease
• hepatitis
• liver cirrhosis

• Humans
• SARS-CoV-2
• COVID-19/complications
• Peptidyl-Dipeptidase A
• Liver Diseases/complications
• Liver Cirrhosis

• COVID-19
• Covishield
• cirrhosis
• compensated
• decompensated

The coronavirus disease 2019 (COVID-19) pandemic continues to be a global problem with over 438 million cases reported so far. Although it mostly affects the respiratory system, the involvement of extrapulmonary organs, including the liver, is not uncommon. Since the beginning of the pandemic, metabolic com-orbidities, such as obesity, diabetes, hypertension, and dyslipidemia, have been identified as poor prognostic indicators. Subsequent metabolic and lipidomic studies have identified several metabolic dysfunctions in patients with COVID-19. The metabolic alterations appear to be linked to the course of the disease and inflammatory reaction in the body. The liver is an important organ with high metabolic activity, and a significant proportion of COVID-19 patients have metabolic comorbidities; thus, this factor could play a key role in orchestrating systemic metabolic changes during infection. Evidence suggests that metabolic dysregulation in COVID-19 has both short- and long-term metabolic implications. Furthermore, COVID-19 has adverse associations with metabolic-associated fatty liver disease. Due to the ensuing effects on the renin-angiotensin-aldosterone system and ammonia metabolism, COVID-19 can have significant implications in patients with advanced chronic liver disease. A thorough understanding of COVID-19-associated metabolic dysfunction could lead to the identification of important plasma biomarkers and novel treatment targets. In this review, we discuss the current understanding of metabolic dysfunction in COVID-19, focusing on the liver and exploring the underlying mechanistic pathogenesis and clinical implications.

• COVID-19
• Coronavirus
• Metabolism
• Metabolic syndrome
• Metabolic inflammation
• Hepatic dysfunction

• ACLF, acute-on-chronic liver failure
• AD, acute decompensation
• AIH, autoimmune hepatitis
• ALT, alanine aminotransferase
• AST, aspartate aminotransferase
• Alk P, alkaline phosphatase
• COVID-19, Coronavirus disease-2019
• CTP, Child-Turcotte-Pugh
• EHPVO, extrahepatic portal vein obstruction
• HBV
• HBV, hepatitis B virus
• HCV
• HCV, hepatitis C virus
• INR, international normalized ratio
• MELD, model for end-stage liver disease
• MODS, multiorgan dysfunction syndrome
• NAAT, Nucleic Acid Amplification Test
• NAFLD
• NAFLD, nonalcoholic fatty liver disease
• NCPF, noncirrhotic portal fibrosis
• TLC, Total leukocyte count
• VOC, variants of concern
• VOI, variants of interest
• alcohol
• portal hypertension

Background

Coronavirus disease 2019 (COVID-19) infection in chronic liver disease patients is associated with poor outcomes. In this study, we aimed to evaluate the predictors of severity and mortality in this group of patients during the second wave of the COVID-19 pandemic in India. In addition, we compared cirrhotic patients with COVID-19 with cirrhotic patients from the pre-COVID-19 period.

Methodology

This was a single-center observational study. We included data from 50 patients with cirrhosis and COVID-19 retrospectively from the discharge/death files. A comparison group of 100 patients with cirrhosis from the pre-COVID period was also analyzed retrospectively.

Results

The majority of patients had predominantly respiratory symptoms, with fever being the most common symptom (85%). The most common presentation was acute on chronic liver failure (ACLF). The most common form of decompensation was jaundice followed by hepatic encephalopathy. The overall mortality in cirrhotic patients with COVID-19 was double than that in cirrhotic patients from the pre-COVID-19 period. All patients with ACLF succumbed to multiorgan failure. Diabetes was the only comorbidity that was associated with severe infection. Higher creatinine on admission and high D-dimer levels correlated with severity. D-dimer was the only parameter that correlated with severity and mortality on multivariate analysis. None of the comorbidities predicted mortality. Among various composite scores, the Child-Turcotte-Pugh (CTP) score and CURB-65 correlated with mortality. On the area under the receiver operating characteristic analysis, a D-dimer level of >1.1 mg/L was associated with mortality.

Conclusions

COVID-19 infection in patients with cirrhosis is associated with poor outcomes. D-dimer levels of >1.1 mg/L on admission are a simple parameter to predict mortality. CTP and CURB-65 are composite scores that correlate with mortality in this group of patients.

• ACE2, Angiotensin-converting enzyme 2
• AD, acute decompensation
• AIH, autoimmune hepatitis
• ALT, alanine aminotransferase
• AST, aspartate aminotransferase
• Alk P, alkaline phosphatase
• COVID-19, coronavirus disease-2019
• CTP, Child-Turcotte-Pugh
• GI, Gastrointestinal
• HBV, hepatitis B virus
• HCV, hepatitis C virus
• INR, international normalized ratio
• IQR, interquartile range
• MELD, model for end-stage liver disease
• NAFLD, nonalcoholic fatty liver disease
• TLC, Total leukocyte count
• chronic liver disease
• coronavirus
• mortality
• pandemic
• virus

• COVID-19
• Chronic liver disease
• Liver injury
• Prognosis
• SARS-CoV-2

• COVID-19
• cirrhosis
• hepatitis
• liver transplant
• vaccination

• COVID-19
• COVID-19 Vaccines
• Humans
• Liver Diseases/epidemiology
• SARS-CoV-2

• Acute-on-chronic liver failure
• Cirrhosis
• Coronavirus
• Critical care
• Hepatic encephalopathy
• Multiple-organ failure
• Portal hypertension
• Sepsis

Chronic liver disease, particularly cirrhosis, is associated with worse outcomes in patients infected with coronavirus disease 2019 (COVID-19).

To assess outcomes of COVID-19 infection among patients with pre-existing hepatitis C with or without liver cirrhosis.

This multicenter, retrospective cohort study included all cases of confirmed co-infection of severe acute respiratory syndrome coronavirus 2 and chronic hepatitis C with or without liver cirrhosis who were admitted to six hospitals (Al-Sahel Hospital, Al-Matareya Hospital, Al-Ahrar Hospital, Ahmed Maher Teaching Hospital, Al-Gomhoreya Hospital, and the National Hepatology and Tropical Medicine Research Institute) affiliated with the General Organization for Teaching Hospitals and Institutes in Egypt. Patients were recruited from May 1, 2020, to July 31, 2020. Demographic, laboratory, imaging features, and outcomes were collected. Multivariate regression analysis was performed to detect factors affecting mortality.

This retrospective cohort study included 125 patients with chronic hepatitis C and COVID-19 co-infection, of which 64 (51.20%) had liver cirrhosis and 40 (32.00%) died. Fever, cough, dyspnea, and fatigue were the most frequent symptoms in patients with liver cirrhosis. Cough, sore throat, fatigue, myalgia, and diarrhea were significantly more common in patients with liver cirrhosis than in non-cirrhotic patients. There was no difference between patients with and without cirrhosis regarding comorbidities. Fifteen patients (23.40%) with liver cirrhosis presented with hepatic encephalopathy. Patients with liver cirrhosis were more likely than non-cirrhotic patients to have combined ground-glass opacities and consolidations in CT chest scans: 28 (43.75%) vs 4 (6.55%), respectively (P value < 0.001). These patients also were more likely to have severe COVID-19 infection, compared to patients without liver cirrhosis: 29 (45.31%) vs 11 (18.04%), respectively (P value < 0.003). Mortality was higher in patients with liver cirrhosis, compared to those with no cirrhosis: 33 (51.56%) vs 9 (14.75%), respectively (P value < 0.001). All patients in Child-Pugh class A recovered and were discharged. Cirrhotic mortality occurred among decompensated patients only. A multivariate regression analysis revealed the following independent factors affecting mortality: Male gender (OR 7.17, 95%CI: 2.19–23.51; P value = 0.001), diabetes mellitus (OR 4.03, 95%CI: 1.49–10.91; P value = 0.006), and liver cirrhosis (OR 1.103, 95%CI: 1.037–1.282; P value < 0.0001). We found no differences in liver function, COVID-19 disease severity, or outcomes between patients who previously received direct-acting antiviral therapy (and achieved sustained virological response) and patients who did not receive this therapy.

Patients with liver cirrhosis are susceptible to higher severity and mortality if infected with COVID-19. Male gender, diabetes mellitus, and liver cirrhosis are independent factors associated with increased mortality risk.

• COVID-19
• Egypt
• Outcome
• Liver cirrhosis
• Chronic hepatitis C

• Antiviral Agents/therapeutic use
• COVID-19
• Coinfection/drug therapy
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/drug therapy
• Humans
• Liver Cirrhosis/complications
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/epidemiology
• Male
• Retrospective Studies
• SARS-CoV-2

Novel coronavirus SARS-CoV2 is evolving continuously with emergence of several variants of increasing transmission capabilities and pandemic potential. Generation of variants occurs through accumulation of mutations due to the RNA nature of viral genome, which is further enhanced by variable selection pressures of this ongoing pandemic. COVID-19 presentations of SARS-CoV2 are mainly pulmonary manifestations with or without mild gastrointestinal (GI) and hepatic symptoms. However, the virus has evolved beyond pulmonary manifestations to multisystem disorder due to systemic inflammation and cytokine storm. Definitive cause of acute or late onset of inflammation, infection in various organs, and host response to emerging variants lacks clarity and needs elucidation. Several studies have reported underlying diseases including diabetes, hypertension, obesity, cardio- and cerebrovascular disorders, and immunocompromised conditions as significant risk factors for severe form of COVID-19. Pre-existing liver and GI diseases are also highly predominant in the population, which can alter COVID-19 outcome due to altered immune status and host response. We aim to review the emerging variants of SARS-CoV2 and host response in patients with pre-existing liver and GI diseases.

In this review, we have elucidated the emergence and characteristic features of new SARS-CoV2 variants, mechanisms of infection and host immune response, GI and hepatic manifestation with radiologic features of COVID-19, and outcomes in pre-existing liver and GI diseases.

Emerging variants of concern (VOC) have shown increased transmissibility and virulence with severe COVID-19 presentation and mortality. There is a drastic swift of variants from the first wave to the next wave of infections with predominated major VOC including alpha (B.1.1.7, UK), beta (B.1.351, South Africa), gamma (B.1.1.28.1, Brazil), and delta (B1.1.617, India) variants. The mutations in the spike protein of VOC are implicated for increased receptor binding (N501Y, P681R) and immune escape (L452R, E484K/Q, T478K/R) to host response. Pre-existing liver and GI diseases not only have altered tissue expression and distribution of viral entry ACE2 receptor but also host protease TMPRSS2, which is required for both spike protein binding and cleavage to initiate infection. Altered immune status due to pre-existing conditions results in delayed virus clearance or prolonged viremia. Even though GI and hepatic manifestations of SARS-CoV2 are less severe, the detection of virus in patient’s stool indicates GI tropism, replication, and shedding from the GI tract. COVID-19-induced liver injury, acute hepatic decompensation, and incidences of acute-on-chronic liver failure may change the disease outcomes.

The changes in the spike protein of emerging variants, immunomodulation by viral proteins, and altered expression of host viral entry receptor in pre-existing diseases are the key determinants of host response to SARS-CoV2 and its disease outcome.

• COVID-19
• SARS-CoV2
• emerging variants
• gastrointestinal disease
• liver
• manifestations
• variants of concern

• COVID-19
• clinical manifestations
• liver disease

• COVID-19
• chronic liver disease
• cirrhosis

• Autoimmune
• COVID-19
• Hepatitis
• Immunosuppressive agents
• Liver cirrhosis
• SARS-CoV-2 infection

• COVID-19
• SARS-CoV-2
• liver transplant recipients
• liver transplantation
• solid organ transplantation

• cirrhosis

• COVID-19
• Drug-induced liver injury
• Drugs
• Liver

• Acute liver injury
• COVID-19
• Cirrhosis
• Prognosis
• SARS-CoV-2
• Therapy

The coronavirus disease 2019 (COVID-19) outbreak has drawn the scientific community's attention to pre-existing metabolic conditions that could aggravate the infection, causing extended viral shedding, prolonged hospitalization, and high death rates. Metabolic dysfunction-associated fatty liver disease (MAFLD) emerges as a surrogate for COVID-19 severity due to the constellation of metabolic alterations it entails. This review outlines the impact MAFLD exerts on COVID-19 severity in obese subjects, besides the possible mechanistic links to the poor outcomes. The data collected showed that MAFLD patients had poorer COVID-19 outcomes than non-MAFLD obese subjects. MAFLD is generally accompanied by impaired glycemic control and systemic arterial hypertension, both of which can decompensate during the COVID-19 clinical course. Also, MAFLD subjects had higher plasma inflammatory marker concentrations than non-MAFLD subjects, which might be related to an intensified cytokine storm syndrome frequently associated with the need for mechanical ventilation and death. In conclusion, MAFLD represents a higher risk than obesity for COVID-19 severity, resulting in poor outcomes and even progression to non-alcoholic steatohepatitis. Hepatologists should include MAFLD subjects in the high-risk group, intensify preventive measurements, and prioritize their vaccination.

• Metabolic dysfunction-associated fatty liver disease
• Obesity
• COVID-19
• Severity
• Cytokine storm syndrome

• COVID-19
• Humans
• Non-alcoholic Fatty Liver Disease
• Obesity/complications
• Obesity/epidemiology
• Risk Factors
• SARS-CoV-2

• ACLF
• Cirrhosis
• Transaminitis
• Vaccine

Coronavirus disease 2019 is a pandemic disease caused by a novel RNA coronavirus, SARS coronavirus 2 (SARS-CoV-2), which is implicated in the respiratory system. SARS-CoV-2 also targets extrapulmonary systems, including the gastrointestinal tract, liver, central nervous system and others. SARS-CoV-2, like other RNA viruses, targets the liver and produces liver injury. This literature review showed that SARS-CoV-2-induced liver injury is different from other RNA viruses by a transient elevation of hepatic enzymes and does not progress to liver fibrosis or other unfavorable events. Moreover, SARS-CoV-2-induced liver injury usually occurs in the presence of risk factors, such as nonalcoholic liver fatty disease. This review highlights the important differences between RNA viruses inducing liver injury taking into consideration the clinical, biochemical, histopathological, postmortem findings and the chronicity of liver injury that ultimately leads to liver fibrosis and hepatocellular carcinoma.

• Liver injury
• COVID-19
• RNA-viruses
• Risk factors
• Liver enzymes
• Liver fibrosis

• AD, Acute decompensation
• AIH, Autoimmune hepatitis
• AIMS65, Albumin, international normalized ratio, mental status, systolic blood pressure, age > 65
• CLD, Chronic liver disease
• COVID-19, Coronavirus disease −2019
• CRS, Clinical Rockall Score
• Carvedilol
• Endoscopy
• FFP, Fresh frozen plasma
• GAVE, Gastric antral vascular ectasia
• GBS, Glasgow-Blatchford bleeding score
• GI, Gastrointestinal
• HE, Hepatic encephalopathy
• HVPG, Hepatic venous pressure gradient
• INR, International normalized ratio
• LGI, Lower gastrointestinal
• Liver transplant
• MOHFW, Ministry of Health and Family Welfare
• NSAIDs, Non-steroidal anti-inflammatory drugs
• PPE, Personal protective equipment
• PRBC, Packed red blood cells
• Prognosis
• Proton pump inhibitors
• RR, Respiratory rate
• RT-PCR, Reverse transcriptase polymerase chain reaction
• SARS-CoV2, Severe acute respiratory syndrome Coronavirus 2
• UGI, Upper gastrointestinal
• Variceal bleeding
• mGBS, Modified Glasgow-Blatchford bleeding score

• ACE, angiotensin-converting enzyme related carboxypeptidase receptors
• ACLF, acute-on chronic liver failure
• ALI, acute liver injury
• ALT, alanine transaminase
• AST, aspartate aminotransferase
• CLD, chronic liver disease
• COVID-19, Coronavirus disease 2019
• HCWs, health care workers
• HR, hazard ratio
• LFT, liver function tests
• LT, liver transplantation
• MELD, model for end-stage liver disease
• NAFLD, non-alcoholic fatty liver disease
• NASH, non-alcoholic steatohepatitis
• OR, Odds ratio
• SARS-CoV-2
• SARS-CoV-2, severe acute respiratory syndrome coronavirus 2
• immunosuppression
• liver diseases
• mortality
• nash

• Acute-on-chronic liver failure
• COVID-19
• Cirrhosis
• Coronavirus
• Death
• Pandemic

• Body Mass Index
• COVID-19/epidemiology
• Comorbidity
• Female
• Follow-Up Studies
• Hospitalization
• Humans
• Liver Cirrhosis/diagnosis
• Liver Cirrhosis/epidemiology
• Male
• Middle Aged
• Prospective Studies
• SARS-CoV-2
• South America/epidemiology
• Survival Rate/trends

• ARDS
• Acute kidney injury
• Alcoholic liver disease
• COVID-19

• Aged
• Aged, 80 and over
• COVID-19/diagnosis
• COVID-19/epidemiology
• COVID-19/mortality
• Chronic Disease
• Comorbidity
• Female
• Hospital Mortality
• Hospitalization
• Humans
• Italy/epidemiology
• Liver Diseases/diagnosis
• Liver Diseases/epidemiology
• Liver Diseases/mortality
• Male
• Middle Aged
• Prognosis
• Retrospective Studies
• SARS-CoV-2/isolation & purification

• Adult
• COVID-19/complications
• COVID-19/epidemiology
• COVID-19 Testing/statistics & numerical data
• Female
• Gastrointestinal Diseases/epidemiology
• Gastrointestinal Diseases/virology
• Hospitals, University
• Humans
• India/epidemiology
• Logistic Models
• Male
• Middle Aged
• Multivariate Analysis
• Prospective Studies
• SARS-CoV-2
• Severity of Illness Index
• Symptom Assessment
• Young Adult