Introduction
Hepatotropism of SARS-CoV-2 virus
SARS-Cov-2 related liver injury in the absence of chronic liver disease
SARS-CoV-2 infection on the background of chronic liver disease
Cirrhosis and acute-on-chronic liver failure
Study | Study design | Location of study | Number of patients included | Main result |
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Marjot et al. (2021) | Multinational cohort study | 29 countries | COVID-19 with non-cirrhosis CLD (n = 359); COVD-19 with cirrhosis (n = 386) | COVID-19 patients with cirrhosis were associated with higher rates for admission to ICU (p < 0.001), requirement to ICU (p < 0.001); renal replacement therapy (p = 0.002) and death (p = < 0.001) Overall mortality: COVID-19 with cirrhosis (32%) vs. COVID-19 with non-cirrhosis CLD (8%; P < 0.001) |
Singh et al. (2020) | Multicentre research network study | United States | COVID-19 with non-cirrhosis CLD (n = 250); COVID-19 with cirrhosis (n = 50); COVID-19 without CLD (n = 2530) | Higher relative risk of mortality was found in COVID-19 patient with cirrhosis compared to COVID-19 patients without CLD (RR 4.6; 95% CI 2.6–8.3; p < 0.001) |
Iavarone et al. (2020) | Multicentre retrospective cohort study | Italy | COVID-19 with without cirrhosis (n = 399); COVID-19 with cirrhosis (n = 50) | 30-day mortality was significantly lower in COVID-19 patients without cirrhosis compared to those patients with cirrhosis (18% vs. 34%; p = 0.035) Decompensated cirrhosis was independently related to adverse outcomes of COVID-19 |
Ioannou et al. (2020) | Population-based study | North America | COVID-19 without cirrhosis (n = 9,826); COVID-19 with cirrhosis (n = 305) | COVID-19 patients with cirrhosis had significantly higher risk of hospitalisation (aHR1.37; 95% CI 1.12–1.66), death (aHR 1.65; 95% CI 1.18–2.30) and mechanical ventilation (aHR1.61; 95%: 1.05–2.46) |
Sarin et al. (2020) | Multinational registry study | 13 countries in Asia | COVID-19 with non-cirrhosis CLD (n = 185); COVID-19 with cirrhosis (n = 43) | 20% of cirrhosis patients had either acute hepatic decompensation or acute-on-chronic liver failure 43% of mortality was found in patients with decompensated cirrhosis |
Ge et al. (2021) | National electronic health dataset-based study | N/A | COVID-19 without cirrhosis (n = 29,446); COVID-19 with cirrhosis (n = 8,941); non COVID-19 without cirrhosis (n = 128,864); non-COVID-19 with cirrhosis (n = 53,476) | The presence of cirrhosis among COVID-19 patients was associated with 3.31 times adjust hazard of death (aHR 3.31; 95% CI 2.91–3.77; p < 0.01) COVID-19 infection was associated with 2.38 times adjust hazard of 30 days mortality among cirrhotic parents (aHR 2.38; 95% CI 2.18–2.59; p < 0.01) |
Bajaj et al. (2021) | Multicentre retrospective cohort study | North America | Cirrhosis alone (n = 127); COVID-19 without cirrhosis (n = 108); COVID-19 with cirrhosis (n = 37) | The presence of cirrhosis was associated with increased mortality compared to COVID-19 alone (30% vs.13%, p = 0.03) No difference was found in mortality between COVID-19 with cirrhosis and cirrhosis alone (30% vs. 20%, p = 0.11) |
Middleton et al. (2021) | Systematic review and meta-analysis | N/A | COVID-19 without cirrhosis (n = 31,082); COVID-19 with cirrhosis (n = 1,603) | The presence of cirrhosis was associated with increased all causes mortality (aOR 1.81; 95% CI 1.36–2.42) |
Mandour et al. (2020) | Single centre retrospective study | United Kingdom | COVID-19 with cirrhosis (n = 10); non-COVID-19 with cirrhosis (n = 85) | COVID-19 infection was associated with longer hospitalisation stays with 11.5 days among cirrhotic patients (p = 0.047) |
Suresh et al. (2020) | Hospital-based retrospective study | United States | COVID-19 without CLD (n = 1869); COVID-19 with non-cirrhosis CLD (n = 66); COVID-19 with cirrhosis (n = 21) | The presence of cirrhosis was associated with higher mortality rate (RR 2.1; 95% CI 1.33–3.62; p = 0.0022) compared to non-cirrhosis but no difference found in 30-day re-admission, ICU admission rate and intubation rate |
Shalimar et al. (2020) | Single-centre retrospective study | India | COVID-19 alone (n = 722); COVID-19 with cirrhosis (n = 26); COVID-19 with NAFLD (n = 1); COVID-19 with extrahepatic portal venous obstruction (EHPVO) | COVID-19 was associated with higher mortality in cirrhotic patients compared to historical controls (42.3% vs. 23.1%, P = 0.077) Mechanical ventilation was associated with higher mortality in cirrhotic patients |
Qi et al. (2020) | Multi-centre retrospective study | China | COVID-19 with cirrhosis survivor (n = 16); COVID-19 with cirrhosis non-survivors (n = 5) | Non-survivors were associated with higher rate of ICU admission (80% vs. 6.3%, p < 0.004), higher rate of non-invasive ventilation (60% vs. 6.3%, p = 0.028), higher rate of invasive mechanical ventilation (60% vs. 0%, p < 0.008) |
Moon et al. (2020) | Multi-centre retrospective study | 21 countries from 4 continents | COVID-19 with non-cirrhosis CLD (n = 49); COVID-19 with cirrhosis (n = 103) | Mortality was associated with the presence of cirrhosis with CTP-B (OR 4.90; 95% CI 1.16–20.61; p = 0.030) or CTP-C (OR 28.07; 96% CI: 4.42–178.46; p < 0.001) in patients with COVID-19 |
Liu et al. (2020) | Hospital-based retrospective study | China | COVID-19 with cirrhosis and CSPH (n = 6); COVID-19 with cirrhosis and non-CSPH (n = 11) | The presence of CSPH was not associated with CTP class (p = 0.125) and aetiology (p = 0.361) of cirrhosis, incubation (p = 0.472) of COVID-19 |
Alcohol-related liver disease
Study | Aim | Design | Location | Number of patients included | Main results |
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Alcohol-related liver disease | |||||
Kim et al. (2021) | To identify the factors associated with adverse outcomes in patients with CLD who acquire COVID-19 | Multicentre observational study | North America | COVID-19 with ALD (n = 94) | ALD independently predicted all-cause moryality (HR: 2.42; 95% CI 1.29–4.55; p = 0.006) |
Marjot et al. (2021) | To determine the impact of COVID-19 on patients with pre-existing liver disease | Multinational cohort study | 29 countries | Alive COVID-19 with ALD (n = 115); Dead COVID-19 with ALD (n = 64) | ALD was an independent risk factor for death from COVID-19 (adjusted OR 1.79; 95% CI1.03–3.13; p = 0.040) |
Autoimmune liver disease | |||||
Di Giorgio et al. (2020) | To explore the clinical features of SARS-CoV-2 infection in patients with AILD under immunosuppression | Phone-based survey | Italy | COVID-19 with immunosuppressed AILD (n = 4); immunosuppressed AILD only (n = 148) | Immunosuppression was not related to severe COVID-19 infection in patients with AILD |
Efe et al. (2021) | To assess the clinical characteristics and outcomes of patients with AIH infected with COVID‐19 | Multicentre cohort study | Europe and United States | COVID-19 with AIH (n = 110; 102 under immunosuppression) | Immunosuppression was not related to adverse outcomes of COVID-19 in patient with AIH AIH was not associated with higher hospitalisation (46.4% vs. 50.0%; p = 0.560), need for supplemental oxygen (38.2% vs. 42.2%; p = 0.553), all-cause mortality (10.0% vs. 11.5%; p = 0.852), or severe COVID-19 (15.5% vs. 20.2%; p = 0.231) |
Non-alcoholic fatty liver disease | |||||
Ji et al. (2020) | To examine the liver injury patterns and implication of NAFLD on clinical outcomes in Chinese patients with COVID-19 | Hospital-based retrospective study | China | Stable COVID-19 (n = 163); stable COVID-19 with NAFLD (n = 42); progressive COVID-19 (n = 39); progressive COVID-19 with NAFLD (n = 34) | NAFLD was significantly associated with COVID-19 progression (OR 6.4; 95% CI 1.5–31.2). Patients with NAFLD presented higher risk of developing abnormal liver function from admission to discharge (11.1% vs. 70%; p < 0.0001) and longer viral shedding time (12.1 ± 4.4 days vs. 17.5 ± 5.2 days; p < 0.0001) |
Zheng et al. (2020) | To investigate the association between MAFLD and COVID-19 severity | Multicentre retrospective cohort study | China | Obese COVID-19 with MAFLD (n = 45); non-obese COVID-19 with MAFLD (n = 21); Severe COVID-19 with obese and MAFLD (n = 17); severe COVID-19 with non-obese and MAFLD (n = 2) | Obese MAFLD patients had a sixfold increased risk of developing severe COVID-19 compared to non-obese MAFLD patients (adjusted OR 6.32; 95% CI 1.16–34.54; P = 0.033) |
Targher et al. (2020) | To study whether MAFLD with increased non-invasive liver fibrosis scores are at higher risk of severe illness from COVID-19 | Multicentre retrospective cohort study | China | COVID-19 with MAFLD and low FIB-4 (n = 44); with intermediate FIB-4 (n = 36); with high FIB-4 (n = 14) | Severe COVID-19 was associated with presence of intermediate (OR 4.32; 95% CI 1.94–9.59) or high FIB-4 scores (OR 5.73; 95% CI 1.84–17.9) among patients with MAFLD |
Hepatitis B virus | |||||
Liu et al. (2020) | To investigate liver function changes of COVID-19 patients with HBV infection, and how SARS-CoV-2 infection affects the course of chronic HBV infection | Retrospective cohort study | China | COVID-19 without chronic HBV infection (n = 51); COVID-19 with chronic HBV infection (n = 20) | Severe COVID-19 was similar in patients with and without HBV infection (30% vs. 31.4%; p = 0.97). Patient with HBV infection did not show longer median time to SARS-CoV-2 clearance compared with patients without HBV (21 days vs. 14 days; p = 0.1) |
Chen et al. (2020) | To investigate the clinical characterizes of patients coinfected with SARS-CoV-2 and HBV | Hospital-based retrospective study | China | COVID-19 without HBV infection (n = 108); COVID-19 with HBV infection (n = 15) | HBV infection was associated with higher mortality rate compared to patients without HBV infection (13.3% vs. 2.8%) |
Autoimmune liver disease
Non-alcoholic fatty liver disease
Hepatitis B virus infection
Hepatitis C virus infection
Post-liver transplantation
Hepatocellular carcinoma
Study | Aim | Design | Location | Number of patients included | Main results |
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Hepatocellular carcinoma | |||||
Marjot et al. (2021) | To determine the impact of COVID-19 on patients with pre-existing liver disease, which currently remains ill-defined | Multinational cohort study | 29 countries | Alive COVID-19 with HCC (n = 34); died COVID-19 with HCC (n = 14) | Presence of HCC was not independently associated with mortality compared to patients without HCC (OR1.46; 95% CI 0.67–3.18; p = 0.346) |
Kim et al. (2021) | To identify the factors associated with adverse outcomes in patients with CLD who acquire COVID-19 | Multicentre observational cohort study | North America | Alive COVID-19 with HCC (n = 10); died COVID-19 with HCC (n = 9); Severe COVID-19 with HCC (n = 18); non-severe COVID-19 with HCC (n = 3) | HCC was one independent predictor of death in patients with COVID-19 (HR:3.31; 95% CI 1.53–7.16) |
COVID-19 vaccination in chronic liver disease and liver transplant recipients
Study | Aim | Study design | Vaccine brand | Number of patients | Main result |
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Boyarski et al. (Transplantation 2021) | To evaluate safety of the first dose | Participants completed a detailed online questionnaire 1 week following their first dose | Pfizer/BioNTech (50%) or Moderna (50%) | 187 solid organ transplant recipients | No cases SARS-CoV-2, acute rejection, neurological diagnoses (Guillain–Barr syndrome, Bell’s Palsy, or neuropathy), or allergic reactions requiring epinephrine. Two cases of a new infection (acute-on-chronic pouchitis and influenza A) requiring treatment. Local site reactions included mild pain (61%), mild redness (7%), and mild swelling (16%). Systemic reactions such as fever and chills were uncommon (4% and 9%), although more-than-baseline fatigue was reported by 38%, headache by 32%, and myalgias by 15% |
Boyarsky et al. (JAMA 2021) | To study the proportion of positive antibody response after a single dose | Antibodies to the S1 domain and anti-RBD of the SARS-CoV-2 spike protein at a median of 20 days after the first dose | mRNA (52% BNT162b2 vaccine and 48% mRNA-1273 vaccine) | 436 solid organ transplant recipients | Antibody was detectable in 17% (95% CI 14–21%) of patients. Factors associated with lower response were anti–metabolite immunosuppression therapy (37% vs 63%; adjusted IRR 0.22; P < .001) and older age (adjusted IRR 0.83 per 10 years; P = .002). mRNA-1273 showed higher response than BNT162b2 (69%vs 31%; adjusted IRR 2.15; p = 0.003) |
Timmermann et al. (Vaccines 2021) | To investigate the immune response alongside the influence of underlying diseases and immunosuppressive regimen | Anti-spike-protein-IgG testing at least 21 days after complete SARS-CoV-2 vaccination | BNT162b2 (n = 114), mRNA-1273 (n = 3) and JNJ-78436735 (n = 1) | 118 liver transplant recipients | 78% developed anti-spike-protein-IgG antibodies. Alcoholic liver disease before transplantation (p = 0.006) and mycophenolate mofetil-based regimen (p < 0.001) were associated with lower response rate. All patients weaned off immunosuppression were seropositive |
Rashidi-Alavijeh et al. (Vaccines 2021) | Analyze immunogenicity | SARS-CoV-2 IgG against the Spike glycoprotein in a median of 15 days after receiving two doses of the vaccine | BNT162b2 | 43 liver transplant recipients and 20 healthcare workers as control group | 79% liver transplant recipients developed antibodies (100% in the control group; p = 0.047). The median IgG titter was significantly lower in the liver transplant recipients (216 vs. > 2080 BAU/mL in controls, p = 0.0001). Mycophenolate mofetil was associated with a reduced response compared to the other liver transplant patients (45.5% vs. 90.6%, p = 0.004) |
Rabinowich et al. (J Hepatol, 2021) | To asses vaccine immunogenicity and safety | SARS-CoV-2 IgG antibodies against the Spike-protein and Nucleocapsid-protein 10–20 days after receiving the second dose | BNT162b2 | 80 liver transplant recipients and 25 healthy controls | 47.5% liver transplant patients presented positive serology (vs 100% in controls; p < 0.001). Antibody titer was also significantly lower in this group (mean 95.41 AU/ml vs. 200.5 AU/ml in controls, p < 0.001). Predictors for negative response were older age, lower eGFR, high dose steroids and mycophenolate mofetil. No serious adverse events were reported in either group |
Thuluvath et al. (J Hepatol, 2021) (29) | To asses vaccine immunogenicity and safety | Antibody responses to spike protein, 4 weeks after complete vaccination | 2 doses of mRNA vaccines or after the single dose of Johnson & Johnson | 62 liver transplant recipients | Antibody levels were undetectable in 11 patients and suboptimal (median titter 17.6, range 0.47–212 U/ml) in 27 patients. Liver transplantation, use of 2 or more immunosuppressive therapies and vaccination with Johnson & Johnson were associated with poor response. No patient had any serious adverse events |
Boyarsky B et al. (JAMA 2021) | To asses antibody response after the second dose | Anti-spike serologic testing which tests for the receptor-binding domain of the SARS-CoV-2 spike protein at a median of 29 days after dose 2 | mRNA | 658 solid organ transplant recipients | Antibody was detectable in 54%. Among the 473 receiving antimetabolites, 8% had response after dose 1 and dose 2; 57% had no response after dose 1 or dose 2; and 35% had no response after dose 1 but subsequent antibody after dose 2. Among the 185 participants not receiving antimetabolites, 32% had response after dose 1 and dose 2; 18% had no response after dose 1 or dose 2; and 50% had no response after dose 1 but subsequent antibody after dose 2 |
Boyarsky B et al. (Transplantation, 2021) | To quantify the antispike antibody response to the Janssen vaccine and compare it to recipients of the mRNA series | Antibodies anti-RBD of the spike protein at 1 month after COVID-19 vaccine | Janssen (n = 12) and mRNA group (n = 725) | 12 solid organ transplant recipients | Anti-RBD antibody was detectable in only 17% of participants who received the Janssen (vs 59% in mRNA series, P = 0.005), with lower odds (aOR0.11; P = 0.006) of developing anti-RBD antibodies than those who completed the mRNA series. Median anti-RBD Ig titers in the Janssen group were significantly lower than the mRNA group (2.39 versus 106.9 U/mL; P = 0.047) |
Herrera et al. (Am J Transplant 2021) | To study cellular and humoral immune response | IgM/IgG antibodies and ELISpot against the S protein 4 weeks after receiving the second dose | mRNA-1273 | 58 liver and 46 heart recipients | 64% developed IgM/IgG antibodies and 79% S-ELISpot positivity. 90% developed either humoral or cellular response (87% in heart and 93% in liver recipients). Factors associated with vaccine unresponsiveness were hypogammaglobulinemia and vaccination during the first year after transplantation. Local and systemic side effects were mild or moderate, and none presented donor-specific antibodies or graft dysfunction after vaccination |
Kamar et al. (NEJM 2021) | To report the humoral response | Antibodies to SARS-CoV-2 spike protein in patients who were given three doses | BNT162b2 | 101 solid organ transplant recipients (78 kidney, 12 liver, 8 lung or heart, and 3 pancreas) | The prevalence of anti–SARS-CoV-2 antibodies was 0% before the first dose, 4% before the second dose, 40% before the third dose, and 68% 4 weeks after the third dose. Among the 59 patients who had been seronegative before the third dose, 44% were seropositive at 4 weeks after the third dose. All 40 patients who had been seropositive before the third dose were still seropositive 4 weeks later; their antibody titers increased from 36 to 2676 1 month after the third dose (P < 0.001). Patients who did not have an antibody response were older, had a higher degree of immunosuppression, and had a lower eGFR. No serious adverse events were reported, and no acute rejection episodes occurred |
Guarino et al. (Clin Gastroenterol Hepatol 2022) | To evaluate immunogenicity and to identify factors associated with negative response | Anti-Spike protein IgG-LIAISON SARS-CoV-2 S1/S2-IgG chemiluminescent assay at 1 and 3 months after 2-dose vaccination | BNT162b2 | 492 liver transplant recipients and 307 controls matched by age and sex | Detectable antibodies were observed in the 75% of patients with a median value of 73.9 AU/mL after 3 months from 2-dose vaccination. Older age (> 40 years, p = 0.016), shorter time from liver transplantation (< 5 years, p = 0.004), and immunosuppression with antimetabolites (p = 0.029) were associated with non-response. Liver transplant recipients showed antibody titers lower than the control group (103 vs 261 AU/ml, p < 0.0001). Both in controls and transplant patients there was a trend of correlation between age and antibody titers (correlation coefficient: − 0.2023 and − 0.2345, respectively) |
Toniutto (J Hepatol 2022) | To assess the long-term antibody response in liver transplant compared to controls | Anti-RBD IgG and anti-nucleocapsid protein IgG measurements at the one, four and six months after the second dose | Pfizer-BioNTech BNT162b2 vaccine | 143 liver transplant and 58 controls | Among COVID-19 naïve, 66.4%, 77%, and 78.8% were anti-RBD positives at one, four and six months following the second dose, while 100% of controls were positive at 4 months (p < 0.001). The median anti-RBD titter at four months was significantly lower (32U/ml) in COVID-19 naïve than in controls (852 U/ml, p < 0.0001). Mycophenolate (p < 0.001), ascites (p = 0.012), and lower leukocyte count (p = 0.016) were independent predictors of anti-RBD negativity at six months |